Neurology

Daily napping may help preserve brain health, new research suggests.

Investigators at University College London, and the University of the Republic of Uruguay, Montevideo, found individuals genetically predisposed to regular napping had larger total brain volume, a surrogate of better cognitive health.

“Our results suggest that napping may improve brain health,” first author Valentina Paz, MSc, a PhD candidate at the University of the Republic of Uruguay said in an interview. “Specifically, our work revealed a 15.8 cubic cm increase in total brain volume with more frequent daytime napping,” she said.

The findings were published online in Sleep Health.
 

Higher brain volume

Previous studies examining the potential link between napping and cognition in older adults have yielded conflicting results.

To clarify this association, Ms. Paz and colleagues used Mendelian randomization to study DNA samples, cognitive outcomes, and functional magnetic resonance imaging data in participants from the ongoing UK Biobank Study.  

Starting with data from 378,932 study participants (mean age 57), investigators compared measures of brain health and cognition of those who are more genetically programmed to nap with people who did not have these genetic variations.

More specifically, the investigators examined 97 sections of genetic code previously linked to the likelihood of regular napping and correlated these results with fMRI and cognitive outcomes between those genetically predisposed to take regular naps and those who weren’t.

Study outcomes included total brain volume, hippocampal volume, reaction time, and visual memory.

The final study sample included 35,080 with neuroimaging, cognitive assessment, and genotype data.

The researchers estimated that the average difference in brain volume between individuals genetically programmed to be habitual nappers and those who were not was equivalent to 15.8 cubic cm, or 2.6-6.5 years of aging.

However, there was no difference in the other three outcomes – hippocampal volume, reaction time, and visual processing – between the two study groups.

Since investigators did not have information on the length of time participants napped, Ms. Paz suggested that “taking a short nap in the early afternoon may help cognition in those needing it.”

However, she added, the study’s findings need to be replicated before any firm conclusions can be made.

“More work is needed to examine the associations between napping and cognition, and the replication of these findings using other datasets and methods,” she said.

The investigators note that the study’s findings augment the knowledge of the “impact of habitual daytime napping on brain health, which is essential to understanding cognitive impairment in the aging population. The lack of evidence for an association between napping and hippocampal volume and cognitive outcomes (for example, alertness) may be affected by habitual daytime napping and should be studied in the future.”
 

Strengths, limitations

Tara Spires-Jones, PhD, president of the British Neuroscience Association and group leader at the UK Dementia Research Institute, said, “the study shows a small but significant increase in brain volume in people who have a genetic signature associated with taking daytime naps.”

Dr. Spires-Jones, who was not involved in the research, noted that while the study is well-conducted, it has limitations. Because Mendelian randomization uses a genetic signature, she noted, outcomes depend on the accuracy of the signature. 

“The napping habits of UK Biobank participants were self-reported, which might not be entirely accurate, and the ‘napping’ signature overlapped substantially with the signature for cognitive outcomes in the study, which makes the causal link weaker,” she said.

“Even with those limitations, this study is interesting because it adds to the data indicating that sleep is important for brain health,” said Dr. Spires-Jones.

The study was supported by Diabetes UK, the British Heart Foundation, and the Diabetes Research and Wellness Foundation. In Uruguay, it was supported by Programa de Desarrollo de las Ciencias Básicas, Agencia Nacional de Investigación e Innovación, Comisión Sectorial de Investigación Científica, and Comisión Académica de Posgrado. In the United States it was supported by the National Heart, Lung, and Blood Institute. There were no disclosures reported.

A version of this article first appeared on Medscape.com.

Daily napping may help preserve brain health, new research suggests.

Investigators at University College London, and the University of the Republic of Uruguay, Montevideo, found individuals genetically predisposed to regular napping had larger total brain volume, a surrogate of better cognitive health.

“Our results suggest that napping may improve brain health,” first author Valentina Paz, MSc, a PhD candidate at the University of the Republic of Uruguay said in an interview. “Specifically, our work revealed a 15.8 cubic cm increase in total brain volume with more frequent daytime napping,” she said.

The findings were published online in Sleep Health.
 

Higher brain volume

Previous studies examining the potential link between napping and cognition in older adults have yielded conflicting results.

To clarify this association, Ms. Paz and colleagues used Mendelian randomization to study DNA samples, cognitive outcomes, and functional magnetic resonance imaging data in participants from the ongoing UK Biobank Study.  

Starting with data from 378,932 study participants (mean age 57), investigators compared measures of brain health and cognition of those who are more genetically programmed to nap with people who did not have these genetic variations.

More specifically, the investigators examined 97 sections of genetic code previously linked to the likelihood of regular napping and correlated these results with fMRI and cognitive outcomes between those genetically predisposed to take regular naps and those who weren’t.

Study outcomes included total brain volume, hippocampal volume, reaction time, and visual memory.

The final study sample included 35,080 with neuroimaging, cognitive assessment, and genotype data.

The researchers estimated that the average difference in brain volume between individuals genetically programmed to be habitual nappers and those who were not was equivalent to 15.8 cubic cm, or 2.6-6.5 years of aging.

However, there was no difference in the other three outcomes – hippocampal volume, reaction time, and visual processing – between the two study groups.

Since investigators did not have information on the length of time participants napped, Ms. Paz suggested that “taking a short nap in the early afternoon may help cognition in those needing it.”

However, she added, the study’s findings need to be replicated before any firm conclusions can be made.

“More work is needed to examine the associations between napping and cognition, and the replication of these findings using other datasets and methods,” she said.

The investigators note that the study’s findings augment the knowledge of the “impact of habitual daytime napping on brain health, which is essential to understanding cognitive impairment in the aging population. The lack of evidence for an association between napping and hippocampal volume and cognitive outcomes (for example, alertness) may be affected by habitual daytime napping and should be studied in the future.”
 

Strengths, limitations

Tara Spires-Jones, PhD, president of the British Neuroscience Association and group leader at the UK Dementia Research Institute, said, “the study shows a small but significant increase in brain volume in people who have a genetic signature associated with taking daytime naps.”

Dr. Spires-Jones, who was not involved in the research, noted that while the study is well-conducted, it has limitations. Because Mendelian randomization uses a genetic signature, she noted, outcomes depend on the accuracy of the signature. 

“The napping habits of UK Biobank participants were self-reported, which might not be entirely accurate, and the ‘napping’ signature overlapped substantially with the signature for cognitive outcomes in the study, which makes the causal link weaker,” she said.

“Even with those limitations, this study is interesting because it adds to the data indicating that sleep is important for brain health,” said Dr. Spires-Jones.

The study was supported by Diabetes UK, the British Heart Foundation, and the Diabetes Research and Wellness Foundation. In Uruguay, it was supported by Programa de Desarrollo de las Ciencias Básicas, Agencia Nacional de Investigación e Innovación, Comisión Sectorial de Investigación Científica, and Comisión Académica de Posgrado. In the United States it was supported by the National Heart, Lung, and Blood Institute. There were no disclosures reported.

A version of this article first appeared on Medscape.com.

Daily napping may help preserve brain health, new research suggests.

Investigators at University College London, and the University of the Republic of Uruguay, Montevideo, found individuals genetically predisposed to regular napping had larger total brain volume, a surrogate of better cognitive health.

“Our results suggest that napping may improve brain health,” first author Valentina Paz, MSc, a PhD candidate at the University of the Republic of Uruguay said in an interview. “Specifically, our work revealed a 15.8 cubic cm increase in total brain volume with more frequent daytime napping,” she said.

The findings were published online in Sleep Health.
 

Higher brain volume

Previous studies examining the potential link between napping and cognition in older adults have yielded conflicting results.

To clarify this association, Ms. Paz and colleagues used Mendelian randomization to study DNA samples, cognitive outcomes, and functional magnetic resonance imaging data in participants from the ongoing UK Biobank Study.  

Starting with data from 378,932 study participants (mean age 57), investigators compared measures of brain health and cognition of those who are more genetically programmed to nap with people who did not have these genetic variations.

More specifically, the investigators examined 97 sections of genetic code previously linked to the likelihood of regular napping and correlated these results with fMRI and cognitive outcomes between those genetically predisposed to take regular naps and those who weren’t.

Study outcomes included total brain volume, hippocampal volume, reaction time, and visual memory.

The final study sample included 35,080 with neuroimaging, cognitive assessment, and genotype data.

The researchers estimated that the average difference in brain volume between individuals genetically programmed to be habitual nappers and those who were not was equivalent to 15.8 cubic cm, or 2.6-6.5 years of aging.

However, there was no difference in the other three outcomes – hippocampal volume, reaction time, and visual processing – between the two study groups.

Since investigators did not have information on the length of time participants napped, Ms. Paz suggested that “taking a short nap in the early afternoon may help cognition in those needing it.”

However, she added, the study’s findings need to be replicated before any firm conclusions can be made.

“More work is needed to examine the associations between napping and cognition, and the replication of these findings using other datasets and methods,” she said.

The investigators note that the study’s findings augment the knowledge of the “impact of habitual daytime napping on brain health, which is essential to understanding cognitive impairment in the aging population. The lack of evidence for an association between napping and hippocampal volume and cognitive outcomes (for example, alertness) may be affected by habitual daytime napping and should be studied in the future.”
 

Strengths, limitations

Tara Spires-Jones, PhD, president of the British Neuroscience Association and group leader at the UK Dementia Research Institute, said, “the study shows a small but significant increase in brain volume in people who have a genetic signature associated with taking daytime naps.”

Dr. Spires-Jones, who was not involved in the research, noted that while the study is well-conducted, it has limitations. Because Mendelian randomization uses a genetic signature, she noted, outcomes depend on the accuracy of the signature. 

“The napping habits of UK Biobank participants were self-reported, which might not be entirely accurate, and the ‘napping’ signature overlapped substantially with the signature for cognitive outcomes in the study, which makes the causal link weaker,” she said.

“Even with those limitations, this study is interesting because it adds to the data indicating that sleep is important for brain health,” said Dr. Spires-Jones.

The study was supported by Diabetes UK, the British Heart Foundation, and the Diabetes Research and Wellness Foundation. In Uruguay, it was supported by Programa de Desarrollo de las Ciencias Básicas, Agencia Nacional de Investigación e Innovación, Comisión Sectorial de Investigación Científica, and Comisión Académica de Posgrado. In the United States it was supported by the National Heart, Lung, and Blood Institute. There were no disclosures reported.

A version of this article first appeared on Medscape.com.

TOPLINE:

A new study provides reassurance about the long-term safety of proton pump inhibitors (PPIs) and histamine-2 receptor antagonist (H2RA) use in older adults, finding no increased risk for dementia or cognitive changes.

METHODOLOGY:

• Post hoc observational study within the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial.
• 18,934 adults aged 65+ from the United States and Australia without dementia at baseline.
• 4,667 (25%) PPI users and 368 (2%) H2RA users at baseline.
• PPI and H2RA use, dementia incidence, and cognitive changes were tracked.

TAKEAWAY:

• In multivariable analysis, baseline PPI use was not associated with incident dementia (hazard ratio, 0.88) or cognitive impairment (HR, 1.00).
• PPI use was not linked to changes in overall cognitive test scores over time (beta –0.002).
• No associations were found between H2RA use and cognitive endpoints.

IN PRACTICE:

“Long-term use of PPIs in older adults is unlikely to have negative effects on cognition,” the study team concludes.

STUDY DETAILS:

The study was led by Raaj Mehta, MD, PhD, with Massachusetts General Hospital and Harvard Medical School in Boston. The study was published online in Gastroenterology. Funding was provided by grants from the National Institute on Aging, the National Cancer Institute, and other institutions.

