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Multivitamins, but not cocoa, tied to slowed brain aging
, with the effects especially pronounced in patients with cardiovascular (CVD) disease, new research suggests.
In addition to testing the effect of a daily multivitamin on cognition, the COSMOS-Mind study examined the effect of cocoa flavanols, but showed no beneficial effect.
The findings “may have important public health implications, particularly for brain health, given the accessibility of multivitamins and minerals, and their low cost and safety,” said study investigator Laura D. Baker, PhD, professor, gerontology and geriatric medicine, Wake Forest University, Winston-Salem, N.C.
The findings were presented at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference.
Placebo-controlled study
The study is a substudy of a large parent trial that compared the effects of cocoa extract (500 mg/day cocoa flavanols) and a standard multivitamin-mineral (MVM) to placebo on cardiovascular and cancer outcomes in more than 21,000 older participants.
COSMOS-Mind included 2,262 adults aged 65 and over without dementia who underwent cognitive testing at baseline and annually for 3 years. The mean age at baseline was 73 years, and 40.4% were men. Most participants (88.7%) were non-Hispanic White and almost half (49.2%) had some post-college education.
All study groups were balanced with respect to demographics, CVD history, diabetes, depression, smoking status, alcohol intake, chocolate intake, and prior multivitamin use. Baseline cognitive scores were similar between study groups. Researchers had complete data on 77% of study participants.
The primary endpoint was the effect of cocoa extract (CE) vs. placebo on Global Cognitive Function composite score. The secondary outcome was the effect of MVM vs. placebo on global cognitive function.
Additional outcomes included the impact of supplements on executive function and memory and the treatment effects for prespecified subgroups, including subjects with a history of CVD.
Using a graph of change over time, Dr. Baker showed there was no effect of cocoa on global cognitive function (effect: 0.03; 95% confidence interval, –0.02 to 0.08; P = .28). “We see the to-be-expected practice effects, but there’s no separation between the active and placebo groups,” she said.
It was a different story for MVM. Here, there was the same practice effect, but the graph showed the lines separated for global cognitive function composite score (effect: 0.07; 95% CI, 0.02-0.12; P = .007).
“We see a positive effect of multivitamins for the active group relative to placebo, peaking at 2 years and then remaining stable over time,” said Dr. Baker.
There were similar findings with MVM for the memory composite score, and the executive function composite score. “We have significance in all three, where the two lines do separate over and above the practice effects,” said Dr. Baker.
New evidence
Investigators found a baseline history of CVD, including transient ischemic attack, heart failure, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, and stent, but not myocardial infarction or stroke as these were excluded in the parent trial because they affected the response to multivitamins.
As expected, those with CVD had lower cognitive scores at baseline. “But after an initial bump due to practice effect, at year 1, the cardiovascular disease history folks continue to benefit from multivitamins, whereas those who got placebo multivitamins continue to decline over time,” said Dr. Baker.
Based on information from a baseline scatter plot of cognitive function scores by age, the study’s modeling estimated the multivitamin treatment effect had a positive benefit of .028 standard deviations (SD) per year.
“Daily multivitamin-mineral supplementation appears to slow cognitive aging by 60% or by 1.8 years,” Dr. Baker added.
To date, the effect of MVM supplementation on cognition has been tested in only one large randomized clinical trial – the Physicians Health Study II. That study did not show an effect, but included only older male physicians – and cognitive testing began 2.5 years after randomization, said Dr. Baker.
“Our study provides new evidence that daily multivitamin supplementation may benefit cognitive function in older women and men, and the multivitamin effects may be more pronounced in participants with cardiovascular disease,” she noted.
For effects of multivitamins on Alzheimer’s disease prevalence and progression, “stay tuned,” Dr. Baker concluded.
Following the presentation, session cochair Suzanne Schindler, MD, PhD, instructor in the department of neurology at Washington University, St. Louis, said she and her colleagues “always check vitamin B12 levels” in patients with memory and cognitive difficulties and wondered if study subjects with a low level or deficiency of vitamin B12 benefited from the intervention.
“We are asking ourselves that as well,” said Dr. Baker.
“Some of this is a work in progress,” Dr. Baker added. “We still need to look at that more in-depth to understand whether it might be a mechanism for improvement. I think the results are still out on that topic.”
The study received support from the National Institute on Aging. Pfizer Consumer Healthcare (now GSK Consumer Healthcare) provided study pills and packaging. Dr. Baker has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, with the effects especially pronounced in patients with cardiovascular (CVD) disease, new research suggests.
In addition to testing the effect of a daily multivitamin on cognition, the COSMOS-Mind study examined the effect of cocoa flavanols, but showed no beneficial effect.
The findings “may have important public health implications, particularly for brain health, given the accessibility of multivitamins and minerals, and their low cost and safety,” said study investigator Laura D. Baker, PhD, professor, gerontology and geriatric medicine, Wake Forest University, Winston-Salem, N.C.
The findings were presented at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference.
Placebo-controlled study
The study is a substudy of a large parent trial that compared the effects of cocoa extract (500 mg/day cocoa flavanols) and a standard multivitamin-mineral (MVM) to placebo on cardiovascular and cancer outcomes in more than 21,000 older participants.
COSMOS-Mind included 2,262 adults aged 65 and over without dementia who underwent cognitive testing at baseline and annually for 3 years. The mean age at baseline was 73 years, and 40.4% were men. Most participants (88.7%) were non-Hispanic White and almost half (49.2%) had some post-college education.
All study groups were balanced with respect to demographics, CVD history, diabetes, depression, smoking status, alcohol intake, chocolate intake, and prior multivitamin use. Baseline cognitive scores were similar between study groups. Researchers had complete data on 77% of study participants.
The primary endpoint was the effect of cocoa extract (CE) vs. placebo on Global Cognitive Function composite score. The secondary outcome was the effect of MVM vs. placebo on global cognitive function.
Additional outcomes included the impact of supplements on executive function and memory and the treatment effects for prespecified subgroups, including subjects with a history of CVD.
Using a graph of change over time, Dr. Baker showed there was no effect of cocoa on global cognitive function (effect: 0.03; 95% confidence interval, –0.02 to 0.08; P = .28). “We see the to-be-expected practice effects, but there’s no separation between the active and placebo groups,” she said.
It was a different story for MVM. Here, there was the same practice effect, but the graph showed the lines separated for global cognitive function composite score (effect: 0.07; 95% CI, 0.02-0.12; P = .007).
“We see a positive effect of multivitamins for the active group relative to placebo, peaking at 2 years and then remaining stable over time,” said Dr. Baker.
There were similar findings with MVM for the memory composite score, and the executive function composite score. “We have significance in all three, where the two lines do separate over and above the practice effects,” said Dr. Baker.
New evidence
Investigators found a baseline history of CVD, including transient ischemic attack, heart failure, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, and stent, but not myocardial infarction or stroke as these were excluded in the parent trial because they affected the response to multivitamins.
As expected, those with CVD had lower cognitive scores at baseline. “But after an initial bump due to practice effect, at year 1, the cardiovascular disease history folks continue to benefit from multivitamins, whereas those who got placebo multivitamins continue to decline over time,” said Dr. Baker.
Based on information from a baseline scatter plot of cognitive function scores by age, the study’s modeling estimated the multivitamin treatment effect had a positive benefit of .028 standard deviations (SD) per year.
“Daily multivitamin-mineral supplementation appears to slow cognitive aging by 60% or by 1.8 years,” Dr. Baker added.
To date, the effect of MVM supplementation on cognition has been tested in only one large randomized clinical trial – the Physicians Health Study II. That study did not show an effect, but included only older male physicians – and cognitive testing began 2.5 years after randomization, said Dr. Baker.
“Our study provides new evidence that daily multivitamin supplementation may benefit cognitive function in older women and men, and the multivitamin effects may be more pronounced in participants with cardiovascular disease,” she noted.
For effects of multivitamins on Alzheimer’s disease prevalence and progression, “stay tuned,” Dr. Baker concluded.
Following the presentation, session cochair Suzanne Schindler, MD, PhD, instructor in the department of neurology at Washington University, St. Louis, said she and her colleagues “always check vitamin B12 levels” in patients with memory and cognitive difficulties and wondered if study subjects with a low level or deficiency of vitamin B12 benefited from the intervention.
“We are asking ourselves that as well,” said Dr. Baker.
“Some of this is a work in progress,” Dr. Baker added. “We still need to look at that more in-depth to understand whether it might be a mechanism for improvement. I think the results are still out on that topic.”
The study received support from the National Institute on Aging. Pfizer Consumer Healthcare (now GSK Consumer Healthcare) provided study pills and packaging. Dr. Baker has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, with the effects especially pronounced in patients with cardiovascular (CVD) disease, new research suggests.
In addition to testing the effect of a daily multivitamin on cognition, the COSMOS-Mind study examined the effect of cocoa flavanols, but showed no beneficial effect.
The findings “may have important public health implications, particularly for brain health, given the accessibility of multivitamins and minerals, and their low cost and safety,” said study investigator Laura D. Baker, PhD, professor, gerontology and geriatric medicine, Wake Forest University, Winston-Salem, N.C.
The findings were presented at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference.
Placebo-controlled study
The study is a substudy of a large parent trial that compared the effects of cocoa extract (500 mg/day cocoa flavanols) and a standard multivitamin-mineral (MVM) to placebo on cardiovascular and cancer outcomes in more than 21,000 older participants.
COSMOS-Mind included 2,262 adults aged 65 and over without dementia who underwent cognitive testing at baseline and annually for 3 years. The mean age at baseline was 73 years, and 40.4% were men. Most participants (88.7%) were non-Hispanic White and almost half (49.2%) had some post-college education.
All study groups were balanced with respect to demographics, CVD history, diabetes, depression, smoking status, alcohol intake, chocolate intake, and prior multivitamin use. Baseline cognitive scores were similar between study groups. Researchers had complete data on 77% of study participants.
The primary endpoint was the effect of cocoa extract (CE) vs. placebo on Global Cognitive Function composite score. The secondary outcome was the effect of MVM vs. placebo on global cognitive function.
Additional outcomes included the impact of supplements on executive function and memory and the treatment effects for prespecified subgroups, including subjects with a history of CVD.
Using a graph of change over time, Dr. Baker showed there was no effect of cocoa on global cognitive function (effect: 0.03; 95% confidence interval, –0.02 to 0.08; P = .28). “We see the to-be-expected practice effects, but there’s no separation between the active and placebo groups,” she said.
It was a different story for MVM. Here, there was the same practice effect, but the graph showed the lines separated for global cognitive function composite score (effect: 0.07; 95% CI, 0.02-0.12; P = .007).
“We see a positive effect of multivitamins for the active group relative to placebo, peaking at 2 years and then remaining stable over time,” said Dr. Baker.
There were similar findings with MVM for the memory composite score, and the executive function composite score. “We have significance in all three, where the two lines do separate over and above the practice effects,” said Dr. Baker.
New evidence
Investigators found a baseline history of CVD, including transient ischemic attack, heart failure, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, and stent, but not myocardial infarction or stroke as these were excluded in the parent trial because they affected the response to multivitamins.
As expected, those with CVD had lower cognitive scores at baseline. “But after an initial bump due to practice effect, at year 1, the cardiovascular disease history folks continue to benefit from multivitamins, whereas those who got placebo multivitamins continue to decline over time,” said Dr. Baker.
Based on information from a baseline scatter plot of cognitive function scores by age, the study’s modeling estimated the multivitamin treatment effect had a positive benefit of .028 standard deviations (SD) per year.
“Daily multivitamin-mineral supplementation appears to slow cognitive aging by 60% or by 1.8 years,” Dr. Baker added.
To date, the effect of MVM supplementation on cognition has been tested in only one large randomized clinical trial – the Physicians Health Study II. That study did not show an effect, but included only older male physicians – and cognitive testing began 2.5 years after randomization, said Dr. Baker.
“Our study provides new evidence that daily multivitamin supplementation may benefit cognitive function in older women and men, and the multivitamin effects may be more pronounced in participants with cardiovascular disease,” she noted.
For effects of multivitamins on Alzheimer’s disease prevalence and progression, “stay tuned,” Dr. Baker concluded.
Following the presentation, session cochair Suzanne Schindler, MD, PhD, instructor in the department of neurology at Washington University, St. Louis, said she and her colleagues “always check vitamin B12 levels” in patients with memory and cognitive difficulties and wondered if study subjects with a low level or deficiency of vitamin B12 benefited from the intervention.
“We are asking ourselves that as well,” said Dr. Baker.
“Some of this is a work in progress,” Dr. Baker added. “We still need to look at that more in-depth to understand whether it might be a mechanism for improvement. I think the results are still out on that topic.”
The study received support from the National Institute on Aging. Pfizer Consumer Healthcare (now GSK Consumer Healthcare) provided study pills and packaging. Dr. Baker has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Do adolescents develop CNS autoimmunity after COVID-19?
Recent research suggests that some pediatric patients who develop neuropsychiatric symptoms from COVID-19 may have intrathecal antineural SARS-CoV-2 autoantibodies, which may hint at central nervous system (CNS) autoimmunity in these patients.
“Overall, these findings indicate that severe neuropsychiatric symptoms can occur in the setting of pediatric COVID-19, including patients who lack many of the cardinal systemic features,” Christopher M. Bartley, MD, PhD, of the Weill Institute for Neurosciences at the University of California, San Francisco, and colleagues wrote in their study. “These data highlight the possibility of SARS-CoV-2 neuroinvasion and/or CNS autoimmunity in pediatric patients with COVID-19 and neuropsychiatric symptoms.”
In a case series published Oct. 25 in JAMA Neurology (doi: 10.1001/jamaneurol.2021.3821), Dr. Bartley and colleagues examined three pediatric patients who were infected with SARS-CoV-2 and, over a period of 5 months in 2020, were admitted to the hospital – where they received a neurology consultation for “subacute, functionally impairing behavioral changes.”
Patient 1 had a history of unspecified anxiety and depression, and was admitted for erratic behavior, paranoia-like fears, social withdrawal, and insomnia. The patient did not respond to treatment with risperidone and gabapentin, and was readmitted soon after discharge, then treated with olanzapine followed by a transition to valproate and lorazepam. It was found the patient had cerebrospinal fluid (CSF) abnormalities in the form of elevated protein levels, and an elevated IgG index, and was given intravenous immunoglobulin followed by IV methylprednisolone. While symptoms such as paranoia improved and the patient was able to better organize thoughts after 5 days, other symptoms such as delusions and hyperreflexia persisted for at least 1 month before resolving, and some symptoms, such as lability, did not resolve before discharge.
Patient 2 had a history of motor tics and anxiety, but showed signs of insomnia, mood lability, impaired concentration, difficulty finding words, and problems completing homework following a SARS-CoV-2 infection. The patient’s father previously had been diagnosed with COVID-19 and the patient developed respiratory symptoms and fever; an IgG serology test later confirmed a SARS-CoV-2 infection. The patient went on to experience internal preoccupation, aggression, and suicidal ideation. The patients was treated with aripiprazole and risperidone, but did not respond, and was admitted to the hospital. As with patient 1, patient 2 had CSF abnormalities in the form of elevated protein levels, and responded to IV methylprednisolone, with working memory and bradyphrenia improving. However, the patient developed insomnia, extreme anxiety, suicidal ideation, aggression, and sadness after discharge, and was readmitted. The patient was treated with IV immunoglobulin, and discharged with quetiapine and lithium.
“Six months later, although improved from initial presentation, the patient required academic accommodations and continued to endorse forgetfulness and attention difficulties. The patient’s chronic tics and anxiety were unchanged,” Dr. Bartley and colleagues wrote.
Patient 3 had no psychiatric history but started to demonstrate “odd behavior, including repetitive behaviors, anorexia, and insomnia” following a SARS-CoV-2 infection. After being hospitalized, the patient showed signs of “ideomotor apraxia, abulia, disorganized behavior, agitation, and diffusely brisk reflexes” and had a high white blood cell count, creatine kinase level, and C-reactive protein level. CSF was also abnormal for this patient, with three unique oligoclonal bands identified. The patient was treated with lorazepam and olanzapine, did not receive immunotherapy, and was discharged without psychiatric medications after 4 days.
When the researchers performed testing on each of the three patients, they found intrathecal anti–SARS-CoV-2 IgG and immunostained mouse brain tissue, and “a diverse set of candidate autoantigens by human phage immunoprecipitation sequencing” in patient 1 and patient 2. In comparison, patient 3 “neither appreciably immunostained nor enriched candidates by human phage immunoprecipitation sequencing,” the researchers said.
