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ADHD and dyslexia may affect evaluation of concussion
, a new study shows.
“Our results suggest kids with certain learning disorders may respond differently to concussion tests, and this needs to be taken into account when advising on recovery times and when they can return to sport,” said lead author Mathew Stokes, MD. Dr. Stokes is assistant professor of pediatrics and neurology/neurotherapeutics at the University of Texas–Southwestern Medical Center, Dallas.
The study was presented at the American Academy of Neurology Sports Concussion Virtual Conference, held online July 31 to Aug. 1.
Learning disorders affected scores
The researchers analyzed data from participants aged 10-18 years who were enrolled in the North Texas Concussion Registry (ConTex). Participants had been diagnosed with a concussion that was sustained within 30 days of enrollment. The researchers investigated whether there were differences between patients who had no history of learning disorders and those with a history of dyslexia and/or ADD/ADHD with regard to results of clinical testing following concussion.
Of the 1,298 individuals in the study, 58 had been diagnosed with dyslexia, 158 had been diagnosed with ADD/ADHD, and 35 had been diagnosed with both conditions. There was no difference in age, time since injury, or history of concussion between those with learning disorders and those without, but there were more male patients in the ADD/ADHD group.
Results showed that in the dyslexia group, mean time was slower (P = .011), and there was an increase in error scores on the King-Devick (KD) test (P = .028). That test assesses eye movements and involves the rapid naming of numbers that are spaced differently. In addition, those with ADD/ADHD had significantly higher impulse control scores (P = .007) on the ImPACT series of tests, which are commonly used in the evaluation of concussion. Participants with both dyslexia and ADHD demonstrated slower KD times (P = .009) and had higher depression scores and anxiety scores.
Dr. Stokes noted that a limiting factor of the study was that baseline scores were not available. “It is possible that kids with ADD have less impulse control even at baseline, and this would need to be taken into account,” he said. “You may perhaps also expect someone with dyslexia to have a worse score on the KD tests, so we need more data on how these scores are affected from baseline in these individuals. But our results show that when evaluating kids pre- or post concussion, it is important to know about learning disorders, as this will affect how we interpret the data.”
At 3-month follow-up, there were no longer significant differences in anxiety and depression scores for those with and those without learning disorders. “This suggests anxiety and depression may well be worse temporarily after concussion for those with ADD/ADHD but gets better with time,” Dr. Stokes said.
Follow-up data were not available for the other cognitive tests.
Are recovery times longer?
Asked whether young people with these learning disorders needed a longer time to recover after concussion, Dr. Stokes said: “That is a million-dollar question. Studies so far on this have shown conflicting results. Our results add to a growing body of literature on this.” He stressed that it is important to include anxiety and depression scores on both baseline and postconcussion tests. “People don’t tend to think of these symptoms as being associated with concussion, but they are actually very prominent in this situation,” he noted. “Our results suggest that individuals with ADHD may be more prone to anxiety and depression, and a blow to the head may tip them more into these symptoms.”
Discussing the study at a virtual press conference as part of the AAN Sports Concussion meeting, the codirector of the meeting, David Dodick, MD, Mayo Clinic, Scottsdale, Ariz., said: “This is a very interesting and important study which suggests there are differences between adolescents with a history of dyslexia/ADHD and those without these conditions in performance in concussion tests. Understanding the differences in these groups will help health care providers in evaluating these athletes and assisting in counseling them and their families with regard to their risk of injury.
“It is important to recognize that athletes with ADHD, whether or not they are on medication, may take longer to recover from a concussion,” Dr. Dodick added. They also exhibit greater reductions in cognitive skills and visual motor speed regarding hand-eye coordination, he said. There is an increase in the severity of symptoms. “Symptoms that exist in both groups tend to more severe in those individuals with ADHD,” he noted.
“Ascertaining the presence or absence of ADHD or dyslexia in those who are participating in sport is important, especially when trying to interpret the results of baseline testing, the results of postinjury testing, decisions on when to return to play, and assessing for individuals and their families the risk of long-term repeat concussions and adverse outcomes,” he concluded.
The other codirector of the AAN meeting, Brian Hainline, MD, chief medical officer of the National Collegiate Athletic Association, added: “It appears that athletes with ADHD may suffer more with concussion and have a longer recovery time. This can inform our decision making and help these individuals to understand that they are at higher risk.”
Dr. Hainline said this raises another important point: “Concussion is not a homogeneous entity. It is a brain injury that can manifest in multiple parts of the brain, and the way the brain is from a premorbid or comorbid point of view can influence the manifestation of concussion as well,” he said. “All these things need to be taken into account.”
Attentional deficit may itself make an individual more susceptible to sustaining an injury in the first place, he said. “All of this is an evolving body of research which is helping clinicians to make better-informed decisions for athletes who may manifest differently.”
A version of this article originally appeared on Medscape.com.
, a new study shows.
“Our results suggest kids with certain learning disorders may respond differently to concussion tests, and this needs to be taken into account when advising on recovery times and when they can return to sport,” said lead author Mathew Stokes, MD. Dr. Stokes is assistant professor of pediatrics and neurology/neurotherapeutics at the University of Texas–Southwestern Medical Center, Dallas.
The study was presented at the American Academy of Neurology Sports Concussion Virtual Conference, held online July 31 to Aug. 1.
Learning disorders affected scores
The researchers analyzed data from participants aged 10-18 years who were enrolled in the North Texas Concussion Registry (ConTex). Participants had been diagnosed with a concussion that was sustained within 30 days of enrollment. The researchers investigated whether there were differences between patients who had no history of learning disorders and those with a history of dyslexia and/or ADD/ADHD with regard to results of clinical testing following concussion.
Of the 1,298 individuals in the study, 58 had been diagnosed with dyslexia, 158 had been diagnosed with ADD/ADHD, and 35 had been diagnosed with both conditions. There was no difference in age, time since injury, or history of concussion between those with learning disorders and those without, but there were more male patients in the ADD/ADHD group.
Results showed that in the dyslexia group, mean time was slower (P = .011), and there was an increase in error scores on the King-Devick (KD) test (P = .028). That test assesses eye movements and involves the rapid naming of numbers that are spaced differently. In addition, those with ADD/ADHD had significantly higher impulse control scores (P = .007) on the ImPACT series of tests, which are commonly used in the evaluation of concussion. Participants with both dyslexia and ADHD demonstrated slower KD times (P = .009) and had higher depression scores and anxiety scores.
Dr. Stokes noted that a limiting factor of the study was that baseline scores were not available. “It is possible that kids with ADD have less impulse control even at baseline, and this would need to be taken into account,” he said. “You may perhaps also expect someone with dyslexia to have a worse score on the KD tests, so we need more data on how these scores are affected from baseline in these individuals. But our results show that when evaluating kids pre- or post concussion, it is important to know about learning disorders, as this will affect how we interpret the data.”
At 3-month follow-up, there were no longer significant differences in anxiety and depression scores for those with and those without learning disorders. “This suggests anxiety and depression may well be worse temporarily after concussion for those with ADD/ADHD but gets better with time,” Dr. Stokes said.
Follow-up data were not available for the other cognitive tests.
Are recovery times longer?
Asked whether young people with these learning disorders needed a longer time to recover after concussion, Dr. Stokes said: “That is a million-dollar question. Studies so far on this have shown conflicting results. Our results add to a growing body of literature on this.” He stressed that it is important to include anxiety and depression scores on both baseline and postconcussion tests. “People don’t tend to think of these symptoms as being associated with concussion, but they are actually very prominent in this situation,” he noted. “Our results suggest that individuals with ADHD may be more prone to anxiety and depression, and a blow to the head may tip them more into these symptoms.”
Discussing the study at a virtual press conference as part of the AAN Sports Concussion meeting, the codirector of the meeting, David Dodick, MD, Mayo Clinic, Scottsdale, Ariz., said: “This is a very interesting and important study which suggests there are differences between adolescents with a history of dyslexia/ADHD and those without these conditions in performance in concussion tests. Understanding the differences in these groups will help health care providers in evaluating these athletes and assisting in counseling them and their families with regard to their risk of injury.
“It is important to recognize that athletes with ADHD, whether or not they are on medication, may take longer to recover from a concussion,” Dr. Dodick added. They also exhibit greater reductions in cognitive skills and visual motor speed regarding hand-eye coordination, he said. There is an increase in the severity of symptoms. “Symptoms that exist in both groups tend to more severe in those individuals with ADHD,” he noted.
“Ascertaining the presence or absence of ADHD or dyslexia in those who are participating in sport is important, especially when trying to interpret the results of baseline testing, the results of postinjury testing, decisions on when to return to play, and assessing for individuals and their families the risk of long-term repeat concussions and adverse outcomes,” he concluded.
The other codirector of the AAN meeting, Brian Hainline, MD, chief medical officer of the National Collegiate Athletic Association, added: “It appears that athletes with ADHD may suffer more with concussion and have a longer recovery time. This can inform our decision making and help these individuals to understand that they are at higher risk.”
Dr. Hainline said this raises another important point: “Concussion is not a homogeneous entity. It is a brain injury that can manifest in multiple parts of the brain, and the way the brain is from a premorbid or comorbid point of view can influence the manifestation of concussion as well,” he said. “All these things need to be taken into account.”
Attentional deficit may itself make an individual more susceptible to sustaining an injury in the first place, he said. “All of this is an evolving body of research which is helping clinicians to make better-informed decisions for athletes who may manifest differently.”
A version of this article originally appeared on Medscape.com.
, a new study shows.
“Our results suggest kids with certain learning disorders may respond differently to concussion tests, and this needs to be taken into account when advising on recovery times and when they can return to sport,” said lead author Mathew Stokes, MD. Dr. Stokes is assistant professor of pediatrics and neurology/neurotherapeutics at the University of Texas–Southwestern Medical Center, Dallas.
The study was presented at the American Academy of Neurology Sports Concussion Virtual Conference, held online July 31 to Aug. 1.
Learning disorders affected scores
The researchers analyzed data from participants aged 10-18 years who were enrolled in the North Texas Concussion Registry (ConTex). Participants had been diagnosed with a concussion that was sustained within 30 days of enrollment. The researchers investigated whether there were differences between patients who had no history of learning disorders and those with a history of dyslexia and/or ADD/ADHD with regard to results of clinical testing following concussion.
Of the 1,298 individuals in the study, 58 had been diagnosed with dyslexia, 158 had been diagnosed with ADD/ADHD, and 35 had been diagnosed with both conditions. There was no difference in age, time since injury, or history of concussion between those with learning disorders and those without, but there were more male patients in the ADD/ADHD group.
Results showed that in the dyslexia group, mean time was slower (P = .011), and there was an increase in error scores on the King-Devick (KD) test (P = .028). That test assesses eye movements and involves the rapid naming of numbers that are spaced differently. In addition, those with ADD/ADHD had significantly higher impulse control scores (P = .007) on the ImPACT series of tests, which are commonly used in the evaluation of concussion. Participants with both dyslexia and ADHD demonstrated slower KD times (P = .009) and had higher depression scores and anxiety scores.
Dr. Stokes noted that a limiting factor of the study was that baseline scores were not available. “It is possible that kids with ADD have less impulse control even at baseline, and this would need to be taken into account,” he said. “You may perhaps also expect someone with dyslexia to have a worse score on the KD tests, so we need more data on how these scores are affected from baseline in these individuals. But our results show that when evaluating kids pre- or post concussion, it is important to know about learning disorders, as this will affect how we interpret the data.”
At 3-month follow-up, there were no longer significant differences in anxiety and depression scores for those with and those without learning disorders. “This suggests anxiety and depression may well be worse temporarily after concussion for those with ADD/ADHD but gets better with time,” Dr. Stokes said.
Follow-up data were not available for the other cognitive tests.
Are recovery times longer?
Asked whether young people with these learning disorders needed a longer time to recover after concussion, Dr. Stokes said: “That is a million-dollar question. Studies so far on this have shown conflicting results. Our results add to a growing body of literature on this.” He stressed that it is important to include anxiety and depression scores on both baseline and postconcussion tests. “People don’t tend to think of these symptoms as being associated with concussion, but they are actually very prominent in this situation,” he noted. “Our results suggest that individuals with ADHD may be more prone to anxiety and depression, and a blow to the head may tip them more into these symptoms.”
Discussing the study at a virtual press conference as part of the AAN Sports Concussion meeting, the codirector of the meeting, David Dodick, MD, Mayo Clinic, Scottsdale, Ariz., said: “This is a very interesting and important study which suggests there are differences between adolescents with a history of dyslexia/ADHD and those without these conditions in performance in concussion tests. Understanding the differences in these groups will help health care providers in evaluating these athletes and assisting in counseling them and their families with regard to their risk of injury.
“It is important to recognize that athletes with ADHD, whether or not they are on medication, may take longer to recover from a concussion,” Dr. Dodick added. They also exhibit greater reductions in cognitive skills and visual motor speed regarding hand-eye coordination, he said. There is an increase in the severity of symptoms. “Symptoms that exist in both groups tend to more severe in those individuals with ADHD,” he noted.
“Ascertaining the presence or absence of ADHD or dyslexia in those who are participating in sport is important, especially when trying to interpret the results of baseline testing, the results of postinjury testing, decisions on when to return to play, and assessing for individuals and their families the risk of long-term repeat concussions and adverse outcomes,” he concluded.
The other codirector of the AAN meeting, Brian Hainline, MD, chief medical officer of the National Collegiate Athletic Association, added: “It appears that athletes with ADHD may suffer more with concussion and have a longer recovery time. This can inform our decision making and help these individuals to understand that they are at higher risk.”
Dr. Hainline said this raises another important point: “Concussion is not a homogeneous entity. It is a brain injury that can manifest in multiple parts of the brain, and the way the brain is from a premorbid or comorbid point of view can influence the manifestation of concussion as well,” he said. “All these things need to be taken into account.”
Attentional deficit may itself make an individual more susceptible to sustaining an injury in the first place, he said. “All of this is an evolving body of research which is helping clinicians to make better-informed decisions for athletes who may manifest differently.”
A version of this article originally appeared on Medscape.com.
From AAN Sports Concussion Conference
More evidence links gum disease and dementia risk
especially in those with severe gum inflammation and edentulism, new research suggests.
Over a 20-year period, investigators prospectively followed more than 8,000 individuals aged around 63 years who did not have cognitive impairment or dementia at baseline, grouping them based on the extent and severity of their periodontal disease and number of lost teeth.
Results showed that 14% of participants with healthy gums and all their teeth at baseline developed dementia, compared with 18% of those with mild periodontal disease and 22% who had severe periodontal disease. The highest percentage (23%) of participants who developed dementia was found in those who were edentulous.
After accounting for comorbidities that might affect dementia risk, edentulous participants had a 20% higher risk for developing MCI or dementia, compared with the healthy group.
Because the study was observational, “we don’t have knowledge of causality so we cannot state that if you treat periodontal disease you can prevent or treat dementia,” said lead author Ryan T. Demmer, PhD, MPH, associate professor, division of epidemiology and community health, University of Minnesota, Minneapolis. However, “the take-home message from this paper is that it further supports the possibility that oral infections could be a risk factor for dementia.”
The study was published online July 29 in Neurology.
The ARIC trial
Prior studies have “described the interrelation of tooth loss or periodontal disease and cognitive outcomes, although many reports were cross-sectional or case-control … and often lacked robust confounder adjustment,” the investigators noted. Additionally, lack of longitudinal data impedes the “potential for baseline periodontal status to predict incident MCI.”
To explore the associations between periodontal status and incident MCI and dementia, the researchers studied participants in the ARIC study, a community-based longitudinal cohort consisting of 15,792 predominantly Black and White participants aged 45-64 years. The current analysis included 8,275 individuals (55% women; 21% black; mean age, 63 years) who at baseline did not meet criteria for dementia or MCI.
A full-mouth periodontal examination was conducted at baseline and participants were categorized according to the severity and extent of gingival inflammation and tooth attachment loss based on the Periodontal Profile Class (PPC) seven-category model. Potential confounding variables included age, race, education level, physical activity, smoking status, oral hygiene and access to care, plasma lipid levels, APOE genotype, body mass index, blood pressure, type 2 diabetes, and heart failure.
Based on PPC categorization, 22% of the patients had healthy gums, 12% had mild periodontal disease, 8% had a high gingival inflammation index, and 12% had posterior disease (with 6% having severe disease). In addition, 9% had tooth loss, 11% had severe tooth loss, and 20% were edentulous.
Infection hypothesis
Results showed that participants with worse periodontal status were more likely to have risk factors for vascular disease and dementia, such as smoking, hypertension, diabetes, and coronary heart disease. During median follow-up of 18.4 years, 19% of participants overall (n = 1,569) developed dementia, translating into 11.8 cases per 1,000 person-years. There were notable differences between the PPC categories in rates of incident dementia, with edentulous participants at twice the risk for developing dementia, compared with those who had healthy gums.
For participants with severe PPC, including severe tooth loss and severe disease, the multivariable-adjusted hazard ratio for incident dementia was 1.22 (95% confidence interval, 1.01-1.47) versus those who were periodontally healthy. For participants with edentulism, the HR was 1.21 (95% CI, 0.99-1.48). The adjusted risk ratios for the combined dementia/MCI outcome among participants with mild to intermediate PPC, severe PPC, or edentulism versus the periodontal healthy group were 1.22 (95% CI, 1.00-1.48), 1.15 (95% CI, 0.88-1.51), and 1.90 (95% CI, 1.40-2.58), respectively.
These findings were most pronounced among younger (median age at dental exam, younger than 62) versus older (62 years and older) participants (P = .02). Severe disease or total tooth loss were associated with an approximately 20% greater dementia incidence during the follow-up period, compared with healthy gums.
The investigators noted that the findings were “generally consistent” when considering the combined outcome of MCI and dementia. However, they noted that the association between edentulism and MCI was “markedly stronger,” with an approximate 100% increase in MCI or MCI plus dementia.
The association between periodontal disease and MCI or dementia “is rooted in the infection hypothesis, meaning adverse microbial exposures in the mucosal surfaces of the mouth, especially the subgingival space,” Dr. Demmer said. “One notion is that there could somehow be a direct infection of the brain with oral organisms, which posits that the oral organism could travel to the brain, colonize there, and cause damage that impairs cognition.”
Another possible mechanism is that chronic systemic inflammation in response to oral infections can eventually lead to vascular disease which, in turn, is a known risk factor for future dementia, he noted.
“Brush and floss”
Commenting on the research findings, James M. Noble, MD, associate professor of neurology, Taub Institute for Research on Alzheimer’s and the Aging Brain, Columbia University, New York, called the study “well characterized both by whole-mouth assessments and cognitive assessments performed in a standardized manner.” Moreover, “the study was sufficiently sized to allow for exploration of age and suggests that oral health may be a more important factor earlier in the course of aging, in late adulthood,” said Dr. Noble, who was not involved with the research.
The study also “makes an important contribution to this field through a rigorously followed cohort and robust design for both periodontal predictor and cognitive outcome assessments,” he said, noting that, “as always, the take-home message is ‘brush and floss.’
“Although we don’t know if treating periodontal disease can help treat dementia, this study suggests that we have to pay attention to good oral hygiene and make referrals to dentists when appropriate,” Dr. Demmer added.
The ARIC trial is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute. Dr. Demmer, the study coauthors, and Dr. Noble have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
especially in those with severe gum inflammation and edentulism, new research suggests.
Over a 20-year period, investigators prospectively followed more than 8,000 individuals aged around 63 years who did not have cognitive impairment or dementia at baseline, grouping them based on the extent and severity of their periodontal disease and number of lost teeth.
Results showed that 14% of participants with healthy gums and all their teeth at baseline developed dementia, compared with 18% of those with mild periodontal disease and 22% who had severe periodontal disease. The highest percentage (23%) of participants who developed dementia was found in those who were edentulous.
After accounting for comorbidities that might affect dementia risk, edentulous participants had a 20% higher risk for developing MCI or dementia, compared with the healthy group.
Because the study was observational, “we don’t have knowledge of causality so we cannot state that if you treat periodontal disease you can prevent or treat dementia,” said lead author Ryan T. Demmer, PhD, MPH, associate professor, division of epidemiology and community health, University of Minnesota, Minneapolis. However, “the take-home message from this paper is that it further supports the possibility that oral infections could be a risk factor for dementia.”
The study was published online July 29 in Neurology.
The ARIC trial
Prior studies have “described the interrelation of tooth loss or periodontal disease and cognitive outcomes, although many reports were cross-sectional or case-control … and often lacked robust confounder adjustment,” the investigators noted. Additionally, lack of longitudinal data impedes the “potential for baseline periodontal status to predict incident MCI.”
To explore the associations between periodontal status and incident MCI and dementia, the researchers studied participants in the ARIC study, a community-based longitudinal cohort consisting of 15,792 predominantly Black and White participants aged 45-64 years. The current analysis included 8,275 individuals (55% women; 21% black; mean age, 63 years) who at baseline did not meet criteria for dementia or MCI.
A full-mouth periodontal examination was conducted at baseline and participants were categorized according to the severity and extent of gingival inflammation and tooth attachment loss based on the Periodontal Profile Class (PPC) seven-category model. Potential confounding variables included age, race, education level, physical activity, smoking status, oral hygiene and access to care, plasma lipid levels, APOE genotype, body mass index, blood pressure, type 2 diabetes, and heart failure.
Based on PPC categorization, 22% of the patients had healthy gums, 12% had mild periodontal disease, 8% had a high gingival inflammation index, and 12% had posterior disease (with 6% having severe disease). In addition, 9% had tooth loss, 11% had severe tooth loss, and 20% were edentulous.
Infection hypothesis
Results showed that participants with worse periodontal status were more likely to have risk factors for vascular disease and dementia, such as smoking, hypertension, diabetes, and coronary heart disease. During median follow-up of 18.4 years, 19% of participants overall (n = 1,569) developed dementia, translating into 11.8 cases per 1,000 person-years. There were notable differences between the PPC categories in rates of incident dementia, with edentulous participants at twice the risk for developing dementia, compared with those who had healthy gums.
For participants with severe PPC, including severe tooth loss and severe disease, the multivariable-adjusted hazard ratio for incident dementia was 1.22 (95% confidence interval, 1.01-1.47) versus those who were periodontally healthy. For participants with edentulism, the HR was 1.21 (95% CI, 0.99-1.48). The adjusted risk ratios for the combined dementia/MCI outcome among participants with mild to intermediate PPC, severe PPC, or edentulism versus the periodontal healthy group were 1.22 (95% CI, 1.00-1.48), 1.15 (95% CI, 0.88-1.51), and 1.90 (95% CI, 1.40-2.58), respectively.
These findings were most pronounced among younger (median age at dental exam, younger than 62) versus older (62 years and older) participants (P = .02). Severe disease or total tooth loss were associated with an approximately 20% greater dementia incidence during the follow-up period, compared with healthy gums.
The investigators noted that the findings were “generally consistent” when considering the combined outcome of MCI and dementia. However, they noted that the association between edentulism and MCI was “markedly stronger,” with an approximate 100% increase in MCI or MCI plus dementia.
The association between periodontal disease and MCI or dementia “is rooted in the infection hypothesis, meaning adverse microbial exposures in the mucosal surfaces of the mouth, especially the subgingival space,” Dr. Demmer said. “One notion is that there could somehow be a direct infection of the brain with oral organisms, which posits that the oral organism could travel to the brain, colonize there, and cause damage that impairs cognition.”
Another possible mechanism is that chronic systemic inflammation in response to oral infections can eventually lead to vascular disease which, in turn, is a known risk factor for future dementia, he noted.
“Brush and floss”
Commenting on the research findings, James M. Noble, MD, associate professor of neurology, Taub Institute for Research on Alzheimer’s and the Aging Brain, Columbia University, New York, called the study “well characterized both by whole-mouth assessments and cognitive assessments performed in a standardized manner.” Moreover, “the study was sufficiently sized to allow for exploration of age and suggests that oral health may be a more important factor earlier in the course of aging, in late adulthood,” said Dr. Noble, who was not involved with the research.