LIMITATIONS:

Potential for residual confounding and underestimation of PPI and H2RA use, lack of data on medication dose and duration, and the absence of ApoE4 allele status.

DISCLOSURES:

Dr. Mehta has disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

A new study provides reassurance about the long-term safety of proton pump inhibitors (PPIs) and histamine-2 receptor antagonist (H2RA) use in older adults, finding no increased risk for dementia or cognitive changes.

METHODOLOGY:

• Post hoc observational study within the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial.
• 18,934 adults aged 65+ from the United States and Australia without dementia at baseline.
• 4,667 (25%) PPI users and 368 (2%) H2RA users at baseline.
• PPI and H2RA use, dementia incidence, and cognitive changes were tracked.

TAKEAWAY:

• In multivariable analysis, baseline PPI use was not associated with incident dementia (hazard ratio, 0.88) or cognitive impairment (HR, 1.00).
• PPI use was not linked to changes in overall cognitive test scores over time (beta –0.002).
• No associations were found between H2RA use and cognitive endpoints.

IN PRACTICE:

“Long-term use of PPIs in older adults is unlikely to have negative effects on cognition,” the study team concludes.

STUDY DETAILS:

The study was led by Raaj Mehta, MD, PhD, with Massachusetts General Hospital and Harvard Medical School in Boston. The study was published online in Gastroenterology. Funding was provided by grants from the National Institute on Aging, the National Cancer Institute, and other institutions.

LIMITATIONS:

Potential for residual confounding and underestimation of PPI and H2RA use, lack of data on medication dose and duration, and the absence of ApoE4 allele status.

DISCLOSURES:

Dr. Mehta has disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

A new study provides reassurance about the long-term safety of proton pump inhibitors (PPIs) and histamine-2 receptor antagonist (H2RA) use in older adults, finding no increased risk for dementia or cognitive changes.

METHODOLOGY:

• Post hoc observational study within the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial.
• 18,934 adults aged 65+ from the United States and Australia without dementia at baseline.
• 4,667 (25%) PPI users and 368 (2%) H2RA users at baseline.
• PPI and H2RA use, dementia incidence, and cognitive changes were tracked.

TAKEAWAY:

• In multivariable analysis, baseline PPI use was not associated with incident dementia (hazard ratio, 0.88) or cognitive impairment (HR, 1.00).
• PPI use was not linked to changes in overall cognitive test scores over time (beta –0.002).
• No associations were found between H2RA use and cognitive endpoints.

IN PRACTICE:

“Long-term use of PPIs in older adults is unlikely to have negative effects on cognition,” the study team concludes.

STUDY DETAILS:

The study was led by Raaj Mehta, MD, PhD, with Massachusetts General Hospital and Harvard Medical School in Boston. The study was published online in Gastroenterology. Funding was provided by grants from the National Institute on Aging, the National Cancer Institute, and other institutions.

LIMITATIONS:

Potential for residual confounding and underestimation of PPI and H2RA use, lack of data on medication dose and duration, and the absence of ApoE4 allele status.

DISCLOSURES:

Dr. Mehta has disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

The composition of gut bacteria in people with preclinical Alzheimer’s disease (AD) differs from that of healthy people, a new study shows.

The findings open up the possibility of analyzing the gut microbiome to identify individuals at a higher risk for dementia and perhaps designing microbiome-altering preventive treatments to help stave off cognitive decline, researchers noted.

Study investigator Gautam Dantas, PhD, cautioned that it’s not known whether the gut is influencing the brain, or the brain is influencing the gut, “but this association is valuable to know in either case.

“It could be that the changes in the gut microbiome are just a readout of pathological changes in the brain. The other alternative is that the gut microbiome is contributing to AD, in which case, altering the gut microbiome with probiotics or fecal transfers might help change the course of the disease,” Dr. Dantas, Washington University, St. Louis, said in a news release.

The study was published online in Science Translational Medicine.
 

Stool test?

Multiple lines of evidence suggest a role for gut microbes in the evolution of AD pathogenesis. However, less is known about gut microbiome changes in the preclinical (presymptomatic) phase of AD.

To investigate, Dr. Dantas and colleagues studied 164 cognitively normal adults, 49 of whom had biomarker evidence of preclinical AD.

After the researchers accounted for clinical covariates and diet, those with preclinical AD had distinct gut microbial taxonomic profiles compared with their healthy controls.

The observed microbiome features correlated with amyloid and tau but not neurodegeneration biomarkers, “suggesting that the gut microbial community changes early in the disease process,” the researchers suggested.

They identified specific taxa that were associated with preclinical AD and including these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status.

The findings suggest “markers in the stool might complement early screening measures for preclinical AD,” the researchers noted.

“The nice thing about using the gut microbiome as a screening tool is its simplicity and ease,” Beau Ances, MD, PhD, professor of neurology, at Washington University, St. Louis, said in the release.

“One day, individuals may be able to provide a stool sample and find out if they are at increased risk for developing AD. It would be much easier and less invasive and more accessible for a large proportion of the population, especially underrepresented groups, compared to brain scans or spinal taps,” Dr. Ances added.

The researchers have launched a 5-year follow-up study designed to help determine whether the differences in the gut microbiome are a cause or a result of the brain changes seen in early AD.
 

Caveats, cautionary notes

In a comment, Claire Sexton, DPhil, Alzheimer’s Association senior director of scientific programs and outreach, cautioned that the study design means that it’s “not possible to prove one thing causes another. What it can show is that two or more aspects are in some way related, thus setting the stage for further research.”

Dr. Sexton noted that though the authors accounted for a number of variables in their models, including age, sex, race, education, body mass index, hypertension, and diabetes, and observed no differences in intake of any major nutrient group, “it’s still not possible to rule out that additional factors beyond the variations in gut microbiome contributed to the changes in brain markers of Alzheimer’s.”

Dr. Sexton also noted that the study population is not representative of all people living with AD, with the vast majority of those with preclinical AD in the study being White.

“If these findings are replicated and confirmed in study groups that are representative of our communities, it is possible that gut microbiome signatures could be a further addition to the suite of diagnostic tools employed in certain settings,” Dr. Sexton said.

This research was supported by the Infection Disease Society of America Foundation, the National Institute on Aging, the Brennan Fund and the Paula and Rodger Riney Foundation. Dr. Dantas, Dr. Ances and Dr. Sexton have no relevant disclosures.

A version of this article first appeared on Medscape.com.

The composition of gut bacteria in people with preclinical Alzheimer’s disease (AD) differs from that of healthy people, a new study shows.

The findings open up the possibility of analyzing the gut microbiome to identify individuals at a higher risk for dementia and perhaps designing microbiome-altering preventive treatments to help stave off cognitive decline, researchers noted.

Study investigator Gautam Dantas, PhD, cautioned that it’s not known whether the gut is influencing the brain, or the brain is influencing the gut, “but this association is valuable to know in either case.

“It could be that the changes in the gut microbiome are just a readout of pathological changes in the brain. The other alternative is that the gut microbiome is contributing to AD, in which case, altering the gut microbiome with probiotics or fecal transfers might help change the course of the disease,” Dr. Dantas, Washington University, St. Louis, said in a news release.

The study was published online in Science Translational Medicine.
 

Stool test?

Multiple lines of evidence suggest a role for gut microbes in the evolution of AD pathogenesis. However, less is known about gut microbiome changes in the preclinical (presymptomatic) phase of AD.

To investigate, Dr. Dantas and colleagues studied 164 cognitively normal adults, 49 of whom had biomarker evidence of preclinical AD.

After the researchers accounted for clinical covariates and diet, those with preclinical AD had distinct gut microbial taxonomic profiles compared with their healthy controls.

The observed microbiome features correlated with amyloid and tau but not neurodegeneration biomarkers, “suggesting that the gut microbial community changes early in the disease process,” the researchers suggested.

They identified specific taxa that were associated with preclinical AD and including these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status.

The findings suggest “markers in the stool might complement early screening measures for preclinical AD,” the researchers noted.

“The nice thing about using the gut microbiome as a screening tool is its simplicity and ease,” Beau Ances, MD, PhD, professor of neurology, at Washington University, St. Louis, said in the release.

“One day, individuals may be able to provide a stool sample and find out if they are at increased risk for developing AD. It would be much easier and less invasive and more accessible for a large proportion of the population, especially underrepresented groups, compared to brain scans or spinal taps,” Dr. Ances added.

The researchers have launched a 5-year follow-up study designed to help determine whether the differences in the gut microbiome are a cause or a result of the brain changes seen in early AD.
 

Caveats, cautionary notes

In a comment, Claire Sexton, DPhil, Alzheimer’s Association senior director of scientific programs and outreach, cautioned that the study design means that it’s “not possible to prove one thing causes another. What it can show is that two or more aspects are in some way related, thus setting the stage for further research.”

Dr. Sexton noted that though the authors accounted for a number of variables in their models, including age, sex, race, education, body mass index, hypertension, and diabetes, and observed no differences in intake of any major nutrient group, “it’s still not possible to rule out that additional factors beyond the variations in gut microbiome contributed to the changes in brain markers of Alzheimer’s.”

Dr. Sexton also noted that the study population is not representative of all people living with AD, with the vast majority of those with preclinical AD in the study being White.

“If these findings are replicated and confirmed in study groups that are representative of our communities, it is possible that gut microbiome signatures could be a further addition to the suite of diagnostic tools employed in certain settings,” Dr. Sexton said.

This research was supported by the Infection Disease Society of America Foundation, the National Institute on Aging, the Brennan Fund and the Paula and Rodger Riney Foundation. Dr. Dantas, Dr. Ances and Dr. Sexton have no relevant disclosures.

A version of this article first appeared on Medscape.com.

The composition of gut bacteria in people with preclinical Alzheimer’s disease (AD) differs from that of healthy people, a new study shows.

The findings open up the possibility of analyzing the gut microbiome to identify individuals at a higher risk for dementia and perhaps designing microbiome-altering preventive treatments to help stave off cognitive decline, researchers noted.

Study investigator Gautam Dantas, PhD, cautioned that it’s not known whether the gut is influencing the brain, or the brain is influencing the gut, “but this association is valuable to know in either case.

“It could be that the changes in the gut microbiome are just a readout of pathological changes in the brain. The other alternative is that the gut microbiome is contributing to AD, in which case, altering the gut microbiome with probiotics or fecal transfers might help change the course of the disease,” Dr. Dantas, Washington University, St. Louis, said in a news release.

The study was published online in Science Translational Medicine.
 

Stool test?

Multiple lines of evidence suggest a role for gut microbes in the evolution of AD pathogenesis. However, less is known about gut microbiome changes in the preclinical (presymptomatic) phase of AD.

To investigate, Dr. Dantas and colleagues studied 164 cognitively normal adults, 49 of whom had biomarker evidence of preclinical AD.

After the researchers accounted for clinical covariates and diet, those with preclinical AD had distinct gut microbial taxonomic profiles compared with their healthy controls.

The observed microbiome features correlated with amyloid and tau but not neurodegeneration biomarkers, “suggesting that the gut microbial community changes early in the disease process,” the researchers suggested.

They identified specific taxa that were associated with preclinical AD and including these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status.

The findings suggest “markers in the stool might complement early screening measures for preclinical AD,” the researchers noted.

“The nice thing about using the gut microbiome as a screening tool is its simplicity and ease,” Beau Ances, MD, PhD, professor of neurology, at Washington University, St. Louis, said in the release.

“One day, individuals may be able to provide a stool sample and find out if they are at increased risk for developing AD. It would be much easier and less invasive and more accessible for a large proportion of the population, especially underrepresented groups, compared to brain scans or spinal taps,” Dr. Ances added.

The researchers have launched a 5-year follow-up study designed to help determine whether the differences in the gut microbiome are a cause or a result of the brain changes seen in early AD.
 