“ and the potential for immunotherapy in some,” Dr. Bartley and colleagues concluded.
Potential of CNS autoimmunity
Evan J. Kyzar, MD, PhD, a resident physician in psychiatry at New York State Psychiatric Institute in New York Presbyterian–Columbia Campus, said in an interview that the results of the case series show some pediatric patients with neuropsychiatric symptoms can have anti-SARS-CoV-2 antibodies after viral clearance.
“Interestingly, some of the patients in this study also had antibodies in the CSF that targeted native proteins, demonstrating that COVID-19 may lead to autoimmunity directed at the brain,” he said. “This study increases our knowledge of how COVID-19 interacts with the nervous system and how autoimmune mechanisms might be contributing to at least a portion of patients with neuropsychiatric symptoms during acute infection, and possibly even after viral clearance.”
Dr. Kyzar noted that the immunological methods in the study were “cutting-edge” and the validation exploring the immune responses was detailed, but was limited because of the small sample size.
“[T]he researchers are using similar techniques to explore psychiatric disorders such as depression and schizophrenia to determine if some patients diagnosed with these conditions may have CNS-targeting autoantibodies that contribute to their symptoms and clinical presentation,” Dr. Kyzar said. “This work has the potential to discover novel neuroimmune mechanisms contributing to neuropsychiatric disease and offer possible pathways for the discovery of new treatments.”
The authors reported financial relationships with Allen & Company, the Chan Zuckerberg Initiative, National Institutes of Health, Novartis, Public Health Company, Roche/Genentech, Sandler Foundation, and Takeda in the form of grants and personal fees. They reported funding and/or support from the Brain Research Foundation, Hanna H. Gray Fellowship, Howard Hughes Medical Institute, John A. Watson Scholar Program, Latinx Center of Excellence, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, President’s Postdoctoral Fellowship Program, and Shared Instrumentation grant. Dr. Kyzar reported no relevant financial disclosures.
Recent research suggests that some pediatric patients who develop neuropsychiatric symptoms from COVID-19 may have intrathecal antineural SARS-CoV-2 autoantibodies, which may hint at central nervous system (CNS) autoimmunity in these patients.
“Overall, these findings indicate that severe neuropsychiatric symptoms can occur in the setting of pediatric COVID-19, including patients who lack many of the cardinal systemic features,” Christopher M. Bartley, MD, PhD, of the Weill Institute for Neurosciences at the University of California, San Francisco, and colleagues wrote in their study. “These data highlight the possibility of SARS-CoV-2 neuroinvasion and/or CNS autoimmunity in pediatric patients with COVID-19 and neuropsychiatric symptoms.”
In a case series published Oct. 25 in JAMA Neurology (doi: 10.1001/jamaneurol.2021.3821), Dr. Bartley and colleagues examined three pediatric patients who were infected with SARS-CoV-2 and, over a period of 5 months in 2020, were admitted to the hospital – where they received a neurology consultation for “subacute, functionally impairing behavioral changes.”
Patient 1 had a history of unspecified anxiety and depression, and was admitted for erratic behavior, paranoia-like fears, social withdrawal, and insomnia. The patient did not respond to treatment with risperidone and gabapentin, and was readmitted soon after discharge, then treated with olanzapine followed by a transition to valproate and lorazepam. It was found the patient had cerebrospinal fluid (CSF) abnormalities in the form of elevated protein levels, and an elevated IgG index, and was given intravenous immunoglobulin followed by IV methylprednisolone. While symptoms such as paranoia improved and the patient was able to better organize thoughts after 5 days, other symptoms such as delusions and hyperreflexia persisted for at least 1 month before resolving, and some symptoms, such as lability, did not resolve before discharge.
Patient 2 had a history of motor tics and anxiety, but showed signs of insomnia, mood lability, impaired concentration, difficulty finding words, and problems completing homework following a SARS-CoV-2 infection. The patient’s father previously had been diagnosed with COVID-19 and the patient developed respiratory symptoms and fever; an IgG serology test later confirmed a SARS-CoV-2 infection. The patient went on to experience internal preoccupation, aggression, and suicidal ideation. The patients was treated with aripiprazole and risperidone, but did not respond, and was admitted to the hospital. As with patient 1, patient 2 had CSF abnormalities in the form of elevated protein levels, and responded to IV methylprednisolone, with working memory and bradyphrenia improving. However, the patient developed insomnia, extreme anxiety, suicidal ideation, aggression, and sadness after discharge, and was readmitted. The patient was treated with IV immunoglobulin, and discharged with quetiapine and lithium.
“Six months later, although improved from initial presentation, the patient required academic accommodations and continued to endorse forgetfulness and attention difficulties. The patient’s chronic tics and anxiety were unchanged,” Dr. Bartley and colleagues wrote.
Patient 3 had no psychiatric history but started to demonstrate “odd behavior, including repetitive behaviors, anorexia, and insomnia” following a SARS-CoV-2 infection. After being hospitalized, the patient showed signs of “ideomotor apraxia, abulia, disorganized behavior, agitation, and diffusely brisk reflexes” and had a high white blood cell count, creatine kinase level, and C-reactive protein level. CSF was also abnormal for this patient, with three unique oligoclonal bands identified. The patient was treated with lorazepam and olanzapine, did not receive immunotherapy, and was discharged without psychiatric medications after 4 days.
When the researchers performed testing on each of the three patients, they found intrathecal anti–SARS-CoV-2 IgG and immunostained mouse brain tissue, and “a diverse set of candidate autoantigens by human phage immunoprecipitation sequencing” in patient 1 and patient 2. In comparison, patient 3 “neither appreciably immunostained nor enriched candidates by human phage immunoprecipitation sequencing,” the researchers said.
“ and the potential for immunotherapy in some,” Dr. Bartley and colleagues concluded.
Potential of CNS autoimmunity
Evan J. Kyzar, MD, PhD, a resident physician in psychiatry at New York State Psychiatric Institute in New York Presbyterian–Columbia Campus, said in an interview that the results of the case series show some pediatric patients with neuropsychiatric symptoms can have anti-SARS-CoV-2 antibodies after viral clearance.
“Interestingly, some of the patients in this study also had antibodies in the CSF that targeted native proteins, demonstrating that COVID-19 may lead to autoimmunity directed at the brain,” he said. “This study increases our knowledge of how COVID-19 interacts with the nervous system and how autoimmune mechanisms might be contributing to at least a portion of patients with neuropsychiatric symptoms during acute infection, and possibly even after viral clearance.”
Dr. Kyzar noted that the immunological methods in the study were “cutting-edge” and the validation exploring the immune responses was detailed, but was limited because of the small sample size.
“[T]he researchers are using similar techniques to explore psychiatric disorders such as depression and schizophrenia to determine if some patients diagnosed with these conditions may have CNS-targeting autoantibodies that contribute to their symptoms and clinical presentation,” Dr. Kyzar said. “This work has the potential to discover novel neuroimmune mechanisms contributing to neuropsychiatric disease and offer possible pathways for the discovery of new treatments.”
The authors reported financial relationships with Allen & Company, the Chan Zuckerberg Initiative, National Institutes of Health, Novartis, Public Health Company, Roche/Genentech, Sandler Foundation, and Takeda in the form of grants and personal fees. They reported funding and/or support from the Brain Research Foundation, Hanna H. Gray Fellowship, Howard Hughes Medical Institute, John A. Watson Scholar Program, Latinx Center of Excellence, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, President’s Postdoctoral Fellowship Program, and Shared Instrumentation grant. Dr. Kyzar reported no relevant financial disclosures.
Recent research suggests that some pediatric patients who develop neuropsychiatric symptoms from COVID-19 may have intrathecal antineural SARS-CoV-2 autoantibodies, which may hint at central nervous system (CNS) autoimmunity in these patients.
“Overall, these findings indicate that severe neuropsychiatric symptoms can occur in the setting of pediatric COVID-19, including patients who lack many of the cardinal systemic features,” Christopher M. Bartley, MD, PhD, of the Weill Institute for Neurosciences at the University of California, San Francisco, and colleagues wrote in their study. “These data highlight the possibility of SARS-CoV-2 neuroinvasion and/or CNS autoimmunity in pediatric patients with COVID-19 and neuropsychiatric symptoms.”
In a case series published Oct. 25 in JAMA Neurology (doi: 10.1001/jamaneurol.2021.3821), Dr. Bartley and colleagues examined three pediatric patients who were infected with SARS-CoV-2 and, over a period of 5 months in 2020, were admitted to the hospital – where they received a neurology consultation for “subacute, functionally impairing behavioral changes.”
Patient 1 had a history of unspecified anxiety and depression, and was admitted for erratic behavior, paranoia-like fears, social withdrawal, and insomnia. The patient did not respond to treatment with risperidone and gabapentin, and was readmitted soon after discharge, then treated with olanzapine followed by a transition to valproate and lorazepam. It was found the patient had cerebrospinal fluid (CSF) abnormalities in the form of elevated protein levels, and an elevated IgG index, and was given intravenous immunoglobulin followed by IV methylprednisolone. While symptoms such as paranoia improved and the patient was able to better organize thoughts after 5 days, other symptoms such as delusions and hyperreflexia persisted for at least 1 month before resolving, and some symptoms, such as lability, did not resolve before discharge.
Patient 2 had a history of motor tics and anxiety, but showed signs of insomnia, mood lability, impaired concentration, difficulty finding words, and problems completing homework following a SARS-CoV-2 infection. The patient’s father previously had been diagnosed with COVID-19 and the patient developed respiratory symptoms and fever; an IgG serology test later confirmed a SARS-CoV-2 infection. The patient went on to experience internal preoccupation, aggression, and suicidal ideation. The patients was treated with aripiprazole and risperidone, but did not respond, and was admitted to the hospital. As with patient 1, patient 2 had CSF abnormalities in the form of elevated protein levels, and responded to IV methylprednisolone, with working memory and bradyphrenia improving. However, the patient developed insomnia, extreme anxiety, suicidal ideation, aggression, and sadness after discharge, and was readmitted. The patient was treated with IV immunoglobulin, and discharged with quetiapine and lithium.
“Six months later, although improved from initial presentation, the patient required academic accommodations and continued to endorse forgetfulness and attention difficulties. The patient’s chronic tics and anxiety were unchanged,” Dr. Bartley and colleagues wrote.
Patient 3 had no psychiatric history but started to demonstrate “odd behavior, including repetitive behaviors, anorexia, and insomnia” following a SARS-CoV-2 infection. After being hospitalized, the patient showed signs of “ideomotor apraxia, abulia, disorganized behavior, agitation, and diffusely brisk reflexes” and had a high white blood cell count, creatine kinase level, and C-reactive protein level. CSF was also abnormal for this patient, with three unique oligoclonal bands identified. The patient was treated with lorazepam and olanzapine, did not receive immunotherapy, and was discharged without psychiatric medications after 4 days.
When the researchers performed testing on each of the three patients, they found intrathecal anti–SARS-CoV-2 IgG and immunostained mouse brain tissue, and “a diverse set of candidate autoantigens by human phage immunoprecipitation sequencing” in patient 1 and patient 2. In comparison, patient 3 “neither appreciably immunostained nor enriched candidates by human phage immunoprecipitation sequencing,” the researchers said.
“ and the potential for immunotherapy in some,” Dr. Bartley and colleagues concluded.
Potential of CNS autoimmunity
Evan J. Kyzar, MD, PhD, a resident physician in psychiatry at New York State Psychiatric Institute in New York Presbyterian–Columbia Campus, said in an interview that the results of the case series show some pediatric patients with neuropsychiatric symptoms can have anti-SARS-CoV-2 antibodies after viral clearance.
“Interestingly, some of the patients in this study also had antibodies in the CSF that targeted native proteins, demonstrating that COVID-19 may lead to autoimmunity directed at the brain,” he said. “This study increases our knowledge of how COVID-19 interacts with the nervous system and how autoimmune mechanisms might be contributing to at least a portion of patients with neuropsychiatric symptoms during acute infection, and possibly even after viral clearance.”
Dr. Kyzar noted that the immunological methods in the study were “cutting-edge” and the validation exploring the immune responses was detailed, but was limited because of the small sample size.
“[T]he researchers are using similar techniques to explore psychiatric disorders such as depression and schizophrenia to determine if some patients diagnosed with these conditions may have CNS-targeting autoantibodies that contribute to their symptoms and clinical presentation,” Dr. Kyzar said. “This work has the potential to discover novel neuroimmune mechanisms contributing to neuropsychiatric disease and offer possible pathways for the discovery of new treatments.”
The authors reported financial relationships with Allen & Company, the Chan Zuckerberg Initiative, National Institutes of Health, Novartis, Public Health Company, Roche/Genentech, Sandler Foundation, and Takeda in the form of grants and personal fees. They reported funding and/or support from the Brain Research Foundation, Hanna H. Gray Fellowship, Howard Hughes Medical Institute, John A. Watson Scholar Program, Latinx Center of Excellence, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, President’s Postdoctoral Fellowship Program, and Shared Instrumentation grant. Dr. Kyzar reported no relevant financial disclosures.
FROM JAMA NEUROLOGY
Brain rhythm predicts response to DBS for severe depression
Brain beta rhythm predicts early and robust response to deep brain stimulation (DBS) for severe depression in new findings that could help optimize and personalize DBS treatment protocols, early research suggests.
In a small study, investigators found brief stimulation at the time of implantation of DBS leads induced a rapid and consistent decrease in beta power measured at the site of stimulation, which correlated with significant and sustained decrease in depressive symptoms.
“Patient by patient, the magnitude of the decrease in the left beta power could predict how well they were doing a week later,” study investigator Helen Mayberg, MD, founding director of the Nash Family Center for Advanced Circuit Therapeutics at Mount Sinai in New York, told this news organization.
The study was published online Nov. 3 in Translational Psychiatry.
Optimal targets identified
Eight adults with treatment-resistant depression underwent intraoperative electrophysiological recording at the time that bilateral DBS leads were implanted in the subcallosal cingulate (SCC).
Using patient-specific tractography models prior to surgery, the investigators identified the optimal target within the SCC for lead placement.
During surgery, 20 minutes of stimulation in the optimal tractography-defined targets was delivered, with no stimulation in the 4 weeks after surgery. Local field potentials (LFPs) – electrical signals between neurons deep in the brain – were simultaneously recorded during intraoperative stimulation.
One week after brief intraoperative stimulation, patient depression scores had declined by 45.6% on the 17-item Hamilton Depression Rating Scale (HDRS-17).
This early antidepressant response correlated with a decrease in the beta power recorded from the left hemisphere SCC. The correlation of symptom improvement with reduction in SCC beta power suggests that this electrophysiological finding is a “biomarker for treatment optimization,” the investigators note.
“This study shows reproducible and consistent changes in a brain readout over the first minutes of optimized stimulation in the operating room in individual patients,” Dr. Mayberg said in a press release.
“Within minutes of stimulation inside the operating room, there was a change in the beta brain rhythm. Patients who showed larger changes then experienced greater relief from their depression in the week after surgery,” added Allison Waters, PhD, a co–first author on the study and electrophysiology core leader at Mount Sinai’s Nash Center.
It appears that the early decline in depressive symptoms is “partially but not completely lost” during a postoperative, one-month washout period, the researchers note.
In addition, it remains unknown whether intraoperative stimulation-induced changes in beta power are predictive of eventual sustained clinical response to chronic therapeutic SCC DBS for treatment-resistant depression.
To this point, however, chronic SCC DBS at the tractography-defined “optimal” locations led to a response rate of 88% (7 of 8) after 6 months of treatment, they report.
One step closer to precision psychiatry
“This line of work is moving the field one step closer to precision psychiatry,” Shaheen E. Lakhan, MD, PhD, a neurologist in Newton, Massachusetts, said in an interview.
“Outside of psychiatry, many diseases have measurable biomarkers that correlate with whether the disease is present or its severity. For example, for diabetes there is hemoglobin A1c, and for multiple sclerosis, brain lesions on MRI are both diagnostic and prognostic. Sadly, within psychiatry, biomarkers are few and far between,” said Dr. Lakhan, who wasn’t involved in this study.