The study also “makes an important contribution to this field through a rigorously followed cohort and robust design for both periodontal predictor and cognitive outcome assessments,” he said, noting that, “as always, the take-home message is ‘brush and floss.’
“Although we don’t know if treating periodontal disease can help treat dementia, this study suggests that we have to pay attention to good oral hygiene and make referrals to dentists when appropriate,” Dr. Demmer added.
The ARIC trial is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute. Dr. Demmer, the study coauthors, and Dr. Noble have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
especially in those with severe gum inflammation and edentulism, new research suggests.
Over a 20-year period, investigators prospectively followed more than 8,000 individuals aged around 63 years who did not have cognitive impairment or dementia at baseline, grouping them based on the extent and severity of their periodontal disease and number of lost teeth.
Results showed that 14% of participants with healthy gums and all their teeth at baseline developed dementia, compared with 18% of those with mild periodontal disease and 22% who had severe periodontal disease. The highest percentage (23%) of participants who developed dementia was found in those who were edentulous.
After accounting for comorbidities that might affect dementia risk, edentulous participants had a 20% higher risk for developing MCI or dementia, compared with the healthy group.
Because the study was observational, “we don’t have knowledge of causality so we cannot state that if you treat periodontal disease you can prevent or treat dementia,” said lead author Ryan T. Demmer, PhD, MPH, associate professor, division of epidemiology and community health, University of Minnesota, Minneapolis. However, “the take-home message from this paper is that it further supports the possibility that oral infections could be a risk factor for dementia.”
The study was published online July 29 in Neurology.
The ARIC trial
Prior studies have “described the interrelation of tooth loss or periodontal disease and cognitive outcomes, although many reports were cross-sectional or case-control … and often lacked robust confounder adjustment,” the investigators noted. Additionally, lack of longitudinal data impedes the “potential for baseline periodontal status to predict incident MCI.”
To explore the associations between periodontal status and incident MCI and dementia, the researchers studied participants in the ARIC study, a community-based longitudinal cohort consisting of 15,792 predominantly Black and White participants aged 45-64 years. The current analysis included 8,275 individuals (55% women; 21% black; mean age, 63 years) who at baseline did not meet criteria for dementia or MCI.
A full-mouth periodontal examination was conducted at baseline and participants were categorized according to the severity and extent of gingival inflammation and tooth attachment loss based on the Periodontal Profile Class (PPC) seven-category model. Potential confounding variables included age, race, education level, physical activity, smoking status, oral hygiene and access to care, plasma lipid levels, APOE genotype, body mass index, blood pressure, type 2 diabetes, and heart failure.
Based on PPC categorization, 22% of the patients had healthy gums, 12% had mild periodontal disease, 8% had a high gingival inflammation index, and 12% had posterior disease (with 6% having severe disease). In addition, 9% had tooth loss, 11% had severe tooth loss, and 20% were edentulous.
Infection hypothesis
Results showed that participants with worse periodontal status were more likely to have risk factors for vascular disease and dementia, such as smoking, hypertension, diabetes, and coronary heart disease. During median follow-up of 18.4 years, 19% of participants overall (n = 1,569) developed dementia, translating into 11.8 cases per 1,000 person-years. There were notable differences between the PPC categories in rates of incident dementia, with edentulous participants at twice the risk for developing dementia, compared with those who had healthy gums.
For participants with severe PPC, including severe tooth loss and severe disease, the multivariable-adjusted hazard ratio for incident dementia was 1.22 (95% confidence interval, 1.01-1.47) versus those who were periodontally healthy. For participants with edentulism, the HR was 1.21 (95% CI, 0.99-1.48). The adjusted risk ratios for the combined dementia/MCI outcome among participants with mild to intermediate PPC, severe PPC, or edentulism versus the periodontal healthy group were 1.22 (95% CI, 1.00-1.48), 1.15 (95% CI, 0.88-1.51), and 1.90 (95% CI, 1.40-2.58), respectively.
These findings were most pronounced among younger (median age at dental exam, younger than 62) versus older (62 years and older) participants (P = .02). Severe disease or total tooth loss were associated with an approximately 20% greater dementia incidence during the follow-up period, compared with healthy gums.
The investigators noted that the findings were “generally consistent” when considering the combined outcome of MCI and dementia. However, they noted that the association between edentulism and MCI was “markedly stronger,” with an approximate 100% increase in MCI or MCI plus dementia.
The association between periodontal disease and MCI or dementia “is rooted in the infection hypothesis, meaning adverse microbial exposures in the mucosal surfaces of the mouth, especially the subgingival space,” Dr. Demmer said. “One notion is that there could somehow be a direct infection of the brain with oral organisms, which posits that the oral organism could travel to the brain, colonize there, and cause damage that impairs cognition.”
Another possible mechanism is that chronic systemic inflammation in response to oral infections can eventually lead to vascular disease which, in turn, is a known risk factor for future dementia, he noted.
“Brush and floss”
Commenting on the research findings, James M. Noble, MD, associate professor of neurology, Taub Institute for Research on Alzheimer’s and the Aging Brain, Columbia University, New York, called the study “well characterized both by whole-mouth assessments and cognitive assessments performed in a standardized manner.” Moreover, “the study was sufficiently sized to allow for exploration of age and suggests that oral health may be a more important factor earlier in the course of aging, in late adulthood,” said Dr. Noble, who was not involved with the research.
The study also “makes an important contribution to this field through a rigorously followed cohort and robust design for both periodontal predictor and cognitive outcome assessments,” he said, noting that, “as always, the take-home message is ‘brush and floss.’
“Although we don’t know if treating periodontal disease can help treat dementia, this study suggests that we have to pay attention to good oral hygiene and make referrals to dentists when appropriate,” Dr. Demmer added.
The ARIC trial is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute. Dr. Demmer, the study coauthors, and Dr. Noble have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Managing acute pain in inpatients on OUD therapy
“This is something we’re going to see more frequently, and many of us already have,” Theresa E. Vettese, MD, said at HM20 Virtual, hosted by the Society of Hospital Medicine.
The drastic drop in prescriptions for opioid pain medications in the last several years hasn’t curtailed the current opioid epidemic. Instead, the epidemic has to a great extent morphed into expanded use of illicit heroin and fentanyl, noted Dr. Vettese, an internist, hospitalist, and palliative care physician at Emory University and Grady Memorial Hospital in Atlanta.
Mythbusting
Treatment of acute pain in hospitalized patients on opioid agonist therapy for opioid use disorder (OUD) is actually pretty straightforward once a few common myths have been dispelled, she said.
One of these myths –common among both physicians and patients in treatment for OUD – is that prescribing opioids for management of acute pain will place such patients at risk for OUD relapse.
“In fact, the data really strongly suggest this is not the case,” Dr. Vettese said. “It will not worsen addiction. But if we don’t aggressively treat these patients’ acute pain, it puts them at higher risk for bad outcomes.”
Another myth – this one not uncommon among hospital pharmacy departments – is that only physicians with a special certification can prescribe methadone for inpatients.
“The federal laws are clear: Any physician who has a DEA license can prescribe methadone in the hospital acute care setting, not only for pain management, but also for treatment of opioid withdrawal. You can’t prescribe it in the outpatient setting for opioid withdrawal – that has to be dispensed through a federally regulated methadone outpatient treatment program. But in the hospital, we can feel safe that we can do so. You may need to educate your pharmacist about this,” she said.
Hospitalists also can prescribe buprenorphine in the acute care inpatient setting, both for pain and treatment of opioid withdrawal, without need for a DEA waiver.
“It’s useful to get some skills in using buprenorphine in the inpatient setting. You don’t need an X waiver, but I encourage everyone to do the X-waiver training because it’s a terrific educational session. It’s 8 hours for physicians and well worth it,” Dr. Vettese noted.
By federal law the inpatient physician also can prescribe 3 days of buprenorphine at discharge to get the patient to an outpatient provider.
Misconceptions also abound about NSAIDs as a nonopioid component of acute pain management in hospitalized patients. They actually are extremely effective for the treatment of musculoskeletal, orthopedic, procedural, migraine, and some types of cancer pain. The number needed to treat (NNT) for postoperative pain relief for ibuprofen or celecoxib is 2.5, and when used in conjunction with acetaminophen at 325 mg every 4 hours, that NNT drops to 1.5, similar to the NNT of 1.7 for oxycodone at 15 mg. It should be noted, however, that the bar defining effective pain relief in randomized studies is set rather low: A 50% greater reduction in pain than achieved with placebo.
Many hospitalists would like to use NSAIDs more often, but they’re leery of the associated risks of GI bleeding, ischemic cardiovascular events, and worsening kidney function. Dr. Vettese offered several risk-mitigation strategies to increase the use of NSAIDs as opioid-sparing agents for acute pain management.
She has changed her own clinical practice with regard to using NSAIDs in patients with chronic kidney disease in response to a 2019 systematic review by investigators at the University of Ottawa.
“This was a game changer for me because in this review, low-dose NSAIDs were safe in that they didn’t significantly increase the risk of worsening kidney failure even in patients with stage 3 chronic kidney disease. So this has expanded my use of NSAIDs in this population through stage 3 CKD. With a creatinine clearance below 30, however, kidney failure worsened rapidly, so I don’t do it in patients with CKD stage 4,” Dr. Vettese said.
Gastroenterologists categorize patients as being at high risk of GI bleeding related to NSAID use if they have a history of a complicated ulcer or they have at least three of the following risk factors: Age above 65 years, history of an uncomplicated ulcer, being on high-dose NSAID therapy, or concurrent use of aspirin, glucocorticoids, or anticoagulants. Patients are considered at moderate risk if they have one or two of the risk factors, and low risk if they have none. Dr. Vettese said that, while NSAIDs clearly should be avoided in the high-risk group, moderate-risk patients are a different matter.
“Many avoid the use of NSAIDs with moderate risk, but I think we can expand their use if we use the right NSAID and we use protective strategies,” Dr. Vettese said.
Celecoxib is the safest drug in terms of upper GI bleeding risk, but ibuprofen is close. They are associated with a 2.2-fold increased risk of bleeding when compared with risk in patients not on an NSAID. Naproxen or indeomethacin use carries a fourfold to fivefold increased risk.
“Celecoxib with a proton pump inhibitor is safest, followed by celecoxib alone, followed by ibuprofen with a proton pump inhibitor. So I advocate using NSAIDs more frequently in people who are at moderate risk by using them with a PPI,” she said.
There is persuasive evidence of increased cardiovascular risk in association with even short-duration NSAIDs, as the drugs are utilized in the treatment of acute pain in hospitalized patients. That being said, Dr. Vettese believes hospitalists can use these drugs safely in more patients by following a thoughtful cardiovascular risk-mitigation strategy developed by Italian investigators.
Communicating about pain management
“Communication is always the key to effective pain management in every situation,” Dr. Vettese emphasized.
“I talk to the patient about the goals of effective pain management. I’ll discourage the use of the 1-10 pain scale, and instead, I’ll be honest about expectations, saying, ‘You have a problem that will cause acute pain, and it’s unlikely that I will be able to completely relieve your pain. The goal is to improve your function so that you can get up and go the bathroom by yourself, and so that you can sleep for a few hours. That’s how we’re going to measure the efficacy of our pain-management program.’ ”
She explains to the patient that she’ll be using nonopioid medications and nondrug therapies along with oral opioid pain medications, which are less risky than IV opioids. She offers reassurance that this treatment strategy won’t cause an OUD relapse. She lets the patient know up-front that the opioids will be tapered as the acute pain improves.
For the patient who comes into the hospital on buprenorphine for OUD, she immediately checks with the state prescription drug monitoring program to make sure everything is above board and there’s no indication of doctor shopping for prescriptions. For in-hospital acute pain, it’s safe and effective to continue the outpatient dose. On an outpatient basis, however, the drug is given once daily. On that dosing schedule both the euphoric effect as well as the analgesic effect are lost, so for acute pain management in the hospital it’s recommended to split the dose into twice- or thrice-daily doses to achieve an analgesic effect.
Oral NSAIDs are part of the treatment strategy whenever possible. For severe acute pain, Dr. Vettese will prescribe an immediate-release opioid having a high affinity to the mu opioid receptor, such as oral hydromorphone, on an as-needed basis. The drug has onset of effect in 30 minutes, peak effect in 1 hour, and a duration of effect of 4-6 hours, although she recommends going with 4 hours to provide adequate analgesia.
“These patients will require much higher doses than the patients who are opioid naive,” she advised.
For the patient with acute pain who is admitted while on methadone for OUD, it’s important to call the outpatient treatment program to verify the dosage.
“You can split the dose of methadone to try to get better analgesia, although I can tell you that patients who are treated with methadone for OUD frequently don’t want to do that. And if they don’t want to, then I don’t,” the hospitalist said.
As with the patient on buprenorphine for OUD, she’ll use additional oral immediate-release opioids as needed for acute severe pain in a patient on methadone for medication-assisted OUD treatment.
Dr. Vettese reported having no financial conflicts regarding her presentation.
“This is something we’re going to see more frequently, and many of us already have,” Theresa E. Vettese, MD, said at HM20 Virtual, hosted by the Society of Hospital Medicine.
The drastic drop in prescriptions for opioid pain medications in the last several years hasn’t curtailed the current opioid epidemic. Instead, the epidemic has to a great extent morphed into expanded use of illicit heroin and fentanyl, noted Dr. Vettese, an internist, hospitalist, and palliative care physician at Emory University and Grady Memorial Hospital in Atlanta.
Mythbusting
Treatment of acute pain in hospitalized patients on opioid agonist therapy for opioid use disorder (OUD) is actually pretty straightforward once a few common myths have been dispelled, she said.
One of these myths –common among both physicians and patients in treatment for OUD – is that prescribing opioids for management of acute pain will place such patients at risk for OUD relapse.
“In fact, the data really strongly suggest this is not the case,” Dr. Vettese said. “It will not worsen addiction. But if we don’t aggressively treat these patients’ acute pain, it puts them at higher risk for bad outcomes.”
Another myth – this one not uncommon among hospital pharmacy departments – is that only physicians with a special certification can prescribe methadone for inpatients.
“The federal laws are clear: Any physician who has a DEA license can prescribe methadone in the hospital acute care setting, not only for pain management, but also for treatment of opioid withdrawal. You can’t prescribe it in the outpatient setting for opioid withdrawal – that has to be dispensed through a federally regulated methadone outpatient treatment program. But in the hospital, we can feel safe that we can do so. You may need to educate your pharmacist about this,” she said.
Hospitalists also can prescribe buprenorphine in the acute care inpatient setting, both for pain and treatment of opioid withdrawal, without need for a DEA waiver.
“It’s useful to get some skills in using buprenorphine in the inpatient setting. You don’t need an X waiver, but I encourage everyone to do the X-waiver training because it’s a terrific educational session. It’s 8 hours for physicians and well worth it,” Dr. Vettese noted.
By federal law the inpatient physician also can prescribe 3 days of buprenorphine at discharge to get the patient to an outpatient provider.
Misconceptions also abound about NSAIDs as a nonopioid component of acute pain management in hospitalized patients. They actually are extremely effective for the treatment of musculoskeletal, orthopedic, procedural, migraine, and some types of cancer pain. The number needed to treat (NNT) for postoperative pain relief for ibuprofen or celecoxib is 2.5, and when used in conjunction with acetaminophen at 325 mg every 4 hours, that NNT drops to 1.5, similar to the NNT of 1.7 for oxycodone at 15 mg. It should be noted, however, that the bar defining effective pain relief in randomized studies is set rather low: A 50% greater reduction in pain than achieved with placebo.
Many hospitalists would like to use NSAIDs more often, but they’re leery of the associated risks of GI bleeding, ischemic cardiovascular events, and worsening kidney function. Dr. Vettese offered several risk-mitigation strategies to increase the use of NSAIDs as opioid-sparing agents for acute pain management.
She has changed her own clinical practice with regard to using NSAIDs in patients with chronic kidney disease in response to a 2019 systematic review by investigators at the University of Ottawa.
“This was a game changer for me because in this review, low-dose NSAIDs were safe in that they didn’t significantly increase the risk of worsening kidney failure even in patients with stage 3 chronic kidney disease. So this has expanded my use of NSAIDs in this population through stage 3 CKD. With a creatinine clearance below 30, however, kidney failure worsened rapidly, so I don’t do it in patients with CKD stage 4,” Dr. Vettese said.
Gastroenterologists categorize patients as being at high risk of GI bleeding related to NSAID use if they have a history of a complicated ulcer or they have at least three of the following risk factors: Age above 65 years, history of an uncomplicated ulcer, being on high-dose NSAID therapy, or concurrent use of aspirin, glucocorticoids, or anticoagulants. Patients are considered at moderate risk if they have one or two of the risk factors, and low risk if they have none. Dr. Vettese said that, while NSAIDs clearly should be avoided in the high-risk group, moderate-risk patients are a different matter.
“Many avoid the use of NSAIDs with moderate risk, but I think we can expand their use if we use the right NSAID and we use protective strategies,” Dr. Vettese said.
Celecoxib is the safest drug in terms of upper GI bleeding risk, but ibuprofen is close. They are associated with a 2.2-fold increased risk of bleeding when compared with risk in patients not on an NSAID. Naproxen or indeomethacin use carries a fourfold to fivefold increased risk.
“Celecoxib with a proton pump inhibitor is safest, followed by celecoxib alone, followed by ibuprofen with a proton pump inhibitor. So I advocate using NSAIDs more frequently in people who are at moderate risk by using them with a PPI,” she said.
There is persuasive evidence of increased cardiovascular risk in association with even short-duration NSAIDs, as the drugs are utilized in the treatment of acute pain in hospitalized patients. That being said, Dr. Vettese believes hospitalists can use these drugs safely in more patients by following a thoughtful cardiovascular risk-mitigation strategy developed by Italian investigators.
Communicating about pain management
“Communication is always the key to effective pain management in every situation,” Dr. Vettese emphasized.
“I talk to the patient about the goals of effective pain management. I’ll discourage the use of the 1-10 pain scale, and instead, I’ll be honest about expectations, saying, ‘You have a problem that will cause acute pain, and it’s unlikely that I will be able to completely relieve your pain. The goal is to improve your function so that you can get up and go the bathroom by yourself, and so that you can sleep for a few hours. That’s how we’re going to measure the efficacy of our pain-management program.’ ”
She explains to the patient that she’ll be using nonopioid medications and nondrug therapies along with oral opioid pain medications, which are less risky than IV opioids. She offers reassurance that this treatment strategy won’t cause an OUD relapse. She lets the patient know up-front that the opioids will be tapered as the acute pain improves.
For the patient who comes into the hospital on buprenorphine for OUD, she immediately checks with the state prescription drug monitoring program to make sure everything is above board and there’s no indication of doctor shopping for prescriptions. For in-hospital acute pain, it’s safe and effective to continue the outpatient dose. On an outpatient basis, however, the drug is given once daily. On that dosing schedule both the euphoric effect as well as the analgesic effect are lost, so for acute pain management in the hospital it’s recommended to split the dose into twice- or thrice-daily doses to achieve an analgesic effect.
Oral NSAIDs are part of the treatment strategy whenever possible. For severe acute pain, Dr. Vettese will prescribe an immediate-release opioid having a high affinity to the mu opioid receptor, such as oral hydromorphone, on an as-needed basis. The drug has onset of effect in 30 minutes, peak effect in 1 hour, and a duration of effect of 4-6 hours, although she recommends going with 4 hours to provide adequate analgesia.
“These patients will require much higher doses than the patients who are opioid naive,” she advised.
For the patient with acute pain who is admitted while on methadone for OUD, it’s important to call the outpatient treatment program to verify the dosage.
“You can split the dose of methadone to try to get better analgesia, although I can tell you that patients who are treated with methadone for OUD frequently don’t want to do that. And if they don’t want to, then I don’t,” the hospitalist said.
As with the patient on buprenorphine for OUD, she’ll use additional oral immediate-release opioids as needed for acute severe pain in a patient on methadone for medication-assisted OUD treatment.
Dr. Vettese reported having no financial conflicts regarding her presentation.
“This is something we’re going to see more frequently, and many of us already have,” Theresa E. Vettese, MD, said at HM20 Virtual, hosted by the Society of Hospital Medicine.
The drastic drop in prescriptions for opioid pain medications in the last several years hasn’t curtailed the current opioid epidemic. Instead, the epidemic has to a great extent morphed into expanded use of illicit heroin and fentanyl, noted Dr. Vettese, an internist, hospitalist, and palliative care physician at Emory University and Grady Memorial Hospital in Atlanta.
Mythbusting
Treatment of acute pain in hospitalized patients on opioid agonist therapy for opioid use disorder (OUD) is actually pretty straightforward once a few common myths have been dispelled, she said.
One of these myths –common among both physicians and patients in treatment for OUD – is that prescribing opioids for management of acute pain will place such patients at risk for OUD relapse.
“In fact, the data really strongly suggest this is not the case,” Dr. Vettese said. “It will not worsen addiction. But if we don’t aggressively treat these patients’ acute pain, it puts them at higher risk for bad outcomes.”
Another myth – this one not uncommon among hospital pharmacy departments – is that only physicians with a special certification can prescribe methadone for inpatients.
“The federal laws are clear: Any physician who has a DEA license can prescribe methadone in the hospital acute care setting, not only for pain management, but also for treatment of opioid withdrawal. You can’t prescribe it in the outpatient setting for opioid withdrawal – that has to be dispensed through a federally regulated methadone outpatient treatment program. But in the hospital, we can feel safe that we can do so. You may need to educate your pharmacist about this,” she said.
Hospitalists also can prescribe buprenorphine in the acute care inpatient setting, both for pain and treatment of opioid withdrawal, without need for a DEA waiver.
“It’s useful to get some skills in using buprenorphine in the inpatient setting. You don’t need an X waiver, but I encourage everyone to do the X-waiver training because it’s a terrific educational session. It’s 8 hours for physicians and well worth it,” Dr. Vettese noted.
By federal law the inpatient physician also can prescribe 3 days of buprenorphine at discharge to get the patient to an outpatient provider.
Misconceptions also abound about NSAIDs as a nonopioid component of acute pain management in hospitalized patients. They actually are extremely effective for the treatment of musculoskeletal, orthopedic, procedural, migraine, and some types of cancer pain. The number needed to treat (NNT) for postoperative pain relief for ibuprofen or celecoxib is 2.5, and when used in conjunction with acetaminophen at 325 mg every 4 hours, that NNT drops to 1.5, similar to the NNT of 1.7 for oxycodone at 15 mg. It should be noted, however, that the bar defining effective pain relief in randomized studies is set rather low: A 50% greater reduction in pain than achieved with placebo.
Many hospitalists would like to use NSAIDs more often, but they’re leery of the associated risks of GI bleeding, ischemic cardiovascular events, and worsening kidney function. Dr. Vettese offered several risk-mitigation strategies to increase the use of NSAIDs as opioid-sparing agents for acute pain management.
She has changed her own clinical practice with regard to using NSAIDs in patients with chronic kidney disease in response to a 2019 systematic review by investigators at the University of Ottawa.
“This was a game changer for me because in this review, low-dose NSAIDs were safe in that they didn’t significantly increase the risk of worsening kidney failure even in patients with stage 3 chronic kidney disease. So this has expanded my use of NSAIDs in this population through stage 3 CKD. With a creatinine clearance below 30, however, kidney failure worsened rapidly, so I don’t do it in patients with CKD stage 4,” Dr. Vettese said.
Gastroenterologists categorize patients as being at high risk of GI bleeding related to NSAID use if they have a history of a complicated ulcer or they have at least three of the following risk factors: Age above 65 years, history of an uncomplicated ulcer, being on high-dose NSAID therapy, or concurrent use of aspirin, glucocorticoids, or anticoagulants. Patients are considered at moderate risk if they have one or two of the risk factors, and low risk if they have none. Dr. Vettese said that, while NSAIDs clearly should be avoided in the high-risk group, moderate-risk patients are a different matter.