Caveats, cautionary notes

In a comment, Claire Sexton, DPhil, Alzheimer’s Association senior director of scientific programs and outreach, cautioned that the study design means that it’s “not possible to prove one thing causes another. What it can show is that two or more aspects are in some way related, thus setting the stage for further research.”

Dr. Sexton noted that though the authors accounted for a number of variables in their models, including age, sex, race, education, body mass index, hypertension, and diabetes, and observed no differences in intake of any major nutrient group, “it’s still not possible to rule out that additional factors beyond the variations in gut microbiome contributed to the changes in brain markers of Alzheimer’s.”

Dr. Sexton also noted that the study population is not representative of all people living with AD, with the vast majority of those with preclinical AD in the study being White.

“If these findings are replicated and confirmed in study groups that are representative of our communities, it is possible that gut microbiome signatures could be a further addition to the suite of diagnostic tools employed in certain settings,” Dr. Sexton said.

This research was supported by the Infection Disease Society of America Foundation, the National Institute on Aging, the Brennan Fund and the Paula and Rodger Riney Foundation. Dr. Dantas, Dr. Ances and Dr. Sexton have no relevant disclosures.

A version of this article first appeared on Medscape.com.

Patients with persistent depressive or cognitive symptoms after mild to moderate COVID-19 (COVID-DC) may have gliosis and inflammation, data suggest.

In a case-control study of 40 patients who were treated at a tertiary care psychiatric hospital in Canada, the level of translocator protein total distribution volume (TSPO VT), a marker of gliosis, was 9.23 mL/cm³ among patients with COVID-DC and 7.72 mL/cm³ among control persons. Differences were particularly notable in the ventral striatum and dorsal putamen.

“Most theories assume there is inflammation in the brain [with] long COVID,” but that assumption had not been studied, author Jeffrey H. Meyer, MD, PhD, Canada Research Chair in Neurochemistry of Major Depressive Disorder at the University of Toronto, said in an interview. “Such information is pivotal to developing treatments.”

The study was published online in JAMA Psychiatry.
 

Quantifiable marker

The investigators sought to determine whether levels of TSPO VT, which are quantifiable with PET, are elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of patients with COVID-DC, compared with patients without this syndrome. These brain regions were chosen, according to the authors, “because injury in these regions, which can cause gliosis, also induces symptoms of COVID-DC.”

The study was conducted from April 2021 through June 30, 2022. The investigators compared levels of TSPO VT in the selected brain regions of 20 participants with COVID-DC (mean age, 32.7 years; 60% women) with that of 20 control persons (mean age, 33.3 years; 55% women). TSPO VT was measured with fluorine F18–labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide PET.

The difference in TSPO VT was most noticeable in the ventral striatum (mean difference, 1.97 mL/cm³) and dorsal putamen (mean difference, 1.70 mL/cm³). The study authors suggest that gliosis in these areas may explain some of the persistent symptoms reported in structured clinical interviews and assessed on neuropsychological and psychological testing.

For patients with COVID-DC, motor speed on the finger-tapping test was negatively associated with dorsal putamen TSPO VT (r, −0.53). The 10 participants with COVID-DC whose speed was lowest had higher mean dorsal putamen TSPO VT levels than those of control persons by 2.3 mL/cm³.

The investigators could not assess a possible association between the ventral striatum TSPO VT and anhedonia because all participants had these symptoms. No significant correlations were found between depression and TSPO VT in the prefrontal cortex or anterior cingulate cortex.

The authors acknowledged that the study was cross-sectional, and so the duration of persistently elevated TSPO VT is not yet known. In addition, elevation in TSPO VT is not completely specific to glial cells, and although correlations with finger-tapping test performance reflect associations between brain changes and symptoms, they do not prove cause and effect.

“Presently, clinicians can use treatments for symptoms in other illnesses that are [also] common with long COVID. We need better than this,” said Dr. Meyer. “Clients with long COVID should be able to state their symptoms, and the practitioner should have an evidence-based matching treatment to recommend.”

Research is ongoing. “We are acquiring more information regarding different types of inflammation in the brain, whether there is ongoing injury, and whether treatments that influence inflammation are helpful,” said Dr. Meyer.
 

Jigsaw puzzle

“While this is an important piece in the jigsaw puzzle of neuroinflammation in chronic neurological disease, it is important to keep in mind that we still lack understanding of the complex picture for several reasons,” Alexander Gerhard, MD, honorary senior lecturer in neuroscience at the University of Manchester, England, wrote in an accompanying editorial.

Among these reasons is that the PET technique used in the study is noisy and not restricted to glial cells, he wrote. TSPO expression is only one part of the brain’s neuroinflammatory response, but PET techniques “do not currently allow us to distinguish between different states of microglial activation.” In addition, “a much more detailed understanding of microglial activation at different time points” is needed before neuroinflammatory changes can be targeted therapeutically, Dr. Gerhard wrote.

In a comment, Vilma Gabbay, MD, professor of psychiatry and neuroscience and director of biomarkers and dimensional psychiatry in the Psychiatry Research Institute at Montefiore Einstein, Albert Einstein College of Medicine, New York, said that “this is an important initial step to better understand the neuropsychiatric consequences of COVID even in only a mild and moderate viral illness.” TSPO imaging through PET scanning has been used as an index for neuroinflammation and gliosis. Researchers have used it to study neurodegenerative diseases, but as the authors noted, the ligand is not specific for gliosis.

“Follow-up large cohort studies including other measures of neuroimaging modalities assessing circuitry and neurochemistry are needed,” she said. “Similarly, studying the blood-brain barrier will also allow us to better understand how the immune reaction in the blood transitions to the brain.”

This field of research is evolving, and clinical trials are ongoing, Dr. Gabbay added. Meanwhile, clinicians should monitor for, assess, and treat neuropsychiatric symptoms and “follow the literature for new research and management recommendations.”

The study was primarily funded by a Canadian Institutes of Health Research Project grant to the authors, with some funding from the Canadian Institute for Military and Veteran Health Research. Dr. Meyer received support from their Canada Research Chair awards and received grants and support from several pharmaceutical companies outside of the submitted work. Dr. Gerhard and Dr. Gabbay disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with persistent depressive or cognitive symptoms after mild to moderate COVID-19 (COVID-DC) may have gliosis and inflammation, data suggest.

In a case-control study of 40 patients who were treated at a tertiary care psychiatric hospital in Canada, the level of translocator protein total distribution volume (TSPO VT), a marker of gliosis, was 9.23 mL/cm³ among patients with COVID-DC and 7.72 mL/cm³ among control persons. Differences were particularly notable in the ventral striatum and dorsal putamen.

“Most theories assume there is inflammation in the brain [with] long COVID,” but that assumption had not been studied, author Jeffrey H. Meyer, MD, PhD, Canada Research Chair in Neurochemistry of Major Depressive Disorder at the University of Toronto, said in an interview. “Such information is pivotal to developing treatments.”

The study was published online in JAMA Psychiatry.
 

Quantifiable marker

The investigators sought to determine whether levels of TSPO VT, which are quantifiable with PET, are elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of patients with COVID-DC, compared with patients without this syndrome. These brain regions were chosen, according to the authors, “because injury in these regions, which can cause gliosis, also induces symptoms of COVID-DC.”

The study was conducted from April 2021 through June 30, 2022. The investigators compared levels of TSPO VT in the selected brain regions of 20 participants with COVID-DC (mean age, 32.7 years; 60% women) with that of 20 control persons (mean age, 33.3 years; 55% women). TSPO VT was measured with fluorine F18–labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide PET.

The difference in TSPO VT was most noticeable in the ventral striatum (mean difference, 1.97 mL/cm³) and dorsal putamen (mean difference, 1.70 mL/cm³). The study authors suggest that gliosis in these areas may explain some of the persistent symptoms reported in structured clinical interviews and assessed on neuropsychological and psychological testing.

For patients with COVID-DC, motor speed on the finger-tapping test was negatively associated with dorsal putamen TSPO VT (r, −0.53). The 10 participants with COVID-DC whose speed was lowest had higher mean dorsal putamen TSPO VT levels than those of control persons by 2.3 mL/cm³.

The investigators could not assess a possible association between the ventral striatum TSPO VT and anhedonia because all participants had these symptoms. No significant correlations were found between depression and TSPO VT in the prefrontal cortex or anterior cingulate cortex.

The authors acknowledged that the study was cross-sectional, and so the duration of persistently elevated TSPO VT is not yet known. In addition, elevation in TSPO VT is not completely specific to glial cells, and although correlations with finger-tapping test performance reflect associations between brain changes and symptoms, they do not prove cause and effect.

“Presently, clinicians can use treatments for symptoms in other illnesses that are [also] common with long COVID. We need better than this,” said Dr. Meyer. “Clients with long COVID should be able to state their symptoms, and the practitioner should have an evidence-based matching treatment to recommend.”

Research is ongoing. “We are acquiring more information regarding different types of inflammation in the brain, whether there is ongoing injury, and whether treatments that influence inflammation are helpful,” said Dr. Meyer.
 

Jigsaw puzzle

“While this is an important piece in the jigsaw puzzle of neuroinflammation in chronic neurological disease, it is important to keep in mind that we still lack understanding of the complex picture for several reasons,” Alexander Gerhard, MD, honorary senior lecturer in neuroscience at the University of Manchester, England, wrote in an accompanying editorial.

Among these reasons is that the PET technique used in the study is noisy and not restricted to glial cells, he wrote. TSPO expression is only one part of the brain’s neuroinflammatory response, but PET techniques “do not currently allow us to distinguish between different states of microglial activation.” In addition, “a much more detailed understanding of microglial activation at different time points” is needed before neuroinflammatory changes can be targeted therapeutically, Dr. Gerhard wrote.

In a comment, Vilma Gabbay, MD, professor of psychiatry and neuroscience and director of biomarkers and dimensional psychiatry in the Psychiatry Research Institute at Montefiore Einstein, Albert Einstein College of Medicine, New York, said that “this is an important initial step to better understand the neuropsychiatric consequences of COVID even in only a mild and moderate viral illness.” TSPO imaging through PET scanning has been used as an index for neuroinflammation and gliosis. Researchers have used it to study neurodegenerative diseases, but as the authors noted, the ligand is not specific for gliosis.

“Follow-up large cohort studies including other measures of neuroimaging modalities assessing circuitry and neurochemistry are needed,” she said. “Similarly, studying the blood-brain barrier will also allow us to better understand how the immune reaction in the blood transitions to the brain.”

This field of research is evolving, and clinical trials are ongoing, Dr. Gabbay added. Meanwhile, clinicians should monitor for, assess, and treat neuropsychiatric symptoms and “follow the literature for new research and management recommendations.”

The study was primarily funded by a Canadian Institutes of Health Research Project grant to the authors, with some funding from the Canadian Institute for Military and Veteran Health Research. Dr. Meyer received support from their Canada Research Chair awards and received grants and support from several pharmaceutical companies outside of the submitted work. Dr. Gerhard and Dr. Gabbay disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with persistent depressive or cognitive symptoms after mild to moderate COVID-19 (COVID-DC) may have gliosis and inflammation, data suggest.

In a case-control study of 40 patients who were treated at a tertiary care psychiatric hospital in Canada, the level of translocator protein total distribution volume (TSPO VT), a marker of gliosis, was 9.23 mL/cm³ among patients with COVID-DC and 7.72 mL/cm³ among control persons. Differences were particularly notable in the ventral striatum and dorsal putamen.

“Most theories assume there is inflammation in the brain [with] long COVID,” but that assumption had not been studied, author Jeffrey H. Meyer, MD, PhD, Canada Research Chair in Neurochemistry of Major Depressive Disorder at the University of Toronto, said in an interview. “Such information is pivotal to developing treatments.”