“Over the last decades, an interesting phenomenon occurs with DBS for patients with advanced Parkinson’s – often their depression abates and mood improves. Several lines of studies have tried to tease apart whether this was primarily from alleviating the motor symptoms of Parkinson’s or [if] DBS is directly implicated in mood enhancement. Lo and behold a subset of patients with treatment-resistant depression demonstrate improvement on standardized depression testing,” Dr. Lakhan added.
This study now shows that beta rhythm – a signal deep in the brain that traditional EEG can’t pick up – “predicted who would later benefit from DBS right at the time of implantation,” Dr. Lakhan said.
“(deep beta rhythm) in and outside of brain surgery,” he told this news organization.
“Other therapy trials, for instance, with drugs or non-invasive, digital neuroactivation and modulation (DiNaMo), may use this key biomarker to optimize its development and maximize effect, one day, for a given individual,” Dr. Lakhan predicted.
“The challenge remains that these signals are deep in the brain and currently require surgical implantation of electrodes for recordings. However, technologies such as magnetoencephalography (MEG) that use powerful external magnetics may substitute,” he added.
Funding support was provided by the National Institutes of Health, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, and the Hope for Depression Research Foundation. Implanted devices used in this research were donated by Medtronic. Dr. Mayberg receives consulting and licensing fees from Abbott Labs. Dr. Lakhan has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Brain beta rhythm predicts early and robust response to deep brain stimulation (DBS) for severe depression in new findings that could help optimize and personalize DBS treatment protocols, early research suggests.
In a small study, investigators found brief stimulation at the time of implantation of DBS leads induced a rapid and consistent decrease in beta power measured at the site of stimulation, which correlated with significant and sustained decrease in depressive symptoms.
“Patient by patient, the magnitude of the decrease in the left beta power could predict how well they were doing a week later,” study investigator Helen Mayberg, MD, founding director of the Nash Family Center for Advanced Circuit Therapeutics at Mount Sinai in New York, told this news organization.
The study was published online Nov. 3 in Translational Psychiatry.
Optimal targets identified
Eight adults with treatment-resistant depression underwent intraoperative electrophysiological recording at the time that bilateral DBS leads were implanted in the subcallosal cingulate (SCC).
Using patient-specific tractography models prior to surgery, the investigators identified the optimal target within the SCC for lead placement.
During surgery, 20 minutes of stimulation in the optimal tractography-defined targets was delivered, with no stimulation in the 4 weeks after surgery. Local field potentials (LFPs) – electrical signals between neurons deep in the brain – were simultaneously recorded during intraoperative stimulation.
One week after brief intraoperative stimulation, patient depression scores had declined by 45.6% on the 17-item Hamilton Depression Rating Scale (HDRS-17).
This early antidepressant response correlated with a decrease in the beta power recorded from the left hemisphere SCC. The correlation of symptom improvement with reduction in SCC beta power suggests that this electrophysiological finding is a “biomarker for treatment optimization,” the investigators note.
“This study shows reproducible and consistent changes in a brain readout over the first minutes of optimized stimulation in the operating room in individual patients,” Dr. Mayberg said in a press release.
“Within minutes of stimulation inside the operating room, there was a change in the beta brain rhythm. Patients who showed larger changes then experienced greater relief from their depression in the week after surgery,” added Allison Waters, PhD, a co–first author on the study and electrophysiology core leader at Mount Sinai’s Nash Center.
It appears that the early decline in depressive symptoms is “partially but not completely lost” during a postoperative, one-month washout period, the researchers note.
In addition, it remains unknown whether intraoperative stimulation-induced changes in beta power are predictive of eventual sustained clinical response to chronic therapeutic SCC DBS for treatment-resistant depression.
To this point, however, chronic SCC DBS at the tractography-defined “optimal” locations led to a response rate of 88% (7 of 8) after 6 months of treatment, they report.
One step closer to precision psychiatry
“This line of work is moving the field one step closer to precision psychiatry,” Shaheen E. Lakhan, MD, PhD, a neurologist in Newton, Massachusetts, said in an interview.
“Outside of psychiatry, many diseases have measurable biomarkers that correlate with whether the disease is present or its severity. For example, for diabetes there is hemoglobin A1c, and for multiple sclerosis, brain lesions on MRI are both diagnostic and prognostic. Sadly, within psychiatry, biomarkers are few and far between,” said Dr. Lakhan, who wasn’t involved in this study.
“Over the last decades, an interesting phenomenon occurs with DBS for patients with advanced Parkinson’s – often their depression abates and mood improves. Several lines of studies have tried to tease apart whether this was primarily from alleviating the motor symptoms of Parkinson’s or [if] DBS is directly implicated in mood enhancement. Lo and behold a subset of patients with treatment-resistant depression demonstrate improvement on standardized depression testing,” Dr. Lakhan added.
This study now shows that beta rhythm – a signal deep in the brain that traditional EEG can’t pick up – “predicted who would later benefit from DBS right at the time of implantation,” Dr. Lakhan said.
“(deep beta rhythm) in and outside of brain surgery,” he told this news organization.
“Other therapy trials, for instance, with drugs or non-invasive, digital neuroactivation and modulation (DiNaMo), may use this key biomarker to optimize its development and maximize effect, one day, for a given individual,” Dr. Lakhan predicted.
“The challenge remains that these signals are deep in the brain and currently require surgical implantation of electrodes for recordings. However, technologies such as magnetoencephalography (MEG) that use powerful external magnetics may substitute,” he added.
Funding support was provided by the National Institutes of Health, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, and the Hope for Depression Research Foundation. Implanted devices used in this research were donated by Medtronic. Dr. Mayberg receives consulting and licensing fees from Abbott Labs. Dr. Lakhan has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Brain beta rhythm predicts early and robust response to deep brain stimulation (DBS) for severe depression in new findings that could help optimize and personalize DBS treatment protocols, early research suggests.
In a small study, investigators found brief stimulation at the time of implantation of DBS leads induced a rapid and consistent decrease in beta power measured at the site of stimulation, which correlated with significant and sustained decrease in depressive symptoms.
“Patient by patient, the magnitude of the decrease in the left beta power could predict how well they were doing a week later,” study investigator Helen Mayberg, MD, founding director of the Nash Family Center for Advanced Circuit Therapeutics at Mount Sinai in New York, told this news organization.
The study was published online Nov. 3 in Translational Psychiatry.
Optimal targets identified
Eight adults with treatment-resistant depression underwent intraoperative electrophysiological recording at the time that bilateral DBS leads were implanted in the subcallosal cingulate (SCC).
Using patient-specific tractography models prior to surgery, the investigators identified the optimal target within the SCC for lead placement.
During surgery, 20 minutes of stimulation in the optimal tractography-defined targets was delivered, with no stimulation in the 4 weeks after surgery. Local field potentials (LFPs) – electrical signals between neurons deep in the brain – were simultaneously recorded during intraoperative stimulation.
One week after brief intraoperative stimulation, patient depression scores had declined by 45.6% on the 17-item Hamilton Depression Rating Scale (HDRS-17).
This early antidepressant response correlated with a decrease in the beta power recorded from the left hemisphere SCC. The correlation of symptom improvement with reduction in SCC beta power suggests that this electrophysiological finding is a “biomarker for treatment optimization,” the investigators note.
“This study shows reproducible and consistent changes in a brain readout over the first minutes of optimized stimulation in the operating room in individual patients,” Dr. Mayberg said in a press release.
“Within minutes of stimulation inside the operating room, there was a change in the beta brain rhythm. Patients who showed larger changes then experienced greater relief from their depression in the week after surgery,” added Allison Waters, PhD, a co–first author on the study and electrophysiology core leader at Mount Sinai’s Nash Center.
It appears that the early decline in depressive symptoms is “partially but not completely lost” during a postoperative, one-month washout period, the researchers note.
In addition, it remains unknown whether intraoperative stimulation-induced changes in beta power are predictive of eventual sustained clinical response to chronic therapeutic SCC DBS for treatment-resistant depression.
To this point, however, chronic SCC DBS at the tractography-defined “optimal” locations led to a response rate of 88% (7 of 8) after 6 months of treatment, they report.
One step closer to precision psychiatry
“This line of work is moving the field one step closer to precision psychiatry,” Shaheen E. Lakhan, MD, PhD, a neurologist in Newton, Massachusetts, said in an interview.
“Outside of psychiatry, many diseases have measurable biomarkers that correlate with whether the disease is present or its severity. For example, for diabetes there is hemoglobin A1c, and for multiple sclerosis, brain lesions on MRI are both diagnostic and prognostic. Sadly, within psychiatry, biomarkers are few and far between,” said Dr. Lakhan, who wasn’t involved in this study.
“Over the last decades, an interesting phenomenon occurs with DBS for patients with advanced Parkinson’s – often their depression abates and mood improves. Several lines of studies have tried to tease apart whether this was primarily from alleviating the motor symptoms of Parkinson’s or [if] DBS is directly implicated in mood enhancement. Lo and behold a subset of patients with treatment-resistant depression demonstrate improvement on standardized depression testing,” Dr. Lakhan added.
This study now shows that beta rhythm – a signal deep in the brain that traditional EEG can’t pick up – “predicted who would later benefit from DBS right at the time of implantation,” Dr. Lakhan said.
“(deep beta rhythm) in and outside of brain surgery,” he told this news organization.
“Other therapy trials, for instance, with drugs or non-invasive, digital neuroactivation and modulation (DiNaMo), may use this key biomarker to optimize its development and maximize effect, one day, for a given individual,” Dr. Lakhan predicted.
“The challenge remains that these signals are deep in the brain and currently require surgical implantation of electrodes for recordings. However, technologies such as magnetoencephalography (MEG) that use powerful external magnetics may substitute,” he added.
Funding support was provided by the National Institutes of Health, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, and the Hope for Depression Research Foundation. Implanted devices used in this research were donated by Medtronic. Dr. Mayberg receives consulting and licensing fees from Abbott Labs. Dr. Lakhan has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM TRANSLATIONAL PSYCHIATRY
Newly discovered vascular barrier in the brain may explain IBD-related anxiety, depression
A newly discovered vascular brain barrier that blocks the passage of inflammatory molecules triggered by gut bacteria may be why patients with inflammatory bowel disease (IBD) are at increased risk for certain mental health disorders, including anxiety and depression, early research suggests.
The discovery, which was based on a preclinical model, could lead to new therapeutic targets that could have applications for both gastrointestinal and psychiatric conditions, investigators note.
The research team, which was led by immunologist Maria Rescigno, PhD, and neuroscientist Simona Lodato, PhD, both from Humanitas University, Milan, notes that the barrier resides in the choroid plexus, a region of the brain that is involved in filtering cerebrospinal fluid. The researchers found that the region closes in response to inflammatory molecules produced in reaction to the presence of intestinal bacteria in patients with gut disorders.
Dr. Lodato said in an interview that the brain’s choroid plexus vascular barrier, along with another barrier between the gut and liver, known as the gut vascular barrier, appear to control the movement of molecules along the gut-brain axis.
“We show that in addition to the epithelial barrier in the choroid plexus, there is a functional vascular barrier that only becomes evident in blocking entry of various inflammatory molecules under conditions of systemic inflammation,” Dr. Lodato said.
“This interruption of the gut-brain interaction has developed to protect the brain from inflammation. Why this happens is not yet known, but it is likely to prevent epileptic seizures and imbalanced neuronal activity,” added Dr. Rescigno.
The study was published online October 22 in Science.
The gut a root cause of mental illness?
Nearly 40% of patients with IBD also experience depression and anxiety. It was once thought that these conditions arose because of patients’ difficulties in coping with their disease, said Dr. Rescigno.
“People with these disorders conventionally thought to be caused by an imbalance in the brain may actually find the root cause is located in the intestine. This is the first time these symptoms have been associated with the choroid plexus vascular brain barrier and its closure,” she noted.
Dr. Rescigno added that subtle, rather than overt, inflammation may be all that’s required for closure of the choroid plexus and the subsequent effects on mental health.
In 2015, Dr. Rescigno’s group first described the gut vascular barrier that protects the systemic circulation from gut bacteria or associated bacteria-derived molecules. During intestinal inflammation, such as occurs in IBD, this barrier is compromised and becomes more permeable. This allows microbes to pass across the epithelium of the gut barrier and enter the systemic circulation, including the liver and spleen, explained Dr. Rescigno.
Dr. Rescigno and Dr. Lodato then explored whether this systemic inflammatory condition was connected to the brain along a gut-brain axis and found that it was.
The researchers tested the hypothesis that central nervous system symptoms may be due to vascular changes at the interface between the gut or the brain and elsewhere in the body.
“We set out to test whether opening of the gut vascular barrier would allow gut bacteria to trigger the release of inflammatory molecules that spread to more distant areas, possibly leading to a deficiency of certain nutrients and precipitating mental disorders,” they said.
An experimental preclinical model of the choroid plexus vascular barrier closure led to anxiety-like behavior, as well as short-term memory loss. That this behavior occurred independently of inflammation suggested that it was likely a response to closure itself, they note.
In the noninflammatory state, the epithelium of the choroid plexus filters molecules. Those that are ≤70 kDa are allowed to pass through to the brain. However, the investigators found that during systemic inflammation, this filtration stops, and the blood capillaries of the choroid plexus prevent entry of inflammatory molecules such as cytokines.
Dr. Lodato speculated that when the vascular barrier of the choroid plexus shuts off during the systemic inflammatory state, it responds by bathing the brain in cerebrospinal fluid.
“When the choroid plexus closes, like a door slamming shut, then communication between the brain and the rest of the body is halted. This means that the brain is deprived of certain nutrients and other beneficial molecules that usually enter via the cerebrospinal fluid or enriched of potentially dangerous ones, as drainage could also be affected,” she said.
If confirmed in further studies, these results may open the way to new interventions.
‘A significant leap forward’
Commenting on the findings, David T. Rubin, MD, professor of medicine at the University of Chicago, noted that the study’s results represent “a significant leap forward” and that it highlights “another important cost to uncontrolled gut inflammation that is the potential for worsened mental health disorders.”
Dr. Rubin, whose research involves measuring metabolites of the dietary amino acid tryptophan, including melatonin and serotonin, in patients with IBD, added that the findings offer a possible explanation for the association of both Crohn’s disease and ulcerative colitis with anxiety and depressive disorders.
“There was a belief that the association was in the opposite direction, that the mental health disorder was causing or worsening the gut inflammation, but this has been disavowed,” Dr. Rubin said.
“Most recently, the recognition that the major sources of serotonin and other metabolites of tryptophan that come from the gut microbiome has led to the hypothesis that the inflamed bowel and dysbiotic gut biome may in fact be driving the mental health disorders due to the effect of neurotransmitter imbalance,” he added. Dr. Rubin also suggested that the shutdown of the choroid plexus vascular barrier may contribute to this imbalance but that this needs additional study.
“This further supports my ongoing contention that the gut really is the center of the universe,” said Dr. Rubin.
Also commenting on the findings, Miguel Rigueiro, MD, professor in the department of medicine in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, said, “There’s an implication that anxiety and depression and other behavioral health disorders may be explained by this mechanism. If that is the case, there may be a way to target medications against the choroid plexus and potentially treat depression or anxiety.”
This prospect was echoed by Dr. Rubin, who said, “The clinical implication is that treatment of gut inflammation may restore a balance to the neurotransmitters and resolve anxiety or depressive disorders.”
To identify new therapeutic targets, investigators will study the regions and circuits of the brain that are more susceptible to this closure of the choroid plexus, said Dr. Lodato.
“If these regions are associated with depression or other psychosocial disorders, then this new understanding around the choroid plexus vascular barrier might eventually have implications for helping treat such disorders,” she noted.
Reflecting a general shift from a brain-centric view of some psychosocial disorders to an intestinal-centric one, Dr. Lodato added, “The brain cannot be considered in isolation. It is part of a much larger body, and we need to think this way.”
Dr. Rescigno, Dr. Lodato, and Dr. Rubin report no relevant financial relationships. Dr. Rigueiro has served on advisory boards and as consultant for AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, SpA, and Bristol-Meyer Squibb.
A version of this article first appeared on Medscape.com.
A newly discovered vascular brain barrier that blocks the passage of inflammatory molecules triggered by gut bacteria may be why patients with inflammatory bowel disease (IBD) are at increased risk for certain mental health disorders, including anxiety and depression, early research suggests.
The discovery, which was based on a preclinical model, could lead to new therapeutic targets that could have applications for both gastrointestinal and psychiatric conditions, investigators note.