“Many avoid the use of NSAIDs with moderate risk, but I think we can expand their use if we use the right NSAID and we use protective strategies,” Dr. Vettese said.
Celecoxib is the safest drug in terms of upper GI bleeding risk, but ibuprofen is close. They are associated with a 2.2-fold increased risk of bleeding when compared with risk in patients not on an NSAID. Naproxen or indeomethacin use carries a fourfold to fivefold increased risk.
“Celecoxib with a proton pump inhibitor is safest, followed by celecoxib alone, followed by ibuprofen with a proton pump inhibitor. So I advocate using NSAIDs more frequently in people who are at moderate risk by using them with a PPI,” she said.
There is persuasive evidence of increased cardiovascular risk in association with even short-duration NSAIDs, as the drugs are utilized in the treatment of acute pain in hospitalized patients. That being said, Dr. Vettese believes hospitalists can use these drugs safely in more patients by following a thoughtful cardiovascular risk-mitigation strategy developed by Italian investigators.
Communicating about pain management
“Communication is always the key to effective pain management in every situation,” Dr. Vettese emphasized.
“I talk to the patient about the goals of effective pain management. I’ll discourage the use of the 1-10 pain scale, and instead, I’ll be honest about expectations, saying, ‘You have a problem that will cause acute pain, and it’s unlikely that I will be able to completely relieve your pain. The goal is to improve your function so that you can get up and go the bathroom by yourself, and so that you can sleep for a few hours. That’s how we’re going to measure the efficacy of our pain-management program.’ ”
She explains to the patient that she’ll be using nonopioid medications and nondrug therapies along with oral opioid pain medications, which are less risky than IV opioids. She offers reassurance that this treatment strategy won’t cause an OUD relapse. She lets the patient know up-front that the opioids will be tapered as the acute pain improves.
For the patient who comes into the hospital on buprenorphine for OUD, she immediately checks with the state prescription drug monitoring program to make sure everything is above board and there’s no indication of doctor shopping for prescriptions. For in-hospital acute pain, it’s safe and effective to continue the outpatient dose. On an outpatient basis, however, the drug is given once daily. On that dosing schedule both the euphoric effect as well as the analgesic effect are lost, so for acute pain management in the hospital it’s recommended to split the dose into twice- or thrice-daily doses to achieve an analgesic effect.
Oral NSAIDs are part of the treatment strategy whenever possible. For severe acute pain, Dr. Vettese will prescribe an immediate-release opioid having a high affinity to the mu opioid receptor, such as oral hydromorphone, on an as-needed basis. The drug has onset of effect in 30 minutes, peak effect in 1 hour, and a duration of effect of 4-6 hours, although she recommends going with 4 hours to provide adequate analgesia.
“These patients will require much higher doses than the patients who are opioid naive,” she advised.
For the patient with acute pain who is admitted while on methadone for OUD, it’s important to call the outpatient treatment program to verify the dosage.
“You can split the dose of methadone to try to get better analgesia, although I can tell you that patients who are treated with methadone for OUD frequently don’t want to do that. And if they don’t want to, then I don’t,” the hospitalist said.
As with the patient on buprenorphine for OUD, she’ll use additional oral immediate-release opioids as needed for acute severe pain in a patient on methadone for medication-assisted OUD treatment.
Dr. Vettese reported having no financial conflicts regarding her presentation.
FROM HM20 VIRTUAL
FDA approves ofatumumab (Kesimpta) for relapsing forms of MS
including relapsing-remitting MS, active secondary progressive MS, and clinically isolated syndrome, Novartis announced in a press release. This is the first FDA approval of a self-administered, targeted B-cell therapy for these conditions, and is delivered via an autoinjector pen.
“This approval is wonderful news for patients with relapsing multiple sclerosis,” Stephen Hauser, MD, director of the Weill Institute for Neurosciences at the University of California, San Francisco, said in the press release. “Through its favorable safety profile and well-tolerated monthly injection regimen, patients can self-administer the treatment at home, avoiding visits to the infusion center,” he noted.
Dr. Hauser is cochair of the steering committee for the phase 3 ASCLEPIOS I and II studies that were part of the basis for the FDA’s approval.
Bruce Bebo, PhD, executive vice president of research at the National MS Society, said because response to disease-modifying treatments varies among individuals with MS, it’s important to have a range of treatment options available with differing mechanisms of action. “We are pleased to have an additional option approved for the treatment of relapsing forms of MS,” he said.
Twin studies
Formerly known as OMB157, ofatumumab is a precisely-dosed anti-CD20 monoclonal antibody administered subcutaneously via once-monthly injection. However, Novartis noted that initial doses are given at weeks 0, 1, and 2 – with the first injection occurring with a health care professional present.
The drug “is thought to work by binding to a distinct epitope on the CD20 molecule inducing potent B-cell lysis and depletion,” the manufacturer noted.
As previously reported, results for the ACLEPIOS I and II studies were presented at the 2019 Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), with additional results presented at the 2020 Virtual Annual Meeting of the Consortium of Multiple Sclerosis Centers. In addition, the findings were published in the New England Journal of Medicine.
The twin, identically designed phase 3 studies assessed the safety and efficacy of the drug at a monthly subcutaneous dose of 20 mg versus once daily teriflunomide 14-mg oral tablets. Together, the studies included 1,882 adult patients at more than 350 sites in 37 countries.
Results showed that the study drug reduced the annualized relapse rate (ARR) by 51% in the first study and by 59% in the second versus teriflunomide (P < .001 in both studies), meeting the primary endpoint. Both studies also showed significant reductions of gadolinium-enhancing (Gd+) T1 lesions (by 98% and 94%, respectively) and new or enlarging T2 lesions (by 82% and 85%).
The most commonly observed treatment-related adverse events for ofatumumab were upper respiratory tract infection, headache, and injection-related reactions.
Although the FDA first approved ofatumumab in 2009 for treating chronic lymphocytic leukemia (CLL), it was administered as a high-dose intravenous infusion by a healthcare provider. “This is a different dosing regimen and route of administration than was previously approved for the CLL indication,” the company noted.
The drug is expected to be available in the United States in September.
A version of this article originally appeared on Medscape.com.
including relapsing-remitting MS, active secondary progressive MS, and clinically isolated syndrome, Novartis announced in a press release. This is the first FDA approval of a self-administered, targeted B-cell therapy for these conditions, and is delivered via an autoinjector pen.
“This approval is wonderful news for patients with relapsing multiple sclerosis,” Stephen Hauser, MD, director of the Weill Institute for Neurosciences at the University of California, San Francisco, said in the press release. “Through its favorable safety profile and well-tolerated monthly injection regimen, patients can self-administer the treatment at home, avoiding visits to the infusion center,” he noted.
Dr. Hauser is cochair of the steering committee for the phase 3 ASCLEPIOS I and II studies that were part of the basis for the FDA’s approval.
Bruce Bebo, PhD, executive vice president of research at the National MS Society, said because response to disease-modifying treatments varies among individuals with MS, it’s important to have a range of treatment options available with differing mechanisms of action. “We are pleased to have an additional option approved for the treatment of relapsing forms of MS,” he said.
Twin studies
Formerly known as OMB157, ofatumumab is a precisely-dosed anti-CD20 monoclonal antibody administered subcutaneously via once-monthly injection. However, Novartis noted that initial doses are given at weeks 0, 1, and 2 – with the first injection occurring with a health care professional present.
The drug “is thought to work by binding to a distinct epitope on the CD20 molecule inducing potent B-cell lysis and depletion,” the manufacturer noted.
As previously reported, results for the ACLEPIOS I and II studies were presented at the 2019 Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), with additional results presented at the 2020 Virtual Annual Meeting of the Consortium of Multiple Sclerosis Centers. In addition, the findings were published in the New England Journal of Medicine.
The twin, identically designed phase 3 studies assessed the safety and efficacy of the drug at a monthly subcutaneous dose of 20 mg versus once daily teriflunomide 14-mg oral tablets. Together, the studies included 1,882 adult patients at more than 350 sites in 37 countries.
Results showed that the study drug reduced the annualized relapse rate (ARR) by 51% in the first study and by 59% in the second versus teriflunomide (P < .001 in both studies), meeting the primary endpoint. Both studies also showed significant reductions of gadolinium-enhancing (Gd+) T1 lesions (by 98% and 94%, respectively) and new or enlarging T2 lesions (by 82% and 85%).
The most commonly observed treatment-related adverse events for ofatumumab were upper respiratory tract infection, headache, and injection-related reactions.
Although the FDA first approved ofatumumab in 2009 for treating chronic lymphocytic leukemia (CLL), it was administered as a high-dose intravenous infusion by a healthcare provider. “This is a different dosing regimen and route of administration than was previously approved for the CLL indication,” the company noted.
The drug is expected to be available in the United States in September.
A version of this article originally appeared on Medscape.com.
including relapsing-remitting MS, active secondary progressive MS, and clinically isolated syndrome, Novartis announced in a press release. This is the first FDA approval of a self-administered, targeted B-cell therapy for these conditions, and is delivered via an autoinjector pen.
“This approval is wonderful news for patients with relapsing multiple sclerosis,” Stephen Hauser, MD, director of the Weill Institute for Neurosciences at the University of California, San Francisco, said in the press release. “Through its favorable safety profile and well-tolerated monthly injection regimen, patients can self-administer the treatment at home, avoiding visits to the infusion center,” he noted.
Dr. Hauser is cochair of the steering committee for the phase 3 ASCLEPIOS I and II studies that were part of the basis for the FDA’s approval.
Bruce Bebo, PhD, executive vice president of research at the National MS Society, said because response to disease-modifying treatments varies among individuals with MS, it’s important to have a range of treatment options available with differing mechanisms of action. “We are pleased to have an additional option approved for the treatment of relapsing forms of MS,” he said.
Twin studies
Formerly known as OMB157, ofatumumab is a precisely-dosed anti-CD20 monoclonal antibody administered subcutaneously via once-monthly injection. However, Novartis noted that initial doses are given at weeks 0, 1, and 2 – with the first injection occurring with a health care professional present.
The drug “is thought to work by binding to a distinct epitope on the CD20 molecule inducing potent B-cell lysis and depletion,” the manufacturer noted.
As previously reported, results for the ACLEPIOS I and II studies were presented at the 2019 Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), with additional results presented at the 2020 Virtual Annual Meeting of the Consortium of Multiple Sclerosis Centers. In addition, the findings were published in the New England Journal of Medicine.
The twin, identically designed phase 3 studies assessed the safety and efficacy of the drug at a monthly subcutaneous dose of 20 mg versus once daily teriflunomide 14-mg oral tablets. Together, the studies included 1,882 adult patients at more than 350 sites in 37 countries.
Results showed that the study drug reduced the annualized relapse rate (ARR) by 51% in the first study and by 59% in the second versus teriflunomide (P < .001 in both studies), meeting the primary endpoint. Both studies also showed significant reductions of gadolinium-enhancing (Gd+) T1 lesions (by 98% and 94%, respectively) and new or enlarging T2 lesions (by 82% and 85%).
The most commonly observed treatment-related adverse events for ofatumumab were upper respiratory tract infection, headache, and injection-related reactions.
Although the FDA first approved ofatumumab in 2009 for treating chronic lymphocytic leukemia (CLL), it was administered as a high-dose intravenous infusion by a healthcare provider. “This is a different dosing regimen and route of administration than was previously approved for the CLL indication,” the company noted.
The drug is expected to be available in the United States in September.
A version of this article originally appeared on Medscape.com.
Are aging physicians a burden?
The evaluation of physicians with alleged cognitive decline
As forensic evaluators, we are often asked to review and assess the cognition of aging colleagues. The premise often involves a minor mistake, a poor choice of words, or a lapse in judgment. A physician gets reported for having difficulty using a new electronic form, forgetting the dose of a brand new medication, or getting upset in a public setting. Those behaviors often lead to mandatory psychiatric evaluations. Those requirements are often perceived by the provider as an insult, and betrayal by peers despite many years of dedicated work.
Interestingly, we have noticed many independent evaluators and hospital administrators using this opportunity to send many of our colleagues to pasture. There seems to be an unspoken rule among some forensic evaluators that physicians should represent some form of apex of humanity, beyond reproach, and beyond any fault. Those evaluators will point to any mistake on cognitive scales as proof that the aging physician is no longer safe to practice.1 Forgetting that Jill is from Illinois in the Saint Louis University Mental Status Examination test or how to copy a three-dimensional cube on the Montreal Cognitive Assessment can cost someone their license.2 We are also aware of some evaluators even taking the step further and opining that physicians not only need to score adequately but also demonstrate cognition significantly above average to maintain their privileges.
There is certainly significant appeal in setting a high bar for physicians. In many ways, physicians are characterized in society by their astuteness, intelligence, and high ethical standards. Patients place their lives in the hands of physicians and should trust that those physicians have the cognitive tools to heal them. It could almost seem evident that physicians should have high IQs, score perfectly on screening tools for dementia, and complete a mandatory psychiatric evaluation without any reproach. Yet the reality is often more complex.
We have two main concerns about the idea that we should be intransigent with aging physicians. The first one is the vast differential diagnosis for minor mistakes. An aging physician refusing to comply with a new form or yelling at a clerk once when asked to learn a new electronic medical record are inappropriate though not specific assessments for dementia. Similarly, having significant difficulty learning a new electronic medical record system more often is a sign of ageism rather than cognitive impairment. Subsequently, when arriving for their evaluation, forgetting the date is a common sign of anxiety. A relatable analogy would be to compare the mistake with a medical student forgetting part of the anatomy while questioning by an attending during surgery. Imagine such medical students being referred to mandatory psychiatric evaluation when failing to answer a question during rounds.
In our practice, the most common reason for those minor mistakes during our clinical evaluation is anxiety. After all, patients who present for problems completely unrelated to cognitive decline make similar mistakes. Psychological stressors in physicians require no introduction. The concept is so prevalent and pervasive that it has its own name, “burnout.” Imagine having dedicated most of one’s life to a profession then being enumerated a list of complaints, having one’s privileges put on hold, then being told to complete an independent psychiatric evaluation. If burnout is in part caused by a lack of control, unclear job expectations, rapidly changing models of health care, and dysfunctional workplace dynamics, imagine the consequence of such a referral.
The militant evaluator will use jargon to vilify the reviewed physician. If the physician complains too voraciously, he will be described as having signs of frontotemporal dementia. If the physician comes with a written list of rebuttals, he will be described as having memory problems requiring aids. If the physician is demoralized and quiet, he will be described as being withdrawn and apathetic. If the physician refuses to use or has difficulty with new forms or electronic systems, he will be described as having “impaired executive function,” an ominous term that surely should not be associated with a practicing physician.
The second concern arises from problems with the validity and use of diagnoses like mild cognitive impairment (MCI). MCI is considered to be a transition stage when one maintains “normal activities of daily living, and normal general cognitive function.”3 The American Psychiatric Association Textbook of Psychiatry mentions that there are “however, many cases of nonprogressive MCI.” Should a disorder with generally normal cognition and unclear progression to a more severe disorder require one to be dispensed of their privileges? Should any disorder trump an assessment of functioning?
It is our experience that many if not most physicians’ practice of medicine is not a job but a profession that defines who they are. As such, their occupational habits are an overly repeated and ingrained series of maneuvers analogous to so-called muscle memory. This kind of ritualistic pattern is precisely the kind of cognition that may persist as one starts to have some deficits. This requires the evaluator to be particularly sensitive and cognizant that one may still be able to perform professionally despite some mild but notable deficits. While it is facile to diagnose someone with MCI and justify removing their license, a review of their actual clinical skills is, despite being more time consuming, more pertinent to the evaluation.
In practice, we find that many cases lie in a gray area, which is hard to define. Physicians may come to our office for an evaluation after having said something odd at work. Maybe they misdosed a medication on one occasion. Maybe they wrote the wrong year on a chart. However, if the physician was 30 years old, would we consider any one of those incidents significant? As a psychiatrist rather than a physician practicing the specialty in review, it is particularly hard and sometimes unwise to condone or sanction individual incidents.
Evaluators find solace in neuropsychological testing. However the relevance to the safety of patients is unclear. Many of those tests end up being a simple proxy for age. A physicians’ ability to sort words or cards at a certain speed might correlate to cognitive performance but has unclear significance to the ability to care for patients. Using such tests becomes a de facto age limit on the practice of medicine. It seems essential to expand and refine our repertoire of evaluation tools for the assessment of physicians. As when we perform capacity evaluation in the hospital, we enlist the assistance of the treating team in understanding the questions being asked for a patient, medical boards could consider creating independent multidisciplinary teams where psychiatry has a seat along with the relevant specialties of the evaluee. Likewise, the assessment would benefit from a broad review of the physicians’ general practice rather than the more typical review of one or two incidents.
We are promoting a more individualized approach by medical boards to the many issues of the aging physician. Retiring is no longer the dream of older physicians, but rather working in the suitable position where their contributions, clinical experience, and wisdom are positive contributions to patient care. Furthermore, we encourage medical boards to consider more nuanced decisions. A binary approach fits few cases that we see. Surgeons are a prime example of this. A surgeon in the early stages of Parkinsonism may be unfit to perform surgery but very capable of continuing to contribute to the well-being of patients in other forms of clinical work, including postsurgical care that doesn’t involve physical dexterity. Similarly, medical boards could consider other forms of partial restrictions, including a ban on procedures, a ban on hospital privileges, as well as required supervision or working in teams. Accumulated clinical wisdom allows older physicians to be excellent mentors and educators for younger doctors. There is no simple method to predict which physicians may have the early stages of a progressive dementia, and which may have a stable MCI. A yearly reevaluation if there are no further complaints, is the best approach to determine progression of cognitive problems.
Few crises like the current COVID-19 pandemic can better remind us of the importance of the place of medicine in society. Many states have encouraged retired physicians to contribute their knowledge and expertise, putting themselves in particular risk because of their age. It is a good time to be reminded that we owe them significant respect and care when deciding to remove their license. We are encouraged by the diligent efforts of medical boards in supervising our colleagues but warn against zealot evaluators who use this opportunity to force physicians into retirement. We also encourage medical boards to expand their tools and approaches when facing such cases, as mislabeled cognitive diagnoses can be an easy scapegoat of a poor understanding of the more important psychological and biological factors in the evaluation.
References
1. Tariq SH et al. Am J Geriatr Psychiatry. 2006;14:900-10.
2. Nasreddine Z. mocatest.org. Version 2004 Nov 7.
3. Hales RE et al. The American Psychiatric Publishing Textbook of Psychiatry. Washington: American Psychiatric Association Publishing, 2014.
Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Among his writings in chapter 7 in the book “Critical Psychiatry: Controversies and Clinical Implications” (Cham, Switzerland: Springer, 2019). He has no disclosures.
Dr. Abrams is a forensic psychiatrist and attorney in San Diego. He is an expert in addictionology, behavioral toxicology, psychopharmacology and correctional mental health. He holds a teaching positions at the University of California, San Diego. Among his writings are chapters about competency in national textbooks. Dr. Abrams has no disclosures.
The evaluation of physicians with alleged cognitive decline
The evaluation of physicians with alleged cognitive decline
As forensic evaluators, we are often asked to review and assess the cognition of aging colleagues. The premise often involves a minor mistake, a poor choice of words, or a lapse in judgment. A physician gets reported for having difficulty using a new electronic form, forgetting the dose of a brand new medication, or getting upset in a public setting. Those behaviors often lead to mandatory psychiatric evaluations. Those requirements are often perceived by the provider as an insult, and betrayal by peers despite many years of dedicated work.
Interestingly, we have noticed many independent evaluators and hospital administrators using this opportunity to send many of our colleagues to pasture. There seems to be an unspoken rule among some forensic evaluators that physicians should represent some form of apex of humanity, beyond reproach, and beyond any fault. Those evaluators will point to any mistake on cognitive scales as proof that the aging physician is no longer safe to practice.1 Forgetting that Jill is from Illinois in the Saint Louis University Mental Status Examination test or how to copy a three-dimensional cube on the Montreal Cognitive Assessment can cost someone their license.2 We are also aware of some evaluators even taking the step further and opining that physicians not only need to score adequately but also demonstrate cognition significantly above average to maintain their privileges.
There is certainly significant appeal in setting a high bar for physicians. In many ways, physicians are characterized in society by their astuteness, intelligence, and high ethical standards. Patients place their lives in the hands of physicians and should trust that those physicians have the cognitive tools to heal them. It could almost seem evident that physicians should have high IQs, score perfectly on screening tools for dementia, and complete a mandatory psychiatric evaluation without any reproach. Yet the reality is often more complex.
We have two main concerns about the idea that we should be intransigent with aging physicians. The first one is the vast differential diagnosis for minor mistakes. An aging physician refusing to comply with a new form or yelling at a clerk once when asked to learn a new electronic medical record are inappropriate though not specific assessments for dementia. Similarly, having significant difficulty learning a new electronic medical record system more often is a sign of ageism rather than cognitive impairment. Subsequently, when arriving for their evaluation, forgetting the date is a common sign of anxiety. A relatable analogy would be to compare the mistake with a medical student forgetting part of the anatomy while questioning by an attending during surgery. Imagine such medical students being referred to mandatory psychiatric evaluation when failing to answer a question during rounds.
In our practice, the most common reason for those minor mistakes during our clinical evaluation is anxiety. After all, patients who present for problems completely unrelated to cognitive decline make similar mistakes. Psychological stressors in physicians require no introduction. The concept is so prevalent and pervasive that it has its own name, “burnout.” Imagine having dedicated most of one’s life to a profession then being enumerated a list of complaints, having one’s privileges put on hold, then being told to complete an independent psychiatric evaluation. If burnout is in part caused by a lack of control, unclear job expectations, rapidly changing models of health care, and dysfunctional workplace dynamics, imagine the consequence of such a referral.
The militant evaluator will use jargon to vilify the reviewed physician. If the physician complains too voraciously, he will be described as having signs of frontotemporal dementia. If the physician comes with a written list of rebuttals, he will be described as having memory problems requiring aids. If the physician is demoralized and quiet, he will be described as being withdrawn and apathetic. If the physician refuses to use or has difficulty with new forms or electronic systems, he will be described as having “impaired executive function,” an ominous term that surely should not be associated with a practicing physician.
The second concern arises from problems with the validity and use of diagnoses like mild cognitive impairment (MCI). MCI is considered to be a transition stage when one maintains “normal activities of daily living, and normal general cognitive function.”3 The American Psychiatric Association Textbook of Psychiatry mentions that there are “however, many cases of nonprogressive MCI.” Should a disorder with generally normal cognition and unclear progression to a more severe disorder require one to be dispensed of their privileges? Should any disorder trump an assessment of functioning?
It is our experience that many if not most physicians’ practice of medicine is not a job but a profession that defines who they are. As such, their occupational habits are an overly repeated and ingrained series of maneuvers analogous to so-called muscle memory. This kind of ritualistic pattern is precisely the kind of cognition that may persist as one starts to have some deficits. This requires the evaluator to be particularly sensitive and cognizant that one may still be able to perform professionally despite some mild but notable deficits. While it is facile to diagnose someone with MCI and justify removing their license, a review of their actual clinical skills is, despite being more time consuming, more pertinent to the evaluation.
In practice, we find that many cases lie in a gray area, which is hard to define. Physicians may come to our office for an evaluation after having said something odd at work. Maybe they misdosed a medication on one occasion. Maybe they wrote the wrong year on a chart. However, if the physician was 30 years old, would we consider any one of those incidents significant? As a psychiatrist rather than a physician practicing the specialty in review, it is particularly hard and sometimes unwise to condone or sanction individual incidents.