The study was published online in JAMA Psychiatry.
 

Quantifiable marker

The investigators sought to determine whether levels of TSPO VT, which are quantifiable with PET, are elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of patients with COVID-DC, compared with patients without this syndrome. These brain regions were chosen, according to the authors, “because injury in these regions, which can cause gliosis, also induces symptoms of COVID-DC.”

The study was conducted from April 2021 through June 30, 2022. The investigators compared levels of TSPO VT in the selected brain regions of 20 participants with COVID-DC (mean age, 32.7 years; 60% women) with that of 20 control persons (mean age, 33.3 years; 55% women). TSPO VT was measured with fluorine F18–labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide PET.

The difference in TSPO VT was most noticeable in the ventral striatum (mean difference, 1.97 mL/cm³) and dorsal putamen (mean difference, 1.70 mL/cm³). The study authors suggest that gliosis in these areas may explain some of the persistent symptoms reported in structured clinical interviews and assessed on neuropsychological and psychological testing.

For patients with COVID-DC, motor speed on the finger-tapping test was negatively associated with dorsal putamen TSPO VT (r, −0.53). The 10 participants with COVID-DC whose speed was lowest had higher mean dorsal putamen TSPO VT levels than those of control persons by 2.3 mL/cm³.

The investigators could not assess a possible association between the ventral striatum TSPO VT and anhedonia because all participants had these symptoms. No significant correlations were found between depression and TSPO VT in the prefrontal cortex or anterior cingulate cortex.

The authors acknowledged that the study was cross-sectional, and so the duration of persistently elevated TSPO VT is not yet known. In addition, elevation in TSPO VT is not completely specific to glial cells, and although correlations with finger-tapping test performance reflect associations between brain changes and symptoms, they do not prove cause and effect.

“Presently, clinicians can use treatments for symptoms in other illnesses that are [also] common with long COVID. We need better than this,” said Dr. Meyer. “Clients with long COVID should be able to state their symptoms, and the practitioner should have an evidence-based matching treatment to recommend.”

Research is ongoing. “We are acquiring more information regarding different types of inflammation in the brain, whether there is ongoing injury, and whether treatments that influence inflammation are helpful,” said Dr. Meyer.
 

Jigsaw puzzle

“While this is an important piece in the jigsaw puzzle of neuroinflammation in chronic neurological disease, it is important to keep in mind that we still lack understanding of the complex picture for several reasons,” Alexander Gerhard, MD, honorary senior lecturer in neuroscience at the University of Manchester, England, wrote in an accompanying editorial.

Among these reasons is that the PET technique used in the study is noisy and not restricted to glial cells, he wrote. TSPO expression is only one part of the brain’s neuroinflammatory response, but PET techniques “do not currently allow us to distinguish between different states of microglial activation.” In addition, “a much more detailed understanding of microglial activation at different time points” is needed before neuroinflammatory changes can be targeted therapeutically, Dr. Gerhard wrote.

In a comment, Vilma Gabbay, MD, professor of psychiatry and neuroscience and director of biomarkers and dimensional psychiatry in the Psychiatry Research Institute at Montefiore Einstein, Albert Einstein College of Medicine, New York, said that “this is an important initial step to better understand the neuropsychiatric consequences of COVID even in only a mild and moderate viral illness.” TSPO imaging through PET scanning has been used as an index for neuroinflammation and gliosis. Researchers have used it to study neurodegenerative diseases, but as the authors noted, the ligand is not specific for gliosis.

“Follow-up large cohort studies including other measures of neuroimaging modalities assessing circuitry and neurochemistry are needed,” she said. “Similarly, studying the blood-brain barrier will also allow us to better understand how the immune reaction in the blood transitions to the brain.”

This field of research is evolving, and clinical trials are ongoing, Dr. Gabbay added. Meanwhile, clinicians should monitor for, assess, and treat neuropsychiatric symptoms and “follow the literature for new research and management recommendations.”

The study was primarily funded by a Canadian Institutes of Health Research Project grant to the authors, with some funding from the Canadian Institute for Military and Veteran Health Research. Dr. Meyer received support from their Canada Research Chair awards and received grants and support from several pharmaceutical companies outside of the submitted work. Dr. Gerhard and Dr. Gabbay disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MADRID – Recent research has confirmed the impact of periodontitis on risk of neurologic diseases, especially the increased risks for stroke and Alzheimer’s disease.

The Spanish Society of Dentistry and Osseointegration (SEPA) and the Spanish Society of Neurology (SEN) recently released a report with the latest data on this topic. The report reviews, updates, and presents the most recent scientific evidence regarding this link. It also provides practical recommendations that, on the basis of the evidence, should be applied in dental clinics and neurology centers.

As Yago Leira, DDS, PhD, periodontist and coordinator of the SEPA-SEN working group, told this news organization, “The main takeaway from this scientific report is that patients with periodontitis are at nearly twice the risk of developing Alzheimer’s disease and at triple the risk of ischemic stroke.”

Data from the report show that individuals with periodontitis are at 2.8 times’ higher risk of ischemic stroke. The available evidence regarding hemorrhagic stroke, however, is conflicting.

How does this dental condition affect the course of cardiovascular disease? Observational studies have shown that those who have had an ischemic stroke and have a confirmed diagnosis of periodontitis are at greater risk of suffering a recurrent vascular event, worse neurologic deficit, and postictal depression than are patients without periodontitis.
 

Immune‐mediated inflammation

As far as its link to Alzheimer’s disease, meta-analyses of epidemiologic studies show that periodontitis is associated with a 1.7 times greater risk of this type of dementia and that the risk triples among patients with more serious forms of periodontitis.

Likewise, studies suggest that individuals with dementia or neurocognitive impairment are at a greater risk of suffering periodontitis. Other studies indicate that individuals with periodontitis have worse outcomes on various neuropsychological tests of cognitive function.

The current report presents the evidence from three clearly defined perspectives: The epidemiologic association between periodontitis and these neurologic diseases, the biological mechanisms that may explain this link, and interventional studies of dental treatment as a means of preventing stroke and Alzheimer’s disease.

“There is a possible biological explanation for these epidemiological findings. The report concludes that the low-grade chronic, systemic, immune-mediated inflammatory response induced by the bacteria and their endotoxins and the proinflammatory mediators circulating through the blood contributes to various biological processes that are involved in neurological impairment and cerebral ischemia,” said Dr. Leira, one of the report’s authors.

Ana Frank, MD, PhD, another author of this study, is head of the neurology department at the La Paz University Hospital in Madrid and a member of the SEPA-SEN group. She said in an interview that the main biological mechanism in stroke and Alzheimer’s disease is chronic exposure of the entire brain (vasculature, neurons, and astrocytes) to the harmful effects of periodontal infection. “Although low in intensity, this [exposure] is sufficient to set off a series of events that eventually lead to vascular endothelial injury, changes to neurons and astrocytes, and damage to the neuropil.”

As far as the evidence of an epidemiologic association between periodontitis and both neurologic diseases, Dr. Frank cited the exponential increase in risk brought on by periodontitis. She said that further epidemiologic studies are necessary to gain a better understanding of the magnitude of the problem.
 

A preventive alternative?

Dr. Leira cited evidence that periodontal treatment could provide a means of preventing stroke and dementia. He pointed out that numerous population studies have observed various oral health interventions (e.g., periodic dental prophylaxis or periodontal treatment) and regular dental visits to reduce the risk of developing dementia and stroke. “However, we don’t currently have randomized clinical trials that were designed to investigate whether periodontal treatment may be a primary or a secondary preventive measure against these neurological conditions.”

According to Dr. Leira, “There are currently several research groups in the United States and Europe, including ours, that are performing clinical trials to assess the impact of periodontal treatment on recurrent vascular events in patients with cerebrovascular disease.

“On the other hand, there are various interventional studies underway that are evaluating the potential effect of periodontal treatment on cognitive function in patients with dementia. Along these lines, there appear to be encouraging results from the 1-year follow-up in the GAIN study, which was a phase 2/3 clinical trial testing atuzaginstat. Atuzaginstat is an inhibitor of gingipain, the endotoxin produced by Porphyromonas gingivalis, which is one of the bacteria thought to be responsible for periodontitis. The drug reduces neurocognitive impairment in patients with high levels of antibodies against this periodontal pathogen.”
 

Toward clinical practice

The report has a practical focus. The intention is that this evidence will make its way into recommendations for dentists to implement in clinical practice, especially with elderly patients or patients with risk factors for stroke.

In this regard, Dr. Leira said, “On one hand, dentists have to know how to approach patients who have already suffered a stroke (most of whom have vascular risk factors like diabetes and hypertension), many of whom have polypharmacy and are [taking] certain drugs like blood thinners that could negatively impact various dental procedures. In such cases, it is important to maintain direct contact with a neurologist, since these patients ought to be treated with a multidisciplinary approach.

“On the other hand, each patient who comes to the dental office and has a diagnosis of periodontitis could be screened to identify potential vascular risk factors, even though the definitive diagnosis would need to be given by a specialist physician. To this end, SEPA is carrying out the Promosalud (“Health Promotion”) project, which will soon be applied in a large number of dental clinics in Spain,” added Dr. Leira.

“Lastly, specialists in odontology must understand the potential positive benefits surrounding systemic vascular inflammation that periodontal treatment could provide, including, for example, metabolic control and lowering blood pressure.”

For patients with cognitive impairment, the authors of the report recommended adhering to the following steps during dental visits: Inform the patient and the patient’s caregiver about the importance of good dental hygiene and monitor for any signs of infection or dental disease; address pain in every patient with cognitive impairment and dental problems, especially those with agitation, even if the patient isn’t specifically complaining of pain (also, try not to give opioids); finally, avoid sedation as much as possible and use the smallest effective dose if it becomes necessary.
 

Prescribe oral hygiene

Regarding recommendations that neurologists should follow during consultations in light of the link between these diseases and periodontitis, Dr. Frank said, “Regardless of how old our patients are, I believe it’s important to emphasize the importance of practicing good oral and dental hygiene. It’s a good strategy to put this in writing in medical reports, alongside the usual recommendations about healthy lifestyle habits and monitoring for diseases like high blood pressure, diabetes, or dyslipidemia. These, among other factors like smoking, a sedentary lifestyle, alcoholism, and other drug addictions, are vascular risk factors and are therefore risk factors for stroke and dementia.”

According to Dr. Frank, the public is largely unaware of the relationship between periodontitis and incident neurologic diseases. “We still have a long way to go before we can say that the public is aware of this potential link. And not just the public, either. I believe we must stress among our colleagues and among health care professionals in general the importance of promoting dental health to improve people’s overall health.”

In this regard, Dr. Leira emphasized the authors’ intention to make this report available not only to oral health and neurologic health care professionals but also to primary care physicians and nurses so that patients with cerebrovascular disease or Alzheimer’s disease and their caregivers can develop a greater awareness and thereby improve prevention.

“This study will also provide the scientific basis to support the SEPA-SEN working group as they implement their future activities and projects,” Dr. Leira concluded.

Dr. Leira and Dr. Frank have disclosed no relevant financial relationships.
 

This article was translated from the Medscape Spanish Edition. A version of this article appeared on Medscape.com.

MADRID – Recent research has confirmed the impact of periodontitis on risk of neurologic diseases, especially the increased risks for stroke and Alzheimer’s disease.

The Spanish Society of Dentistry and Osseointegration (SEPA) and the Spanish Society of Neurology (SEN) recently released a report with the latest data on this topic. The report reviews, updates, and presents the most recent scientific evidence regarding this link. It also provides practical recommendations that, on the basis of the evidence, should be applied in dental clinics and neurology centers.