The research team, which was led by immunologist Maria Rescigno, PhD, and neuroscientist Simona Lodato, PhD, both from Humanitas University, Milan, notes that the barrier resides in the choroid plexus, a region of the brain that is involved in filtering cerebrospinal fluid. The researchers found that the region closes in response to inflammatory molecules produced in reaction to the presence of intestinal bacteria in patients with gut disorders.
Dr. Lodato said in an interview that the brain’s choroid plexus vascular barrier, along with another barrier between the gut and liver, known as the gut vascular barrier, appear to control the movement of molecules along the gut-brain axis.
“We show that in addition to the epithelial barrier in the choroid plexus, there is a functional vascular barrier that only becomes evident in blocking entry of various inflammatory molecules under conditions of systemic inflammation,” Dr. Lodato said.
“This interruption of the gut-brain interaction has developed to protect the brain from inflammation. Why this happens is not yet known, but it is likely to prevent epileptic seizures and imbalanced neuronal activity,” added Dr. Rescigno.
The study was published online October 22 in Science.
The gut a root cause of mental illness?
Nearly 40% of patients with IBD also experience depression and anxiety. It was once thought that these conditions arose because of patients’ difficulties in coping with their disease, said Dr. Rescigno.
“People with these disorders conventionally thought to be caused by an imbalance in the brain may actually find the root cause is located in the intestine. This is the first time these symptoms have been associated with the choroid plexus vascular brain barrier and its closure,” she noted.
Dr. Rescigno added that subtle, rather than overt, inflammation may be all that’s required for closure of the choroid plexus and the subsequent effects on mental health.
In 2015, Dr. Rescigno’s group first described the gut vascular barrier that protects the systemic circulation from gut bacteria or associated bacteria-derived molecules. During intestinal inflammation, such as occurs in IBD, this barrier is compromised and becomes more permeable. This allows microbes to pass across the epithelium of the gut barrier and enter the systemic circulation, including the liver and spleen, explained Dr. Rescigno.
Dr. Rescigno and Dr. Lodato then explored whether this systemic inflammatory condition was connected to the brain along a gut-brain axis and found that it was.
The researchers tested the hypothesis that central nervous system symptoms may be due to vascular changes at the interface between the gut or the brain and elsewhere in the body.
“We set out to test whether opening of the gut vascular barrier would allow gut bacteria to trigger the release of inflammatory molecules that spread to more distant areas, possibly leading to a deficiency of certain nutrients and precipitating mental disorders,” they said.
An experimental preclinical model of the choroid plexus vascular barrier closure led to anxiety-like behavior, as well as short-term memory loss. That this behavior occurred independently of inflammation suggested that it was likely a response to closure itself, they note.
In the noninflammatory state, the epithelium of the choroid plexus filters molecules. Those that are ≤70 kDa are allowed to pass through to the brain. However, the investigators found that during systemic inflammation, this filtration stops, and the blood capillaries of the choroid plexus prevent entry of inflammatory molecules such as cytokines.
Dr. Lodato speculated that when the vascular barrier of the choroid plexus shuts off during the systemic inflammatory state, it responds by bathing the brain in cerebrospinal fluid.
“When the choroid plexus closes, like a door slamming shut, then communication between the brain and the rest of the body is halted. This means that the brain is deprived of certain nutrients and other beneficial molecules that usually enter via the cerebrospinal fluid or enriched of potentially dangerous ones, as drainage could also be affected,” she said.
If confirmed in further studies, these results may open the way to new interventions.
‘A significant leap forward’
Commenting on the findings, David T. Rubin, MD, professor of medicine at the University of Chicago, noted that the study’s results represent “a significant leap forward” and that it highlights “another important cost to uncontrolled gut inflammation that is the potential for worsened mental health disorders.”
Dr. Rubin, whose research involves measuring metabolites of the dietary amino acid tryptophan, including melatonin and serotonin, in patients with IBD, added that the findings offer a possible explanation for the association of both Crohn’s disease and ulcerative colitis with anxiety and depressive disorders.
“There was a belief that the association was in the opposite direction, that the mental health disorder was causing or worsening the gut inflammation, but this has been disavowed,” Dr. Rubin said.
“Most recently, the recognition that the major sources of serotonin and other metabolites of tryptophan that come from the gut microbiome has led to the hypothesis that the inflamed bowel and dysbiotic gut biome may in fact be driving the mental health disorders due to the effect of neurotransmitter imbalance,” he added. Dr. Rubin also suggested that the shutdown of the choroid plexus vascular barrier may contribute to this imbalance but that this needs additional study.
“This further supports my ongoing contention that the gut really is the center of the universe,” said Dr. Rubin.
Also commenting on the findings, Miguel Rigueiro, MD, professor in the department of medicine in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, said, “There’s an implication that anxiety and depression and other behavioral health disorders may be explained by this mechanism. If that is the case, there may be a way to target medications against the choroid plexus and potentially treat depression or anxiety.”
This prospect was echoed by Dr. Rubin, who said, “The clinical implication is that treatment of gut inflammation may restore a balance to the neurotransmitters and resolve anxiety or depressive disorders.”
To identify new therapeutic targets, investigators will study the regions and circuits of the brain that are more susceptible to this closure of the choroid plexus, said Dr. Lodato.
“If these regions are associated with depression or other psychosocial disorders, then this new understanding around the choroid plexus vascular barrier might eventually have implications for helping treat such disorders,” she noted.
Reflecting a general shift from a brain-centric view of some psychosocial disorders to an intestinal-centric one, Dr. Lodato added, “The brain cannot be considered in isolation. It is part of a much larger body, and we need to think this way.”
Dr. Rescigno, Dr. Lodato, and Dr. Rubin report no relevant financial relationships. Dr. Rigueiro has served on advisory boards and as consultant for AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, SpA, and Bristol-Meyer Squibb.
A version of this article first appeared on Medscape.com.
A newly discovered vascular brain barrier that blocks the passage of inflammatory molecules triggered by gut bacteria may be why patients with inflammatory bowel disease (IBD) are at increased risk for certain mental health disorders, including anxiety and depression, early research suggests.
The discovery, which was based on a preclinical model, could lead to new therapeutic targets that could have applications for both gastrointestinal and psychiatric conditions, investigators note.
The research team, which was led by immunologist Maria Rescigno, PhD, and neuroscientist Simona Lodato, PhD, both from Humanitas University, Milan, notes that the barrier resides in the choroid plexus, a region of the brain that is involved in filtering cerebrospinal fluid. The researchers found that the region closes in response to inflammatory molecules produced in reaction to the presence of intestinal bacteria in patients with gut disorders.
Dr. Lodato said in an interview that the brain’s choroid plexus vascular barrier, along with another barrier between the gut and liver, known as the gut vascular barrier, appear to control the movement of molecules along the gut-brain axis.
“We show that in addition to the epithelial barrier in the choroid plexus, there is a functional vascular barrier that only becomes evident in blocking entry of various inflammatory molecules under conditions of systemic inflammation,” Dr. Lodato said.
“This interruption of the gut-brain interaction has developed to protect the brain from inflammation. Why this happens is not yet known, but it is likely to prevent epileptic seizures and imbalanced neuronal activity,” added Dr. Rescigno.
The study was published online October 22 in Science.
The gut a root cause of mental illness?
Nearly 40% of patients with IBD also experience depression and anxiety. It was once thought that these conditions arose because of patients’ difficulties in coping with their disease, said Dr. Rescigno.
“People with these disorders conventionally thought to be caused by an imbalance in the brain may actually find the root cause is located in the intestine. This is the first time these symptoms have been associated with the choroid plexus vascular brain barrier and its closure,” she noted.
Dr. Rescigno added that subtle, rather than overt, inflammation may be all that’s required for closure of the choroid plexus and the subsequent effects on mental health.
In 2015, Dr. Rescigno’s group first described the gut vascular barrier that protects the systemic circulation from gut bacteria or associated bacteria-derived molecules. During intestinal inflammation, such as occurs in IBD, this barrier is compromised and becomes more permeable. This allows microbes to pass across the epithelium of the gut barrier and enter the systemic circulation, including the liver and spleen, explained Dr. Rescigno.
Dr. Rescigno and Dr. Lodato then explored whether this systemic inflammatory condition was connected to the brain along a gut-brain axis and found that it was.
The researchers tested the hypothesis that central nervous system symptoms may be due to vascular changes at the interface between the gut or the brain and elsewhere in the body.
“We set out to test whether opening of the gut vascular barrier would allow gut bacteria to trigger the release of inflammatory molecules that spread to more distant areas, possibly leading to a deficiency of certain nutrients and precipitating mental disorders,” they said.
An experimental preclinical model of the choroid plexus vascular barrier closure led to anxiety-like behavior, as well as short-term memory loss. That this behavior occurred independently of inflammation suggested that it was likely a response to closure itself, they note.
In the noninflammatory state, the epithelium of the choroid plexus filters molecules. Those that are ≤70 kDa are allowed to pass through to the brain. However, the investigators found that during systemic inflammation, this filtration stops, and the blood capillaries of the choroid plexus prevent entry of inflammatory molecules such as cytokines.
Dr. Lodato speculated that when the vascular barrier of the choroid plexus shuts off during the systemic inflammatory state, it responds by bathing the brain in cerebrospinal fluid.
“When the choroid plexus closes, like a door slamming shut, then communication between the brain and the rest of the body is halted. This means that the brain is deprived of certain nutrients and other beneficial molecules that usually enter via the cerebrospinal fluid or enriched of potentially dangerous ones, as drainage could also be affected,” she said.
If confirmed in further studies, these results may open the way to new interventions.
‘A significant leap forward’
Commenting on the findings, David T. Rubin, MD, professor of medicine at the University of Chicago, noted that the study’s results represent “a significant leap forward” and that it highlights “another important cost to uncontrolled gut inflammation that is the potential for worsened mental health disorders.”
Dr. Rubin, whose research involves measuring metabolites of the dietary amino acid tryptophan, including melatonin and serotonin, in patients with IBD, added that the findings offer a possible explanation for the association of both Crohn’s disease and ulcerative colitis with anxiety and depressive disorders.
“There was a belief that the association was in the opposite direction, that the mental health disorder was causing or worsening the gut inflammation, but this has been disavowed,” Dr. Rubin said.
“Most recently, the recognition that the major sources of serotonin and other metabolites of tryptophan that come from the gut microbiome has led to the hypothesis that the inflamed bowel and dysbiotic gut biome may in fact be driving the mental health disorders due to the effect of neurotransmitter imbalance,” he added. Dr. Rubin also suggested that the shutdown of the choroid plexus vascular barrier may contribute to this imbalance but that this needs additional study.
“This further supports my ongoing contention that the gut really is the center of the universe,” said Dr. Rubin.
Also commenting on the findings, Miguel Rigueiro, MD, professor in the department of medicine in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, said, “There’s an implication that anxiety and depression and other behavioral health disorders may be explained by this mechanism. If that is the case, there may be a way to target medications against the choroid plexus and potentially treat depression or anxiety.”
This prospect was echoed by Dr. Rubin, who said, “The clinical implication is that treatment of gut inflammation may restore a balance to the neurotransmitters and resolve anxiety or depressive disorders.”
To identify new therapeutic targets, investigators will study the regions and circuits of the brain that are more susceptible to this closure of the choroid plexus, said Dr. Lodato.
“If these regions are associated with depression or other psychosocial disorders, then this new understanding around the choroid plexus vascular barrier might eventually have implications for helping treat such disorders,” she noted.
Reflecting a general shift from a brain-centric view of some psychosocial disorders to an intestinal-centric one, Dr. Lodato added, “The brain cannot be considered in isolation. It is part of a much larger body, and we need to think this way.”
Dr. Rescigno, Dr. Lodato, and Dr. Rubin report no relevant financial relationships. Dr. Rigueiro has served on advisory boards and as consultant for AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, SpA, and Bristol-Meyer Squibb.
A version of this article first appeared on Medscape.com.
FROM SCIENCE
Expected spike in acute flaccid myelitis did not occur in 2020
suggested researchers at the Centers for Disease Control and Prevention.
Acute flaccid myelitis (AFM) is an uncommon but serious complication of some viral infections, including West Nile virus and nonpolio enteroviruses. It is “characterized by sudden onset of limb weakness and lesions in the gray matter of the spinal cord,” they said, and more than 90% of cases occur in young children.
Cases of AFM, which can lead to respiratory insufficiency and permanent paralysis, spiked during the late summer and early fall in 2014, 2016, and 2018 and were expected to do so again in 2020, Sarah Kidd, MD, and associates at the division of viral diseases at the CDC’s National Center for Immunization and Respiratory Diseases, Atlanta, said in the Morbidity and Mortality Weekly Report.
Monthly peaks in those previous years – each occurring in September – reached 51 cases in 2014, 43 cases in 2016, and 88 cases in 2018, but in 2020 there was only 1 case reported in September, with a high of 4 coming in May, CDC data show. The total number of cases for 2020 (32) was, in fact, lower than in 2019, when 47 were reported.
The investigators’ main objective was to see if there were any differences between the 2018 and 2019-2020 cases. Reports from state health departments to the CDC showed that, in 2019-2020, “patients were older; more likely to have lower limb involvement; and less likely to have upper limb involvement, prodromal illness, [cerebrospinal fluid] pleocytosis, or specimens that tested positive for EV [enterovirus]-D68” than patients from 2018, Dr. Kidd and associates said.
Mask wearing and reduced in-school attendance may have decreased circulation of EV-D68 – the enterovirus type most often detected in the stool and respiratory specimens of AFM patients – as was seen with other respiratory viruses, such as influenza and respiratory syncytial virus, in 2020. Previous studies have suggested that EV-D68 drives the increases in cases during peak years, the researchers noted.
The absence of such an increase “in 2020 reflects a deviation from the previously observed biennial pattern, and it is unclear when the next increase in AFM should be expected. Clinicians should continue to maintain vigilance and suspect AFM in any child with acute flaccid limb weakness, particularly in the setting of recent febrile or respiratory illness,” they wrote.
suggested researchers at the Centers for Disease Control and Prevention.
Acute flaccid myelitis (AFM) is an uncommon but serious complication of some viral infections, including West Nile virus and nonpolio enteroviruses. It is “characterized by sudden onset of limb weakness and lesions in the gray matter of the spinal cord,” they said, and more than 90% of cases occur in young children.
Cases of AFM, which can lead to respiratory insufficiency and permanent paralysis, spiked during the late summer and early fall in 2014, 2016, and 2018 and were expected to do so again in 2020, Sarah Kidd, MD, and associates at the division of viral diseases at the CDC’s National Center for Immunization and Respiratory Diseases, Atlanta, said in the Morbidity and Mortality Weekly Report.
Monthly peaks in those previous years – each occurring in September – reached 51 cases in 2014, 43 cases in 2016, and 88 cases in 2018, but in 2020 there was only 1 case reported in September, with a high of 4 coming in May, CDC data show. The total number of cases for 2020 (32) was, in fact, lower than in 2019, when 47 were reported.
The investigators’ main objective was to see if there were any differences between the 2018 and 2019-2020 cases. Reports from state health departments to the CDC showed that, in 2019-2020, “patients were older; more likely to have lower limb involvement; and less likely to have upper limb involvement, prodromal illness, [cerebrospinal fluid] pleocytosis, or specimens that tested positive for EV [enterovirus]-D68” than patients from 2018, Dr. Kidd and associates said.
Mask wearing and reduced in-school attendance may have decreased circulation of EV-D68 – the enterovirus type most often detected in the stool and respiratory specimens of AFM patients – as was seen with other respiratory viruses, such as influenza and respiratory syncytial virus, in 2020. Previous studies have suggested that EV-D68 drives the increases in cases during peak years, the researchers noted.
The absence of such an increase “in 2020 reflects a deviation from the previously observed biennial pattern, and it is unclear when the next increase in AFM should be expected. Clinicians should continue to maintain vigilance and suspect AFM in any child with acute flaccid limb weakness, particularly in the setting of recent febrile or respiratory illness,” they wrote.
suggested researchers at the Centers for Disease Control and Prevention.
Acute flaccid myelitis (AFM) is an uncommon but serious complication of some viral infections, including West Nile virus and nonpolio enteroviruses. It is “characterized by sudden onset of limb weakness and lesions in the gray matter of the spinal cord,” they said, and more than 90% of cases occur in young children.
Cases of AFM, which can lead to respiratory insufficiency and permanent paralysis, spiked during the late summer and early fall in 2014, 2016, and 2018 and were expected to do so again in 2020, Sarah Kidd, MD, and associates at the division of viral diseases at the CDC’s National Center for Immunization and Respiratory Diseases, Atlanta, said in the Morbidity and Mortality Weekly Report.