Evaluators find solace in neuropsychological testing. However the relevance to the safety of patients is unclear. Many of those tests end up being a simple proxy for age. A physicians’ ability to sort words or cards at a certain speed might correlate to cognitive performance but has unclear significance to the ability to care for patients. Using such tests becomes a de facto age limit on the practice of medicine. It seems essential to expand and refine our repertoire of evaluation tools for the assessment of physicians. As when we perform capacity evaluation in the hospital, we enlist the assistance of the treating team in understanding the questions being asked for a patient, medical boards could consider creating independent multidisciplinary teams where psychiatry has a seat along with the relevant specialties of the evaluee. Likewise, the assessment would benefit from a broad review of the physicians’ general practice rather than the more typical review of one or two incidents.
We are promoting a more individualized approach by medical boards to the many issues of the aging physician. Retiring is no longer the dream of older physicians, but rather working in the suitable position where their contributions, clinical experience, and wisdom are positive contributions to patient care. Furthermore, we encourage medical boards to consider more nuanced decisions. A binary approach fits few cases that we see. Surgeons are a prime example of this. A surgeon in the early stages of Parkinsonism may be unfit to perform surgery but very capable of continuing to contribute to the well-being of patients in other forms of clinical work, including postsurgical care that doesn’t involve physical dexterity. Similarly, medical boards could consider other forms of partial restrictions, including a ban on procedures, a ban on hospital privileges, as well as required supervision or working in teams. Accumulated clinical wisdom allows older physicians to be excellent mentors and educators for younger doctors. There is no simple method to predict which physicians may have the early stages of a progressive dementia, and which may have a stable MCI. A yearly reevaluation if there are no further complaints, is the best approach to determine progression of cognitive problems.
Few crises like the current COVID-19 pandemic can better remind us of the importance of the place of medicine in society. Many states have encouraged retired physicians to contribute their knowledge and expertise, putting themselves in particular risk because of their age. It is a good time to be reminded that we owe them significant respect and care when deciding to remove their license. We are encouraged by the diligent efforts of medical boards in supervising our colleagues but warn against zealot evaluators who use this opportunity to force physicians into retirement. We also encourage medical boards to expand their tools and approaches when facing such cases, as mislabeled cognitive diagnoses can be an easy scapegoat of a poor understanding of the more important psychological and biological factors in the evaluation.
References
1. Tariq SH et al. Am J Geriatr Psychiatry. 2006;14:900-10.
2. Nasreddine Z. mocatest.org. Version 2004 Nov 7.
3. Hales RE et al. The American Psychiatric Publishing Textbook of Psychiatry. Washington: American Psychiatric Association Publishing, 2014.
Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Among his writings in chapter 7 in the book “Critical Psychiatry: Controversies and Clinical Implications” (Cham, Switzerland: Springer, 2019). He has no disclosures.
Dr. Abrams is a forensic psychiatrist and attorney in San Diego. He is an expert in addictionology, behavioral toxicology, psychopharmacology and correctional mental health. He holds a teaching positions at the University of California, San Diego. Among his writings are chapters about competency in national textbooks. Dr. Abrams has no disclosures.
As forensic evaluators, we are often asked to review and assess the cognition of aging colleagues. The premise often involves a minor mistake, a poor choice of words, or a lapse in judgment. A physician gets reported for having difficulty using a new electronic form, forgetting the dose of a brand new medication, or getting upset in a public setting. Those behaviors often lead to mandatory psychiatric evaluations. Those requirements are often perceived by the provider as an insult, and betrayal by peers despite many years of dedicated work.
Interestingly, we have noticed many independent evaluators and hospital administrators using this opportunity to send many of our colleagues to pasture. There seems to be an unspoken rule among some forensic evaluators that physicians should represent some form of apex of humanity, beyond reproach, and beyond any fault. Those evaluators will point to any mistake on cognitive scales as proof that the aging physician is no longer safe to practice.1 Forgetting that Jill is from Illinois in the Saint Louis University Mental Status Examination test or how to copy a three-dimensional cube on the Montreal Cognitive Assessment can cost someone their license.2 We are also aware of some evaluators even taking the step further and opining that physicians not only need to score adequately but also demonstrate cognition significantly above average to maintain their privileges.
There is certainly significant appeal in setting a high bar for physicians. In many ways, physicians are characterized in society by their astuteness, intelligence, and high ethical standards. Patients place their lives in the hands of physicians and should trust that those physicians have the cognitive tools to heal them. It could almost seem evident that physicians should have high IQs, score perfectly on screening tools for dementia, and complete a mandatory psychiatric evaluation without any reproach. Yet the reality is often more complex.
We have two main concerns about the idea that we should be intransigent with aging physicians. The first one is the vast differential diagnosis for minor mistakes. An aging physician refusing to comply with a new form or yelling at a clerk once when asked to learn a new electronic medical record are inappropriate though not specific assessments for dementia. Similarly, having significant difficulty learning a new electronic medical record system more often is a sign of ageism rather than cognitive impairment. Subsequently, when arriving for their evaluation, forgetting the date is a common sign of anxiety. A relatable analogy would be to compare the mistake with a medical student forgetting part of the anatomy while questioning by an attending during surgery. Imagine such medical students being referred to mandatory psychiatric evaluation when failing to answer a question during rounds.
In our practice, the most common reason for those minor mistakes during our clinical evaluation is anxiety. After all, patients who present for problems completely unrelated to cognitive decline make similar mistakes. Psychological stressors in physicians require no introduction. The concept is so prevalent and pervasive that it has its own name, “burnout.” Imagine having dedicated most of one’s life to a profession then being enumerated a list of complaints, having one’s privileges put on hold, then being told to complete an independent psychiatric evaluation. If burnout is in part caused by a lack of control, unclear job expectations, rapidly changing models of health care, and dysfunctional workplace dynamics, imagine the consequence of such a referral.
The militant evaluator will use jargon to vilify the reviewed physician. If the physician complains too voraciously, he will be described as having signs of frontotemporal dementia. If the physician comes with a written list of rebuttals, he will be described as having memory problems requiring aids. If the physician is demoralized and quiet, he will be described as being withdrawn and apathetic. If the physician refuses to use or has difficulty with new forms or electronic systems, he will be described as having “impaired executive function,” an ominous term that surely should not be associated with a practicing physician.
The second concern arises from problems with the validity and use of diagnoses like mild cognitive impairment (MCI). MCI is considered to be a transition stage when one maintains “normal activities of daily living, and normal general cognitive function.”3 The American Psychiatric Association Textbook of Psychiatry mentions that there are “however, many cases of nonprogressive MCI.” Should a disorder with generally normal cognition and unclear progression to a more severe disorder require one to be dispensed of their privileges? Should any disorder trump an assessment of functioning?
It is our experience that many if not most physicians’ practice of medicine is not a job but a profession that defines who they are. As such, their occupational habits are an overly repeated and ingrained series of maneuvers analogous to so-called muscle memory. This kind of ritualistic pattern is precisely the kind of cognition that may persist as one starts to have some deficits. This requires the evaluator to be particularly sensitive and cognizant that one may still be able to perform professionally despite some mild but notable deficits. While it is facile to diagnose someone with MCI and justify removing their license, a review of their actual clinical skills is, despite being more time consuming, more pertinent to the evaluation.
In practice, we find that many cases lie in a gray area, which is hard to define. Physicians may come to our office for an evaluation after having said something odd at work. Maybe they misdosed a medication on one occasion. Maybe they wrote the wrong year on a chart. However, if the physician was 30 years old, would we consider any one of those incidents significant? As a psychiatrist rather than a physician practicing the specialty in review, it is particularly hard and sometimes unwise to condone or sanction individual incidents.
Evaluators find solace in neuropsychological testing. However the relevance to the safety of patients is unclear. Many of those tests end up being a simple proxy for age. A physicians’ ability to sort words or cards at a certain speed might correlate to cognitive performance but has unclear significance to the ability to care for patients. Using such tests becomes a de facto age limit on the practice of medicine. It seems essential to expand and refine our repertoire of evaluation tools for the assessment of physicians. As when we perform capacity evaluation in the hospital, we enlist the assistance of the treating team in understanding the questions being asked for a patient, medical boards could consider creating independent multidisciplinary teams where psychiatry has a seat along with the relevant specialties of the evaluee. Likewise, the assessment would benefit from a broad review of the physicians’ general practice rather than the more typical review of one or two incidents.
We are promoting a more individualized approach by medical boards to the many issues of the aging physician. Retiring is no longer the dream of older physicians, but rather working in the suitable position where their contributions, clinical experience, and wisdom are positive contributions to patient care. Furthermore, we encourage medical boards to consider more nuanced decisions. A binary approach fits few cases that we see. Surgeons are a prime example of this. A surgeon in the early stages of Parkinsonism may be unfit to perform surgery but very capable of continuing to contribute to the well-being of patients in other forms of clinical work, including postsurgical care that doesn’t involve physical dexterity. Similarly, medical boards could consider other forms of partial restrictions, including a ban on procedures, a ban on hospital privileges, as well as required supervision or working in teams. Accumulated clinical wisdom allows older physicians to be excellent mentors and educators for younger doctors. There is no simple method to predict which physicians may have the early stages of a progressive dementia, and which may have a stable MCI. A yearly reevaluation if there are no further complaints, is the best approach to determine progression of cognitive problems.
Few crises like the current COVID-19 pandemic can better remind us of the importance of the place of medicine in society. Many states have encouraged retired physicians to contribute their knowledge and expertise, putting themselves in particular risk because of their age. It is a good time to be reminded that we owe them significant respect and care when deciding to remove their license. We are encouraged by the diligent efforts of medical boards in supervising our colleagues but warn against zealot evaluators who use this opportunity to force physicians into retirement. We also encourage medical boards to expand their tools and approaches when facing such cases, as mislabeled cognitive diagnoses can be an easy scapegoat of a poor understanding of the more important psychological and biological factors in the evaluation.
References
1. Tariq SH et al. Am J Geriatr Psychiatry. 2006;14:900-10.
2. Nasreddine Z. mocatest.org. Version 2004 Nov 7.
3. Hales RE et al. The American Psychiatric Publishing Textbook of Psychiatry. Washington: American Psychiatric Association Publishing, 2014.
Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Among his writings in chapter 7 in the book “Critical Psychiatry: Controversies and Clinical Implications” (Cham, Switzerland: Springer, 2019). He has no disclosures.
Dr. Abrams is a forensic psychiatrist and attorney in San Diego. He is an expert in addictionology, behavioral toxicology, psychopharmacology and correctional mental health. He holds a teaching positions at the University of California, San Diego. Among his writings are chapters about competency in national textbooks. Dr. Abrams has no disclosures.
Impaired senses, especially smell, linked to dementia
new research suggests. The study, which included almost 1,800 participants, adds to emerging evidence that even mild levels of multisensory impairment are associated with accelerated cognitive aging, the researchers noted.
Clinicians should be aware of this link between sensory impairment and dementia risk, said lead author Willa Brenowitz, PhD, assistant professor, department of psychiatry and behavioral sciences, University of California, San Francisco. “Many of these impairments are treatable, or at least physicians can monitor them; and this can improve quality of life, even if it doesn’t improve dementia risk.”
The findings were published online July 12 in Alzheimer’s and Dementia.
Additive effects
Previous research has focused on the link between dementia and individual senses, but this new work is unique in that it focuses on the additive effects of multiple impairments in sensory function, said Dr. Brenowitz. The study included 1,794 dementia-free participants in their 70s from the Health, Aging and Body Composition study, a prospective cohort study of healthy Black and White men and women.
Researchers tested participants’ hearing using a pure tone average without hearing aids and vision using contrast sensitivity with glasses permitted. They also measured vibrations in the big toe to assess touch and had participants identify distinctive odors such as paint thinner, roses, lemons, and onions to assess smell.
A score of 0-3 was assigned based on sample quartiles for each of the four sensory functions. Individuals with the best quartile were assigned a score of 0 and those with the worst were assigned a score of 3.
The investigators added scores across all senses to create a summary score of multisensory function (0-12) and classified the participants into tertiles of good, medium, and poor. Individuals with a score of 0 would have good function in all senses, whereas those with 12 would have poor function in all senses. Those with medium scores could have a mix of impairments.
Participants with good multisensory function were more likely to be healthier than those with poor function. They were also significantly more likely to have completed high school (85.0% vs. 72.1%), were significantly less likely to have diabetes (16.9% vs. 27.9%), and were marginally less likely to have cardiovascular disease, high blood pressure, and history of stroke.
Investigators measured cognition using the Modified Mini-Mental State (3MS) examination, a test of global cognitive function, and the Digit Symbol Substitution Test (DSST), a measure of cognitive processing speed. Cognitive testing was carried out at the beginning of the study and repeated every other year.
Dementia was defined as the use of dementia medication, being hospitalized with dementia as a primary or secondary diagnosis, or having a 3MS score 1.5 standard deviations lower than the race-stratified Health ABC study baseline mean.
Over an average follow-up of 6.3 years, 18% of participants developed dementia.
Dose-response increase
Results showed that, with worsening multisensory function score, the risk for dementia increased in a dose-response manner. In models adjusted for demographics and health conditions, participants with a poor multisensory function score were more than twice as likely to develop dementia than those with a good score (hazard ratio, 2.05; 95% confidence interval, 1.50-2.81; P < .001). Those with a middle multisensory function score were 1.45 times more likely to develop dementia (HR, 1.45; 95% CI, 1.09-1.91; P < .001).
Even a 1-point worse multisensory function score was associated with a 14% higher risk for dementia (95% CI, 8%-21%), while a 4-point worse score was associated with 71% higher risk for dementia (95% CI, 38%-211%).
Smell was the sensory function most strongly associated with dementia risk. Participants whose sense of smell declined by 10% had a 19% higher risk for dementia versus a 1%-3% higher risk for declines in vision, hearing, and touch.
It is not clear why smell was a stronger determinant of dementia risk. However, loss of this sense is often considered to be a marker for Alzheimer’s disease “because it is closely linked with brain regions that are affected” in that disease, said Dr. Brenowitz.
However, that does not necessarily mean smell is more important than vision or hearing, she added. “Even if hearing and vision have a smaller contribution to dementia, they have a stronger potential for intervention.” The findings suggest “some additive or cumulative” effects for loss of the different senses. “There’s an association above and beyond those which can be attributed to individual sensory domains,” she said.
Frailty link
After including mobility, which is a potential mediator, estimates for the multisensory function score were slightly lower. “Walking speed is pretty strongly associated with dementia risk,” Dr. Brenowitz noted. Physical frailty might help explain the link between sensory impairment and dementia risk. “It’s not clear if that’s because people with dementia are declining or because people with frailty are especially vulnerable to dementia,” she said.
The researchers also assessed the role of social support, another potential mechanism by which sensory decline, especially in hearing and vision, could influence dementia risk. Although the study did not find substantial differences in social support measures, the investigators noted that questions assessing social support were limited in scope.
Interactions between multisensory function score and race, APOE e4 allele status, and sex were not significant.
Worsening multisensory function was also linked to faster annual rates of cognitive decline as measured by both the 3MS and DSST. Each 1-point worse score was associated with faster decline (P < .05), even after adjustment for demographics and health conditions.
Possible mechanisms
A number of possible mechanisms may explain the link between poor sensory function and dementia. It could be that neurodegeneration underlying dementia affects the senses, or vision and/or hearing loss leads to social isolation and poor mental health, which in turn could affect dementia risk, the researchers wrote. It also is possible that cardiovascular disease or diabetes affect both dementia risk and sensory impairment.
Dr. Brenowitz noted that, because cognitive tests rely on a certain degree of vision and hearing, impairment of these senses may complicate such tests. Still to be determined is whether correcting sensory impairments, such as wearing corrective lenses or hearing aids, affects dementia risk.
Meanwhile, it might be a good idea to more regularly check sensory function, especially vision and hearing, the researchers suggested. These functions affect various aspects of health and can be assessed rather easily. However, because smell is so strongly associated with dementia risk, Dr. Brenowitz said she would like to see it also become “part of a screening tool.”
A possible study limitation cited was that the researchers checked sensory function only once. “Most likely, some of these would change over time, but at least it captured sensory function at one point,” Dr. Brenowitz said.
“Sheds further light”
Commenting on the study, Jo V. Rushworth, PhD, associate professor and national teaching fellow, De Montfort University Leicester (England), said it “sheds further light on the emerging links” between multisensory impairment and cognitive decline leading to dementia. “The authors show that people with even mild loss of function in various senses are more likely to develop cognitive impairment.”
Dr. Rushworth was not involved with the study but has done research in the area.
The current results suggest that measuring patients’ hearing, vision, sense of smell, and touch might “flag at-risk groups” who could be targeted for dementia prevention strategies, Dr. Rushworth noted. Such tests are noninvasive and potentially less distressing than other methods of diagnosing dementia. “Importantly, the relatively low cost and simplicity of sensory tests offer the potential for more frequent testing and the use of these methods in areas of the world where medical facilities and resources are limited.”
This new study raises the question of whether the observed sensory impairments are a cause or an effect of dementia, Dr. Rushworth noted. “As the authors suggest, decreased sensory function can lead to a decrease in social engagement, mobility, and other factors which would usually contribute to counteracting cognitive decline.”
The study raises other questions, too, said Dr. Rushworth. She noted that the participants who experienced more severe sensory impairments were, on average, 2 years older than those with the least impairments. “To what degree were the observed sensory deficits linked to normal aging rather than dementia?”
As well, Dr. Rushworth pointed out that the molecular mechanisms that “kick-start” dementia are believed to occur in midlife – so possibly at an age younger than the study participants. “Do younger people of a ‘predementia’ age range display multisensory impairments?”
Because study participants could wear glasses during vision tests but were not allowed to wear hearing aids for the hearing tests, further standardization of sensory impairment is required, Dr. Rushworth said.
“Future studies will be essential in determining the value of clinical measurement of multisensory impairment as a possible dementia indicator and prevention strategy,” she concluded.
The study was funded by the National Institute on Aging, the National Institute of Nursing Research, and the Alzheimer’s Association. Dr. Brenowitz and Dr. Rushworth have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
new research suggests. The study, which included almost 1,800 participants, adds to emerging evidence that even mild levels of multisensory impairment are associated with accelerated cognitive aging, the researchers noted.
Clinicians should be aware of this link between sensory impairment and dementia risk, said lead author Willa Brenowitz, PhD, assistant professor, department of psychiatry and behavioral sciences, University of California, San Francisco. “Many of these impairments are treatable, or at least physicians can monitor them; and this can improve quality of life, even if it doesn’t improve dementia risk.”
The findings were published online July 12 in Alzheimer’s and Dementia.
Additive effects
Previous research has focused on the link between dementia and individual senses, but this new work is unique in that it focuses on the additive effects of multiple impairments in sensory function, said Dr. Brenowitz. The study included 1,794 dementia-free participants in their 70s from the Health, Aging and Body Composition study, a prospective cohort study of healthy Black and White men and women.
Researchers tested participants’ hearing using a pure tone average without hearing aids and vision using contrast sensitivity with glasses permitted. They also measured vibrations in the big toe to assess touch and had participants identify distinctive odors such as paint thinner, roses, lemons, and onions to assess smell.
A score of 0-3 was assigned based on sample quartiles for each of the four sensory functions. Individuals with the best quartile were assigned a score of 0 and those with the worst were assigned a score of 3.
The investigators added scores across all senses to create a summary score of multisensory function (0-12) and classified the participants into tertiles of good, medium, and poor. Individuals with a score of 0 would have good function in all senses, whereas those with 12 would have poor function in all senses. Those with medium scores could have a mix of impairments.
Participants with good multisensory function were more likely to be healthier than those with poor function. They were also significantly more likely to have completed high school (85.0% vs. 72.1%), were significantly less likely to have diabetes (16.9% vs. 27.9%), and were marginally less likely to have cardiovascular disease, high blood pressure, and history of stroke.
Investigators measured cognition using the Modified Mini-Mental State (3MS) examination, a test of global cognitive function, and the Digit Symbol Substitution Test (DSST), a measure of cognitive processing speed. Cognitive testing was carried out at the beginning of the study and repeated every other year.
Dementia was defined as the use of dementia medication, being hospitalized with dementia as a primary or secondary diagnosis, or having a 3MS score 1.5 standard deviations lower than the race-stratified Health ABC study baseline mean.
Over an average follow-up of 6.3 years, 18% of participants developed dementia.
Dose-response increase
Results showed that, with worsening multisensory function score, the risk for dementia increased in a dose-response manner. In models adjusted for demographics and health conditions, participants with a poor multisensory function score were more than twice as likely to develop dementia than those with a good score (hazard ratio, 2.05; 95% confidence interval, 1.50-2.81; P < .001). Those with a middle multisensory function score were 1.45 times more likely to develop dementia (HR, 1.45; 95% CI, 1.09-1.91; P < .001).
Even a 1-point worse multisensory function score was associated with a 14% higher risk for dementia (95% CI, 8%-21%), while a 4-point worse score was associated with 71% higher risk for dementia (95% CI, 38%-211%).
Smell was the sensory function most strongly associated with dementia risk. Participants whose sense of smell declined by 10% had a 19% higher risk for dementia versus a 1%-3% higher risk for declines in vision, hearing, and touch.
It is not clear why smell was a stronger determinant of dementia risk. However, loss of this sense is often considered to be a marker for Alzheimer’s disease “because it is closely linked with brain regions that are affected” in that disease, said Dr. Brenowitz.
However, that does not necessarily mean smell is more important than vision or hearing, she added. “Even if hearing and vision have a smaller contribution to dementia, they have a stronger potential for intervention.” The findings suggest “some additive or cumulative” effects for loss of the different senses. “There’s an association above and beyond those which can be attributed to individual sensory domains,” she said.
Frailty link
After including mobility, which is a potential mediator, estimates for the multisensory function score were slightly lower. “Walking speed is pretty strongly associated with dementia risk,” Dr. Brenowitz noted. Physical frailty might help explain the link between sensory impairment and dementia risk. “It’s not clear if that’s because people with dementia are declining or because people with frailty are especially vulnerable to dementia,” she said.
The researchers also assessed the role of social support, another potential mechanism by which sensory decline, especially in hearing and vision, could influence dementia risk. Although the study did not find substantial differences in social support measures, the investigators noted that questions assessing social support were limited in scope.
Interactions between multisensory function score and race, APOE e4 allele status, and sex were not significant.
Worsening multisensory function was also linked to faster annual rates of cognitive decline as measured by both the 3MS and DSST. Each 1-point worse score was associated with faster decline (P < .05), even after adjustment for demographics and health conditions.
Possible mechanisms
A number of possible mechanisms may explain the link between poor sensory function and dementia. It could be that neurodegeneration underlying dementia affects the senses, or vision and/or hearing loss leads to social isolation and poor mental health, which in turn could affect dementia risk, the researchers wrote. It also is possible that cardiovascular disease or diabetes affect both dementia risk and sensory impairment.
Dr. Brenowitz noted that, because cognitive tests rely on a certain degree of vision and hearing, impairment of these senses may complicate such tests. Still to be determined is whether correcting sensory impairments, such as wearing corrective lenses or hearing aids, affects dementia risk.
Meanwhile, it might be a good idea to more regularly check sensory function, especially vision and hearing, the researchers suggested. These functions affect various aspects of health and can be assessed rather easily. However, because smell is so strongly associated with dementia risk, Dr. Brenowitz said she would like to see it also become “part of a screening tool.”
A possible study limitation cited was that the researchers checked sensory function only once. “Most likely, some of these would change over time, but at least it captured sensory function at one point,” Dr. Brenowitz said.
“Sheds further light”
Commenting on the study, Jo V. Rushworth, PhD, associate professor and national teaching fellow, De Montfort University Leicester (England), said it “sheds further light on the emerging links” between multisensory impairment and cognitive decline leading to dementia. “The authors show that people with even mild loss of function in various senses are more likely to develop cognitive impairment.”
Dr. Rushworth was not involved with the study but has done research in the area.
The current results suggest that measuring patients’ hearing, vision, sense of smell, and touch might “flag at-risk groups” who could be targeted for dementia prevention strategies, Dr. Rushworth noted. Such tests are noninvasive and potentially less distressing than other methods of diagnosing dementia. “Importantly, the relatively low cost and simplicity of sensory tests offer the potential for more frequent testing and the use of these methods in areas of the world where medical facilities and resources are limited.”