As Yago Leira, DDS, PhD, periodontist and coordinator of the SEPA-SEN working group, told this news organization, “The main takeaway from this scientific report is that patients with periodontitis are at nearly twice the risk of developing Alzheimer’s disease and at triple the risk of ischemic stroke.”

Data from the report show that individuals with periodontitis are at 2.8 times’ higher risk of ischemic stroke. The available evidence regarding hemorrhagic stroke, however, is conflicting.

How does this dental condition affect the course of cardiovascular disease? Observational studies have shown that those who have had an ischemic stroke and have a confirmed diagnosis of periodontitis are at greater risk of suffering a recurrent vascular event, worse neurologic deficit, and postictal depression than are patients without periodontitis.
 

Immune‐mediated inflammation

As far as its link to Alzheimer’s disease, meta-analyses of epidemiologic studies show that periodontitis is associated with a 1.7 times greater risk of this type of dementia and that the risk triples among patients with more serious forms of periodontitis.

Likewise, studies suggest that individuals with dementia or neurocognitive impairment are at a greater risk of suffering periodontitis. Other studies indicate that individuals with periodontitis have worse outcomes on various neuropsychological tests of cognitive function.

The current report presents the evidence from three clearly defined perspectives: The epidemiologic association between periodontitis and these neurologic diseases, the biological mechanisms that may explain this link, and interventional studies of dental treatment as a means of preventing stroke and Alzheimer’s disease.

“There is a possible biological explanation for these epidemiological findings. The report concludes that the low-grade chronic, systemic, immune-mediated inflammatory response induced by the bacteria and their endotoxins and the proinflammatory mediators circulating through the blood contributes to various biological processes that are involved in neurological impairment and cerebral ischemia,” said Dr. Leira, one of the report’s authors.

Ana Frank, MD, PhD, another author of this study, is head of the neurology department at the La Paz University Hospital in Madrid and a member of the SEPA-SEN group. She said in an interview that the main biological mechanism in stroke and Alzheimer’s disease is chronic exposure of the entire brain (vasculature, neurons, and astrocytes) to the harmful effects of periodontal infection. “Although low in intensity, this [exposure] is sufficient to set off a series of events that eventually lead to vascular endothelial injury, changes to neurons and astrocytes, and damage to the neuropil.”

As far as the evidence of an epidemiologic association between periodontitis and both neurologic diseases, Dr. Frank cited the exponential increase in risk brought on by periodontitis. She said that further epidemiologic studies are necessary to gain a better understanding of the magnitude of the problem.
 

A preventive alternative?

Dr. Leira cited evidence that periodontal treatment could provide a means of preventing stroke and dementia. He pointed out that numerous population studies have observed various oral health interventions (e.g., periodic dental prophylaxis or periodontal treatment) and regular dental visits to reduce the risk of developing dementia and stroke. “However, we don’t currently have randomized clinical trials that were designed to investigate whether periodontal treatment may be a primary or a secondary preventive measure against these neurological conditions.”

According to Dr. Leira, “There are currently several research groups in the United States and Europe, including ours, that are performing clinical trials to assess the impact of periodontal treatment on recurrent vascular events in patients with cerebrovascular disease.

“On the other hand, there are various interventional studies underway that are evaluating the potential effect of periodontal treatment on cognitive function in patients with dementia. Along these lines, there appear to be encouraging results from the 1-year follow-up in the GAIN study, which was a phase 2/3 clinical trial testing atuzaginstat. Atuzaginstat is an inhibitor of gingipain, the endotoxin produced by Porphyromonas gingivalis, which is one of the bacteria thought to be responsible for periodontitis. The drug reduces neurocognitive impairment in patients with high levels of antibodies against this periodontal pathogen.”
 

Toward clinical practice

The report has a practical focus. The intention is that this evidence will make its way into recommendations for dentists to implement in clinical practice, especially with elderly patients or patients with risk factors for stroke.

In this regard, Dr. Leira said, “On one hand, dentists have to know how to approach patients who have already suffered a stroke (most of whom have vascular risk factors like diabetes and hypertension), many of whom have polypharmacy and are [taking] certain drugs like blood thinners that could negatively impact various dental procedures. In such cases, it is important to maintain direct contact with a neurologist, since these patients ought to be treated with a multidisciplinary approach.

“On the other hand, each patient who comes to the dental office and has a diagnosis of periodontitis could be screened to identify potential vascular risk factors, even though the definitive diagnosis would need to be given by a specialist physician. To this end, SEPA is carrying out the Promosalud (“Health Promotion”) project, which will soon be applied in a large number of dental clinics in Spain,” added Dr. Leira.

“Lastly, specialists in odontology must understand the potential positive benefits surrounding systemic vascular inflammation that periodontal treatment could provide, including, for example, metabolic control and lowering blood pressure.”

For patients with cognitive impairment, the authors of the report recommended adhering to the following steps during dental visits: Inform the patient and the patient’s caregiver about the importance of good dental hygiene and monitor for any signs of infection or dental disease; address pain in every patient with cognitive impairment and dental problems, especially those with agitation, even if the patient isn’t specifically complaining of pain (also, try not to give opioids); finally, avoid sedation as much as possible and use the smallest effective dose if it becomes necessary.
 

Prescribe oral hygiene

Regarding recommendations that neurologists should follow during consultations in light of the link between these diseases and periodontitis, Dr. Frank said, “Regardless of how old our patients are, I believe it’s important to emphasize the importance of practicing good oral and dental hygiene. It’s a good strategy to put this in writing in medical reports, alongside the usual recommendations about healthy lifestyle habits and monitoring for diseases like high blood pressure, diabetes, or dyslipidemia. These, among other factors like smoking, a sedentary lifestyle, alcoholism, and other drug addictions, are vascular risk factors and are therefore risk factors for stroke and dementia.”

According to Dr. Frank, the public is largely unaware of the relationship between periodontitis and incident neurologic diseases. “We still have a long way to go before we can say that the public is aware of this potential link. And not just the public, either. I believe we must stress among our colleagues and among health care professionals in general the importance of promoting dental health to improve people’s overall health.”

In this regard, Dr. Leira emphasized the authors’ intention to make this report available not only to oral health and neurologic health care professionals but also to primary care physicians and nurses so that patients with cerebrovascular disease or Alzheimer’s disease and their caregivers can develop a greater awareness and thereby improve prevention.

“This study will also provide the scientific basis to support the SEPA-SEN working group as they implement their future activities and projects,” Dr. Leira concluded.

Dr. Leira and Dr. Frank have disclosed no relevant financial relationships.
 

This article was translated from the Medscape Spanish Edition. A version of this article appeared on Medscape.com.

MADRID – Recent research has confirmed the impact of periodontitis on risk of neurologic diseases, especially the increased risks for stroke and Alzheimer’s disease.

The Spanish Society of Dentistry and Osseointegration (SEPA) and the Spanish Society of Neurology (SEN) recently released a report with the latest data on this topic. The report reviews, updates, and presents the most recent scientific evidence regarding this link. It also provides practical recommendations that, on the basis of the evidence, should be applied in dental clinics and neurology centers.

As Yago Leira, DDS, PhD, periodontist and coordinator of the SEPA-SEN working group, told this news organization, “The main takeaway from this scientific report is that patients with periodontitis are at nearly twice the risk of developing Alzheimer’s disease and at triple the risk of ischemic stroke.”

Data from the report show that individuals with periodontitis are at 2.8 times’ higher risk of ischemic stroke. The available evidence regarding hemorrhagic stroke, however, is conflicting.

How does this dental condition affect the course of cardiovascular disease? Observational studies have shown that those who have had an ischemic stroke and have a confirmed diagnosis of periodontitis are at greater risk of suffering a recurrent vascular event, worse neurologic deficit, and postictal depression than are patients without periodontitis.
 

Immune‐mediated inflammation

As far as its link to Alzheimer’s disease, meta-analyses of epidemiologic studies show that periodontitis is associated with a 1.7 times greater risk of this type of dementia and that the risk triples among patients with more serious forms of periodontitis.

Likewise, studies suggest that individuals with dementia or neurocognitive impairment are at a greater risk of suffering periodontitis. Other studies indicate that individuals with periodontitis have worse outcomes on various neuropsychological tests of cognitive function.

The current report presents the evidence from three clearly defined perspectives: The epidemiologic association between periodontitis and these neurologic diseases, the biological mechanisms that may explain this link, and interventional studies of dental treatment as a means of preventing stroke and Alzheimer’s disease.

“There is a possible biological explanation for these epidemiological findings. The report concludes that the low-grade chronic, systemic, immune-mediated inflammatory response induced by the bacteria and their endotoxins and the proinflammatory mediators circulating through the blood contributes to various biological processes that are involved in neurological impairment and cerebral ischemia,” said Dr. Leira, one of the report’s authors.

Ana Frank, MD, PhD, another author of this study, is head of the neurology department at the La Paz University Hospital in Madrid and a member of the SEPA-SEN group. She said in an interview that the main biological mechanism in stroke and Alzheimer’s disease is chronic exposure of the entire brain (vasculature, neurons, and astrocytes) to the harmful effects of periodontal infection. “Although low in intensity, this [exposure] is sufficient to set off a series of events that eventually lead to vascular endothelial injury, changes to neurons and astrocytes, and damage to the neuropil.”

As far as the evidence of an epidemiologic association between periodontitis and both neurologic diseases, Dr. Frank cited the exponential increase in risk brought on by periodontitis. She said that further epidemiologic studies are necessary to gain a better understanding of the magnitude of the problem.
 

A preventive alternative?

Dr. Leira cited evidence that periodontal treatment could provide a means of preventing stroke and dementia. He pointed out that numerous population studies have observed various oral health interventions (e.g., periodic dental prophylaxis or periodontal treatment) and regular dental visits to reduce the risk of developing dementia and stroke. “However, we don’t currently have randomized clinical trials that were designed to investigate whether periodontal treatment may be a primary or a secondary preventive measure against these neurological conditions.”

According to Dr. Leira, “There are currently several research groups in the United States and Europe, including ours, that are performing clinical trials to assess the impact of periodontal treatment on recurrent vascular events in patients with cerebrovascular disease.

“On the other hand, there are various interventional studies underway that are evaluating the potential effect of periodontal treatment on cognitive function in patients with dementia. Along these lines, there appear to be encouraging results from the 1-year follow-up in the GAIN study, which was a phase 2/3 clinical trial testing atuzaginstat. Atuzaginstat is an inhibitor of gingipain, the endotoxin produced by Porphyromonas gingivalis, which is one of the bacteria thought to be responsible for periodontitis. The drug reduces neurocognitive impairment in patients with high levels of antibodies against this periodontal pathogen.”
 

Toward clinical practice

The report has a practical focus. The intention is that this evidence will make its way into recommendations for dentists to implement in clinical practice, especially with elderly patients or patients with risk factors for stroke.

In this regard, Dr. Leira said, “On one hand, dentists have to know how to approach patients who have already suffered a stroke (most of whom have vascular risk factors like diabetes and hypertension), many of whom have polypharmacy and are [taking] certain drugs like blood thinners that could negatively impact various dental procedures. In such cases, it is important to maintain direct contact with a neurologist, since these patients ought to be treated with a multidisciplinary approach.

“On the other hand, each patient who comes to the dental office and has a diagnosis of periodontitis could be screened to identify potential vascular risk factors, even though the definitive diagnosis would need to be given by a specialist physician. To this end, SEPA is carrying out the Promosalud (“Health Promotion”) project, which will soon be applied in a large number of dental clinics in Spain,” added Dr. Leira.

“Lastly, specialists in odontology must understand the potential positive benefits surrounding systemic vascular inflammation that periodontal treatment could provide, including, for example, metabolic control and lowering blood pressure.”