Monthly peaks in those previous years – each occurring in September – reached 51 cases in 2014, 43 cases in 2016, and 88 cases in 2018, but in 2020 there was only 1 case reported in September, with a high of 4 coming in May, CDC data show. The total number of cases for 2020 (32) was, in fact, lower than in 2019, when 47 were reported.
The investigators’ main objective was to see if there were any differences between the 2018 and 2019-2020 cases. Reports from state health departments to the CDC showed that, in 2019-2020, “patients were older; more likely to have lower limb involvement; and less likely to have upper limb involvement, prodromal illness, [cerebrospinal fluid] pleocytosis, or specimens that tested positive for EV [enterovirus]-D68” than patients from 2018, Dr. Kidd and associates said.
Mask wearing and reduced in-school attendance may have decreased circulation of EV-D68 – the enterovirus type most often detected in the stool and respiratory specimens of AFM patients – as was seen with other respiratory viruses, such as influenza and respiratory syncytial virus, in 2020. Previous studies have suggested that EV-D68 drives the increases in cases during peak years, the researchers noted.
The absence of such an increase “in 2020 reflects a deviation from the previously observed biennial pattern, and it is unclear when the next increase in AFM should be expected. Clinicians should continue to maintain vigilance and suspect AFM in any child with acute flaccid limb weakness, particularly in the setting of recent febrile or respiratory illness,” they wrote.
FROM MMWR
Antihypertensives tied to lower Alzheimer’s disease pathology
new research shows.
Investigators found that use of any antihypertensive was associated with an 18% decrease in Alzheimer’s disease neuropathology, a 22% decrease in Lewy bodies, and a 40% decrease in TAR DNA-binding protein 43 (TDP-43), a protein relevant to several neurodegenerative diseases. Diuretics in particular appear to be driving the association.
Although diuretics might be a better option for preventing brain neuropathology, it’s too early to make firm recommendations solely on the basis of these results as to what blood pressure–lowering agent to prescribe a particular patient, said study investigator Ahmad Sajjadi, MD, assistant professor of neurology, University of California, Irvine.
“This is early stages and preliminary results,” said Dr. Sajjadi, “but it’s food for thought.”
The findings were presented at the 2021 annual meeting of the American Neurological Association.
Autopsy data
The study included 3,315 individuals who had donated their brains to research. The National Alzheimer’s Coordinating Center maintains a database that includes data from 32 Alzheimer’s disease research centers in the United States. Participants in the study must have visited one of these centers within 4 years of death. Each person whose brain was included in the study underwent two or more BP measurements on at least 50% of visits.
The mean age at death was 81.7 years, and the mean time between last visit and death was 13.1 months. About 44.4% of participants were women, 57.0% had at least a college degree, and 84.7% had cognitive impairment.
Researchers defined hypertension as systolic BP of at least 130 mm Hg, diastolic BP of at least 80 mm Hg, mean arterial pressure of at least 100 mm Hg, and pulse pressure of at least 60 mm Hg.
Antihypertensive medications that were evaluated included antiadrenergic agents, ACE inhibitors, angiotensin II receptor blockers, beta blockers, calcium channel blockers, diuretics, vasodilators, and combination therapies.
The investigators assessed the number of neuropathologies. In addition to Alzheimer’s disease neuropathology, which included amyloid-beta, tau, Lewy bodies, and TDP-43, they also assessed for atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, frontotemporal lobar degeneration, and hippocampal sclerosis.
Results showed that use of any antihypertensive was associated with a lower likelihood of Alzheimer’s disease neuropathology (odds ratio, 0.822), Lewy bodies (OR, 0.786), and TDP 43 (OR, 0.597). Use of antihypertensives was also associated with increased odds of atherosclerosis (OR, 1.217) (all P < .5.)
The study showed that hypertensive systolic BP was associated with higher odds of Alzheimer’s disease neuropathology (OR, 1.28; P < .5).
Differences by drug type
Results differed in accordance with antihypertensive class. Angiotensin II receptor blockers decreased the odds of Alzheimer’s disease neuropathology by 40% (OR, 0.60; P < .5). Diuretics decreased the odds of Alzheimer’s disease by 36% (OR, 0.64; P < .001) and of hippocampal sclerosis by 32% (OR, 0.68; P < .5).
“We see diuretics are a main driver, especially for lower odds of Alzheimer’s disease and lower odds of hippocampal sclerosis,” said lead author Hanna L. Nguyen, a first-year medical student at the University of California, Irvine.
The results indicate that it is the medications, not BP levels, that account for these associations, she added.
One potential mechanism linking antihypertensives to brain pathology is that with these agents, BP is maintained in the target zone. Blood pressure that’s too high can damage blood vessels, whereas BP that’s too low may result in less than adequate perfusion, said Ms. Nguyen.
These medications may also alter pathways leading to degeneration and could, for example, affect the apo E mechanism of Alzheimer’s disease, she added.
The researchers plan to conduct subset analyses using apo E genetic status and age of death.
Although this is a “massive database,” it has limitations. For example, said Dr. Sajjadi, it does not reveal when patients started taking BP medication, how long they had been taking it, or why.
“We don’t know the exact the reason they were taking these medications. Was it just hypertension, or did they also have heart disease, stroke, a kidney problem, or was there another explanation,” he said.
Following the study presentation, session comoderator Krish Sathian, MBBS, PhD, professor of neurology, neural, and behavioral sciences, and psychology and director of the Neuroscience Institute, Penn State University, Hershey, called this work “fascinating. It provides a lot of data that really touches on everyday practice,” inasmuch as clinicians often prescribe antihypertensive medications and see patients with these kinds of brain disorders.
The investigators and Dr. Sathian reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research shows.
Investigators found that use of any antihypertensive was associated with an 18% decrease in Alzheimer’s disease neuropathology, a 22% decrease in Lewy bodies, and a 40% decrease in TAR DNA-binding protein 43 (TDP-43), a protein relevant to several neurodegenerative diseases. Diuretics in particular appear to be driving the association.
Although diuretics might be a better option for preventing brain neuropathology, it’s too early to make firm recommendations solely on the basis of these results as to what blood pressure–lowering agent to prescribe a particular patient, said study investigator Ahmad Sajjadi, MD, assistant professor of neurology, University of California, Irvine.
“This is early stages and preliminary results,” said Dr. Sajjadi, “but it’s food for thought.”
The findings were presented at the 2021 annual meeting of the American Neurological Association.
Autopsy data
The study included 3,315 individuals who had donated their brains to research. The National Alzheimer’s Coordinating Center maintains a database that includes data from 32 Alzheimer’s disease research centers in the United States. Participants in the study must have visited one of these centers within 4 years of death. Each person whose brain was included in the study underwent two or more BP measurements on at least 50% of visits.
The mean age at death was 81.7 years, and the mean time between last visit and death was 13.1 months. About 44.4% of participants were women, 57.0% had at least a college degree, and 84.7% had cognitive impairment.
Researchers defined hypertension as systolic BP of at least 130 mm Hg, diastolic BP of at least 80 mm Hg, mean arterial pressure of at least 100 mm Hg, and pulse pressure of at least 60 mm Hg.
Antihypertensive medications that were evaluated included antiadrenergic agents, ACE inhibitors, angiotensin II receptor blockers, beta blockers, calcium channel blockers, diuretics, vasodilators, and combination therapies.
The investigators assessed the number of neuropathologies. In addition to Alzheimer’s disease neuropathology, which included amyloid-beta, tau, Lewy bodies, and TDP-43, they also assessed for atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, frontotemporal lobar degeneration, and hippocampal sclerosis.
Results showed that use of any antihypertensive was associated with a lower likelihood of Alzheimer’s disease neuropathology (odds ratio, 0.822), Lewy bodies (OR, 0.786), and TDP 43 (OR, 0.597). Use of antihypertensives was also associated with increased odds of atherosclerosis (OR, 1.217) (all P < .5.)
The study showed that hypertensive systolic BP was associated with higher odds of Alzheimer’s disease neuropathology (OR, 1.28; P < .5).
Differences by drug type
Results differed in accordance with antihypertensive class. Angiotensin II receptor blockers decreased the odds of Alzheimer’s disease neuropathology by 40% (OR, 0.60; P < .5). Diuretics decreased the odds of Alzheimer’s disease by 36% (OR, 0.64; P < .001) and of hippocampal sclerosis by 32% (OR, 0.68; P < .5).
“We see diuretics are a main driver, especially for lower odds of Alzheimer’s disease and lower odds of hippocampal sclerosis,” said lead author Hanna L. Nguyen, a first-year medical student at the University of California, Irvine.
The results indicate that it is the medications, not BP levels, that account for these associations, she added.
One potential mechanism linking antihypertensives to brain pathology is that with these agents, BP is maintained in the target zone. Blood pressure that’s too high can damage blood vessels, whereas BP that’s too low may result in less than adequate perfusion, said Ms. Nguyen.
These medications may also alter pathways leading to degeneration and could, for example, affect the apo E mechanism of Alzheimer’s disease, she added.
The researchers plan to conduct subset analyses using apo E genetic status and age of death.
Although this is a “massive database,” it has limitations. For example, said Dr. Sajjadi, it does not reveal when patients started taking BP medication, how long they had been taking it, or why.
“We don’t know the exact the reason they were taking these medications. Was it just hypertension, or did they also have heart disease, stroke, a kidney problem, or was there another explanation,” he said.
Following the study presentation, session comoderator Krish Sathian, MBBS, PhD, professor of neurology, neural, and behavioral sciences, and psychology and director of the Neuroscience Institute, Penn State University, Hershey, called this work “fascinating. It provides a lot of data that really touches on everyday practice,” inasmuch as clinicians often prescribe antihypertensive medications and see patients with these kinds of brain disorders.
The investigators and Dr. Sathian reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research shows.
Investigators found that use of any antihypertensive was associated with an 18% decrease in Alzheimer’s disease neuropathology, a 22% decrease in Lewy bodies, and a 40% decrease in TAR DNA-binding protein 43 (TDP-43), a protein relevant to several neurodegenerative diseases. Diuretics in particular appear to be driving the association.
Although diuretics might be a better option for preventing brain neuropathology, it’s too early to make firm recommendations solely on the basis of these results as to what blood pressure–lowering agent to prescribe a particular patient, said study investigator Ahmad Sajjadi, MD, assistant professor of neurology, University of California, Irvine.
“This is early stages and preliminary results,” said Dr. Sajjadi, “but it’s food for thought.”
The findings were presented at the 2021 annual meeting of the American Neurological Association.
Autopsy data
The study included 3,315 individuals who had donated their brains to research. The National Alzheimer’s Coordinating Center maintains a database that includes data from 32 Alzheimer’s disease research centers in the United States. Participants in the study must have visited one of these centers within 4 years of death. Each person whose brain was included in the study underwent two or more BP measurements on at least 50% of visits.
The mean age at death was 81.7 years, and the mean time between last visit and death was 13.1 months. About 44.4% of participants were women, 57.0% had at least a college degree, and 84.7% had cognitive impairment.
Researchers defined hypertension as systolic BP of at least 130 mm Hg, diastolic BP of at least 80 mm Hg, mean arterial pressure of at least 100 mm Hg, and pulse pressure of at least 60 mm Hg.
Antihypertensive medications that were evaluated included antiadrenergic agents, ACE inhibitors, angiotensin II receptor blockers, beta blockers, calcium channel blockers, diuretics, vasodilators, and combination therapies.
The investigators assessed the number of neuropathologies. In addition to Alzheimer’s disease neuropathology, which included amyloid-beta, tau, Lewy bodies, and TDP-43, they also assessed for atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, frontotemporal lobar degeneration, and hippocampal sclerosis.
Results showed that use of any antihypertensive was associated with a lower likelihood of Alzheimer’s disease neuropathology (odds ratio, 0.822), Lewy bodies (OR, 0.786), and TDP 43 (OR, 0.597). Use of antihypertensives was also associated with increased odds of atherosclerosis (OR, 1.217) (all P < .5.)
The study showed that hypertensive systolic BP was associated with higher odds of Alzheimer’s disease neuropathology (OR, 1.28; P < .5).
Differences by drug type
Results differed in accordance with antihypertensive class. Angiotensin II receptor blockers decreased the odds of Alzheimer’s disease neuropathology by 40% (OR, 0.60; P < .5). Diuretics decreased the odds of Alzheimer’s disease by 36% (OR, 0.64; P < .001) and of hippocampal sclerosis by 32% (OR, 0.68; P < .5).
“We see diuretics are a main driver, especially for lower odds of Alzheimer’s disease and lower odds of hippocampal sclerosis,” said lead author Hanna L. Nguyen, a first-year medical student at the University of California, Irvine.
The results indicate that it is the medications, not BP levels, that account for these associations, she added.
One potential mechanism linking antihypertensives to brain pathology is that with these agents, BP is maintained in the target zone. Blood pressure that’s too high can damage blood vessels, whereas BP that’s too low may result in less than adequate perfusion, said Ms. Nguyen.
These medications may also alter pathways leading to degeneration and could, for example, affect the apo E mechanism of Alzheimer’s disease, she added.
The researchers plan to conduct subset analyses using apo E genetic status and age of death.
Although this is a “massive database,” it has limitations. For example, said Dr. Sajjadi, it does not reveal when patients started taking BP medication, how long they had been taking it, or why.
“We don’t know the exact the reason they were taking these medications. Was it just hypertension, or did they also have heart disease, stroke, a kidney problem, or was there another explanation,” he said.
Following the study presentation, session comoderator Krish Sathian, MBBS, PhD, professor of neurology, neural, and behavioral sciences, and psychology and director of the Neuroscience Institute, Penn State University, Hershey, called this work “fascinating. It provides a lot of data that really touches on everyday practice,” inasmuch as clinicians often prescribe antihypertensive medications and see patients with these kinds of brain disorders.
The investigators and Dr. Sathian reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ANA 2021
Alopecia tied to a threefold increased risk for dementia
Alopecia areata (AA) has been linked to a significantly increased risk for dementia, new research shows.
After controlling for an array of potential confounders, investigators found a threefold higher risk of developing any form of dementia and a fourfold higher risk of developing Alzheimer’s disease (AD) in those with AA versus the controls.
“AA shares a similar inflammatory signature with dementia and has great psychological impacts that lead to poor social engagement,” lead author Cheng-Yuan Li, MD, MSc, of the department of dermatology, Taipei (Taiwan) Veterans General Hospital.
“Poor social engagement and shared inflammatory cytokines might both be important links between AA and dementia,” said Dr. Li, who is also affiliated with the School of Medicine and the Institute of Brain Science at National Yang Ming Chiao Tung University, Taipei.
The study was published online Oct. 26, 2021, in the Journal of Clinical Psychiatry (doi: 10.4088/JCP.21m13931).
Significant psychological impact
Patients with AA often experience anxiety and depression, possibly caused by the negative emotional and psychological impact of the hair loss and partial or even complete baldness associated with the disease, the authors noted.
However, AA is also associated with an array of other atopic and autoimmune diseases, including psoriasis and systemic lupus erythematosus (SLE).
Epidemiologic research has suggested a link between dementia and autoimmune diseases such as psoriasis and SLE, with some evidence suggesting that autoimmune and inflammatory mechanisms may “play a role” in the development of AD.
Dementia in general and AD in particular, “have been shown to include an inflammatory component” that may share some of the same mediators seen in AA (eg, IL-1 beta, IL-6, and tumor necrosis factor–alpha).
Moreover, “the great negative psychosocial impact of AA might result in poor social engagement, a typical risk factor for dementia,” said Dr. Li. The investigators sought to investigate whether patients with AA actually do have a higher dementia risk than individuals without AA.
The researchers used data from the Taiwan National Health Insurance Research Database, comparing 2,534 patients with AA against 25,340 controls matched for age, sex, residence, income, dementia-related comorbidities, systemic steroid use, and annual outpatient visits. Participants were enrolled between 1998 and 2011 and followed to the end of 2013.
The mean age of the cohort was 53.9 years, and a little over half (57.6%) were female. The most common comorbidity was hypertension (32.3%), followed by dyslipidemia (27%) and diabetes (15.4%).
Dual intervention
After adjusting for potential confounders, those with AA were more likely to develop dementia, AD, and unspecified dementia, compared with controls. They also had a numerically higher risk for vascular dementia, compared with controls, but it was not statistically significant.