This new study raises the question of whether the observed sensory impairments are a cause or an effect of dementia, Dr. Rushworth noted. “As the authors suggest, decreased sensory function can lead to a decrease in social engagement, mobility, and other factors which would usually contribute to counteracting cognitive decline.”
The study raises other questions, too, said Dr. Rushworth. She noted that the participants who experienced more severe sensory impairments were, on average, 2 years older than those with the least impairments. “To what degree were the observed sensory deficits linked to normal aging rather than dementia?”
As well, Dr. Rushworth pointed out that the molecular mechanisms that “kick-start” dementia are believed to occur in midlife – so possibly at an age younger than the study participants. “Do younger people of a ‘predementia’ age range display multisensory impairments?”
Because study participants could wear glasses during vision tests but were not allowed to wear hearing aids for the hearing tests, further standardization of sensory impairment is required, Dr. Rushworth said.
“Future studies will be essential in determining the value of clinical measurement of multisensory impairment as a possible dementia indicator and prevention strategy,” she concluded.
The study was funded by the National Institute on Aging, the National Institute of Nursing Research, and the Alzheimer’s Association. Dr. Brenowitz and Dr. Rushworth have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
new research suggests. The study, which included almost 1,800 participants, adds to emerging evidence that even mild levels of multisensory impairment are associated with accelerated cognitive aging, the researchers noted.
Clinicians should be aware of this link between sensory impairment and dementia risk, said lead author Willa Brenowitz, PhD, assistant professor, department of psychiatry and behavioral sciences, University of California, San Francisco. “Many of these impairments are treatable, or at least physicians can monitor them; and this can improve quality of life, even if it doesn’t improve dementia risk.”
The findings were published online July 12 in Alzheimer’s and Dementia.
Additive effects
Previous research has focused on the link between dementia and individual senses, but this new work is unique in that it focuses on the additive effects of multiple impairments in sensory function, said Dr. Brenowitz. The study included 1,794 dementia-free participants in their 70s from the Health, Aging and Body Composition study, a prospective cohort study of healthy Black and White men and women.
Researchers tested participants’ hearing using a pure tone average without hearing aids and vision using contrast sensitivity with glasses permitted. They also measured vibrations in the big toe to assess touch and had participants identify distinctive odors such as paint thinner, roses, lemons, and onions to assess smell.
A score of 0-3 was assigned based on sample quartiles for each of the four sensory functions. Individuals with the best quartile were assigned a score of 0 and those with the worst were assigned a score of 3.
The investigators added scores across all senses to create a summary score of multisensory function (0-12) and classified the participants into tertiles of good, medium, and poor. Individuals with a score of 0 would have good function in all senses, whereas those with 12 would have poor function in all senses. Those with medium scores could have a mix of impairments.
Participants with good multisensory function were more likely to be healthier than those with poor function. They were also significantly more likely to have completed high school (85.0% vs. 72.1%), were significantly less likely to have diabetes (16.9% vs. 27.9%), and were marginally less likely to have cardiovascular disease, high blood pressure, and history of stroke.
Investigators measured cognition using the Modified Mini-Mental State (3MS) examination, a test of global cognitive function, and the Digit Symbol Substitution Test (DSST), a measure of cognitive processing speed. Cognitive testing was carried out at the beginning of the study and repeated every other year.
Dementia was defined as the use of dementia medication, being hospitalized with dementia as a primary or secondary diagnosis, or having a 3MS score 1.5 standard deviations lower than the race-stratified Health ABC study baseline mean.
Over an average follow-up of 6.3 years, 18% of participants developed dementia.
Dose-response increase
Results showed that, with worsening multisensory function score, the risk for dementia increased in a dose-response manner. In models adjusted for demographics and health conditions, participants with a poor multisensory function score were more than twice as likely to develop dementia than those with a good score (hazard ratio, 2.05; 95% confidence interval, 1.50-2.81; P < .001). Those with a middle multisensory function score were 1.45 times more likely to develop dementia (HR, 1.45; 95% CI, 1.09-1.91; P < .001).
Even a 1-point worse multisensory function score was associated with a 14% higher risk for dementia (95% CI, 8%-21%), while a 4-point worse score was associated with 71% higher risk for dementia (95% CI, 38%-211%).
Smell was the sensory function most strongly associated with dementia risk. Participants whose sense of smell declined by 10% had a 19% higher risk for dementia versus a 1%-3% higher risk for declines in vision, hearing, and touch.
It is not clear why smell was a stronger determinant of dementia risk. However, loss of this sense is often considered to be a marker for Alzheimer’s disease “because it is closely linked with brain regions that are affected” in that disease, said Dr. Brenowitz.
However, that does not necessarily mean smell is more important than vision or hearing, she added. “Even if hearing and vision have a smaller contribution to dementia, they have a stronger potential for intervention.” The findings suggest “some additive or cumulative” effects for loss of the different senses. “There’s an association above and beyond those which can be attributed to individual sensory domains,” she said.
Frailty link
After including mobility, which is a potential mediator, estimates for the multisensory function score were slightly lower. “Walking speed is pretty strongly associated with dementia risk,” Dr. Brenowitz noted. Physical frailty might help explain the link between sensory impairment and dementia risk. “It’s not clear if that’s because people with dementia are declining or because people with frailty are especially vulnerable to dementia,” she said.
The researchers also assessed the role of social support, another potential mechanism by which sensory decline, especially in hearing and vision, could influence dementia risk. Although the study did not find substantial differences in social support measures, the investigators noted that questions assessing social support were limited in scope.
Interactions between multisensory function score and race, APOE e4 allele status, and sex were not significant.
Worsening multisensory function was also linked to faster annual rates of cognitive decline as measured by both the 3MS and DSST. Each 1-point worse score was associated with faster decline (P < .05), even after adjustment for demographics and health conditions.
Possible mechanisms
A number of possible mechanisms may explain the link between poor sensory function and dementia. It could be that neurodegeneration underlying dementia affects the senses, or vision and/or hearing loss leads to social isolation and poor mental health, which in turn could affect dementia risk, the researchers wrote. It also is possible that cardiovascular disease or diabetes affect both dementia risk and sensory impairment.
Dr. Brenowitz noted that, because cognitive tests rely on a certain degree of vision and hearing, impairment of these senses may complicate such tests. Still to be determined is whether correcting sensory impairments, such as wearing corrective lenses or hearing aids, affects dementia risk.
Meanwhile, it might be a good idea to more regularly check sensory function, especially vision and hearing, the researchers suggested. These functions affect various aspects of health and can be assessed rather easily. However, because smell is so strongly associated with dementia risk, Dr. Brenowitz said she would like to see it also become “part of a screening tool.”
A possible study limitation cited was that the researchers checked sensory function only once. “Most likely, some of these would change over time, but at least it captured sensory function at one point,” Dr. Brenowitz said.
“Sheds further light”
Commenting on the study, Jo V. Rushworth, PhD, associate professor and national teaching fellow, De Montfort University Leicester (England), said it “sheds further light on the emerging links” between multisensory impairment and cognitive decline leading to dementia. “The authors show that people with even mild loss of function in various senses are more likely to develop cognitive impairment.”
Dr. Rushworth was not involved with the study but has done research in the area.
The current results suggest that measuring patients’ hearing, vision, sense of smell, and touch might “flag at-risk groups” who could be targeted for dementia prevention strategies, Dr. Rushworth noted. Such tests are noninvasive and potentially less distressing than other methods of diagnosing dementia. “Importantly, the relatively low cost and simplicity of sensory tests offer the potential for more frequent testing and the use of these methods in areas of the world where medical facilities and resources are limited.”
This new study raises the question of whether the observed sensory impairments are a cause or an effect of dementia, Dr. Rushworth noted. “As the authors suggest, decreased sensory function can lead to a decrease in social engagement, mobility, and other factors which would usually contribute to counteracting cognitive decline.”
The study raises other questions, too, said Dr. Rushworth. She noted that the participants who experienced more severe sensory impairments were, on average, 2 years older than those with the least impairments. “To what degree were the observed sensory deficits linked to normal aging rather than dementia?”
As well, Dr. Rushworth pointed out that the molecular mechanisms that “kick-start” dementia are believed to occur in midlife – so possibly at an age younger than the study participants. “Do younger people of a ‘predementia’ age range display multisensory impairments?”
Because study participants could wear glasses during vision tests but were not allowed to wear hearing aids for the hearing tests, further standardization of sensory impairment is required, Dr. Rushworth said.
“Future studies will be essential in determining the value of clinical measurement of multisensory impairment as a possible dementia indicator and prevention strategy,” she concluded.
The study was funded by the National Institute on Aging, the National Institute of Nursing Research, and the Alzheimer’s Association. Dr. Brenowitz and Dr. Rushworth have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Multiple traits more common in difficult-to-treat patients with migraine
Overall, insufficient responders—patients less likely to get relief shortly after acute treatment—are “more medically and psychosocially complex,” wrote the authors of the study, which appeared in the July/August issue of Headache.
Common characteristics of insufficient responders
The researchers, led by Louise Lombard, M Nutr, of Eli Lilly and Company, analyzed data from a 2014 cross-sectional survey. They tracked 583 patients with migraine, including 200 (34%) who were considered insufficient responders because they failed to achieve freedom from pain within 2 hours of acute treatment in at least four of five attacks.
The insufficient and sufficient responder groups were similar in age (mean = 40 for both) and gender (80% and 75% female, respectively, P = .170) and race (72% and 77% white, P = .279).
However, insufficient responders were clearly more affected by headaches, multiple treatments, and other burdens. Compared with those who had better responses to treatment, they were more likely to have four or more migraine headache days per month (46% vs. 31%), rebound or medication-overuse headaches (16% vs. 7%) and chronic migraine (12% vs. 5%, all P < .05).
They were also more likely have comorbid depression (38% vs. 22%) and psychological conditions other than depression and anxiety (8% vs. 4%, all P < .05).
As for treatment, insufficient response was higher in patients who waited until the appearance of pain to take medication (odds ratio = 1.83, 95% confidence interval [CI] 1.15–2.92, P = .011, after adjustment for covariates). And insufficient responders were more likely to have been prescribed at least three unique preventive regimens (12% vs. 6%), to take over-the-counter medications (50% vs. 38%) and to take opioid painkillers (16% vs. 8%, all P < .05).
The authors, who caution that the study does not prove cause and effect, wrote that insufficient responders “may benefit from education on how and when to use current treatments.”
Managing insufficient responders
Neurology Reviews editor-in-chief Alan M. Rapoport, MD, said the study “confirms a lot of what we knew.” Dr, Rapoport, who was not involved in the study, is clinical professor of neurology at the University of California, Los Angeles.
“As expected, the insufficient responders used more opioids and over-the-counter medications, which is not the ideal way to treat migraine,” he said. “That probably caused them to have medication-overuse headache, which might have caused them to respond poorly to even the best treatment regimen. They also had more severe symptoms, more comorbidities, and a poorer quality of life. They also had more impairment and greater impact on work, with more of them unemployed.”
The insufficient responders also “took medication at the time or after the pain began, rather than before it when they thought the attack was beginning due to premonitory symptoms,” he said.
Dr. Rapoport also noted a surprising and unusual finding: Patients who did not report sensitivity to light as their most bothersome symptom were more likely to be insufficient responders (OR = 2.3, 95% CI [1.21–4.37], P = .011). “In all recent migraine studies,” he said, “the majority of patients selected photophobia as their most bothersome symptom.”
In the big picture, he said, the study suggests that “a third triptan does not seem to work better than the first two, patients with medication-overuse headache and chronic migraine and those not on preventive medication do not respond that well to acute care treatment, and the same is true when depression is present.”
No study funding was reported. Four study authors reported ties with Eli Lilly, and two reported employment by Adelphi Real World, which provided the survey results..
SOURCE: Lombard L et al. Headache. 2020;60(7):1325-39. doi: 10.1111/head.13835.
Overall, insufficient responders—patients less likely to get relief shortly after acute treatment—are “more medically and psychosocially complex,” wrote the authors of the study, which appeared in the July/August issue of Headache.
Common characteristics of insufficient responders
The researchers, led by Louise Lombard, M Nutr, of Eli Lilly and Company, analyzed data from a 2014 cross-sectional survey. They tracked 583 patients with migraine, including 200 (34%) who were considered insufficient responders because they failed to achieve freedom from pain within 2 hours of acute treatment in at least four of five attacks.
The insufficient and sufficient responder groups were similar in age (mean = 40 for both) and gender (80% and 75% female, respectively, P = .170) and race (72% and 77% white, P = .279).
However, insufficient responders were clearly more affected by headaches, multiple treatments, and other burdens. Compared with those who had better responses to treatment, they were more likely to have four or more migraine headache days per month (46% vs. 31%), rebound or medication-overuse headaches (16% vs. 7%) and chronic migraine (12% vs. 5%, all P < .05).
They were also more likely have comorbid depression (38% vs. 22%) and psychological conditions other than depression and anxiety (8% vs. 4%, all P < .05).
As for treatment, insufficient response was higher in patients who waited until the appearance of pain to take medication (odds ratio = 1.83, 95% confidence interval [CI] 1.15–2.92, P = .011, after adjustment for covariates). And insufficient responders were more likely to have been prescribed at least three unique preventive regimens (12% vs. 6%), to take over-the-counter medications (50% vs. 38%) and to take opioid painkillers (16% vs. 8%, all P < .05).
The authors, who caution that the study does not prove cause and effect, wrote that insufficient responders “may benefit from education on how and when to use current treatments.”
Managing insufficient responders
Neurology Reviews editor-in-chief Alan M. Rapoport, MD, said the study “confirms a lot of what we knew.” Dr, Rapoport, who was not involved in the study, is clinical professor of neurology at the University of California, Los Angeles.
“As expected, the insufficient responders used more opioids and over-the-counter medications, which is not the ideal way to treat migraine,” he said. “That probably caused them to have medication-overuse headache, which might have caused them to respond poorly to even the best treatment regimen. They also had more severe symptoms, more comorbidities, and a poorer quality of life. They also had more impairment and greater impact on work, with more of them unemployed.”
The insufficient responders also “took medication at the time or after the pain began, rather than before it when they thought the attack was beginning due to premonitory symptoms,” he said.
Dr. Rapoport also noted a surprising and unusual finding: Patients who did not report sensitivity to light as their most bothersome symptom were more likely to be insufficient responders (OR = 2.3, 95% CI [1.21–4.37], P = .011). “In all recent migraine studies,” he said, “the majority of patients selected photophobia as their most bothersome symptom.”
In the big picture, he said, the study suggests that “a third triptan does not seem to work better than the first two, patients with medication-overuse headache and chronic migraine and those not on preventive medication do not respond that well to acute care treatment, and the same is true when depression is present.”
No study funding was reported. Four study authors reported ties with Eli Lilly, and two reported employment by Adelphi Real World, which provided the survey results..
SOURCE: Lombard L et al. Headache. 2020;60(7):1325-39. doi: 10.1111/head.13835.
Overall, insufficient responders—patients less likely to get relief shortly after acute treatment—are “more medically and psychosocially complex,” wrote the authors of the study, which appeared in the July/August issue of Headache.
Common characteristics of insufficient responders
The researchers, led by Louise Lombard, M Nutr, of Eli Lilly and Company, analyzed data from a 2014 cross-sectional survey. They tracked 583 patients with migraine, including 200 (34%) who were considered insufficient responders because they failed to achieve freedom from pain within 2 hours of acute treatment in at least four of five attacks.
The insufficient and sufficient responder groups were similar in age (mean = 40 for both) and gender (80% and 75% female, respectively, P = .170) and race (72% and 77% white, P = .279).
However, insufficient responders were clearly more affected by headaches, multiple treatments, and other burdens. Compared with those who had better responses to treatment, they were more likely to have four or more migraine headache days per month (46% vs. 31%), rebound or medication-overuse headaches (16% vs. 7%) and chronic migraine (12% vs. 5%, all P < .05).
They were also more likely have comorbid depression (38% vs. 22%) and psychological conditions other than depression and anxiety (8% vs. 4%, all P < .05).
As for treatment, insufficient response was higher in patients who waited until the appearance of pain to take medication (odds ratio = 1.83, 95% confidence interval [CI] 1.15–2.92, P = .011, after adjustment for covariates). And insufficient responders were more likely to have been prescribed at least three unique preventive regimens (12% vs. 6%), to take over-the-counter medications (50% vs. 38%) and to take opioid painkillers (16% vs. 8%, all P < .05).
The authors, who caution that the study does not prove cause and effect, wrote that insufficient responders “may benefit from education on how and when to use current treatments.”
Managing insufficient responders
Neurology Reviews editor-in-chief Alan M. Rapoport, MD, said the study “confirms a lot of what we knew.” Dr, Rapoport, who was not involved in the study, is clinical professor of neurology at the University of California, Los Angeles.
“As expected, the insufficient responders used more opioids and over-the-counter medications, which is not the ideal way to treat migraine,” he said. “That probably caused them to have medication-overuse headache, which might have caused them to respond poorly to even the best treatment regimen. They also had more severe symptoms, more comorbidities, and a poorer quality of life. They also had more impairment and greater impact on work, with more of them unemployed.”
The insufficient responders also “took medication at the time or after the pain began, rather than before it when they thought the attack was beginning due to premonitory symptoms,” he said.
Dr. Rapoport also noted a surprising and unusual finding: Patients who did not report sensitivity to light as their most bothersome symptom were more likely to be insufficient responders (OR = 2.3, 95% CI [1.21–4.37], P = .011). “In all recent migraine studies,” he said, “the majority of patients selected photophobia as their most bothersome symptom.”
In the big picture, he said, the study suggests that “a third triptan does not seem to work better than the first two, patients with medication-overuse headache and chronic migraine and those not on preventive medication do not respond that well to acute care treatment, and the same is true when depression is present.”
No study funding was reported. Four study authors reported ties with Eli Lilly, and two reported employment by Adelphi Real World, which provided the survey results..
SOURCE: Lombard L et al. Headache. 2020;60(7):1325-39. doi: 10.1111/head.13835.
FROM HEADACHE
Immunotherapies Targeting α -Synuclein in Parkinson Disease
Parkinson disease (PD) is a progressive neurodegenerative disorder, characterized by diverse clinical symptoms. PD can present with rest tremor, bradykinesia, rigidity, falls, postural instability, and multiple nonmotor symptoms. Marras and colleagues estimated in a comprehensive meta-analysis that there were 680,000 individuals with PD in the US in 2010; this number is expected to double by 2030 based on the US Census Bureau population projections.1 An estimated 110,000 veterans may be affected by PD; hence, understanding of PD pathology, clinical progression, and effective treatment strategies is of paramount importance to the Veterans Health Administration (VHA).2
The exact pathogenesis underlying clinical features is still being studied. Pathologic diagnosis of PD relies on loss of dopamine neurons in the substantia nigra and accumulation of the abnormal protein, α-synuclein, in the form of Lewy bodies and Lewy neurites. Lewy bodies and neurites accumulate predominantly in the substantia nigra in addition to other brain stem nuclei and cerebral cortex. Lewy bodies are intraneuronal inclusions with a hyaline core and a pale peripheral halo. Central core stains positive for α-synuclein.3,4 Lewy neurites are widespread and are believed to play a larger role in the pathogenesis of PD compared with those of Lewy bodies.5
α-Synuclein
α-synuclein is a small 140 amino-acid protein with a N-terminal region that can interact with cell membranes and a highly acidic unstructured C-terminal region.6 α-synuclein is physiologically present in the presynaptic terminals of neurons and involved in synaptic plasticity and vesicle trafficking.7 There are different hypotheses about the native structure of α-synuclein. The first suggests that it exists in tetrameric form and may be broken down to monomer, which is the pathogenic form of α-synuclein. The second hypothesis suggests that it exists primarily in monomeric form, whereas other studies have shown that both forms exist and with pathologic changes, monomer accumulates in abundance and is neurotoxic.8-11 Work by Burré and colleagues shows that native α-synuclein exists in 2 forms: a soluble, cytosolic α-synuclein, which is monomeric, and a membrane-bound multimeric form.12,13
Alteration in aggregation properties of this protein is believed to play a central role in the pathogenesis of PD.14,15 Pathologic α-synuclein exists in insoluble forms that can aggregate into oligomers and fibrillar structures.16 Lysosomal dysfunction may promote accumulation of insoluble α-synuclein. Prior work has shown that several degradation pathways in lysosomes, including the ubiquitin-proteasome system and autophagy-lysosomal pathway, are down regulated, thus contributing to the accumulation of abnormal α-synuclein.17,18 Accumulation of pathologic α-synuclein leads to mitochondrial dysfunction in PD animal models, contributing further to neurotoxicity.19,20 Aggregates of phosphorylated α-synuclein have been demonstrated in dementia with Lewy body.21
In addition, α-synuclein aggregates may be released into extracellular spaces to be taken up by adjacent cells, where they can cause further misfolding and aggregation of protein.22 Previous work in animal models suggested a prion proteinlike spread of α-synuclein.23 This finding can have long-term therapeutic implications, as preventing extracellular release of abnormal form of α-synuclein will prevent the spread of pathologic protein. This can form the basis of neuroprotection in patients with PD.24
It has been proposed that α-synuclein accumulation and extracellular release initiates an immune response that leads to activation of microglia. This has been shown in PD animal models, overexpressing α-synuclein. In 2008 Park and colleagues demonstrated that microglial activation is enhanced by monomeric α-synuclein, not by the aggregated variant.25 Other studies have reported activated microglia around dopaminergic cells in substantia nigra.26 Sulzer and colleagues showed that peptides from α-synuclein can act as antigens and trigger an autoimmune reaction via T cells.27 PD may be associated with certain HLA-haplotypes.28 In other words, α-synuclein can induce neurodegeneration via different mechanisms, including alteration in synaptic vesicle transmission, mitochondrial dysfunction, neuroinflammation, and induction of humoral immunity.