For patients with cognitive impairment, the authors of the report recommended adhering to the following steps during dental visits: Inform the patient and the patient’s caregiver about the importance of good dental hygiene and monitor for any signs of infection or dental disease; address pain in every patient with cognitive impairment and dental problems, especially those with agitation, even if the patient isn’t specifically complaining of pain (also, try not to give opioids); finally, avoid sedation as much as possible and use the smallest effective dose if it becomes necessary.
 

Prescribe oral hygiene

Regarding recommendations that neurologists should follow during consultations in light of the link between these diseases and periodontitis, Dr. Frank said, “Regardless of how old our patients are, I believe it’s important to emphasize the importance of practicing good oral and dental hygiene. It’s a good strategy to put this in writing in medical reports, alongside the usual recommendations about healthy lifestyle habits and monitoring for diseases like high blood pressure, diabetes, or dyslipidemia. These, among other factors like smoking, a sedentary lifestyle, alcoholism, and other drug addictions, are vascular risk factors and are therefore risk factors for stroke and dementia.”

According to Dr. Frank, the public is largely unaware of the relationship between periodontitis and incident neurologic diseases. “We still have a long way to go before we can say that the public is aware of this potential link. And not just the public, either. I believe we must stress among our colleagues and among health care professionals in general the importance of promoting dental health to improve people’s overall health.”

In this regard, Dr. Leira emphasized the authors’ intention to make this report available not only to oral health and neurologic health care professionals but also to primary care physicians and nurses so that patients with cerebrovascular disease or Alzheimer’s disease and their caregivers can develop a greater awareness and thereby improve prevention.

“This study will also provide the scientific basis to support the SEPA-SEN working group as they implement their future activities and projects,” Dr. Leira concluded.

Dr. Leira and Dr. Frank have disclosed no relevant financial relationships.
 

This article was translated from the Medscape Spanish Edition. A version of this article appeared on Medscape.com.

An oral oil containing tetrahydrocannabinol (THC) and cannabidiol (CBD) led to a significant and meaningful reduction in motor and vocal tics in patients with severe Tourette syndrome (TS), results of a double-blind, placebo-controlled, crossover study show.

“In a methodologically robust manner (and independent of any drug company sponsorship), we provide evidence for the effectiveness of repeated dosing with THC:CBD vs. placebo in tic suppression, as well as reduction of comorbid anxiety and obsessive-compulsive disorder in severe TS,” neuropsychiatrist and lead investigator Philip Mosley, PhD, said in an interview.

The results offer support to people with TS who “want to approach their doctor to try medicinal cannabis when other drugs have not worked or are intolerable,” said Dr. Mosley, of the Wesley Research Institute and QIMR Berghofer Medical Research Institute, Herston, Australia.

The study was published online in NEJM Evidence.
 

A viable treatment option

Twenty-two adults (mean age, 31 years) with severe TS received THC:CBD oil titrated upward over 6 weeks to a daily dose of 20 mg of THC and 20 mg of CBD, followed by a 6-week course of placebo (or vice versa). Six participants had not previously used cannabis.

The primary outcome was the total tic score on the Yale Global Tic Severity Scale (YGTSS; range 0 to 50 with higher scores = greater tic severity).

The mean baseline YGTSS total tic score was 35.7. At 6 weeks, the reduction in total tic score was 8.9 with THC:CBD vs. 2.5 with placebo.

A linear mixed-effects model (intention-to-treat) showed a significant interaction of treatment and visit number (P = .008), indicating a greater decrease (improvement) in tic score over time with THC:CBD, the study team reported.

On average, the magnitude of the tic reduction was “moderate” and comparable to the effect observed with existing treatments such as antipsychotic agents, the investigators noted.

THC:CBD also led to a reduction in other symptoms associated with TS, particularly symptoms of OCD and anxiety.

The symptomatic response to THC:CBD correlated with serum metabolites of the cannabinoids, further supporting a biological relationship, the researchers noted.

There were no serious adverse events. Adverse effects with THC:CBD were generally mild. The most common adverse effect was cognitive difficulties, including slowed mentation, memory lapses, and poor concentration.

“Like many studies of psychoactive compounds, blinding among participants was a problem,” the researchers noted. Despite best efforts to conceal treatment allocation and match placebo to the active agent in terms of color and smell, most participants were able to correctly guess their treatment order.

Based on the findings in this small trial, larger and longer trials of THC:CBD in TS are warranted, they concluded.

“We need a plurality of treatment options in Tourette syndrome. For some, antipsychotics are effective tic-suppressing agents but for many these benefits are complicated by side effects such as weight gain & sedation,” Dr. Mosley tweeted. “Cannabinoids are a biologically plausible therapeutic agent. The body’s own ‘endocannabinoid’ receptors are concentrated in the basal ganglia – the neuroanatomical nexus of TS.”

The study was funded by the Wesley Medical Research Institute, Brisbane, and the Lambert Initiative for Cannabinoid Therapeutics, a philanthropically funded research organization at the University of Sydney, Australia. Dr. Mosley reports no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.

An oral oil containing tetrahydrocannabinol (THC) and cannabidiol (CBD) led to a significant and meaningful reduction in motor and vocal tics in patients with severe Tourette syndrome (TS), results of a double-blind, placebo-controlled, crossover study show.

“In a methodologically robust manner (and independent of any drug company sponsorship), we provide evidence for the effectiveness of repeated dosing with THC:CBD vs. placebo in tic suppression, as well as reduction of comorbid anxiety and obsessive-compulsive disorder in severe TS,” neuropsychiatrist and lead investigator Philip Mosley, PhD, said in an interview.

The results offer support to people with TS who “want to approach their doctor to try medicinal cannabis when other drugs have not worked or are intolerable,” said Dr. Mosley, of the Wesley Research Institute and QIMR Berghofer Medical Research Institute, Herston, Australia.

The study was published online in NEJM Evidence.
 

A viable treatment option

Twenty-two adults (mean age, 31 years) with severe TS received THC:CBD oil titrated upward over 6 weeks to a daily dose of 20 mg of THC and 20 mg of CBD, followed by a 6-week course of placebo (or vice versa). Six participants had not previously used cannabis.

The primary outcome was the total tic score on the Yale Global Tic Severity Scale (YGTSS; range 0 to 50 with higher scores = greater tic severity).

The mean baseline YGTSS total tic score was 35.7. At 6 weeks, the reduction in total tic score was 8.9 with THC:CBD vs. 2.5 with placebo.

A linear mixed-effects model (intention-to-treat) showed a significant interaction of treatment and visit number (P = .008), indicating a greater decrease (improvement) in tic score over time with THC:CBD, the study team reported.

On average, the magnitude of the tic reduction was “moderate” and comparable to the effect observed with existing treatments such as antipsychotic agents, the investigators noted.

THC:CBD also led to a reduction in other symptoms associated with TS, particularly symptoms of OCD and anxiety.

The symptomatic response to THC:CBD correlated with serum metabolites of the cannabinoids, further supporting a biological relationship, the researchers noted.

There were no serious adverse events. Adverse effects with THC:CBD were generally mild. The most common adverse effect was cognitive difficulties, including slowed mentation, memory lapses, and poor concentration.

“Like many studies of psychoactive compounds, blinding among participants was a problem,” the researchers noted. Despite best efforts to conceal treatment allocation and match placebo to the active agent in terms of color and smell, most participants were able to correctly guess their treatment order.

Based on the findings in this small trial, larger and longer trials of THC:CBD in TS are warranted, they concluded.

“We need a plurality of treatment options in Tourette syndrome. For some, antipsychotics are effective tic-suppressing agents but for many these benefits are complicated by side effects such as weight gain & sedation,” Dr. Mosley tweeted. “Cannabinoids are a biologically plausible therapeutic agent. The body’s own ‘endocannabinoid’ receptors are concentrated in the basal ganglia – the neuroanatomical nexus of TS.”

The study was funded by the Wesley Medical Research Institute, Brisbane, and the Lambert Initiative for Cannabinoid Therapeutics, a philanthropically funded research organization at the University of Sydney, Australia. Dr. Mosley reports no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.

An oral oil containing tetrahydrocannabinol (THC) and cannabidiol (CBD) led to a significant and meaningful reduction in motor and vocal tics in patients with severe Tourette syndrome (TS), results of a double-blind, placebo-controlled, crossover study show.

“In a methodologically robust manner (and independent of any drug company sponsorship), we provide evidence for the effectiveness of repeated dosing with THC:CBD vs. placebo in tic suppression, as well as reduction of comorbid anxiety and obsessive-compulsive disorder in severe TS,” neuropsychiatrist and lead investigator Philip Mosley, PhD, said in an interview.

The results offer support to people with TS who “want to approach their doctor to try medicinal cannabis when other drugs have not worked or are intolerable,” said Dr. Mosley, of the Wesley Research Institute and QIMR Berghofer Medical Research Institute, Herston, Australia.

The study was published online in NEJM Evidence.
 

A viable treatment option

Twenty-two adults (mean age, 31 years) with severe TS received THC:CBD oil titrated upward over 6 weeks to a daily dose of 20 mg of THC and 20 mg of CBD, followed by a 6-week course of placebo (or vice versa). Six participants had not previously used cannabis.

The primary outcome was the total tic score on the Yale Global Tic Severity Scale (YGTSS; range 0 to 50 with higher scores = greater tic severity).

The mean baseline YGTSS total tic score was 35.7. At 6 weeks, the reduction in total tic score was 8.9 with THC:CBD vs. 2.5 with placebo.

A linear mixed-effects model (intention-to-treat) showed a significant interaction of treatment and visit number (P = .008), indicating a greater decrease (improvement) in tic score over time with THC:CBD, the study team reported.

On average, the magnitude of the tic reduction was “moderate” and comparable to the effect observed with existing treatments such as antipsychotic agents, the investigators noted.

THC:CBD also led to a reduction in other symptoms associated with TS, particularly symptoms of OCD and anxiety.

The symptomatic response to THC:CBD correlated with serum metabolites of the cannabinoids, further supporting a biological relationship, the researchers noted.

There were no serious adverse events. Adverse effects with THC:CBD were generally mild. The most common adverse effect was cognitive difficulties, including slowed mentation, memory lapses, and poor concentration.

“Like many studies of psychoactive compounds, blinding among participants was a problem,” the researchers noted. Despite best efforts to conceal treatment allocation and match placebo to the active agent in terms of color and smell, most participants were able to correctly guess their treatment order.

Based on the findings in this small trial, larger and longer trials of THC:CBD in TS are warranted, they concluded.

“We need a plurality of treatment options in Tourette syndrome. For some, antipsychotics are effective tic-suppressing agents but for many these benefits are complicated by side effects such as weight gain & sedation,” Dr. Mosley tweeted. “Cannabinoids are a biologically plausible therapeutic agent. The body’s own ‘endocannabinoid’ receptors are concentrated in the basal ganglia – the neuroanatomical nexus of TS.”

The study was funded by the Wesley Medical Research Institute, Brisbane, and the Lambert Initiative for Cannabinoid Therapeutics, a philanthropically funded research organization at the University of Sydney, Australia. Dr. Mosley reports no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.

DENVER – In the ongoing absence of a reliable biomarker for multiple sclerosis (MS), misdiagnosis is a common and persistent problem that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.

“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.

For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.

The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.

A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.

The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
 

The dangers of misdiagnosis

Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.

“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.

There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.

For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.

Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.

In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
 

Best hope for an accurate diagnosis

In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.

Dr. Coyle said that a comprehensive workup should include:

• A thorough neurologic history and exam.
• MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
• Adding spinal fluid evaluation, especially in any atypical cases.
• Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.

“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.

Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.