When participants were stratified by age, investigators found a significant association between AA and higher risk for any dementia as well as unspecified dementia in individuals of all ages and an increased risk for AD in patients with dementia age at onset of 65 years and older.
The mean age of dementia diagnosis was considerably younger in patients with AA versus controls (73.4 vs. 78.9 years, P = .002). The risk for any dementia and unspecified dementia was higher in patients of both sexes, but the risk for AD was higher only in male patients.
Sensitivity analyses that excluded the first year or first 3 years of observation yielded similar and consistent findings.
“Intervention targeting poor social engagement and inflammatory cytokines may be beneficial to AA-associated dementia,” said Dr. Li.
“Physicians should be more aware of this possible association, help reduce disease discrimination among the public, and encourage more social engagement for AA patients,” he said.
“Further studies are needed to elucidate the underlying pathophysiology between AA and dementia risk,” he added.
No cause and effect
Commenting on the study, Heather M. Snyder, PhD, vice president of medical and scientific affairs, Alzheimer’s Association, said, “We continue to learn about and better understand factors that may increase or decrease a person’s risk of dementia.”
“While we know the immune system plays a role in Alzheimer’s and other dementia, we are still investigating links between, and impact of, autoimmune diseases – like alopecia areata, rheumatoid arthritis, and others – on our overall health and our brains, [which] may eventually give us important information on risk reduction strategies as well,” said Dr. Snyder, who was not involved in the research.
She cautioned that although the study did show a correlation between AA and dementia risk, this does not equate to a demonstration of cause and effect.
At present, “the message for clinicians is that when a patient comes to your office with complaints about their memory, they should, No. 1, be taken seriously; and, No. 2, receive a thorough evaluation that takes into account the many factors that may lead to cognitive decline,” Dr. Snyder said.
The study was supported by a grant from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. Dr. Li, coauthors, and Dr. Snyder disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Alopecia areata (AA) has been linked to a significantly increased risk for dementia, new research shows.
After controlling for an array of potential confounders, investigators found a threefold higher risk of developing any form of dementia and a fourfold higher risk of developing Alzheimer’s disease (AD) in those with AA versus the controls.
“AA shares a similar inflammatory signature with dementia and has great psychological impacts that lead to poor social engagement,” lead author Cheng-Yuan Li, MD, MSc, of the department of dermatology, Taipei (Taiwan) Veterans General Hospital.
“Poor social engagement and shared inflammatory cytokines might both be important links between AA and dementia,” said Dr. Li, who is also affiliated with the School of Medicine and the Institute of Brain Science at National Yang Ming Chiao Tung University, Taipei.
The study was published online Oct. 26, 2021, in the Journal of Clinical Psychiatry (doi: 10.4088/JCP.21m13931).
Significant psychological impact
Patients with AA often experience anxiety and depression, possibly caused by the negative emotional and psychological impact of the hair loss and partial or even complete baldness associated with the disease, the authors noted.
However, AA is also associated with an array of other atopic and autoimmune diseases, including psoriasis and systemic lupus erythematosus (SLE).
Epidemiologic research has suggested a link between dementia and autoimmune diseases such as psoriasis and SLE, with some evidence suggesting that autoimmune and inflammatory mechanisms may “play a role” in the development of AD.
Dementia in general and AD in particular, “have been shown to include an inflammatory component” that may share some of the same mediators seen in AA (eg, IL-1 beta, IL-6, and tumor necrosis factor–alpha).
Moreover, “the great negative psychosocial impact of AA might result in poor social engagement, a typical risk factor for dementia,” said Dr. Li. The investigators sought to investigate whether patients with AA actually do have a higher dementia risk than individuals without AA.
The researchers used data from the Taiwan National Health Insurance Research Database, comparing 2,534 patients with AA against 25,340 controls matched for age, sex, residence, income, dementia-related comorbidities, systemic steroid use, and annual outpatient visits. Participants were enrolled between 1998 and 2011 and followed to the end of 2013.
The mean age of the cohort was 53.9 years, and a little over half (57.6%) were female. The most common comorbidity was hypertension (32.3%), followed by dyslipidemia (27%) and diabetes (15.4%).
Dual intervention
After adjusting for potential confounders, those with AA were more likely to develop dementia, AD, and unspecified dementia, compared with controls. They also had a numerically higher risk for vascular dementia, compared with controls, but it was not statistically significant.
When participants were stratified by age, investigators found a significant association between AA and higher risk for any dementia as well as unspecified dementia in individuals of all ages and an increased risk for AD in patients with dementia age at onset of 65 years and older.
The mean age of dementia diagnosis was considerably younger in patients with AA versus controls (73.4 vs. 78.9 years, P = .002). The risk for any dementia and unspecified dementia was higher in patients of both sexes, but the risk for AD was higher only in male patients.
Sensitivity analyses that excluded the first year or first 3 years of observation yielded similar and consistent findings.
“Intervention targeting poor social engagement and inflammatory cytokines may be beneficial to AA-associated dementia,” said Dr. Li.
“Physicians should be more aware of this possible association, help reduce disease discrimination among the public, and encourage more social engagement for AA patients,” he said.
“Further studies are needed to elucidate the underlying pathophysiology between AA and dementia risk,” he added.
No cause and effect
Commenting on the study, Heather M. Snyder, PhD, vice president of medical and scientific affairs, Alzheimer’s Association, said, “We continue to learn about and better understand factors that may increase or decrease a person’s risk of dementia.”
“While we know the immune system plays a role in Alzheimer’s and other dementia, we are still investigating links between, and impact of, autoimmune diseases – like alopecia areata, rheumatoid arthritis, and others – on our overall health and our brains, [which] may eventually give us important information on risk reduction strategies as well,” said Dr. Snyder, who was not involved in the research.
She cautioned that although the study did show a correlation between AA and dementia risk, this does not equate to a demonstration of cause and effect.
At present, “the message for clinicians is that when a patient comes to your office with complaints about their memory, they should, No. 1, be taken seriously; and, No. 2, receive a thorough evaluation that takes into account the many factors that may lead to cognitive decline,” Dr. Snyder said.
The study was supported by a grant from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. Dr. Li, coauthors, and Dr. Snyder disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Alopecia areata (AA) has been linked to a significantly increased risk for dementia, new research shows.
After controlling for an array of potential confounders, investigators found a threefold higher risk of developing any form of dementia and a fourfold higher risk of developing Alzheimer’s disease (AD) in those with AA versus the controls.
“AA shares a similar inflammatory signature with dementia and has great psychological impacts that lead to poor social engagement,” lead author Cheng-Yuan Li, MD, MSc, of the department of dermatology, Taipei (Taiwan) Veterans General Hospital.
“Poor social engagement and shared inflammatory cytokines might both be important links between AA and dementia,” said Dr. Li, who is also affiliated with the School of Medicine and the Institute of Brain Science at National Yang Ming Chiao Tung University, Taipei.
The study was published online Oct. 26, 2021, in the Journal of Clinical Psychiatry (doi: 10.4088/JCP.21m13931).
Significant psychological impact
Patients with AA often experience anxiety and depression, possibly caused by the negative emotional and psychological impact of the hair loss and partial or even complete baldness associated with the disease, the authors noted.
However, AA is also associated with an array of other atopic and autoimmune diseases, including psoriasis and systemic lupus erythematosus (SLE).
Epidemiologic research has suggested a link between dementia and autoimmune diseases such as psoriasis and SLE, with some evidence suggesting that autoimmune and inflammatory mechanisms may “play a role” in the development of AD.
Dementia in general and AD in particular, “have been shown to include an inflammatory component” that may share some of the same mediators seen in AA (eg, IL-1 beta, IL-6, and tumor necrosis factor–alpha).
Moreover, “the great negative psychosocial impact of AA might result in poor social engagement, a typical risk factor for dementia,” said Dr. Li. The investigators sought to investigate whether patients with AA actually do have a higher dementia risk than individuals without AA.
The researchers used data from the Taiwan National Health Insurance Research Database, comparing 2,534 patients with AA against 25,340 controls matched for age, sex, residence, income, dementia-related comorbidities, systemic steroid use, and annual outpatient visits. Participants were enrolled between 1998 and 2011 and followed to the end of 2013.
The mean age of the cohort was 53.9 years, and a little over half (57.6%) were female. The most common comorbidity was hypertension (32.3%), followed by dyslipidemia (27%) and diabetes (15.4%).
Dual intervention
After adjusting for potential confounders, those with AA were more likely to develop dementia, AD, and unspecified dementia, compared with controls. They also had a numerically higher risk for vascular dementia, compared with controls, but it was not statistically significant.
When participants were stratified by age, investigators found a significant association between AA and higher risk for any dementia as well as unspecified dementia in individuals of all ages and an increased risk for AD in patients with dementia age at onset of 65 years and older.
The mean age of dementia diagnosis was considerably younger in patients with AA versus controls (73.4 vs. 78.9 years, P = .002). The risk for any dementia and unspecified dementia was higher in patients of both sexes, but the risk for AD was higher only in male patients.
Sensitivity analyses that excluded the first year or first 3 years of observation yielded similar and consistent findings.
“Intervention targeting poor social engagement and inflammatory cytokines may be beneficial to AA-associated dementia,” said Dr. Li.
“Physicians should be more aware of this possible association, help reduce disease discrimination among the public, and encourage more social engagement for AA patients,” he said.
“Further studies are needed to elucidate the underlying pathophysiology between AA and dementia risk,” he added.
No cause and effect
Commenting on the study, Heather M. Snyder, PhD, vice president of medical and scientific affairs, Alzheimer’s Association, said, “We continue to learn about and better understand factors that may increase or decrease a person’s risk of dementia.”
“While we know the immune system plays a role in Alzheimer’s and other dementia, we are still investigating links between, and impact of, autoimmune diseases – like alopecia areata, rheumatoid arthritis, and others – on our overall health and our brains, [which] may eventually give us important information on risk reduction strategies as well,” said Dr. Snyder, who was not involved in the research.
She cautioned that although the study did show a correlation between AA and dementia risk, this does not equate to a demonstration of cause and effect.
At present, “the message for clinicians is that when a patient comes to your office with complaints about their memory, they should, No. 1, be taken seriously; and, No. 2, receive a thorough evaluation that takes into account the many factors that may lead to cognitive decline,” Dr. Snyder said.
The study was supported by a grant from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. Dr. Li, coauthors, and Dr. Snyder disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FDA not recognizing efficacy of psychopharmacologic therapies
Many years ago, drug development in psychiatry turned to control of specific symptoms across disorders rather than within disorders, but regulatory agencies are still not yet on board, according to an expert psychopharmacologist outlining the ongoing evolution at the virtual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists, sponsored by Medscape Live.
If this reorientation is going to lead to the broad indications the newer drugs likely deserve, which is control of specific types of symptoms regardless of the diagnosis, “we have to move the [Food and Drug Administration] along,” said Stephen M. Stahl, MD, PhD, chairman of the Neuroscience Institute and an adjunct professor of psychiatry at the University of California, San Diego.
On the side of drug development and clinical practice, the reorientation has already taken place. Dr. Stahl described numerous brain circuits known to produce symptoms when function is altered that are now treatment targets. This includes the ventral medial prefrontal cortex where deficient information processing leads to depression and the orbital frontal cortex where altered function leads to impulsivity.
“It is not like each part of the brain does a little bit of everything. Rather, each part of the brain has an assignment and duty and function,” Dr. Stahl explained. By addressing the disturbed signaling in brain circuits that lead to depression, impulsivity, agitation, or other symptoms, there is an opportunity for control, regardless of the psychiatric diagnosis with which the symptom is associated.
For example, Dr. Stahl predicted that pimavanserin, a highly selective 5-HT2A inverse agonist that is already approved for psychosis in Parkinson’s disease, is now likely to be approved for psychosis associated with other conditions on the basis of recent positive clinical studies in these other disorders.
Brexpiprazole, a serotonin-dopamine activity modulator already known to be useful for control of the agitation characteristic of schizophrenia, is now showing the same type of activity against agitation when it is associated with Alzheimer’s disease. Again, Dr. Stahl thinks this drug is on course for an indication across diseases once studies are conducted in each disease individually.
Another drug being evaluated for agitation, the N-methyl-D-aspartate receptor antagonist dextromethorphan bupropion, is also being tested for treatment of symptoms across multiple disorders, he reported.
However, the FDA has so far taken the position that each drug must be tested separately for a given symptom in each disorder for which it is being considered despite the underlying premise that it is the symptom, not the disease, that is important.
Unlike physiological diseases where symptoms, like a fever or abdominal cramps, are the product of a disease, psychiatric symptoms are the disease and a fundamental target – regardless of the DSM-based diagnosis.
To some degree, the symptoms of psychiatric disorders have always been the focus of treatment, but a pivot toward developing therapies that will control a symptom regardless of the underlying diagnosis is an important conceptual change. It is being made possible by advances in the detail with which the neuropathology of these symptoms is understood .
“By my count, 79 symptoms are described in DSM-5, but they are spread across hundreds of syndromes because they are grouped together in different ways,” Dr. Stahl observed.
He noted that clinicians make a diagnosis on the basis symptom groupings, but their interventions are selected to address the manifestations of the disease, not the disease itself.
“If you are a real psychopharmacologist treating real patients, you are treating the specific symptoms of the specific patient,” according to Dr. Stahl.
So far, the FDA has not made this leap, insisting on trials in these categorical disorders rather than permitting trial designs that allow benefit to be demonstrated against a symptom regardless of the syndrome with which it is associated.
Of egregious examples, Dr. Stahl recounted a recent trial of a 5-HT2 antagonist that looked so promising against psychosis in Alzheimer’s disease that the trialists enrolled patients with psychosis regardless of type of dementia, such as vascular dementia and Lewy body disease. The efficacy was impressive.
“It worked so well that they stopped the trial, but the FDA declined to approve it,” Dr. Stahl recounted. Despite clear evidence of benefit, the regulators insisted that the investigators needed to show a significant benefit in each condition individually.
While the trial investigators acknowledged that there was not enough power in the trial to show a statistically significant benefit in each category, they argued that the overall benefit and the consistent response across categories required them to stop the trial for ethical reasons.
“That’s your problem, the FDA said to the investigators,” according to Dr. Stahl.
The failure of the FDA to recognize the efficacy of psychopharmacologic therapies across symptoms regardless of the associated disease is a failure to stay current with an important evolution in medicine, Dr. Stahl indicated.
“What we have come to understand is the neurobiology of any given symptom is likely to be the same across disorders,” he said.
Agency’s arbitrary decisions cited
“I completely agree with Dr. Stahl,” said Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience, University of Cincinnati.
In addition to the fact that symptoms are present across multiple categories, many patients manifest multiple symptoms at one time, Dr. Nasrallah pointed out. For neurodegenerative disorders associated with psychosis, depression, anxiety, aggression, and other symptoms, it is already well known that the heterogeneous symptoms “cannot be treated with a single drug,” he said. Rather different drugs targeting each symptom individually is essential for effective management.
Dr. Nasrallah, who chaired the Psychopharmacology Update meeting, has made this point many times in the past, including in his role as the editor of Current Psychiatry. In one editorial 10 years ago, he wrote that “it makes little sense for the FDA to mandate that a drug must work for a DSM diagnosis instead of specific symptoms.”
“The FDA must update its old policy, which has led to the widespread off-label use of psychiatric drugs, an artificial concept, simply because the FDA arbitrarily decided a long time ago that new drugs must be approved for a specific DSM diagnosis,” Dr. Nasrallah said.
Dr. Stahl reported financial relationships with more than 20 pharmaceutical companies, including those that are involved in the development of drugs included in his talk. Medscape Live and this news organization are owned by the same parent company.
Many years ago, drug development in psychiatry turned to control of specific symptoms across disorders rather than within disorders, but regulatory agencies are still not yet on board, according to an expert psychopharmacologist outlining the ongoing evolution at the virtual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists, sponsored by Medscape Live.
If this reorientation is going to lead to the broad indications the newer drugs likely deserve, which is control of specific types of symptoms regardless of the diagnosis, “we have to move the [Food and Drug Administration] along,” said Stephen M. Stahl, MD, PhD, chairman of the Neuroscience Institute and an adjunct professor of psychiatry at the University of California, San Diego.
On the side of drug development and clinical practice, the reorientation has already taken place. Dr. Stahl described numerous brain circuits known to produce symptoms when function is altered that are now treatment targets. This includes the ventral medial prefrontal cortex where deficient information processing leads to depression and the orbital frontal cortex where altered function leads to impulsivity.