Immunization
Due to these observations, there had been huge interest in developing antibody-based therapies for PD. A similar approach had been tested in Alzheimer disease (AD). Intracellular tangles of tau protein and extracellular aggregates of amyloid are the pathologic substrates in AD. Clinical trials utilizing antibodies targeting amyloid showed reduction in abnormal protein accumulation but no significant improvement in cognition.29 In addition, adverse events (AEs), such as vasogenic edema and intracerebral hemorrhage, were reported.30 Careful analysis of the data suggested that inadequate patient selection or targeting only amyloid, may have contributed to unfavorable results.31 Since then, more recent clinical trials have focused on careful patient selection, use of second generation anti-amyloid antibodies and immunotherapies targeting tau.32
Several studies have tested immunotherapies in PD animal models with the aim of targeting α-synuclein. Immunotherapies can be instituted in 2 ways: active immunization in which the immune system is stimulated to produce antibodies against α-synuclein or passive immunization in which antibodies against α-synuclein are administered directly. Once α-synuclein antibodies have crossed the blood-brain barrier, they are hypothesized to clear the existing α-synuclein. Animal studies have demonstrated the presence of these antibodies within the neurons. The mechanism of entry is unknown. Once inside the cells, the antibodies activate the lysosomal clearance, affecting intracellular accumulation of α-synuclein. Extracellularly, they can bind to receptors on scavenger cells, mainly microglia, activating them to facilitate uptake of extracellular α-synuclein. Binding of the antibodies to α-synuclein directly prevents the uptake of toxic protein by the cells, blocking the transfer and spread of PD pathology.33
Active Immunization
Active immunization against α-synuclein was demonstrated by Masliah and colleagues almost a decade ago. They administered recombinant human α-synuclein in transgenic mice expressing α-synuclein under the control of platelet-derived growth factor β. Reduction of accumulated α-synuclein in neurons with mild microglia activation was noted. It was proposed that the antibodies produced were able to bind to abnormal α-synuclein, were recognized by the lysosomal pathways, and degraded.34 Ghochikyan and colleagues developed vaccines by using α-synuclein-derived peptides. This induced formation of antibodies against α-synuclein in Lewy-bodies and neurites.35 Over time, other animal studies have been able to expand on these results.36
AFFiRiS, an Austrian biotechnology company, has developed 2 peptide vaccines PD01A and PD03A. Both peptides when administered to PD animal models caused antibody-based immune response against aggregated α-synuclein. Humoral autoimmune response was not observed in these studies; no neuroinflammation or neurotoxicity was noted. These peptides did not affect levels of physiologic α-synuclein, targeting only the aggregated form.37 These animal models showed improved motor and cognitive function. Similar results were noted in multiple system atrophy (MSA) animal models.38,39
The first human phase 1, randomized, parallel-group, single-center study recruited 32 subjects with early PD. Twelve subjects each were included in low- or high-dose treatment group, and 8 were included in the control group. Test subjects randomly received 4 vaccinations of low- or high-dose PD01A. Both doses were well tolerated, and no drug-related serious AEs were reported. The study confirmed the tolerability and safety of subcutaneous PD01A vaccine administration. These subjects were included in a 12-month, phase 1b follow-up extension study, AFF008E. In 2018, it was reported that administration of 6 doses of PD01A, 4 primary and 2 booster immunization, was safe. The vaccine showed a clear immune response against the peptide and cross-reactivity against α-synuclein targeted epitope. Booster doses stabilized the antibody titers. Significant increase in antibody titers against PD01A was seen over time, which was translated into a humoral immune response against α-synuclein. In addition, PD01A antibodies also were reported in cerebrospinal fluid.40
AFFiRiS presented results of a phase 1 randomized, placebo-controlled trial in 2017, confirming the safety of PD03A in patients with PD. The study showed a clear dose-dependent immune response against the peptide and cross-reactivity against α-synuclein targeted epitope.41 AFFiRiS recently presented results of another phase 1 clinical study assessing the safety and tolerability of vaccines PD01A and PD03A in patients with early MSA. Both vaccines were well tolerated, and PD01A induced an immune response against the peptide and α-synuclein epitope.42 These results have provided hope for further endeavors to develop active immunization strategies for PD.
Passive Immunization
Passive immunization against α-synuclein was first reported by Masliah and colleagues in 2011. A monoclonal antibody against the C-terminus of α-synuclein, 9E4, was injected into a transgenic mouse model of PD. There was reduction in α-synuclein aggregates in the brain along with improvement in motor and cognitive impairment.43 The C-terminus of α-synuclein plays a key role in the pathogenesis of PD. Changes in the C-terminus of α-synuclein induces formation of α-synuclein oligomers and subsequent neuronal spread. Antibody binds to the C-terminus and prevents structural changes that can lead to oligomerization of α-synuclein. Since the first study by Masliah, few other immunization studies utilized different antibodies against the C-terminus of α-synuclein. It was shown in a mouse model that binding of such antibodies promoted clearance of the α-synuclein by microglia.44
Based on these animal studies, Prothena Biosciences (South San Francisco, CA) designed a phase 1, double-blind, randomized, placebo-controlled clinical trial of prasinezumab (investigational monoclonal antibody against C-terminus of α-synuclein), in subjects without PD. The results showed that it was well tolerated, and there was dose-dependent reduction in the levels of free
BIIB054 is another monoclonal antibody that targets the N-terminal of α-synuclein. In animal models, antibodies targeting the N-terminus reduced α-synuclein triggered cell death and reduced the number of activated microglia.48 BIIB054, from Biogen (Cambridge, MA), was studied in 40 healthy subjects and was well tolerated with a favorable safety profile and could cross the blood-brain barrier. Like the prasinezumab study, this also was an ascending-dose study to assess safety and tolerability. In 2018, a randomized, double-blind, placebo-controlled, single-ascending dose study in patients with PD reported that BIIB054 was well tolerated, and the presence of BIIB054-synuclein complexes in the plasma were confirmed.49 A phase 2, multicenter, randomized, double-blind, placebo-controlled study (SPARK) with an active-treatment dose-blinded period, designed to evaluate the safety, pharmacokinetics, and the pharmacodynamics of BIIB054 is currently recruiting patients with PD.
Finally, BioArctic (Stockholm, Sweden) developed antibodies that are selective for oligomeric forms of α-synuclein, which it licensed to AbbVie (North Chicago, Il).50 These antibodies do not target the N- or C-terminus of α-synuclein. Since α-synuclein oligomers play an important role in the pathogenesis of PD, targeting them with antibodies at an early stage may prove to be an effective strategy for removal of pathogenic α-synuclein. Clinical trials are forthcoming.
Conclusions
Immunotherapy against α-synuclein has provided a new therapeutic avenue in the field of neuroprotection. Results from the first human clinical trial are promising, but despite these results, more work is needed to clarify the role of α-synuclein in the pathogenesis of PD in humans. Most of the work concerning α-synuclein aggregation and propagation has been reported in animal models. Whether similar process exists in humans is a debatable question. Similarly, more knowledge is needed about how and where in the human brain antibodies act to give neuroprotective effects. Timing of administration of immunotherapies in real time will be a crucial question.
PD is clinically evident once 80% of dopaminergic neurons in substantia nigra are lost due to neurodegeneration. Should immunotherapy be administered to symptomatic patients with PD, or if it will be beneficial only for presymptomatic, high-risk patients needs to be determined. Like AD trials, not only careful selection of patients, but determination of optimal timing for treatment will be essential. As the understanding of PD pathogenesis and therapeutics evolves, it will become clear whether immunization targeting α-synuclein will modify disease progression.
1. Marras C, Beck JC, Bower JH, et al; Parkinson’s Foundation P4 Group. Prevalence of Parkinson’s disease across North America. NPJ Parkinsons Dis. 2018;4(1):21. doi:10.1038/s41531-018-0058-0
2. Mantri S, Duda JE, Morley JF. Early and accurate identification of Parkinson disease among US veterans. Fed Pract. 2019;36(suppl 4):S18-S23. doi:10.12788/fp.37-0034
3. Braak H, Del Tredici K. Neuropathological staging of brain pathology in sporadic Parkinson’s disease: separating the wheat from the chaff. J Parkinsons Dis. 2017;7(suppl 1):S71-S85. doi:10.3233/JPD-179001
4. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. α-synuclein in Lewy bodies. Nature. 1997;388(6645):839-840. doi:10.1038/42166
5. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197-211. doi:10.1016/s0197-4580(02)00065-9
6. Bendor JT, Logan TP, Edwards RH. The function of α-synuclein. Neuron. 2013;79(6):1044-1066. doi:10.1016/j.neuron.2013.09.004
7. Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC. α-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010;329(5999):1663-1667. doi:10.1126/science.1195227
8. Binolfi A, Fernández CO, Sica MP, Delfino JM, Santos J. Recognition between a short unstructured peptide and a partially folded fragment leads to the thioredoxin fold sharing native-like dynamics. Proteins. 2012;80(5):1448-1464. doi:10.1002/prot.24043
9. Fauvet B, Mbefo MK, Fares MB, et al. α-synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer. J Biol Chem. 2012;287(19):15345-15364. doi:10.1074/jbc.M111.318949.
10. Wang W, Perovic I, Chittuluru J, et al. A soluble α-synuclein construct forms a dynamic tetramer. Proc Natl Acad Sci USA. 2011;108(43):17797-17802. doi:10.1073/pnas.1113260108
11. Bellucci A, Zaltieri M, Navarria L, Grigoletto J, Missale C, Spano P. From α-synuclein to synaptic dysfunctions: new insights into the pathophysiology of Parkinson’s disease. Brain Res. 2012;1476:183-202. doi:10.1016/j.brainres.2012.04.014
12. Burré J, Vivona S, Diao J, Sharma M, Brunger AT, Südhof TC. Properties of native α-synuclein. Nature. 2013;498(7453):E4-E7.
13. Burré J, Sharma M, Südhof TC. α-synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc Natl Acad Sci USA. 2014;111(40):E4274-E4283. doi:10.1073/pnas.1416598111
14. Wong YC, Krainc D. α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med. 2017;23(2):1-13. doi:10.1038/nm.4269
15. Burré J, Sharma M, Südhof TC. Definition of a molecular pathway mediating α-synuclein neurotoxicity. J Neurosci. 2015;35(13):5221-5232. doi:10.1523/JNEUROSCI.4650-14.2015
16. Lee HJ, Khoshaghideh F, Patel S, Lee SJ. Clearance of α-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci. 2004;24(8):1888-1896. doi:10.1523/JNEUROSCI.3809-03.2004
17. Rideout HJ, Dietrich P, Wang Q, Dauer WT, Stefanis L . α-synuclein is required for the fibrillar nature of ubiquitinated inclusions induced by proteasomal inhibition in primary neurons. J Biol Chem. 2004;279(45):46915-46920. doi:10.1074/jbc.M405146200
18. Ryan BJ, Hoek S, Fon EA, Wade-Martins R. Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem Sci. 2015;40(4):200-210. doi:10.1016/j.tibs.2015.02.003
19. Winklhofer KF, Haass C. Mitochondrial dysfunction in Parkinson’s disease. Biochem Biophys Acta. 2010;1802(1):29-44. doi:10.1016/j.bbadis.2009.08.013
20. Lee HJ, Bae EJ, Lee SJ. Extracellular α-synuclein: a novel and crucial factor in Lewy body diseases. Nat Rev Neurol. 2014;10(2):92-98. doi:10.1038/nrneurol.2013.275
21. Colom-Cadena M, Pegueroles J, Herrmann AG, et al. Synaptic phosphorylated α-synuclein in dementia with Lewy bodies. Brain. 2017;140(12):3204-3214. doi:10.1093/brain/awx275
22. Volpicelli-Daley LA, Luk KC, Patel TP, et al. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011;72(1):57-71. doi:10.1016/j.neuron.2011.08.033
23. Masuda-Suzukake M, Nonaka T, Hosokawa M, et al. Prion-like spreading of pathological α-synuclein in brain. Brain. 2013;136(pt 4):1128-1138. doi:10.1093/brain/awt037
24. Hasegawa M, Nonaka T, Masuda-Suzukake M. Prion-like mechanisms and potential therapeutic targets in neurodegenerative disorders. Pharmacol Ther. 2017;172:22-33. doi:10.1016/j.pharmthera.2016.11.010
25. Park JY, Paik SR, Jou I, Park SM. Microglial phagocytosis is enhanced by monomeric α-synuclein, not aggregated alpha-synuclein: implications for Parkinson’s disease. Glia. 2008;56(11):1215-1223. doi:10.1002/glia.20691
26. Blandini F. Neural and immune mechanisms in the pathogenesis of Parkinson’s disease. J Neuroimmune Pharmacol. 2013;8(1):189-201. doi:10.1007/s11481-013-9435-y
27. Sulzer D, Alcalay RN, Garretti F, et al. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature. 2017;546(7660):656-661. doi:10.1038/nature22815
28. Hamza TH, Zabetian CP, Tenesa A, et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genetics. 2010;42(9):781-785. doi:10.1038/ng.642
29. Holmes C, Boche D, Wilkinson D, et al. Long term effects of Aβ42 immunisation in Alzheimer’s disease: follow up of a randomized, placebo-controlled phase I trial. Lancet. 2008;372(9634):216-223. doi:10.1016/S0140-6736(08)61075-2
30. Sperling R, Salloway S, Brooks DJ, et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11:241-249. doi:10.1016/S1474-4422(12)70015-7
31. Wisniewski T, Goñi F. Immunotherapy for Alzheimer’s disease. Biochem Pharmacol. 2014;88(4):499-507. doi:10.1016/j.bcp.2013.12.020
32. Herline K, Drummond E, Wisniewski T. Recent advancements toward therapeutic vaccines against Alzheimer’s disease. Expert Rev Vaccines. 2018;17(8):707-721. doi:10.1080/14760584.2018.1500905
33. Bergstrom AL, Kallunki P, Fog K. Development of passive immunotherapies for synucleopathies. Mov Disord. 2015;31(2):203-213. doi:10.1002/mds.26481
34. Masliah E, Rockenstein E, Adame A, et al. Effects of α-synuclein immunization in a mouse model of Parkinson’s disease. Neuron. 2005;46(6):857-868. doi:10.1016/j.neuron.2005.05.010
35. Ghochikyan A, Petrushina I, Davtyan H, et al. Immunogenicity of epitope vaccines targeting different B cell antigenic determinants of human α-synuclein: feasibility study. Neurosci Lett. 2014;560:86-91. doi:10.1016/j.neulet.2013.12.028
36. Sanchez-Guajardo V, Annibali A, Jensen PH, Romero-Ramos M. α-synuclein vaccination prevents the accumulation of Parkinson’s disease-like pathologic inclusions in striatum in association with regulatory T cell recruitment in a rat model. J Neuropathol Exp Neurol. 2013;72(7):624-645. doi:10.1097/NEN.0b013e31829768d2
37. Mandler M, Valera E, Rockenstein E, et al. Next generation active immunization approach for synucleinopathies: Implications for Parkinson’s disease clinical trials. Acta Neuropathol. 2014;127(6):861-879. doi:10.1007/s00401-014-1256-4
38. Mandler M, Valera E, Rockenstein E, et al. Active immunization against α-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multisystem atrophy. Mol Neurodegen. 2015;10:721. doi:10.1186/s13024-015-0008-9
39. Schneeberger A, Tierney L, Mandler M. Active immunization therapies. Mov Disord. 2015;31(2):214-224. doi:10.1002/mds.26377
40. Zella SMA, Metzdorf J, Ciftci E, et al. Emerging immunotherapies for Parkinson disease. Neurol Ther. 2019;8(1):29-44. doi:10.1007/s40120-018-0122-z
41. AFFiRiS AG. AFFiRiS announces top line results of first-in-human clinical study using AFFITOPE PD03A, confirming immunogenicity and safety profile in Parkinson’s disease patients. https://affiris.com/wp-content/uploads/2018/10/praff011prefinal0607wo-embargo-1.pdf. Published June 7, 2017. Accessed July 29, 2020.
42. AFFiRiS AG. AFFiRiS announces results of a phase I clinical study using AFFITOPEs PD01A and PD03A, confirming safety and tolerability for both compounds as well as immunogenicity for PD01A in early MSA patients. http://sympath-project.eu/wp-content/uploads/PR_AFF009_V1.pdf Published March 1, 2018. Accessed July 29, 2020.
43. Masliah E, Rockenstein E, Mante M, et al. Passive immunization reduces behavioral and neuropathological deficits in an alphasynuclein transgenic model of Lewy body disease. PLoS One. 2011;6(4):e19338. doi:10.1371/journal.pone.0019338
44. Bae EJ, Lee HJ, Rockenstein E, et al. Antibody aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J Neurosci. 2012;32(39):1345-13469. doi:10.1523/JNEUROSCI.1292-12.2012
45. Schenk DB, Koller M, Ness DK, et al. First‐in‐human assessment of PRX002, an anti–α‐synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218. doi:10.1002/mds.26878.
46. Jankovic J, Goodman I, Safirstein B, et al. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-α -synuclein monoclonal antibody, in patients with Parkinson disease: a randomized clinical trial. JAMA Neurol. 2018;75(10):1206-1214. doi:10.1001/jamaneurol.2018.1487
47. Jankovic J. Pathogenesis-targeted therapeutic strategies in Parkinson’s disease. Mov Disord. 2019;34(1):41-44. doi:10.1002/mds.27534
48. Shahaduzzaman M, Nash K, Hudson C, et al. Anti-human α-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an AAV-α-synuclein rat model of Parkinson’s disease. PLoS One. 2015;10(2):E0116841. doi:10.1371/journal.pone.0116841
49. Brys M, Hung S, Fanning L, et al. Randomized, double-blind, placebo-controlled, single ascending dose study of anti-α-synuclein antibody BIIB054 in patients with Parkinson disease. Neurology. 2018;90(suppl 15):S26.001. doi:10.1002/mds.27738
50. Brundin P, Dave KD, Kordower JH. Therapeutic approaches to target α-synuclein pathology. Exp Neurol. 2017;298(pt B):225-235. doi:10.1016/j.expneurol.2017.10.003
Parkinson disease (PD) is a progressive neurodegenerative disorder, characterized by diverse clinical symptoms. PD can present with rest tremor, bradykinesia, rigidity, falls, postural instability, and multiple nonmotor symptoms. Marras and colleagues estimated in a comprehensive meta-analysis that there were 680,000 individuals with PD in the US in 2010; this number is expected to double by 2030 based on the US Census Bureau population projections.1 An estimated 110,000 veterans may be affected by PD; hence, understanding of PD pathology, clinical progression, and effective treatment strategies is of paramount importance to the Veterans Health Administration (VHA).2
The exact pathogenesis underlying clinical features is still being studied. Pathologic diagnosis of PD relies on loss of dopamine neurons in the substantia nigra and accumulation of the abnormal protein, α-synuclein, in the form of Lewy bodies and Lewy neurites. Lewy bodies and neurites accumulate predominantly in the substantia nigra in addition to other brain stem nuclei and cerebral cortex. Lewy bodies are intraneuronal inclusions with a hyaline core and a pale peripheral halo. Central core stains positive for α-synuclein.3,4 Lewy neurites are widespread and are believed to play a larger role in the pathogenesis of PD compared with those of Lewy bodies.5
α-Synuclein
α-synuclein is a small 140 amino-acid protein with a N-terminal region that can interact with cell membranes and a highly acidic unstructured C-terminal region.6 α-synuclein is physiologically present in the presynaptic terminals of neurons and involved in synaptic plasticity and vesicle trafficking.7 There are different hypotheses about the native structure of α-synuclein. The first suggests that it exists in tetrameric form and may be broken down to monomer, which is the pathogenic form of α-synuclein. The second hypothesis suggests that it exists primarily in monomeric form, whereas other studies have shown that both forms exist and with pathologic changes, monomer accumulates in abundance and is neurotoxic.8-11 Work by Burré and colleagues shows that native α-synuclein exists in 2 forms: a soluble, cytosolic α-synuclein, which is monomeric, and a membrane-bound multimeric form.12,13
Alteration in aggregation properties of this protein is believed to play a central role in the pathogenesis of PD.14,15 Pathologic α-synuclein exists in insoluble forms that can aggregate into oligomers and fibrillar structures.16 Lysosomal dysfunction may promote accumulation of insoluble α-synuclein. Prior work has shown that several degradation pathways in lysosomes, including the ubiquitin-proteasome system and autophagy-lysosomal pathway, are down regulated, thus contributing to the accumulation of abnormal α-synuclein.17,18 Accumulation of pathologic α-synuclein leads to mitochondrial dysfunction in PD animal models, contributing further to neurotoxicity.19,20 Aggregates of phosphorylated α-synuclein have been demonstrated in dementia with Lewy body.21
In addition, α-synuclein aggregates may be released into extracellular spaces to be taken up by adjacent cells, where they can cause further misfolding and aggregation of protein.22 Previous work in animal models suggested a prion proteinlike spread of α-synuclein.23 This finding can have long-term therapeutic implications, as preventing extracellular release of abnormal form of α-synuclein will prevent the spread of pathologic protein. This can form the basis of neuroprotection in patients with PD.24
It has been proposed that α-synuclein accumulation and extracellular release initiates an immune response that leads to activation of microglia. This has been shown in PD animal models, overexpressing α-synuclein. In 2008 Park and colleagues demonstrated that microglial activation is enhanced by monomeric α-synuclein, not by the aggregated variant.25 Other studies have reported activated microglia around dopaminergic cells in substantia nigra.26 Sulzer and colleagues showed that peptides from α-synuclein can act as antigens and trigger an autoimmune reaction via T cells.27 PD may be associated with certain HLA-haplotypes.28 In other words, α-synuclein can induce neurodegeneration via different mechanisms, including alteration in synaptic vesicle transmission, mitochondrial dysfunction, neuroinflammation, and induction of humoral immunity.
Immunization
Due to these observations, there had been huge interest in developing antibody-based therapies for PD. A similar approach had been tested in Alzheimer disease (AD). Intracellular tangles of tau protein and extracellular aggregates of amyloid are the pathologic substrates in AD. Clinical trials utilizing antibodies targeting amyloid showed reduction in abnormal protein accumulation but no significant improvement in cognition.29 In addition, adverse events (AEs), such as vasogenic edema and intracerebral hemorrhage, were reported.30 Careful analysis of the data suggested that inadequate patient selection or targeting only amyloid, may have contributed to unfavorable results.31 Since then, more recent clinical trials have focused on careful patient selection, use of second generation anti-amyloid antibodies and immunotherapies targeting tau.32
Several studies have tested immunotherapies in PD animal models with the aim of targeting α-synuclein. Immunotherapies can be instituted in 2 ways: active immunization in which the immune system is stimulated to produce antibodies against α-synuclein or passive immunization in which antibodies against α-synuclein are administered directly. Once α-synuclein antibodies have crossed the blood-brain barrier, they are hypothesized to clear the existing α-synuclein. Animal studies have demonstrated the presence of these antibodies within the neurons. The mechanism of entry is unknown. Once inside the cells, the antibodies activate the lysosomal clearance, affecting intracellular accumulation of α-synuclein. Extracellularly, they can bind to receptors on scavenger cells, mainly microglia, activating them to facilitate uptake of extracellular α-synuclein. Binding of the antibodies to α-synuclein directly prevents the uptake of toxic protein by the cells, blocking the transfer and spread of PD pathology.33
Active Immunization
Active immunization against α-synuclein was demonstrated by Masliah and colleagues almost a decade ago. They administered recombinant human α-synuclein in transgenic mice expressing α-synuclein under the control of platelet-derived growth factor β. Reduction of accumulated α-synuclein in neurons with mild microglia activation was noted. It was proposed that the antibodies produced were able to bind to abnormal α-synuclein, were recognized by the lysosomal pathways, and degraded.34 Ghochikyan and colleagues developed vaccines by using α-synuclein-derived peptides. This induced formation of antibodies against α-synuclein in Lewy-bodies and neurites.35 Over time, other animal studies have been able to expand on these results.36
AFFiRiS, an Austrian biotechnology company, has developed 2 peptide vaccines PD01A and PD03A. Both peptides when administered to PD animal models caused antibody-based immune response against aggregated α-synuclein. Humoral autoimmune response was not observed in these studies; no neuroinflammation or neurotoxicity was noted. These peptides did not affect levels of physiologic α-synuclein, targeting only the aggregated form.37 These animal models showed improved motor and cognitive function. Similar results were noted in multiple system atrophy (MSA) animal models.38,39
The first human phase 1, randomized, parallel-group, single-center study recruited 32 subjects with early PD. Twelve subjects each were included in low- or high-dose treatment group, and 8 were included in the control group. Test subjects randomly received 4 vaccinations of low- or high-dose PD01A. Both doses were well tolerated, and no drug-related serious AEs were reported. The study confirmed the tolerability and safety of subcutaneous PD01A vaccine administration. These subjects were included in a 12-month, phase 1b follow-up extension study, AFF008E. In 2018, it was reported that administration of 6 doses of PD01A, 4 primary and 2 booster immunization, was safe. The vaccine showed a clear immune response against the peptide and cross-reactivity against α-synuclein targeted epitope. Booster doses stabilized the antibody titers. Significant increase in antibody titers against PD01A was seen over time, which was translated into a humoral immune response against α-synuclein. In addition, PD01A antibodies also were reported in cerebrospinal fluid.40
AFFiRiS presented results of a phase 1 randomized, placebo-controlled trial in 2017, confirming the safety of PD03A in patients with PD. The study showed a clear dose-dependent immune response against the peptide and cross-reactivity against α-synuclein targeted epitope.41 AFFiRiS recently presented results of another phase 1 clinical study assessing the safety and tolerability of vaccines PD01A and PD03A in patients with early MSA. Both vaccines were well tolerated, and PD01A induced an immune response against the peptide and α-synuclein epitope.42 These results have provided hope for further endeavors to develop active immunization strategies for PD.