A version of this article originally appeared on Medscape.com.

DENVER – In the ongoing absence of a reliable biomarker for multiple sclerosis (MS), misdiagnosis is a common and persistent problem that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.

“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.

For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.

The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.

A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.

The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
 

The dangers of misdiagnosis

Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.

“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.

There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.

For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.

Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.

In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
 

Best hope for an accurate diagnosis

In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.

Dr. Coyle said that a comprehensive workup should include:

• A thorough neurologic history and exam.
• MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
• Adding spinal fluid evaluation, especially in any atypical cases.
• Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.

“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.

Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.

A version of this article originally appeared on Medscape.com.

DENVER – In the ongoing absence of a reliable biomarker for multiple sclerosis (MS), misdiagnosis is a common and persistent problem that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.

“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.

For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.

The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.

A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.

The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
 

The dangers of misdiagnosis

Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.

“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.

There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.

For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.

Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.

In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
 

Best hope for an accurate diagnosis

In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.

Dr. Coyle said that a comprehensive workup should include:

• A thorough neurologic history and exam.
• MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
• Adding spinal fluid evaluation, especially in any atypical cases.
• Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.

“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.

Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.

A version of this article originally appeared on Medscape.com.

Intranasal (IN) ketamine may be a feasible treatment alternative for people with chronic, refractory migraine who don’t respond to other medications, new research shows.

Half of the study participants who used IN ketamine for chronic, treatment-refractory migraine in a new retrospective cohort study reported it as “very effective” and over one-third said it boosted their quality of life.

“In our study, we showed that with even a few uses per day, intranasal ketamine can still improve patients’ quality of life,” lead investigator Hsiangkuo Yuan, MD, PhD, said in an interview. Dr. Yuan is associate professor of neurology at Thomas Jefferson University, Philadelphia, and director of clinical research at the Jefferson Headache Center.

He added that “multiple medications failed these patients, and the majority of patients were having daily headaches. So, if anything works, even partially and shortly, it may still give patients some relief to get through the day.”

The findings were published online in Regional Anesthesia & Pain Medicine.  
 

Daily migraine, failed medications

Use of IN ketamine has not been studied for the treatment of chronic, treatment-refractory migraine – although it has been studied in patients with cluster headache and migraine, the investigators note.

Ketamine is not yet approved by the Food and Drug Administration to treat migraine.

To further explore ketamine’s effect in those with chronic, treatment-refractory migraine, the investigators retrospectively analyzed electronic health records of patients at the Jefferson Headache Center who had received IN ketamine for the treatment of migraine between January 2019 and February 2020.

Of 242 patients who had received IN ketamine, Dr. Yuan’s team followed up with 169 who agreed to be part of the study.

The majority (67%) had daily migraine, and 85% had tried more than three classes of preventive medications for migraine. They currently used a median of two medications, the most common of which was a CGRP monoclonal antibody.

On average, patients used six sprays per day for a median 10 days per month. Median pain relief onset was 52 minutes after dosage.

Almost three-quarters of patients reported at least one side effect from the ketamine, most commonly fatigue (22%), double/blurred vision (21%), and confusion/dissociation (21%). These effects were mostly temporary, the researchers report.

The most common reasons for initiating IN ketamine included an incomplete response to prior acute medications (59%), incomplete response to prior preventive medications (31%), and prior benefit from IV ketamine (23%).

Study investigators noted that ketamine has the potential to become addictive and indicated that “clinicians should only consider the use of a potentially addictive medication such as ketamine for significantly disabled patients with migraine.”

About half of the participants who used IN ketamine found it “very effective,” and 40% found it “somewhat effective.” Within the same group, 36% and 43% found the overall impact of IN ketamine on their quality of life was much better and somewhat better, respectively.

Among those still using ketamine during study follow-up, 82% reported that ketamine was very effective.

Compared with other acute headache medications, IN ketamine was considered much better (43%) or somewhat better (30%).

Nearly 75% of participants reported using fewer pain relievers when using IN ketamine.

Dr. Yuan said that future research might focus on finding predictors for IN ketamine response or determining the optimal effective and safe dose for the drug in those with chronic, treatment-refractory migraine.  

“We still need a prospective, randomized controlled trial to assess the efficacy and tolerability of intranasal ketamine,” he added.
 

‘Impressive result’

Commenting on the findings for this article, Richard Lipton, MD, professor of neurology, psychiatry and behavioral sciences and director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, said that “in this refractory population with multiple treatment failures, this is a very impressive, open-label result.”

“This real-world data suggests that ketamine is an effective option for people with medically intractable chronic migraine,” said Dr. Lipton, who was not part of the study. “In these very difficult to treat patients, 65% of those who started on ketamine persisted. Of those who remained on ketamine, 82% found it very effective.”

“This study makes me more confident that intranasal ketamine is a helpful treatment option, and I plan to use it more often in the future,” he added.

Like Dr. Yuan, Dr. Lipton highlighted the need for “well-designed placebo-controlled trials” and “rigorous comparative effectiveness studies.”

The study was funded by Miles for Migraine. Dr. Yuan has received institutional support for serving as an investigator from Teva and AbbVie, and royalties from Cambridge University Press and MedLink. Dr. Lipton has received compensation for consultation from Alder/Lumbeck, Axsome, Supernus, Theranica, Upsher-Smith, and Satsuma. He has participated in speaker bureaus for Eli Lilly and Amgen/Novartis and has received institutional support for serving as principal investigator from Teva, GammaCore, and Allergan/AbbVie. He has received payments for authorship or royalties from Demos Medical, Cambridge University Press, and MedLink.

A version of this article originally appeared on Medscape.com.

Intranasal (IN) ketamine may be a feasible treatment alternative for people with chronic, refractory migraine who don’t respond to other medications, new research shows.

Half of the study participants who used IN ketamine for chronic, treatment-refractory migraine in a new retrospective cohort study reported it as “very effective” and over one-third said it boosted their quality of life.

“In our study, we showed that with even a few uses per day, intranasal ketamine can still improve patients’ quality of life,” lead investigator Hsiangkuo Yuan, MD, PhD, said in an interview. Dr. Yuan is associate professor of neurology at Thomas Jefferson University, Philadelphia, and director of clinical research at the Jefferson Headache Center.

He added that “multiple medications failed these patients, and the majority of patients were having daily headaches. So, if anything works, even partially and shortly, it may still give patients some relief to get through the day.”

The findings were published online in Regional Anesthesia & Pain Medicine.  
 

Daily migraine, failed medications

Use of IN ketamine has not been studied for the treatment of chronic, treatment-refractory migraine – although it has been studied in patients with cluster headache and migraine, the investigators note.

Ketamine is not yet approved by the Food and Drug Administration to treat migraine.

To further explore ketamine’s effect in those with chronic, treatment-refractory migraine, the investigators retrospectively analyzed electronic health records of patients at the Jefferson Headache Center who had received IN ketamine for the treatment of migraine between January 2019 and February 2020.

Of 242 patients who had received IN ketamine, Dr. Yuan’s team followed up with 169 who agreed to be part of the study.

The majority (67%) had daily migraine, and 85% had tried more than three classes of preventive medications for migraine. They currently used a median of two medications, the most common of which was a CGRP monoclonal antibody.

On average, patients used six sprays per day for a median 10 days per month. Median pain relief onset was 52 minutes after dosage.

Almost three-quarters of patients reported at least one side effect from the ketamine, most commonly fatigue (22%), double/blurred vision (21%), and confusion/dissociation (21%). These effects were mostly temporary, the researchers report.

The most common reasons for initiating IN ketamine included an incomplete response to prior acute medications (59%), incomplete response to prior preventive medications (31%), and prior benefit from IV ketamine (23%).

Study investigators noted that ketamine has the potential to become addictive and indicated that “clinicians should only consider the use of a potentially addictive medication such as ketamine for significantly disabled patients with migraine.”

About half of the participants who used IN ketamine found it “very effective,” and 40% found it “somewhat effective.” Within the same group, 36% and 43% found the overall impact of IN ketamine on their quality of life was much better and somewhat better, respectively.

Among those still using ketamine during study follow-up, 82% reported that ketamine was very effective.

Compared with other acute headache medications, IN ketamine was considered much better (43%) or somewhat better (30%).

Nearly 75% of participants reported using fewer pain relievers when using IN ketamine.

Dr. Yuan said that future research might focus on finding predictors for IN ketamine response or determining the optimal effective and safe dose for the drug in those with chronic, treatment-refractory migraine.  

“We still need a prospective, randomized controlled trial to assess the efficacy and tolerability of intranasal ketamine,” he added.
 

‘Impressive result’

Commenting on the findings for this article, Richard Lipton, MD, professor of neurology, psychiatry and behavioral sciences and director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, said that “in this refractory population with multiple treatment failures, this is a very impressive, open-label result.”

“This real-world data suggests that ketamine is an effective option for people with medically intractable chronic migraine,” said Dr. Lipton, who was not part of the study. “In these very difficult to treat patients, 65% of those who started on ketamine persisted. Of those who remained on ketamine, 82% found it very effective.”

“This study makes me more confident that intranasal ketamine is a helpful treatment option, and I plan to use it more often in the future,” he added.

Like Dr. Yuan, Dr. Lipton highlighted the need for “well-designed placebo-controlled trials” and “rigorous comparative effectiveness studies.”

The study was funded by Miles for Migraine. Dr. Yuan has received institutional support for serving as an investigator from Teva and AbbVie, and royalties from Cambridge University Press and MedLink. Dr. Lipton has received compensation for consultation from Alder/Lumbeck, Axsome, Supernus, Theranica, Upsher-Smith, and Satsuma. He has participated in speaker bureaus for Eli Lilly and Amgen/Novartis and has received institutional support for serving as principal investigator from Teva, GammaCore, and Allergan/AbbVie. He has received payments for authorship or royalties from Demos Medical, Cambridge University Press, and MedLink.

A version of this article originally appeared on Medscape.com.

Intranasal (IN) ketamine may be a feasible treatment alternative for people with chronic, refractory migraine who don’t respond to other medications, new research shows.

Half of the study participants who used IN ketamine for chronic, treatment-refractory migraine in a new retrospective cohort study reported it as “very effective” and over one-third said it boosted their quality of life.

“In our study, we showed that with even a few uses per day, intranasal ketamine can still improve patients’ quality of life,” lead investigator Hsiangkuo Yuan, MD, PhD, said in an interview. Dr. Yuan is associate professor of neurology at Thomas Jefferson University, Philadelphia, and director of clinical research at the Jefferson Headache Center.

He added that “multiple medications failed these patients, and the majority of patients were having daily headaches. So, if anything works, even partially and shortly, it may still give patients some relief to get through the day.”

The findings were published online in Regional Anesthesia & Pain Medicine.  
 

Daily migraine, failed medications

Use of IN ketamine has not been studied for the treatment of chronic, treatment-refractory migraine – although it has been studied in patients with cluster headache and migraine, the investigators note.

Ketamine is not yet approved by the Food and Drug Administration to treat migraine.

To further explore ketamine’s effect in those with chronic, treatment-refractory migraine, the investigators retrospectively analyzed electronic health records of patients at the Jefferson Headache Center who had received IN ketamine for the treatment of migraine between January 2019 and February 2020.

Of 242 patients who had received IN ketamine, Dr. Yuan’s team followed up with 169 who agreed to be part of the study.

The majority (67%) had daily migraine, and 85% had tried more than three classes of preventive medications for migraine. They currently used a median of two medications, the most common of which was a CGRP monoclonal antibody.

On average, patients used six sprays per day for a median 10 days per month. Median pain relief onset was 52 minutes after dosage.

Almost three-quarters of patients reported at least one side effect from the ketamine, most commonly fatigue (22%), double/blurred vision (21%), and confusion/dissociation (21%). These effects were mostly temporary, the researchers report.