“It is not like each part of the brain does a little bit of everything. Rather, each part of the brain has an assignment and duty and function,” Dr. Stahl explained. By addressing the disturbed signaling in brain circuits that lead to depression, impulsivity, agitation, or other symptoms, there is an opportunity for control, regardless of the psychiatric diagnosis with which the symptom is associated.
For example, Dr. Stahl predicted that pimavanserin, a highly selective 5-HT2A inverse agonist that is already approved for psychosis in Parkinson’s disease, is now likely to be approved for psychosis associated with other conditions on the basis of recent positive clinical studies in these other disorders.
Brexpiprazole, a serotonin-dopamine activity modulator already known to be useful for control of the agitation characteristic of schizophrenia, is now showing the same type of activity against agitation when it is associated with Alzheimer’s disease. Again, Dr. Stahl thinks this drug is on course for an indication across diseases once studies are conducted in each disease individually.
Another drug being evaluated for agitation, the N-methyl-D-aspartate receptor antagonist dextromethorphan bupropion, is also being tested for treatment of symptoms across multiple disorders, he reported.
However, the FDA has so far taken the position that each drug must be tested separately for a given symptom in each disorder for which it is being considered despite the underlying premise that it is the symptom, not the disease, that is important.
Unlike physiological diseases where symptoms, like a fever or abdominal cramps, are the product of a disease, psychiatric symptoms are the disease and a fundamental target – regardless of the DSM-based diagnosis.
To some degree, the symptoms of psychiatric disorders have always been the focus of treatment, but a pivot toward developing therapies that will control a symptom regardless of the underlying diagnosis is an important conceptual change. It is being made possible by advances in the detail with which the neuropathology of these symptoms is understood .
“By my count, 79 symptoms are described in DSM-5, but they are spread across hundreds of syndromes because they are grouped together in different ways,” Dr. Stahl observed.
He noted that clinicians make a diagnosis on the basis symptom groupings, but their interventions are selected to address the manifestations of the disease, not the disease itself.
“If you are a real psychopharmacologist treating real patients, you are treating the specific symptoms of the specific patient,” according to Dr. Stahl.
So far, the FDA has not made this leap, insisting on trials in these categorical disorders rather than permitting trial designs that allow benefit to be demonstrated against a symptom regardless of the syndrome with which it is associated.
Of egregious examples, Dr. Stahl recounted a recent trial of a 5-HT2 antagonist that looked so promising against psychosis in Alzheimer’s disease that the trialists enrolled patients with psychosis regardless of type of dementia, such as vascular dementia and Lewy body disease. The efficacy was impressive.
“It worked so well that they stopped the trial, but the FDA declined to approve it,” Dr. Stahl recounted. Despite clear evidence of benefit, the regulators insisted that the investigators needed to show a significant benefit in each condition individually.
While the trial investigators acknowledged that there was not enough power in the trial to show a statistically significant benefit in each category, they argued that the overall benefit and the consistent response across categories required them to stop the trial for ethical reasons.
“That’s your problem, the FDA said to the investigators,” according to Dr. Stahl.
The failure of the FDA to recognize the efficacy of psychopharmacologic therapies across symptoms regardless of the associated disease is a failure to stay current with an important evolution in medicine, Dr. Stahl indicated.
“What we have come to understand is the neurobiology of any given symptom is likely to be the same across disorders,” he said.
Agency’s arbitrary decisions cited
“I completely agree with Dr. Stahl,” said Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience, University of Cincinnati.
In addition to the fact that symptoms are present across multiple categories, many patients manifest multiple symptoms at one time, Dr. Nasrallah pointed out. For neurodegenerative disorders associated with psychosis, depression, anxiety, aggression, and other symptoms, it is already well known that the heterogeneous symptoms “cannot be treated with a single drug,” he said. Rather different drugs targeting each symptom individually is essential for effective management.
Dr. Nasrallah, who chaired the Psychopharmacology Update meeting, has made this point many times in the past, including in his role as the editor of Current Psychiatry. In one editorial 10 years ago, he wrote that “it makes little sense for the FDA to mandate that a drug must work for a DSM diagnosis instead of specific symptoms.”
“The FDA must update its old policy, which has led to the widespread off-label use of psychiatric drugs, an artificial concept, simply because the FDA arbitrarily decided a long time ago that new drugs must be approved for a specific DSM diagnosis,” Dr. Nasrallah said.
Dr. Stahl reported financial relationships with more than 20 pharmaceutical companies, including those that are involved in the development of drugs included in his talk. Medscape Live and this news organization are owned by the same parent company.
Many years ago, drug development in psychiatry turned to control of specific symptoms across disorders rather than within disorders, but regulatory agencies are still not yet on board, according to an expert psychopharmacologist outlining the ongoing evolution at the virtual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists, sponsored by Medscape Live.
If this reorientation is going to lead to the broad indications the newer drugs likely deserve, which is control of specific types of symptoms regardless of the diagnosis, “we have to move the [Food and Drug Administration] along,” said Stephen M. Stahl, MD, PhD, chairman of the Neuroscience Institute and an adjunct professor of psychiatry at the University of California, San Diego.
On the side of drug development and clinical practice, the reorientation has already taken place. Dr. Stahl described numerous brain circuits known to produce symptoms when function is altered that are now treatment targets. This includes the ventral medial prefrontal cortex where deficient information processing leads to depression and the orbital frontal cortex where altered function leads to impulsivity.
“It is not like each part of the brain does a little bit of everything. Rather, each part of the brain has an assignment and duty and function,” Dr. Stahl explained. By addressing the disturbed signaling in brain circuits that lead to depression, impulsivity, agitation, or other symptoms, there is an opportunity for control, regardless of the psychiatric diagnosis with which the symptom is associated.
For example, Dr. Stahl predicted that pimavanserin, a highly selective 5-HT2A inverse agonist that is already approved for psychosis in Parkinson’s disease, is now likely to be approved for psychosis associated with other conditions on the basis of recent positive clinical studies in these other disorders.
Brexpiprazole, a serotonin-dopamine activity modulator already known to be useful for control of the agitation characteristic of schizophrenia, is now showing the same type of activity against agitation when it is associated with Alzheimer’s disease. Again, Dr. Stahl thinks this drug is on course for an indication across diseases once studies are conducted in each disease individually.
Another drug being evaluated for agitation, the N-methyl-D-aspartate receptor antagonist dextromethorphan bupropion, is also being tested for treatment of symptoms across multiple disorders, he reported.
However, the FDA has so far taken the position that each drug must be tested separately for a given symptom in each disorder for which it is being considered despite the underlying premise that it is the symptom, not the disease, that is important.
Unlike physiological diseases where symptoms, like a fever or abdominal cramps, are the product of a disease, psychiatric symptoms are the disease and a fundamental target – regardless of the DSM-based diagnosis.
To some degree, the symptoms of psychiatric disorders have always been the focus of treatment, but a pivot toward developing therapies that will control a symptom regardless of the underlying diagnosis is an important conceptual change. It is being made possible by advances in the detail with which the neuropathology of these symptoms is understood .
“By my count, 79 symptoms are described in DSM-5, but they are spread across hundreds of syndromes because they are grouped together in different ways,” Dr. Stahl observed.
He noted that clinicians make a diagnosis on the basis symptom groupings, but their interventions are selected to address the manifestations of the disease, not the disease itself.
“If you are a real psychopharmacologist treating real patients, you are treating the specific symptoms of the specific patient,” according to Dr. Stahl.
So far, the FDA has not made this leap, insisting on trials in these categorical disorders rather than permitting trial designs that allow benefit to be demonstrated against a symptom regardless of the syndrome with which it is associated.
Of egregious examples, Dr. Stahl recounted a recent trial of a 5-HT2 antagonist that looked so promising against psychosis in Alzheimer’s disease that the trialists enrolled patients with psychosis regardless of type of dementia, such as vascular dementia and Lewy body disease. The efficacy was impressive.
“It worked so well that they stopped the trial, but the FDA declined to approve it,” Dr. Stahl recounted. Despite clear evidence of benefit, the regulators insisted that the investigators needed to show a significant benefit in each condition individually.
While the trial investigators acknowledged that there was not enough power in the trial to show a statistically significant benefit in each category, they argued that the overall benefit and the consistent response across categories required them to stop the trial for ethical reasons.
“That’s your problem, the FDA said to the investigators,” according to Dr. Stahl.
The failure of the FDA to recognize the efficacy of psychopharmacologic therapies across symptoms regardless of the associated disease is a failure to stay current with an important evolution in medicine, Dr. Stahl indicated.
“What we have come to understand is the neurobiology of any given symptom is likely to be the same across disorders,” he said.
Agency’s arbitrary decisions cited
“I completely agree with Dr. Stahl,” said Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience, University of Cincinnati.
In addition to the fact that symptoms are present across multiple categories, many patients manifest multiple symptoms at one time, Dr. Nasrallah pointed out. For neurodegenerative disorders associated with psychosis, depression, anxiety, aggression, and other symptoms, it is already well known that the heterogeneous symptoms “cannot be treated with a single drug,” he said. Rather different drugs targeting each symptom individually is essential for effective management.
Dr. Nasrallah, who chaired the Psychopharmacology Update meeting, has made this point many times in the past, including in his role as the editor of Current Psychiatry. In one editorial 10 years ago, he wrote that “it makes little sense for the FDA to mandate that a drug must work for a DSM diagnosis instead of specific symptoms.”
“The FDA must update its old policy, which has led to the widespread off-label use of psychiatric drugs, an artificial concept, simply because the FDA arbitrarily decided a long time ago that new drugs must be approved for a specific DSM diagnosis,” Dr. Nasrallah said.
Dr. Stahl reported financial relationships with more than 20 pharmaceutical companies, including those that are involved in the development of drugs included in his talk. Medscape Live and this news organization are owned by the same parent company.
FROM PSYCHOPHARMACOLOGY UPDATE
Patients given NSAIDs over antiemetics for headaches spend less time in the ED
based on data from approximately 7,000 patients.
Headache is the fourth-most common chief complaint in the ED, accounting for approximately 3% of all ED visits, said Philip Wang, a medical student at the Cleveland Clinic, in a presentation at the annual meeting of the American College of Emergency Physicians.
A variety of pharmacotherapies are used to manage headache, which leads to a range of resource use, he said.
To understand the association between route of drug administration and length of ED stay, Mr. Wang and colleagues reviewed data from 7,233 visits by 6,715 patients at any of the 21 Cleveland Clinic Health System EDs in 2018 with headache as the primary discharge diagnosis. Patients admitted to the hospital were excluded; those treated with opioids, antiemetics, and/or NSAIDs were included. The average age of the study population was 31 years, 57% were White, and approximately half were Medicaid or Medicare patients.
Approximately 68% of patients received antiemetics, 66.8% received NSAIDs, and 9.8% received opioids. Approximately 42% of patients received parenteral-only treatment and 42% received oral-only treatment; 15% received mixed treatment. The average length of ED stay was 202 minutes.
In a multivariate analysis adjusted for sex, age, income, race, insurance status, ED type, and arrival time, treatment with oral drugs only was associated with an 11% reduction of length of stay, compared with treatment with parenteral medication only (P < .001). However, the length of stay for patients treated with mixed route of administration was 10% longer, compared with parenteral only (P < .001).
In terms of drug class (a secondary outcome), patients treated with opioids had a 10% increase in length of stay (P < .01) and those treated with antiemetics had a 14% increase in length of stay; however, patients treated with NSAIDs had a 7% decrease in length of stay.
The study findings were limited in part by the challenge of isolating patients presenting with a primary headache diagnosis, Mr. Wang noted in the presentation.
The challenge of controlling for all the potential factors impacting length of stay, which is “provider, resource, and situation dependent,” is an additional limitation, he said.
However, the results show that route of administration has a significant impact on length of ED stay in patients presenting with headache, he concluded.
The study received no outside funding. The researchers disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
based on data from approximately 7,000 patients.
Headache is the fourth-most common chief complaint in the ED, accounting for approximately 3% of all ED visits, said Philip Wang, a medical student at the Cleveland Clinic, in a presentation at the annual meeting of the American College of Emergency Physicians.
A variety of pharmacotherapies are used to manage headache, which leads to a range of resource use, he said.
To understand the association between route of drug administration and length of ED stay, Mr. Wang and colleagues reviewed data from 7,233 visits by 6,715 patients at any of the 21 Cleveland Clinic Health System EDs in 2018 with headache as the primary discharge diagnosis. Patients admitted to the hospital were excluded; those treated with opioids, antiemetics, and/or NSAIDs were included. The average age of the study population was 31 years, 57% were White, and approximately half were Medicaid or Medicare patients.
Approximately 68% of patients received antiemetics, 66.8% received NSAIDs, and 9.8% received opioids. Approximately 42% of patients received parenteral-only treatment and 42% received oral-only treatment; 15% received mixed treatment. The average length of ED stay was 202 minutes.
In a multivariate analysis adjusted for sex, age, income, race, insurance status, ED type, and arrival time, treatment with oral drugs only was associated with an 11% reduction of length of stay, compared with treatment with parenteral medication only (P < .001). However, the length of stay for patients treated with mixed route of administration was 10% longer, compared with parenteral only (P < .001).
In terms of drug class (a secondary outcome), patients treated with opioids had a 10% increase in length of stay (P < .01) and those treated with antiemetics had a 14% increase in length of stay; however, patients treated with NSAIDs had a 7% decrease in length of stay.
The study findings were limited in part by the challenge of isolating patients presenting with a primary headache diagnosis, Mr. Wang noted in the presentation.
The challenge of controlling for all the potential factors impacting length of stay, which is “provider, resource, and situation dependent,” is an additional limitation, he said.
However, the results show that route of administration has a significant impact on length of ED stay in patients presenting with headache, he concluded.
The study received no outside funding. The researchers disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
based on data from approximately 7,000 patients.
Headache is the fourth-most common chief complaint in the ED, accounting for approximately 3% of all ED visits, said Philip Wang, a medical student at the Cleveland Clinic, in a presentation at the annual meeting of the American College of Emergency Physicians.
A variety of pharmacotherapies are used to manage headache, which leads to a range of resource use, he said.
To understand the association between route of drug administration and length of ED stay, Mr. Wang and colleagues reviewed data from 7,233 visits by 6,715 patients at any of the 21 Cleveland Clinic Health System EDs in 2018 with headache as the primary discharge diagnosis. Patients admitted to the hospital were excluded; those treated with opioids, antiemetics, and/or NSAIDs were included. The average age of the study population was 31 years, 57% were White, and approximately half were Medicaid or Medicare patients.
Approximately 68% of patients received antiemetics, 66.8% received NSAIDs, and 9.8% received opioids. Approximately 42% of patients received parenteral-only treatment and 42% received oral-only treatment; 15% received mixed treatment. The average length of ED stay was 202 minutes.
In a multivariate analysis adjusted for sex, age, income, race, insurance status, ED type, and arrival time, treatment with oral drugs only was associated with an 11% reduction of length of stay, compared with treatment with parenteral medication only (P < .001). However, the length of stay for patients treated with mixed route of administration was 10% longer, compared with parenteral only (P < .001).
In terms of drug class (a secondary outcome), patients treated with opioids had a 10% increase in length of stay (P < .01) and those treated with antiemetics had a 14% increase in length of stay; however, patients treated with NSAIDs had a 7% decrease in length of stay.
The study findings were limited in part by the challenge of isolating patients presenting with a primary headache diagnosis, Mr. Wang noted in the presentation.
The challenge of controlling for all the potential factors impacting length of stay, which is “provider, resource, and situation dependent,” is an additional limitation, he said.
However, the results show that route of administration has a significant impact on length of ED stay in patients presenting with headache, he concluded.
The study received no outside funding. The researchers disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Influenza tied to long-term increased risk for Parkinson’s disease
Influenza infection is linked to a subsequent diagnosis of Parkinson’s disease (PD) more than 10 years later, resurfacing a long-held debate about whether infection increases the risk for movement disorders over the long term.
In a large case-control study, investigators found and by more than 70% for PD occurring more than 10 years after the flu.
“This study is not definitive by any means, but it certainly suggests there are potential long-term consequences from influenza,” study investigator Noelle M. Cocoros, DSc, research scientist at Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, said in an interview.
The study was published online Oct. 25 in JAMA Neurology.