Passive Immunization
Passive immunization against α-synuclein was first reported by Masliah and colleagues in 2011. A monoclonal antibody against the C-terminus of α-synuclein, 9E4, was injected into a transgenic mouse model of PD. There was reduction in α-synuclein aggregates in the brain along with improvement in motor and cognitive impairment.43 The C-terminus of α-synuclein plays a key role in the pathogenesis of PD. Changes in the C-terminus of α-synuclein induces formation of α-synuclein oligomers and subsequent neuronal spread. Antibody binds to the C-terminus and prevents structural changes that can lead to oligomerization of α-synuclein. Since the first study by Masliah, few other immunization studies utilized different antibodies against the C-terminus of α-synuclein. It was shown in a mouse model that binding of such antibodies promoted clearance of the α-synuclein by microglia.44
Based on these animal studies, Prothena Biosciences (South San Francisco, CA) designed a phase 1, double-blind, randomized, placebo-controlled clinical trial of prasinezumab (investigational monoclonal antibody against C-terminus of α-synuclein), in subjects without PD. The results showed that it was well tolerated, and there was dose-dependent reduction in the levels of free
BIIB054 is another monoclonal antibody that targets the N-terminal of α-synuclein. In animal models, antibodies targeting the N-terminus reduced α-synuclein triggered cell death and reduced the number of activated microglia.48 BIIB054, from Biogen (Cambridge, MA), was studied in 40 healthy subjects and was well tolerated with a favorable safety profile and could cross the blood-brain barrier. Like the prasinezumab study, this also was an ascending-dose study to assess safety and tolerability. In 2018, a randomized, double-blind, placebo-controlled, single-ascending dose study in patients with PD reported that BIIB054 was well tolerated, and the presence of BIIB054-synuclein complexes in the plasma were confirmed.49 A phase 2, multicenter, randomized, double-blind, placebo-controlled study (SPARK) with an active-treatment dose-blinded period, designed to evaluate the safety, pharmacokinetics, and the pharmacodynamics of BIIB054 is currently recruiting patients with PD.
Finally, BioArctic (Stockholm, Sweden) developed antibodies that are selective for oligomeric forms of α-synuclein, which it licensed to AbbVie (North Chicago, Il).50 These antibodies do not target the N- or C-terminus of α-synuclein. Since α-synuclein oligomers play an important role in the pathogenesis of PD, targeting them with antibodies at an early stage may prove to be an effective strategy for removal of pathogenic α-synuclein. Clinical trials are forthcoming.
Conclusions
Immunotherapy against α-synuclein has provided a new therapeutic avenue in the field of neuroprotection. Results from the first human clinical trial are promising, but despite these results, more work is needed to clarify the role of α-synuclein in the pathogenesis of PD in humans. Most of the work concerning α-synuclein aggregation and propagation has been reported in animal models. Whether similar process exists in humans is a debatable question. Similarly, more knowledge is needed about how and where in the human brain antibodies act to give neuroprotective effects. Timing of administration of immunotherapies in real time will be a crucial question.
PD is clinically evident once 80% of dopaminergic neurons in substantia nigra are lost due to neurodegeneration. Should immunotherapy be administered to symptomatic patients with PD, or if it will be beneficial only for presymptomatic, high-risk patients needs to be determined. Like AD trials, not only careful selection of patients, but determination of optimal timing for treatment will be essential. As the understanding of PD pathogenesis and therapeutics evolves, it will become clear whether immunization targeting α-synuclein will modify disease progression.
Parkinson disease (PD) is a progressive neurodegenerative disorder, characterized by diverse clinical symptoms. PD can present with rest tremor, bradykinesia, rigidity, falls, postural instability, and multiple nonmotor symptoms. Marras and colleagues estimated in a comprehensive meta-analysis that there were 680,000 individuals with PD in the US in 2010; this number is expected to double by 2030 based on the US Census Bureau population projections.1 An estimated 110,000 veterans may be affected by PD; hence, understanding of PD pathology, clinical progression, and effective treatment strategies is of paramount importance to the Veterans Health Administration (VHA).2
The exact pathogenesis underlying clinical features is still being studied. Pathologic diagnosis of PD relies on loss of dopamine neurons in the substantia nigra and accumulation of the abnormal protein, α-synuclein, in the form of Lewy bodies and Lewy neurites. Lewy bodies and neurites accumulate predominantly in the substantia nigra in addition to other brain stem nuclei and cerebral cortex. Lewy bodies are intraneuronal inclusions with a hyaline core and a pale peripheral halo. Central core stains positive for α-synuclein.3,4 Lewy neurites are widespread and are believed to play a larger role in the pathogenesis of PD compared with those of Lewy bodies.5
α-Synuclein
α-synuclein is a small 140 amino-acid protein with a N-terminal region that can interact with cell membranes and a highly acidic unstructured C-terminal region.6 α-synuclein is physiologically present in the presynaptic terminals of neurons and involved in synaptic plasticity and vesicle trafficking.7 There are different hypotheses about the native structure of α-synuclein. The first suggests that it exists in tetrameric form and may be broken down to monomer, which is the pathogenic form of α-synuclein. The second hypothesis suggests that it exists primarily in monomeric form, whereas other studies have shown that both forms exist and with pathologic changes, monomer accumulates in abundance and is neurotoxic.8-11 Work by Burré and colleagues shows that native α-synuclein exists in 2 forms: a soluble, cytosolic α-synuclein, which is monomeric, and a membrane-bound multimeric form.12,13
Alteration in aggregation properties of this protein is believed to play a central role in the pathogenesis of PD.14,15 Pathologic α-synuclein exists in insoluble forms that can aggregate into oligomers and fibrillar structures.16 Lysosomal dysfunction may promote accumulation of insoluble α-synuclein. Prior work has shown that several degradation pathways in lysosomes, including the ubiquitin-proteasome system and autophagy-lysosomal pathway, are down regulated, thus contributing to the accumulation of abnormal α-synuclein.17,18 Accumulation of pathologic α-synuclein leads to mitochondrial dysfunction in PD animal models, contributing further to neurotoxicity.19,20 Aggregates of phosphorylated α-synuclein have been demonstrated in dementia with Lewy body.21
In addition, α-synuclein aggregates may be released into extracellular spaces to be taken up by adjacent cells, where they can cause further misfolding and aggregation of protein.22 Previous work in animal models suggested a prion proteinlike spread of α-synuclein.23 This finding can have long-term therapeutic implications, as preventing extracellular release of abnormal form of α-synuclein will prevent the spread of pathologic protein. This can form the basis of neuroprotection in patients with PD.24
It has been proposed that α-synuclein accumulation and extracellular release initiates an immune response that leads to activation of microglia. This has been shown in PD animal models, overexpressing α-synuclein. In 2008 Park and colleagues demonstrated that microglial activation is enhanced by monomeric α-synuclein, not by the aggregated variant.25 Other studies have reported activated microglia around dopaminergic cells in substantia nigra.26 Sulzer and colleagues showed that peptides from α-synuclein can act as antigens and trigger an autoimmune reaction via T cells.27 PD may be associated with certain HLA-haplotypes.28 In other words, α-synuclein can induce neurodegeneration via different mechanisms, including alteration in synaptic vesicle transmission, mitochondrial dysfunction, neuroinflammation, and induction of humoral immunity.
Immunization
Due to these observations, there had been huge interest in developing antibody-based therapies for PD. A similar approach had been tested in Alzheimer disease (AD). Intracellular tangles of tau protein and extracellular aggregates of amyloid are the pathologic substrates in AD. Clinical trials utilizing antibodies targeting amyloid showed reduction in abnormal protein accumulation but no significant improvement in cognition.29 In addition, adverse events (AEs), such as vasogenic edema and intracerebral hemorrhage, were reported.30 Careful analysis of the data suggested that inadequate patient selection or targeting only amyloid, may have contributed to unfavorable results.31 Since then, more recent clinical trials have focused on careful patient selection, use of second generation anti-amyloid antibodies and immunotherapies targeting tau.32
Several studies have tested immunotherapies in PD animal models with the aim of targeting α-synuclein. Immunotherapies can be instituted in 2 ways: active immunization in which the immune system is stimulated to produce antibodies against α-synuclein or passive immunization in which antibodies against α-synuclein are administered directly. Once α-synuclein antibodies have crossed the blood-brain barrier, they are hypothesized to clear the existing α-synuclein. Animal studies have demonstrated the presence of these antibodies within the neurons. The mechanism of entry is unknown. Once inside the cells, the antibodies activate the lysosomal clearance, affecting intracellular accumulation of α-synuclein. Extracellularly, they can bind to receptors on scavenger cells, mainly microglia, activating them to facilitate uptake of extracellular α-synuclein. Binding of the antibodies to α-synuclein directly prevents the uptake of toxic protein by the cells, blocking the transfer and spread of PD pathology.33
Active Immunization
Active immunization against α-synuclein was demonstrated by Masliah and colleagues almost a decade ago. They administered recombinant human α-synuclein in transgenic mice expressing α-synuclein under the control of platelet-derived growth factor β. Reduction of accumulated α-synuclein in neurons with mild microglia activation was noted. It was proposed that the antibodies produced were able to bind to abnormal α-synuclein, were recognized by the lysosomal pathways, and degraded.34 Ghochikyan and colleagues developed vaccines by using α-synuclein-derived peptides. This induced formation of antibodies against α-synuclein in Lewy-bodies and neurites.35 Over time, other animal studies have been able to expand on these results.36
AFFiRiS, an Austrian biotechnology company, has developed 2 peptide vaccines PD01A and PD03A. Both peptides when administered to PD animal models caused antibody-based immune response against aggregated α-synuclein. Humoral autoimmune response was not observed in these studies; no neuroinflammation or neurotoxicity was noted. These peptides did not affect levels of physiologic α-synuclein, targeting only the aggregated form.37 These animal models showed improved motor and cognitive function. Similar results were noted in multiple system atrophy (MSA) animal models.38,39
The first human phase 1, randomized, parallel-group, single-center study recruited 32 subjects with early PD. Twelve subjects each were included in low- or high-dose treatment group, and 8 were included in the control group. Test subjects randomly received 4 vaccinations of low- or high-dose PD01A. Both doses were well tolerated, and no drug-related serious AEs were reported. The study confirmed the tolerability and safety of subcutaneous PD01A vaccine administration. These subjects were included in a 12-month, phase 1b follow-up extension study, AFF008E. In 2018, it was reported that administration of 6 doses of PD01A, 4 primary and 2 booster immunization, was safe. The vaccine showed a clear immune response against the peptide and cross-reactivity against α-synuclein targeted epitope. Booster doses stabilized the antibody titers. Significant increase in antibody titers against PD01A was seen over time, which was translated into a humoral immune response against α-synuclein. In addition, PD01A antibodies also were reported in cerebrospinal fluid.40
AFFiRiS presented results of a phase 1 randomized, placebo-controlled trial in 2017, confirming the safety of PD03A in patients with PD. The study showed a clear dose-dependent immune response against the peptide and cross-reactivity against α-synuclein targeted epitope.41 AFFiRiS recently presented results of another phase 1 clinical study assessing the safety and tolerability of vaccines PD01A and PD03A in patients with early MSA. Both vaccines were well tolerated, and PD01A induced an immune response against the peptide and α-synuclein epitope.42 These results have provided hope for further endeavors to develop active immunization strategies for PD.
Passive Immunization
Passive immunization against α-synuclein was first reported by Masliah and colleagues in 2011. A monoclonal antibody against the C-terminus of α-synuclein, 9E4, was injected into a transgenic mouse model of PD. There was reduction in α-synuclein aggregates in the brain along with improvement in motor and cognitive impairment.43 The C-terminus of α-synuclein plays a key role in the pathogenesis of PD. Changes in the C-terminus of α-synuclein induces formation of α-synuclein oligomers and subsequent neuronal spread. Antibody binds to the C-terminus and prevents structural changes that can lead to oligomerization of α-synuclein. Since the first study by Masliah, few other immunization studies utilized different antibodies against the C-terminus of α-synuclein. It was shown in a mouse model that binding of such antibodies promoted clearance of the α-synuclein by microglia.44
Based on these animal studies, Prothena Biosciences (South San Francisco, CA) designed a phase 1, double-blind, randomized, placebo-controlled clinical trial of prasinezumab (investigational monoclonal antibody against C-terminus of α-synuclein), in subjects without PD. The results showed that it was well tolerated, and there was dose-dependent reduction in the levels of free
BIIB054 is another monoclonal antibody that targets the N-terminal of α-synuclein. In animal models, antibodies targeting the N-terminus reduced α-synuclein triggered cell death and reduced the number of activated microglia.48 BIIB054, from Biogen (Cambridge, MA), was studied in 40 healthy subjects and was well tolerated with a favorable safety profile and could cross the blood-brain barrier. Like the prasinezumab study, this also was an ascending-dose study to assess safety and tolerability. In 2018, a randomized, double-blind, placebo-controlled, single-ascending dose study in patients with PD reported that BIIB054 was well tolerated, and the presence of BIIB054-synuclein complexes in the plasma were confirmed.49 A phase 2, multicenter, randomized, double-blind, placebo-controlled study (SPARK) with an active-treatment dose-blinded period, designed to evaluate the safety, pharmacokinetics, and the pharmacodynamics of BIIB054 is currently recruiting patients with PD.
Finally, BioArctic (Stockholm, Sweden) developed antibodies that are selective for oligomeric forms of α-synuclein, which it licensed to AbbVie (North Chicago, Il).50 These antibodies do not target the N- or C-terminus of α-synuclein. Since α-synuclein oligomers play an important role in the pathogenesis of PD, targeting them with antibodies at an early stage may prove to be an effective strategy for removal of pathogenic α-synuclein. Clinical trials are forthcoming.
Conclusions
Immunotherapy against α-synuclein has provided a new therapeutic avenue in the field of neuroprotection. Results from the first human clinical trial are promising, but despite these results, more work is needed to clarify the role of α-synuclein in the pathogenesis of PD in humans. Most of the work concerning α-synuclein aggregation and propagation has been reported in animal models. Whether similar process exists in humans is a debatable question. Similarly, more knowledge is needed about how and where in the human brain antibodies act to give neuroprotective effects. Timing of administration of immunotherapies in real time will be a crucial question.
PD is clinically evident once 80% of dopaminergic neurons in substantia nigra are lost due to neurodegeneration. Should immunotherapy be administered to symptomatic patients with PD, or if it will be beneficial only for presymptomatic, high-risk patients needs to be determined. Like AD trials, not only careful selection of patients, but determination of optimal timing for treatment will be essential. As the understanding of PD pathogenesis and therapeutics evolves, it will become clear whether immunization targeting α-synuclein will modify disease progression.
1. Marras C, Beck JC, Bower JH, et al; Parkinson’s Foundation P4 Group. Prevalence of Parkinson’s disease across North America. NPJ Parkinsons Dis. 2018;4(1):21. doi:10.1038/s41531-018-0058-0
2. Mantri S, Duda JE, Morley JF. Early and accurate identification of Parkinson disease among US veterans. Fed Pract. 2019;36(suppl 4):S18-S23. doi:10.12788/fp.37-0034
3. Braak H, Del Tredici K. Neuropathological staging of brain pathology in sporadic Parkinson’s disease: separating the wheat from the chaff. J Parkinsons Dis. 2017;7(suppl 1):S71-S85. doi:10.3233/JPD-179001
4. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. α-synuclein in Lewy bodies. Nature. 1997;388(6645):839-840. doi:10.1038/42166
5. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197-211. doi:10.1016/s0197-4580(02)00065-9
6. Bendor JT, Logan TP, Edwards RH. The function of α-synuclein. Neuron. 2013;79(6):1044-1066. doi:10.1016/j.neuron.2013.09.004
7. Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC. α-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010;329(5999):1663-1667. doi:10.1126/science.1195227
8. Binolfi A, Fernández CO, Sica MP, Delfino JM, Santos J. Recognition between a short unstructured peptide and a partially folded fragment leads to the thioredoxin fold sharing native-like dynamics. Proteins. 2012;80(5):1448-1464. doi:10.1002/prot.24043
9. Fauvet B, Mbefo MK, Fares MB, et al. α-synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer. J Biol Chem. 2012;287(19):15345-15364. doi:10.1074/jbc.M111.318949.
10. Wang W, Perovic I, Chittuluru J, et al. A soluble α-synuclein construct forms a dynamic tetramer. Proc Natl Acad Sci USA. 2011;108(43):17797-17802. doi:10.1073/pnas.1113260108
11. Bellucci A, Zaltieri M, Navarria L, Grigoletto J, Missale C, Spano P. From α-synuclein to synaptic dysfunctions: new insights into the pathophysiology of Parkinson’s disease. Brain Res. 2012;1476:183-202. doi:10.1016/j.brainres.2012.04.014
12. Burré J, Vivona S, Diao J, Sharma M, Brunger AT, Südhof TC. Properties of native α-synuclein. Nature. 2013;498(7453):E4-E7.
13. Burré J, Sharma M, Südhof TC. α-synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc Natl Acad Sci USA. 2014;111(40):E4274-E4283. doi:10.1073/pnas.1416598111
14. Wong YC, Krainc D. α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med. 2017;23(2):1-13. doi:10.1038/nm.4269
15. Burré J, Sharma M, Südhof TC. Definition of a molecular pathway mediating α-synuclein neurotoxicity. J Neurosci. 2015;35(13):5221-5232. doi:10.1523/JNEUROSCI.4650-14.2015
16. Lee HJ, Khoshaghideh F, Patel S, Lee SJ. Clearance of α-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci. 2004;24(8):1888-1896. doi:10.1523/JNEUROSCI.3809-03.2004
17. Rideout HJ, Dietrich P, Wang Q, Dauer WT, Stefanis L . α-synuclein is required for the fibrillar nature of ubiquitinated inclusions induced by proteasomal inhibition in primary neurons. J Biol Chem. 2004;279(45):46915-46920. doi:10.1074/jbc.M405146200
18. Ryan BJ, Hoek S, Fon EA, Wade-Martins R. Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem Sci. 2015;40(4):200-210. doi:10.1016/j.tibs.2015.02.003
19. Winklhofer KF, Haass C. Mitochondrial dysfunction in Parkinson’s disease. Biochem Biophys Acta. 2010;1802(1):29-44. doi:10.1016/j.bbadis.2009.08.013
20. Lee HJ, Bae EJ, Lee SJ. Extracellular α-synuclein: a novel and crucial factor in Lewy body diseases. Nat Rev Neurol. 2014;10(2):92-98. doi:10.1038/nrneurol.2013.275
21. Colom-Cadena M, Pegueroles J, Herrmann AG, et al. Synaptic phosphorylated α-synuclein in dementia with Lewy bodies. Brain. 2017;140(12):3204-3214. doi:10.1093/brain/awx275
22. Volpicelli-Daley LA, Luk KC, Patel TP, et al. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011;72(1):57-71. doi:10.1016/j.neuron.2011.08.033
23. Masuda-Suzukake M, Nonaka T, Hosokawa M, et al. Prion-like spreading of pathological α-synuclein in brain. Brain. 2013;136(pt 4):1128-1138. doi:10.1093/brain/awt037
24. Hasegawa M, Nonaka T, Masuda-Suzukake M. Prion-like mechanisms and potential therapeutic targets in neurodegenerative disorders. Pharmacol Ther. 2017;172:22-33. doi:10.1016/j.pharmthera.2016.11.010
25. Park JY, Paik SR, Jou I, Park SM. Microglial phagocytosis is enhanced by monomeric α-synuclein, not aggregated alpha-synuclein: implications for Parkinson’s disease. Glia. 2008;56(11):1215-1223. doi:10.1002/glia.20691
26. Blandini F. Neural and immune mechanisms in the pathogenesis of Parkinson’s disease. J Neuroimmune Pharmacol. 2013;8(1):189-201. doi:10.1007/s11481-013-9435-y
27. Sulzer D, Alcalay RN, Garretti F, et al. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature. 2017;546(7660):656-661. doi:10.1038/nature22815
28. Hamza TH, Zabetian CP, Tenesa A, et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genetics. 2010;42(9):781-785. doi:10.1038/ng.642
29. Holmes C, Boche D, Wilkinson D, et al. Long term effects of Aβ42 immunisation in Alzheimer’s disease: follow up of a randomized, placebo-controlled phase I trial. Lancet. 2008;372(9634):216-223. doi:10.1016/S0140-6736(08)61075-2
30. Sperling R, Salloway S, Brooks DJ, et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11:241-249. doi:10.1016/S1474-4422(12)70015-7
31. Wisniewski T, Goñi F. Immunotherapy for Alzheimer’s disease. Biochem Pharmacol. 2014;88(4):499-507. doi:10.1016/j.bcp.2013.12.020
32. Herline K, Drummond E, Wisniewski T. Recent advancements toward therapeutic vaccines against Alzheimer’s disease. Expert Rev Vaccines. 2018;17(8):707-721. doi:10.1080/14760584.2018.1500905
33. Bergstrom AL, Kallunki P, Fog K. Development of passive immunotherapies for synucleopathies. Mov Disord. 2015;31(2):203-213. doi:10.1002/mds.26481
34. Masliah E, Rockenstein E, Adame A, et al. Effects of α-synuclein immunization in a mouse model of Parkinson’s disease. Neuron. 2005;46(6):857-868. doi:10.1016/j.neuron.2005.05.010
35. Ghochikyan A, Petrushina I, Davtyan H, et al. Immunogenicity of epitope vaccines targeting different B cell antigenic determinants of human α-synuclein: feasibility study. Neurosci Lett. 2014;560:86-91. doi:10.1016/j.neulet.2013.12.028
36. Sanchez-Guajardo V, Annibali A, Jensen PH, Romero-Ramos M. α-synuclein vaccination prevents the accumulation of Parkinson’s disease-like pathologic inclusions in striatum in association with regulatory T cell recruitment in a rat model. J Neuropathol Exp Neurol. 2013;72(7):624-645. doi:10.1097/NEN.0b013e31829768d2
37. Mandler M, Valera E, Rockenstein E, et al. Next generation active immunization approach for synucleinopathies: Implications for Parkinson’s disease clinical trials. Acta Neuropathol. 2014;127(6):861-879. doi:10.1007/s00401-014-1256-4
38. Mandler M, Valera E, Rockenstein E, et al. Active immunization against α-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multisystem atrophy. Mol Neurodegen. 2015;10:721. doi:10.1186/s13024-015-0008-9
39. Schneeberger A, Tierney L, Mandler M. Active immunization therapies. Mov Disord. 2015;31(2):214-224. doi:10.1002/mds.26377
40. Zella SMA, Metzdorf J, Ciftci E, et al. Emerging immunotherapies for Parkinson disease. Neurol Ther. 2019;8(1):29-44. doi:10.1007/s40120-018-0122-z
41. AFFiRiS AG. AFFiRiS announces top line results of first-in-human clinical study using AFFITOPE PD03A, confirming immunogenicity and safety profile in Parkinson’s disease patients. https://affiris.com/wp-content/uploads/2018/10/praff011prefinal0607wo-embargo-1.pdf. Published June 7, 2017. Accessed July 29, 2020.
42. AFFiRiS AG. AFFiRiS announces results of a phase I clinical study using AFFITOPEs PD01A and PD03A, confirming safety and tolerability for both compounds as well as immunogenicity for PD01A in early MSA patients. http://sympath-project.eu/wp-content/uploads/PR_AFF009_V1.pdf Published March 1, 2018. Accessed July 29, 2020.
43. Masliah E, Rockenstein E, Mante M, et al. Passive immunization reduces behavioral and neuropathological deficits in an alphasynuclein transgenic model of Lewy body disease. PLoS One. 2011;6(4):e19338. doi:10.1371/journal.pone.0019338
44. Bae EJ, Lee HJ, Rockenstein E, et al. Antibody aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J Neurosci. 2012;32(39):1345-13469. doi:10.1523/JNEUROSCI.1292-12.2012
45. Schenk DB, Koller M, Ness DK, et al. First‐in‐human assessment of PRX002, an anti–α‐synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218. doi:10.1002/mds.26878.