The most common reasons for initiating IN ketamine included an incomplete response to prior acute medications (59%), incomplete response to prior preventive medications (31%), and prior benefit from IV ketamine (23%).

Study investigators noted that ketamine has the potential to become addictive and indicated that “clinicians should only consider the use of a potentially addictive medication such as ketamine for significantly disabled patients with migraine.”

About half of the participants who used IN ketamine found it “very effective,” and 40% found it “somewhat effective.” Within the same group, 36% and 43% found the overall impact of IN ketamine on their quality of life was much better and somewhat better, respectively.

Among those still using ketamine during study follow-up, 82% reported that ketamine was very effective.

Compared with other acute headache medications, IN ketamine was considered much better (43%) or somewhat better (30%).

Nearly 75% of participants reported using fewer pain relievers when using IN ketamine.

Dr. Yuan said that future research might focus on finding predictors for IN ketamine response or determining the optimal effective and safe dose for the drug in those with chronic, treatment-refractory migraine.  

“We still need a prospective, randomized controlled trial to assess the efficacy and tolerability of intranasal ketamine,” he added.
 

‘Impressive result’

Commenting on the findings for this article, Richard Lipton, MD, professor of neurology, psychiatry and behavioral sciences and director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, said that “in this refractory population with multiple treatment failures, this is a very impressive, open-label result.”

“This real-world data suggests that ketamine is an effective option for people with medically intractable chronic migraine,” said Dr. Lipton, who was not part of the study. “In these very difficult to treat patients, 65% of those who started on ketamine persisted. Of those who remained on ketamine, 82% found it very effective.”

“This study makes me more confident that intranasal ketamine is a helpful treatment option, and I plan to use it more often in the future,” he added.

Like Dr. Yuan, Dr. Lipton highlighted the need for “well-designed placebo-controlled trials” and “rigorous comparative effectiveness studies.”

The study was funded by Miles for Migraine. Dr. Yuan has received institutional support for serving as an investigator from Teva and AbbVie, and royalties from Cambridge University Press and MedLink. Dr. Lipton has received compensation for consultation from Alder/Lumbeck, Axsome, Supernus, Theranica, Upsher-Smith, and Satsuma. He has participated in speaker bureaus for Eli Lilly and Amgen/Novartis and has received institutional support for serving as principal investigator from Teva, GammaCore, and Allergan/AbbVie. He has received payments for authorship or royalties from Demos Medical, Cambridge University Press, and MedLink.

A version of this article originally appeared on Medscape.com.

This transcript has been edited for clarity.

This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent randomized clinical trial suggesting that multivitamins may improve memory and slow cognitive aging, compared with placebo, known as COSMOS (Cocoa Supplement and Multivitamins Outcome Study). This is the second COSMOS trial to show a benefit of multivitamins on memory and cognition. This trial involved a collaboration between Brigham and Columbia University and was published in the American Journal of Clinical Nutrition. I’d like to acknowledge that I am a coauthor of this study, together with Dr. Howard Sesso, who co-leads the main COSMOS trial with me.

Preserving memory and cognitive function is of critical importance to older adults. Nutritional interventions play an important role because we know the brain requires several nutrients for optimal health, and deficiencies in one or more of these nutrients may accelerate cognitive decline. Some of the micronutrients that are known to be important for brain health include vitamin B12, thiamin, other B vitamins, lutein, magnesium, and zinc, among others.

The current trial included 3,500 participants aged 60 or older, looking at performance on a web-based memory test. The multivitamin group did significantly better than the placebo group on memory tests and word recall, a finding that was estimated as the equivalent of slowing age-related memory loss by about 3 years. The benefit was first seen at 1 year and was sustained across the 3 years of the trial.

Intriguingly, in both COSMOS and COSMOS-Web, and the earlier COSMOS-Mind study, which was done in collaboration with Wake Forest, the participants with a history of cardiovascular disease showed the greatest benefits from multivitamins, perhaps due to lower nutrient status. But the basis for this finding needs to be explored further.

A few important caveats need to be emphasized. First, multivitamins and other dietary supplements will never be a substitute for a healthy diet and healthy lifestyle and should not distract from those goals. But multivitamins may have a role as a complementary strategy. Another caveat is that the randomized trials tested recommended dietary allowances and not megadoses of these micronutrients. In fact, randomized trials of high doses of isolated micronutrients have not clearly shown cognitive benefits, and this suggests that more is not necessarily better and may be worse. High doses also may be associated with toxicity, or they may interfere with absorption or bioavailability of other nutrients.

In COSMOS, over the average 3.6 years of follow-up and in the earlier Physicians’ Health Study II,  over 1 year of supplementation, multivitamins were found to be safe without any clear risks or safety concerns. A further caveat is that although Centrum Silver was tested in this trial, we would not expect that this is a brand-specific benefit, and other high-quality multivitamin brands would be expected to confer similar benefits. Of course, it’s important to check bottles for quality-control documentation such as the seals of the U.S. Pharmacopeia, National Science Foundation, ConsumerLab.com, and other auditors.

Overall, the finding that a daily multivitamin improved memory and slowed cognitive decline in two separate COSMOS randomized trials is exciting, suggesting that multivitamin supplementation holds promise as a safe, accessible, and affordable approach to protecting cognitive health in older adults. Further research will be needed to understand who is most likely to benefit and the biological mechanisms involved. Expert committees will have to look at the research and decide whether any changes in guidelines are indicated in the future.

Dr. Manson is Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School and director of the Division of Preventive Medicine, Brigham and Women’s Hospital, both in Boston. She reported receiving funding/donations from Mars Symbioscience.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent randomized clinical trial suggesting that multivitamins may improve memory and slow cognitive aging, compared with placebo, known as COSMOS (Cocoa Supplement and Multivitamins Outcome Study). This is the second COSMOS trial to show a benefit of multivitamins on memory and cognition. This trial involved a collaboration between Brigham and Columbia University and was published in the American Journal of Clinical Nutrition. I’d like to acknowledge that I am a coauthor of this study, together with Dr. Howard Sesso, who co-leads the main COSMOS trial with me.

Preserving memory and cognitive function is of critical importance to older adults. Nutritional interventions play an important role because we know the brain requires several nutrients for optimal health, and deficiencies in one or more of these nutrients may accelerate cognitive decline. Some of the micronutrients that are known to be important for brain health include vitamin B12, thiamin, other B vitamins, lutein, magnesium, and zinc, among others.

The current trial included 3,500 participants aged 60 or older, looking at performance on a web-based memory test. The multivitamin group did significantly better than the placebo group on memory tests and word recall, a finding that was estimated as the equivalent of slowing age-related memory loss by about 3 years. The benefit was first seen at 1 year and was sustained across the 3 years of the trial.

Intriguingly, in both COSMOS and COSMOS-Web, and the earlier COSMOS-Mind study, which was done in collaboration with Wake Forest, the participants with a history of cardiovascular disease showed the greatest benefits from multivitamins, perhaps due to lower nutrient status. But the basis for this finding needs to be explored further.

A few important caveats need to be emphasized. First, multivitamins and other dietary supplements will never be a substitute for a healthy diet and healthy lifestyle and should not distract from those goals. But multivitamins may have a role as a complementary strategy. Another caveat is that the randomized trials tested recommended dietary allowances and not megadoses of these micronutrients. In fact, randomized trials of high doses of isolated micronutrients have not clearly shown cognitive benefits, and this suggests that more is not necessarily better and may be worse. High doses also may be associated with toxicity, or they may interfere with absorption or bioavailability of other nutrients.

In COSMOS, over the average 3.6 years of follow-up and in the earlier Physicians’ Health Study II,  over 1 year of supplementation, multivitamins were found to be safe without any clear risks or safety concerns. A further caveat is that although Centrum Silver was tested in this trial, we would not expect that this is a brand-specific benefit, and other high-quality multivitamin brands would be expected to confer similar benefits. Of course, it’s important to check bottles for quality-control documentation such as the seals of the U.S. Pharmacopeia, National Science Foundation, ConsumerLab.com, and other auditors.

Overall, the finding that a daily multivitamin improved memory and slowed cognitive decline in two separate COSMOS randomized trials is exciting, suggesting that multivitamin supplementation holds promise as a safe, accessible, and affordable approach to protecting cognitive health in older adults. Further research will be needed to understand who is most likely to benefit and the biological mechanisms involved. Expert committees will have to look at the research and decide whether any changes in guidelines are indicated in the future.

Dr. Manson is Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School and director of the Division of Preventive Medicine, Brigham and Women’s Hospital, both in Boston. She reported receiving funding/donations from Mars Symbioscience.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent randomized clinical trial suggesting that multivitamins may improve memory and slow cognitive aging, compared with placebo, known as COSMOS (Cocoa Supplement and Multivitamins Outcome Study). This is the second COSMOS trial to show a benefit of multivitamins on memory and cognition. This trial involved a collaboration between Brigham and Columbia University and was published in the American Journal of Clinical Nutrition. I’d like to acknowledge that I am a coauthor of this study, together with Dr. Howard Sesso, who co-leads the main COSMOS trial with me.

Preserving memory and cognitive function is of critical importance to older adults. Nutritional interventions play an important role because we know the brain requires several nutrients for optimal health, and deficiencies in one or more of these nutrients may accelerate cognitive decline. Some of the micronutrients that are known to be important for brain health include vitamin B12, thiamin, other B vitamins, lutein, magnesium, and zinc, among others.

The current trial included 3,500 participants aged 60 or older, looking at performance on a web-based memory test. The multivitamin group did significantly better than the placebo group on memory tests and word recall, a finding that was estimated as the equivalent of slowing age-related memory loss by about 3 years. The benefit was first seen at 1 year and was sustained across the 3 years of the trial.

Intriguingly, in both COSMOS and COSMOS-Web, and the earlier COSMOS-Mind study, which was done in collaboration with Wake Forest, the participants with a history of cardiovascular disease showed the greatest benefits from multivitamins, perhaps due to lower nutrient status. But the basis for this finding needs to be explored further.

A few important caveats need to be emphasized. First, multivitamins and other dietary supplements will never be a substitute for a healthy diet and healthy lifestyle and should not distract from those goals. But multivitamins may have a role as a complementary strategy. Another caveat is that the randomized trials tested recommended dietary allowances and not megadoses of these micronutrients. In fact, randomized trials of high doses of isolated micronutrients have not clearly shown cognitive benefits, and this suggests that more is not necessarily better and may be worse. High doses also may be associated with toxicity, or they may interfere with absorption or bioavailability of other nutrients.

In COSMOS, over the average 3.6 years of follow-up and in the earlier Physicians’ Health Study II,  over 1 year of supplementation, multivitamins were found to be safe without any clear risks or safety concerns. A further caveat is that although Centrum Silver was tested in this trial, we would not expect that this is a brand-specific benefit, and other high-quality multivitamin brands would be expected to confer similar benefits. Of course, it’s important to check bottles for quality-control documentation such as the seals of the U.S. Pharmacopeia, National Science Foundation, ConsumerLab.com, and other auditors.

Overall, the finding that a daily multivitamin improved memory and slowed cognitive decline in two separate COSMOS randomized trials is exciting, suggesting that multivitamin supplementation holds promise as a safe, accessible, and affordable approach to protecting cognitive health in older adults. Further research will be needed to understand who is most likely to benefit and the biological mechanisms involved. Expert committees will have to look at the research and decide whether any changes in guidelines are indicated in the future.

Dr. Manson is Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School and director of the Division of Preventive Medicine, Brigham and Women’s Hospital, both in Boston. She reported receiving funding/donations from Mars Symbioscience.

A version of this article first appeared on Medscape.com.

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.