Ongoing debate
The debate about whether influenza is associated with PD has been going on as far back as the 1918 influenza pandemic, when experts documented parkinsonism in affected individuals.
Using data from the Danish patient registry, researchers identified 10,271 subjects diagnosed with PD during a 17-year period (2000-2016). Of these, 38.7% were female, and the mean age was 71.4 years.
They matched these subjects for age and sex to 51,355 controls without PD. Compared with controls, slightly fewer individuals with PD had chronic obstructive pulmonary disease (COPD) or emphysema, but there was a similar distribution of cardiovascular disease and various other conditions.
Researchers collected data on influenza diagnoses from inpatient and outpatient hospital clinics from 1977 to 2016. They plotted these by month and year on a graph, calculated the median number of diagnoses per month, and identified peaks as those with more than threefold the median.
They categorized cases in groups related to the time between the infection and PD: More than 10 years, 10-15 years, and more than 15 years.
The time lapse accounts for a rather long “run-up” to PD, said Dr. Cocoros. There’s a sometimes decades-long preclinical phase before patients develop typical motor signs and a prodromal phase where they may present with nonmotor symptoms such as sleep disorders and constipation.
“We expected there would be at least 10 years between any infection and PD if there was an association present,” said Dr. Cocoros.
Investigators found an association between influenza exposure and PD diagnosis “that held up over time,” she said.
For more than 10 years before PD, the likelihood of a diagnosis for the infected compared with the unexposed was increased 73% (odds ratio [OR] 1.73; 95% confidence interval, 1.11-2.71; P = .02) after adjustment for cardiovascular disease, diabetes, chronic obstructive pulmonary disease, emphysema, lung cancer, Crohn’s disease, and ulcerative colitis.
The odds increased with more time from infection. For more than 15 years, the adjusted OR was 1.91 (95% CI, 1.14 - 3.19; P =.01).
However, for the 10- to 15-year time frame, the point estimate was reduced and the CI nonsignificant (OR, 1.33; 95% CI, 0.54-3.27; P = .53). This “is a little hard to interpret,” but could be a result of the small numbers, exposure misclassification, or because “the longer time interval is what’s meaningful,” said Dr. Cocoros.
Potential COVID-19–related PD surge?
In a sensitivity analysis, researchers looked at peak infection activity. “We wanted to increase the likelihood of these diagnoses representing actual infection,” Dr. Cocoros noted.
Here, the OR was still elevated at more than 10 years, but the CI was quite wide and included 1 (OR, 1.52; 95% CI, 0.80-2.89; P = .21). “So the association holds up, but the estimates are quite unstable,” said Dr. Cocoros.
Researchers examined associations with numerous other infection types, but did not see the same trend over time. Some infections – for example, gastrointestinal infections and septicemia – were associated with PD within 5 years, but most associations appeared to be null after more than 10 years.
“There seemed to be associations earlier between the infection and PD, which we interpret to suggest there’s actually not a meaningful association,” said Dr. Cocoros.
An exception might be urinary tract infections (UTIs), where after 10 years, the adjusted OR was 1.19 (95% CI, 1.01-1.40). Research suggests patients with PD often have UTIs and neurogenic bladder.
“It’s possible that UTIs could be an early symptom of PD rather than a causative factor,” said Dr. Cocoros.
It’s unclear how influenza might lead to PD but it could be that the virus gets into the central nervous system, resulting in neuroinflammation. Cytokines generated in response to the influenza infection might damage the brain.
“The infection could be a ‘primer’ or an initial ‘hit’ to the system, maybe setting people up for PD,” said Dr. Cocoros.
As for the current COVID-19 pandemic, some experts are concerned about a potential surge in PD cases in decades to come, and are calling for prospective monitoring of patients with this infection, said Dr. Cocoros.
However, she noted that infections don’t account for all PD cases and that genetic and environmental factors also influence risk.
Many individuals who contract influenza don’t seek medical care or get tested, so it’s possible the study counted those who had the infection as unexposed. Another potential study limitation was that small numbers for some infections, for example, Helicobacter pylori and hepatitis C, limited the ability to interpret results.
‘Exciting and important’ findings
Commenting on the research for this news organization, Aparna Wagle Shukla, MD, professor, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, said the results amid the current pandemic are “exciting and important” and “have reinvigorated interest” in the role of infection in PD.
However, the study had some limitations, an important one being lack of accounting for confounding factors, including environmental factors, she said. Exposure to pesticides, living in a rural area, drinking well water, and having had a head injury may increase PD risk, whereas high intake of caffeine, nicotine, alcohol, and nonsteroidal anti-inflammatory drugs might lower the risk.
The researchers did not take into account exposure to multiple microbes or “infection burden,” said Dr. Wagle Shukla, who was not involved in the current study. In addition, as the data are from a single country with exposure to specific influenza strains, application of the findings elsewhere may be limited.
Dr. Wagle Shukla noted that a case-control design “isn’t ideal” from an epidemiological perspective. “Future studies should involve large cohorts followed longitudinally.”
The study was supported by grants from the Lundbeck Foundation and the Augustinus Foundation. Dr. Cocoros has disclosed no relevant financial relationships. Several coauthors have disclosed relationships with industry. The full list can be found with the original article.
A version of this article first appeared on Medscape.com.
Influenza infection is linked to a subsequent diagnosis of Parkinson’s disease (PD) more than 10 years later, resurfacing a long-held debate about whether infection increases the risk for movement disorders over the long term.
In a large case-control study, investigators found and by more than 70% for PD occurring more than 10 years after the flu.
“This study is not definitive by any means, but it certainly suggests there are potential long-term consequences from influenza,” study investigator Noelle M. Cocoros, DSc, research scientist at Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, said in an interview.
The study was published online Oct. 25 in JAMA Neurology.
Ongoing debate
The debate about whether influenza is associated with PD has been going on as far back as the 1918 influenza pandemic, when experts documented parkinsonism in affected individuals.
Using data from the Danish patient registry, researchers identified 10,271 subjects diagnosed with PD during a 17-year period (2000-2016). Of these, 38.7% were female, and the mean age was 71.4 years.
They matched these subjects for age and sex to 51,355 controls without PD. Compared with controls, slightly fewer individuals with PD had chronic obstructive pulmonary disease (COPD) or emphysema, but there was a similar distribution of cardiovascular disease and various other conditions.
Researchers collected data on influenza diagnoses from inpatient and outpatient hospital clinics from 1977 to 2016. They plotted these by month and year on a graph, calculated the median number of diagnoses per month, and identified peaks as those with more than threefold the median.
They categorized cases in groups related to the time between the infection and PD: More than 10 years, 10-15 years, and more than 15 years.
The time lapse accounts for a rather long “run-up” to PD, said Dr. Cocoros. There’s a sometimes decades-long preclinical phase before patients develop typical motor signs and a prodromal phase where they may present with nonmotor symptoms such as sleep disorders and constipation.
“We expected there would be at least 10 years between any infection and PD if there was an association present,” said Dr. Cocoros.
Investigators found an association between influenza exposure and PD diagnosis “that held up over time,” she said.
For more than 10 years before PD, the likelihood of a diagnosis for the infected compared with the unexposed was increased 73% (odds ratio [OR] 1.73; 95% confidence interval, 1.11-2.71; P = .02) after adjustment for cardiovascular disease, diabetes, chronic obstructive pulmonary disease, emphysema, lung cancer, Crohn’s disease, and ulcerative colitis.
The odds increased with more time from infection. For more than 15 years, the adjusted OR was 1.91 (95% CI, 1.14 - 3.19; P =.01).
However, for the 10- to 15-year time frame, the point estimate was reduced and the CI nonsignificant (OR, 1.33; 95% CI, 0.54-3.27; P = .53). This “is a little hard to interpret,” but could be a result of the small numbers, exposure misclassification, or because “the longer time interval is what’s meaningful,” said Dr. Cocoros.
Potential COVID-19–related PD surge?
In a sensitivity analysis, researchers looked at peak infection activity. “We wanted to increase the likelihood of these diagnoses representing actual infection,” Dr. Cocoros noted.
Here, the OR was still elevated at more than 10 years, but the CI was quite wide and included 1 (OR, 1.52; 95% CI, 0.80-2.89; P = .21). “So the association holds up, but the estimates are quite unstable,” said Dr. Cocoros.
Researchers examined associations with numerous other infection types, but did not see the same trend over time. Some infections – for example, gastrointestinal infections and septicemia – were associated with PD within 5 years, but most associations appeared to be null after more than 10 years.
“There seemed to be associations earlier between the infection and PD, which we interpret to suggest there’s actually not a meaningful association,” said Dr. Cocoros.
An exception might be urinary tract infections (UTIs), where after 10 years, the adjusted OR was 1.19 (95% CI, 1.01-1.40). Research suggests patients with PD often have UTIs and neurogenic bladder.
“It’s possible that UTIs could be an early symptom of PD rather than a causative factor,” said Dr. Cocoros.
It’s unclear how influenza might lead to PD but it could be that the virus gets into the central nervous system, resulting in neuroinflammation. Cytokines generated in response to the influenza infection might damage the brain.
“The infection could be a ‘primer’ or an initial ‘hit’ to the system, maybe setting people up for PD,” said Dr. Cocoros.
As for the current COVID-19 pandemic, some experts are concerned about a potential surge in PD cases in decades to come, and are calling for prospective monitoring of patients with this infection, said Dr. Cocoros.
However, she noted that infections don’t account for all PD cases and that genetic and environmental factors also influence risk.
Many individuals who contract influenza don’t seek medical care or get tested, so it’s possible the study counted those who had the infection as unexposed. Another potential study limitation was that small numbers for some infections, for example, Helicobacter pylori and hepatitis C, limited the ability to interpret results.
‘Exciting and important’ findings
Commenting on the research for this news organization, Aparna Wagle Shukla, MD, professor, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, said the results amid the current pandemic are “exciting and important” and “have reinvigorated interest” in the role of infection in PD.
However, the study had some limitations, an important one being lack of accounting for confounding factors, including environmental factors, she said. Exposure to pesticides, living in a rural area, drinking well water, and having had a head injury may increase PD risk, whereas high intake of caffeine, nicotine, alcohol, and nonsteroidal anti-inflammatory drugs might lower the risk.
The researchers did not take into account exposure to multiple microbes or “infection burden,” said Dr. Wagle Shukla, who was not involved in the current study. In addition, as the data are from a single country with exposure to specific influenza strains, application of the findings elsewhere may be limited.
Dr. Wagle Shukla noted that a case-control design “isn’t ideal” from an epidemiological perspective. “Future studies should involve large cohorts followed longitudinally.”
The study was supported by grants from the Lundbeck Foundation and the Augustinus Foundation. Dr. Cocoros has disclosed no relevant financial relationships. Several coauthors have disclosed relationships with industry. The full list can be found with the original article.
A version of this article first appeared on Medscape.com.
Influenza infection is linked to a subsequent diagnosis of Parkinson’s disease (PD) more than 10 years later, resurfacing a long-held debate about whether infection increases the risk for movement disorders over the long term.
In a large case-control study, investigators found and by more than 70% for PD occurring more than 10 years after the flu.
“This study is not definitive by any means, but it certainly suggests there are potential long-term consequences from influenza,” study investigator Noelle M. Cocoros, DSc, research scientist at Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, said in an interview.
The study was published online Oct. 25 in JAMA Neurology.
Ongoing debate
The debate about whether influenza is associated with PD has been going on as far back as the 1918 influenza pandemic, when experts documented parkinsonism in affected individuals.
Using data from the Danish patient registry, researchers identified 10,271 subjects diagnosed with PD during a 17-year period (2000-2016). Of these, 38.7% were female, and the mean age was 71.4 years.
They matched these subjects for age and sex to 51,355 controls without PD. Compared with controls, slightly fewer individuals with PD had chronic obstructive pulmonary disease (COPD) or emphysema, but there was a similar distribution of cardiovascular disease and various other conditions.
Researchers collected data on influenza diagnoses from inpatient and outpatient hospital clinics from 1977 to 2016. They plotted these by month and year on a graph, calculated the median number of diagnoses per month, and identified peaks as those with more than threefold the median.
They categorized cases in groups related to the time between the infection and PD: More than 10 years, 10-15 years, and more than 15 years.
The time lapse accounts for a rather long “run-up” to PD, said Dr. Cocoros. There’s a sometimes decades-long preclinical phase before patients develop typical motor signs and a prodromal phase where they may present with nonmotor symptoms such as sleep disorders and constipation.
“We expected there would be at least 10 years between any infection and PD if there was an association present,” said Dr. Cocoros.
Investigators found an association between influenza exposure and PD diagnosis “that held up over time,” she said.
For more than 10 years before PD, the likelihood of a diagnosis for the infected compared with the unexposed was increased 73% (odds ratio [OR] 1.73; 95% confidence interval, 1.11-2.71; P = .02) after adjustment for cardiovascular disease, diabetes, chronic obstructive pulmonary disease, emphysema, lung cancer, Crohn’s disease, and ulcerative colitis.
The odds increased with more time from infection. For more than 15 years, the adjusted OR was 1.91 (95% CI, 1.14 - 3.19; P =.01).
However, for the 10- to 15-year time frame, the point estimate was reduced and the CI nonsignificant (OR, 1.33; 95% CI, 0.54-3.27; P = .53). This “is a little hard to interpret,” but could be a result of the small numbers, exposure misclassification, or because “the longer time interval is what’s meaningful,” said Dr. Cocoros.
Potential COVID-19–related PD surge?
In a sensitivity analysis, researchers looked at peak infection activity. “We wanted to increase the likelihood of these diagnoses representing actual infection,” Dr. Cocoros noted.
Here, the OR was still elevated at more than 10 years, but the CI was quite wide and included 1 (OR, 1.52; 95% CI, 0.80-2.89; P = .21). “So the association holds up, but the estimates are quite unstable,” said Dr. Cocoros.
Researchers examined associations with numerous other infection types, but did not see the same trend over time. Some infections – for example, gastrointestinal infections and septicemia – were associated with PD within 5 years, but most associations appeared to be null after more than 10 years.
“There seemed to be associations earlier between the infection and PD, which we interpret to suggest there’s actually not a meaningful association,” said Dr. Cocoros.
An exception might be urinary tract infections (UTIs), where after 10 years, the adjusted OR was 1.19 (95% CI, 1.01-1.40). Research suggests patients with PD often have UTIs and neurogenic bladder.
“It’s possible that UTIs could be an early symptom of PD rather than a causative factor,” said Dr. Cocoros.
It’s unclear how influenza might lead to PD but it could be that the virus gets into the central nervous system, resulting in neuroinflammation. Cytokines generated in response to the influenza infection might damage the brain.
“The infection could be a ‘primer’ or an initial ‘hit’ to the system, maybe setting people up for PD,” said Dr. Cocoros.
As for the current COVID-19 pandemic, some experts are concerned about a potential surge in PD cases in decades to come, and are calling for prospective monitoring of patients with this infection, said Dr. Cocoros.
However, she noted that infections don’t account for all PD cases and that genetic and environmental factors also influence risk.
Many individuals who contract influenza don’t seek medical care or get tested, so it’s possible the study counted those who had the infection as unexposed. Another potential study limitation was that small numbers for some infections, for example, Helicobacter pylori and hepatitis C, limited the ability to interpret results.
‘Exciting and important’ findings
Commenting on the research for this news organization, Aparna Wagle Shukla, MD, professor, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, said the results amid the current pandemic are “exciting and important” and “have reinvigorated interest” in the role of infection in PD.
However, the study had some limitations, an important one being lack of accounting for confounding factors, including environmental factors, she said. Exposure to pesticides, living in a rural area, drinking well water, and having had a head injury may increase PD risk, whereas high intake of caffeine, nicotine, alcohol, and nonsteroidal anti-inflammatory drugs might lower the risk.
The researchers did not take into account exposure to multiple microbes or “infection burden,” said Dr. Wagle Shukla, who was not involved in the current study. In addition, as the data are from a single country with exposure to specific influenza strains, application of the findings elsewhere may be limited.
Dr. Wagle Shukla noted that a case-control design “isn’t ideal” from an epidemiological perspective. “Future studies should involve large cohorts followed longitudinally.”
The study was supported by grants from the Lundbeck Foundation and the Augustinus Foundation. Dr. Cocoros has disclosed no relevant financial relationships. Several coauthors have disclosed relationships with industry. The full list can be found with the original article.
A version of this article first appeared on Medscape.com.