46. Jankovic J, Goodman I, Safirstein B, et al. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-α -synuclein monoclonal antibody, in patients with Parkinson disease: a randomized clinical trial. JAMA Neurol. 2018;75(10):1206-1214. doi:10.1001/jamaneurol.2018.1487
47. Jankovic J. Pathogenesis-targeted therapeutic strategies in Parkinson’s disease. Mov Disord. 2019;34(1):41-44. doi:10.1002/mds.27534
48. Shahaduzzaman M, Nash K, Hudson C, et al. Anti-human α-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an AAV-α-synuclein rat model of Parkinson’s disease. PLoS One. 2015;10(2):E0116841. doi:10.1371/journal.pone.0116841
49. Brys M, Hung S, Fanning L, et al. Randomized, double-blind, placebo-controlled, single ascending dose study of anti-α-synuclein antibody BIIB054 in patients with Parkinson disease. Neurology. 2018;90(suppl 15):S26.001. doi:10.1002/mds.27738
50. Brundin P, Dave KD, Kordower JH. Therapeutic approaches to target α-synuclein pathology. Exp Neurol. 2017;298(pt B):225-235. doi:10.1016/j.expneurol.2017.10.003
1. Marras C, Beck JC, Bower JH, et al; Parkinson’s Foundation P4 Group. Prevalence of Parkinson’s disease across North America. NPJ Parkinsons Dis. 2018;4(1):21. doi:10.1038/s41531-018-0058-0
2. Mantri S, Duda JE, Morley JF. Early and accurate identification of Parkinson disease among US veterans. Fed Pract. 2019;36(suppl 4):S18-S23. doi:10.12788/fp.37-0034
3. Braak H, Del Tredici K. Neuropathological staging of brain pathology in sporadic Parkinson’s disease: separating the wheat from the chaff. J Parkinsons Dis. 2017;7(suppl 1):S71-S85. doi:10.3233/JPD-179001
4. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. α-synuclein in Lewy bodies. Nature. 1997;388(6645):839-840. doi:10.1038/42166
5. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197-211. doi:10.1016/s0197-4580(02)00065-9
6. Bendor JT, Logan TP, Edwards RH. The function of α-synuclein. Neuron. 2013;79(6):1044-1066. doi:10.1016/j.neuron.2013.09.004
7. Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC. α-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010;329(5999):1663-1667. doi:10.1126/science.1195227
8. Binolfi A, Fernández CO, Sica MP, Delfino JM, Santos J. Recognition between a short unstructured peptide and a partially folded fragment leads to the thioredoxin fold sharing native-like dynamics. Proteins. 2012;80(5):1448-1464. doi:10.1002/prot.24043
9. Fauvet B, Mbefo MK, Fares MB, et al. α-synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer. J Biol Chem. 2012;287(19):15345-15364. doi:10.1074/jbc.M111.318949.
10. Wang W, Perovic I, Chittuluru J, et al. A soluble α-synuclein construct forms a dynamic tetramer. Proc Natl Acad Sci USA. 2011;108(43):17797-17802. doi:10.1073/pnas.1113260108
11. Bellucci A, Zaltieri M, Navarria L, Grigoletto J, Missale C, Spano P. From α-synuclein to synaptic dysfunctions: new insights into the pathophysiology of Parkinson’s disease. Brain Res. 2012;1476:183-202. doi:10.1016/j.brainres.2012.04.014
12. Burré J, Vivona S, Diao J, Sharma M, Brunger AT, Südhof TC. Properties of native α-synuclein. Nature. 2013;498(7453):E4-E7.
13. Burré J, Sharma M, Südhof TC. α-synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc Natl Acad Sci USA. 2014;111(40):E4274-E4283. doi:10.1073/pnas.1416598111
14. Wong YC, Krainc D. α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med. 2017;23(2):1-13. doi:10.1038/nm.4269
15. Burré J, Sharma M, Südhof TC. Definition of a molecular pathway mediating α-synuclein neurotoxicity. J Neurosci. 2015;35(13):5221-5232. doi:10.1523/JNEUROSCI.4650-14.2015
16. Lee HJ, Khoshaghideh F, Patel S, Lee SJ. Clearance of α-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci. 2004;24(8):1888-1896. doi:10.1523/JNEUROSCI.3809-03.2004
17. Rideout HJ, Dietrich P, Wang Q, Dauer WT, Stefanis L . α-synuclein is required for the fibrillar nature of ubiquitinated inclusions induced by proteasomal inhibition in primary neurons. J Biol Chem. 2004;279(45):46915-46920. doi:10.1074/jbc.M405146200
18. Ryan BJ, Hoek S, Fon EA, Wade-Martins R. Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem Sci. 2015;40(4):200-210. doi:10.1016/j.tibs.2015.02.003
19. Winklhofer KF, Haass C. Mitochondrial dysfunction in Parkinson’s disease. Biochem Biophys Acta. 2010;1802(1):29-44. doi:10.1016/j.bbadis.2009.08.013
20. Lee HJ, Bae EJ, Lee SJ. Extracellular α-synuclein: a novel and crucial factor in Lewy body diseases. Nat Rev Neurol. 2014;10(2):92-98. doi:10.1038/nrneurol.2013.275
21. Colom-Cadena M, Pegueroles J, Herrmann AG, et al. Synaptic phosphorylated α-synuclein in dementia with Lewy bodies. Brain. 2017;140(12):3204-3214. doi:10.1093/brain/awx275
22. Volpicelli-Daley LA, Luk KC, Patel TP, et al. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011;72(1):57-71. doi:10.1016/j.neuron.2011.08.033
23. Masuda-Suzukake M, Nonaka T, Hosokawa M, et al. Prion-like spreading of pathological α-synuclein in brain. Brain. 2013;136(pt 4):1128-1138. doi:10.1093/brain/awt037
24. Hasegawa M, Nonaka T, Masuda-Suzukake M. Prion-like mechanisms and potential therapeutic targets in neurodegenerative disorders. Pharmacol Ther. 2017;172:22-33. doi:10.1016/j.pharmthera.2016.11.010
25. Park JY, Paik SR, Jou I, Park SM. Microglial phagocytosis is enhanced by monomeric α-synuclein, not aggregated alpha-synuclein: implications for Parkinson’s disease. Glia. 2008;56(11):1215-1223. doi:10.1002/glia.20691
26. Blandini F. Neural and immune mechanisms in the pathogenesis of Parkinson’s disease. J Neuroimmune Pharmacol. 2013;8(1):189-201. doi:10.1007/s11481-013-9435-y
27. Sulzer D, Alcalay RN, Garretti F, et al. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature. 2017;546(7660):656-661. doi:10.1038/nature22815
28. Hamza TH, Zabetian CP, Tenesa A, et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genetics. 2010;42(9):781-785. doi:10.1038/ng.642
29. Holmes C, Boche D, Wilkinson D, et al. Long term effects of Aβ42 immunisation in Alzheimer’s disease: follow up of a randomized, placebo-controlled phase I trial. Lancet. 2008;372(9634):216-223. doi:10.1016/S0140-6736(08)61075-2
30. Sperling R, Salloway S, Brooks DJ, et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11:241-249. doi:10.1016/S1474-4422(12)70015-7
31. Wisniewski T, Goñi F. Immunotherapy for Alzheimer’s disease. Biochem Pharmacol. 2014;88(4):499-507. doi:10.1016/j.bcp.2013.12.020
32. Herline K, Drummond E, Wisniewski T. Recent advancements toward therapeutic vaccines against Alzheimer’s disease. Expert Rev Vaccines. 2018;17(8):707-721. doi:10.1080/14760584.2018.1500905
33. Bergstrom AL, Kallunki P, Fog K. Development of passive immunotherapies for synucleopathies. Mov Disord. 2015;31(2):203-213. doi:10.1002/mds.26481
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Stress-induced brain activity linked to chest pain in CAD patients
The brain’s reaction to stress may be an important contributor to chest pain in patients with coronary artery disease (CAD), according to results of a cohort study.
“Although more research is needed, these results may potentially shift the paradigm by which angina is evaluated by refocusing clinical evaluation and management of psychological stress as adjunct to traditional cardiac evaluations,” wrote Kasra Moazzami, MD, MPH, of Emory University in Atlanta, and his coauthors in Circulation: Cardiovascular Imaging.
To determine if an association exists between stress-induced frontal lobe activity and angina, the researchers launched a study of 148 patients with stable CAD. Their mean age was 62, 69% were male, and roughly 36% were Black. Angina symptoms were assessed at baseline and also after 2 years through the Seattle Angina Questionnaire’s angina frequency subscale.
As the patients underwent stress testing that included both speech and arithmetic stressors, they also received eight brain scans via high-resolution positron emission tomography (HR-PET) brain imaging. Two scans occurred during each of the two control and two stress conditions. Subsequent analysis of these images evaluated regional blood flow relative to total brain flow. Each patient also underwent myocardial perfusion imaging (MPI) at rest, under stress conditions, and during conventional stress testing.
At baseline, patients who reported experiencing angina monthly (35) or daily/weekly (19) had higher rates of mental stress–induced ischemia, more common symptoms of depression and anxiety, and more use of antidepressants and nitrates. Patients reporting angina during stress testing with MPI had higher inferior frontal lobe activation (1.43), compared with patients without active chest pain (1.19; P = 0.03). Patients reporting angina during stress testing also had fewer years of education, higher Beck Depression Inventory scores, and higher posttraumatic stress disorder (PTSD) checklist scores.
More angina correlates with more mental stress
At 2-year-follow-up, 28 (24%) of the 112 returning patients reported an increase in angina episodes. Those patients had a higher mean inferior frontal lobe activation with mental stress at baseline, compared with returning patients who reported a decrease in chest pain frequency (1.82 versus 0.92; P = .01).
After adjustment for sociodemographic and lifestyle variables, any doubling in inferior frontal lobe activation led to an increase in angina frequency by 13.7 units at baseline (95% confidence interval, 6.3-21.7; P = .008) and 11.6 units during follow-up (95% CI, 4.1-19.2; P = .01). After relative importance analysis, the most important correlate of angina was found to be inferior frontal lobe activation at 36.5%, followed by Beck Depression Inventory score and PTSD checklist score.
‘It shows that the heart and brain are connected’
“Previous studies have linked mental stress with ischemia using nuclear stress testing. This study is unique in that it looked at brain activity associated with mental stress and was able to correlate that activity with angina,” said cardiologist Nieca Goldberg, MD, of NYU Langone in New York City in an interview. “It shows that the heart and brain are connected.”
The authors acknowledged their study’s limitations, including using standard stress-inducing protocols that did not account for or reflect any real-life stressors. In addition, although their methods are still considered clinically relevant, retrospectively collecting angina symptoms via questionnaire rather than a prospective diary could have led to incomplete responses.
Dr. Goldberg noted that additional research should include a more diverse population – women in particular were underrepresented in this study – while focusing on how interventions for stress can play a role in angina symptoms and brain activity.
That said, she added, “until there are more studies, it is important to consider mental stress in assessing angina symptoms in patients.”
The study was supported by grants from the National Institutes of Health. The authors reported no potential conflicts of interest.
SOURCE: Moazzami K et al. Circ Cardiovasc Imaging. 2020 Aug 10. doi: 10.1161/circimaging.120.010710.
The brain’s reaction to stress may be an important contributor to chest pain in patients with coronary artery disease (CAD), according to results of a cohort study.
“Although more research is needed, these results may potentially shift the paradigm by which angina is evaluated by refocusing clinical evaluation and management of psychological stress as adjunct to traditional cardiac evaluations,” wrote Kasra Moazzami, MD, MPH, of Emory University in Atlanta, and his coauthors in Circulation: Cardiovascular Imaging.
To determine if an association exists between stress-induced frontal lobe activity and angina, the researchers launched a study of 148 patients with stable CAD. Their mean age was 62, 69% were male, and roughly 36% were Black. Angina symptoms were assessed at baseline and also after 2 years through the Seattle Angina Questionnaire’s angina frequency subscale.
As the patients underwent stress testing that included both speech and arithmetic stressors, they also received eight brain scans via high-resolution positron emission tomography (HR-PET) brain imaging. Two scans occurred during each of the two control and two stress conditions. Subsequent analysis of these images evaluated regional blood flow relative to total brain flow. Each patient also underwent myocardial perfusion imaging (MPI) at rest, under stress conditions, and during conventional stress testing.
At baseline, patients who reported experiencing angina monthly (35) or daily/weekly (19) had higher rates of mental stress–induced ischemia, more common symptoms of depression and anxiety, and more use of antidepressants and nitrates. Patients reporting angina during stress testing with MPI had higher inferior frontal lobe activation (1.43), compared with patients without active chest pain (1.19; P = 0.03). Patients reporting angina during stress testing also had fewer years of education, higher Beck Depression Inventory scores, and higher posttraumatic stress disorder (PTSD) checklist scores.
More angina correlates with more mental stress
At 2-year-follow-up, 28 (24%) of the 112 returning patients reported an increase in angina episodes. Those patients had a higher mean inferior frontal lobe activation with mental stress at baseline, compared with returning patients who reported a decrease in chest pain frequency (1.82 versus 0.92; P = .01).
After adjustment for sociodemographic and lifestyle variables, any doubling in inferior frontal lobe activation led to an increase in angina frequency by 13.7 units at baseline (95% confidence interval, 6.3-21.7; P = .008) and 11.6 units during follow-up (95% CI, 4.1-19.2; P = .01). After relative importance analysis, the most important correlate of angina was found to be inferior frontal lobe activation at 36.5%, followed by Beck Depression Inventory score and PTSD checklist score.
‘It shows that the heart and brain are connected’
“Previous studies have linked mental stress with ischemia using nuclear stress testing. This study is unique in that it looked at brain activity associated with mental stress and was able to correlate that activity with angina,” said cardiologist Nieca Goldberg, MD, of NYU Langone in New York City in an interview. “It shows that the heart and brain are connected.”
The authors acknowledged their study’s limitations, including using standard stress-inducing protocols that did not account for or reflect any real-life stressors. In addition, although their methods are still considered clinically relevant, retrospectively collecting angina symptoms via questionnaire rather than a prospective diary could have led to incomplete responses.
Dr. Goldberg noted that additional research should include a more diverse population – women in particular were underrepresented in this study – while focusing on how interventions for stress can play a role in angina symptoms and brain activity.
That said, she added, “until there are more studies, it is important to consider mental stress in assessing angina symptoms in patients.”
The study was supported by grants from the National Institutes of Health. The authors reported no potential conflicts of interest.
SOURCE: Moazzami K et al. Circ Cardiovasc Imaging. 2020 Aug 10. doi: 10.1161/circimaging.120.010710.
The brain’s reaction to stress may be an important contributor to chest pain in patients with coronary artery disease (CAD), according to results of a cohort study.
“Although more research is needed, these results may potentially shift the paradigm by which angina is evaluated by refocusing clinical evaluation and management of psychological stress as adjunct to traditional cardiac evaluations,” wrote Kasra Moazzami, MD, MPH, of Emory University in Atlanta, and his coauthors in Circulation: Cardiovascular Imaging.
To determine if an association exists between stress-induced frontal lobe activity and angina, the researchers launched a study of 148 patients with stable CAD. Their mean age was 62, 69% were male, and roughly 36% were Black. Angina symptoms were assessed at baseline and also after 2 years through the Seattle Angina Questionnaire’s angina frequency subscale.
As the patients underwent stress testing that included both speech and arithmetic stressors, they also received eight brain scans via high-resolution positron emission tomography (HR-PET) brain imaging. Two scans occurred during each of the two control and two stress conditions. Subsequent analysis of these images evaluated regional blood flow relative to total brain flow. Each patient also underwent myocardial perfusion imaging (MPI) at rest, under stress conditions, and during conventional stress testing.
At baseline, patients who reported experiencing angina monthly (35) or daily/weekly (19) had higher rates of mental stress–induced ischemia, more common symptoms of depression and anxiety, and more use of antidepressants and nitrates. Patients reporting angina during stress testing with MPI had higher inferior frontal lobe activation (1.43), compared with patients without active chest pain (1.19; P = 0.03). Patients reporting angina during stress testing also had fewer years of education, higher Beck Depression Inventory scores, and higher posttraumatic stress disorder (PTSD) checklist scores.
More angina correlates with more mental stress
At 2-year-follow-up, 28 (24%) of the 112 returning patients reported an increase in angina episodes. Those patients had a higher mean inferior frontal lobe activation with mental stress at baseline, compared with returning patients who reported a decrease in chest pain frequency (1.82 versus 0.92; P = .01).
After adjustment for sociodemographic and lifestyle variables, any doubling in inferior frontal lobe activation led to an increase in angina frequency by 13.7 units at baseline (95% confidence interval, 6.3-21.7; P = .008) and 11.6 units during follow-up (95% CI, 4.1-19.2; P = .01). After relative importance analysis, the most important correlate of angina was found to be inferior frontal lobe activation at 36.5%, followed by Beck Depression Inventory score and PTSD checklist score.
‘It shows that the heart and brain are connected’
“Previous studies have linked mental stress with ischemia using nuclear stress testing. This study is unique in that it looked at brain activity associated with mental stress and was able to correlate that activity with angina,” said cardiologist Nieca Goldberg, MD, of NYU Langone in New York City in an interview. “It shows that the heart and brain are connected.”
The authors acknowledged their study’s limitations, including using standard stress-inducing protocols that did not account for or reflect any real-life stressors. In addition, although their methods are still considered clinically relevant, retrospectively collecting angina symptoms via questionnaire rather than a prospective diary could have led to incomplete responses.
Dr. Goldberg noted that additional research should include a more diverse population – women in particular were underrepresented in this study – while focusing on how interventions for stress can play a role in angina symptoms and brain activity.
That said, she added, “until there are more studies, it is important to consider mental stress in assessing angina symptoms in patients.”
The study was supported by grants from the National Institutes of Health. The authors reported no potential conflicts of interest.
SOURCE: Moazzami K et al. Circ Cardiovasc Imaging. 2020 Aug 10. doi: 10.1161/circimaging.120.010710.
FROM CIRCULATION: CARDIOVASCULAR IMAGING
Continued extension of time for thrombolysis in stroke
Background: Current guidelines for ischemic stroke recommend the time to thrombolysis be within 4.5 hours after onset of stroke. Guidelines are based on noncontrasted CT, but CT perfusion and perfusion-diffusion MRI may show salvageable brain tissue beyond the 4.5 hours. Studies have shown better outcomes in patients who were chosen for reperfusion based on tissue viability rather than time from onset of stroke. This has resulted in a disparity between the time windows used for thrombolysis.
Study design: Multicenter, randomized, placebo-controlled trial.
Setting: Hospitalized patients with acute ischemic stroke from 16 centers in Australia, 10 centers in Taiwan, 1 center in New Zealand, and 1 center in Finland.
Synopsis: 225 patients (aged 18 years and older) with acute ischemic stroke with hypoperfused but salvageable areas of brain detected on CT perfusion imaging or perfusion-diffusion MRI were randomly assigned to receive IV alteplase or placebo between 4.5 and 9 hours after onset of stroke or on awakening with stroke. Primary outcome measured on modified Rankin scale was 0 (no neurologic deficit) or 1. Before the trial was fully enrolled, it was terminated because of a loss of equipoise based on positive results from a previous trial. Of the patients enrolled, the primary outcome occurred in 35.4% of the alteplase group and 29.5% in the placebo group (adjusted risk ratio, 1.44). Symptomatic intracerebral hemorrhage was experienced in 6.2% of the patients in the alteplase group and 0.9% of patients in the placebo group (adjusted risk ratio, 7.22).
Not all centers may have access to perfusion imaging, so the study’s findings may not be applicable to multiple sites.
Bottom line: Diffusion-perfusion imaging may be useful in determining salvageable brain tissue in acute ischemic stroke that may benefit from thrombolysis after the standard 4.5-hour window, but further studies need to be conducted before guidelines are changed.
Citation: Ma H et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019;380(19):1795-803.
Dr. Rogers is a hospitalist at Ochsner Health System, New Orleans.
Background: Current guidelines for ischemic stroke recommend the time to thrombolysis be within 4.5 hours after onset of stroke. Guidelines are based on noncontrasted CT, but CT perfusion and perfusion-diffusion MRI may show salvageable brain tissue beyond the 4.5 hours. Studies have shown better outcomes in patients who were chosen for reperfusion based on tissue viability rather than time from onset of stroke. This has resulted in a disparity between the time windows used for thrombolysis.
Study design: Multicenter, randomized, placebo-controlled trial.
Setting: Hospitalized patients with acute ischemic stroke from 16 centers in Australia, 10 centers in Taiwan, 1 center in New Zealand, and 1 center in Finland.
Synopsis: 225 patients (aged 18 years and older) with acute ischemic stroke with hypoperfused but salvageable areas of brain detected on CT perfusion imaging or perfusion-diffusion MRI were randomly assigned to receive IV alteplase or placebo between 4.5 and 9 hours after onset of stroke or on awakening with stroke. Primary outcome measured on modified Rankin scale was 0 (no neurologic deficit) or 1. Before the trial was fully enrolled, it was terminated because of a loss of equipoise based on positive results from a previous trial. Of the patients enrolled, the primary outcome occurred in 35.4% of the alteplase group and 29.5% in the placebo group (adjusted risk ratio, 1.44). Symptomatic intracerebral hemorrhage was experienced in 6.2% of the patients in the alteplase group and 0.9% of patients in the placebo group (adjusted risk ratio, 7.22).
Not all centers may have access to perfusion imaging, so the study’s findings may not be applicable to multiple sites.
Bottom line: Diffusion-perfusion imaging may be useful in determining salvageable brain tissue in acute ischemic stroke that may benefit from thrombolysis after the standard 4.5-hour window, but further studies need to be conducted before guidelines are changed.
Citation: Ma H et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019;380(19):1795-803.
Dr. Rogers is a hospitalist at Ochsner Health System, New Orleans.
Background: Current guidelines for ischemic stroke recommend the time to thrombolysis be within 4.5 hours after onset of stroke. Guidelines are based on noncontrasted CT, but CT perfusion and perfusion-diffusion MRI may show salvageable brain tissue beyond the 4.5 hours. Studies have shown better outcomes in patients who were chosen for reperfusion based on tissue viability rather than time from onset of stroke. This has resulted in a disparity between the time windows used for thrombolysis.
Study design: Multicenter, randomized, placebo-controlled trial.
Setting: Hospitalized patients with acute ischemic stroke from 16 centers in Australia, 10 centers in Taiwan, 1 center in New Zealand, and 1 center in Finland.
Synopsis: 225 patients (aged 18 years and older) with acute ischemic stroke with hypoperfused but salvageable areas of brain detected on CT perfusion imaging or perfusion-diffusion MRI were randomly assigned to receive IV alteplase or placebo between 4.5 and 9 hours after onset of stroke or on awakening with stroke. Primary outcome measured on modified Rankin scale was 0 (no neurologic deficit) or 1. Before the trial was fully enrolled, it was terminated because of a loss of equipoise based on positive results from a previous trial. Of the patients enrolled, the primary outcome occurred in 35.4% of the alteplase group and 29.5% in the placebo group (adjusted risk ratio, 1.44). Symptomatic intracerebral hemorrhage was experienced in 6.2% of the patients in the alteplase group and 0.9% of patients in the placebo group (adjusted risk ratio, 7.22).
Not all centers may have access to perfusion imaging, so the study’s findings may not be applicable to multiple sites.
Bottom line: Diffusion-perfusion imaging may be useful in determining salvageable brain tissue in acute ischemic stroke that may benefit from thrombolysis after the standard 4.5-hour window, but further studies need to be conducted before guidelines are changed.
Citation: Ma H et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019;380(19):1795-803.
Dr. Rogers is a hospitalist at Ochsner Health System, New Orleans.