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Patients with post-COVID cognitive symptoms may have gliosis
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.
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.
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.
FROM JAMA PSYCHIATRY
Are periodontitis, stroke, and Alzheimer’s disease linked?
MADRID –
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 –
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 –
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.
Daily multivitamins boost memory in older adults: A randomized trial
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. , 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. , 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. , 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.
FDA panel unanimously endorses lecanemab for Alzheimer’s
“Overall, the study demonstrated clearly that this is an effective treatment,” said acting chair Robert C. Alexander, MD, chief scientific officer, Alzheimer’s Prevention Initiative, Banner Alzheimer’s Institute, and research professor, department of psychiatry, University of Arizona, Phoenix, during the meeting.
An intravenous infusion targeting amyloid-beta, lecanemab received accelerated FDA approved earlier in 2023 for the treatment of early Alzheimer’s disease (AD). The company was required to complete a confirmatory study to verify and describe the product’s clinical benefit.
The Peripheral and Central Nervous System Drugs Advisory Committee met to discuss this phase 3 study (CLARITY-AD). The multicenter, double-blind study included 1,795 patients (mean age, 71 years) who had mild cognitive impairment caused by AD or mild AD dementia.
Delayed progression
Study participants had a broad range of comorbidities, and many were concomitantly receiving other medications. Black people were underrepresented in the study at just 3% of the total cohort.
Patients were randomly assigned to receive placebo or lecanemab 10 mg/kg biweekly. In addition to a placebo-controlled period and safety follow-up, the study has an ongoing extension phase of up to 4 years.
The study met its primary endpoint, showing a highly statistically significant 27% less decline on the Clinical Dementia Rating-Sum of Boxes at 18 months (difference in adjusted mean, –0.45; 95% CI, –0.67 to –0.23; P = .00005).
This was supported by a significant 26% difference on the AD Assessment Scale–Cognitive Subscale with 14 tasks (ADAS-Cog 14).
The drug also affected function, with a 37% decrease, compared with placebo, on the AD Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment.
Committee members heard that the results signal delays in disease progression by about 5 months, giving patients more time to live independently and participate in hobbies and interests.
Patients who received the active drug also experienced quality of life benefits. Compared with patients who received placebo, those who took lecanemab had 49% less decline as measured with the European Quality of Life–5 Dimensions scale and 56% less decline as measured by the Quality of Life in AD scale, and caregivers reported less burden.
Lecanemab also affected biomarkers of amyloid, tau, and neurodegeneration, providing a biological basis for the treatment effects consistent with slowing of disease progression.
Unanimous support
All six committee members agreed by vote that the study provides evidence of clinical benefit. They variously descried the study and results as “robust,” “compelling,” “well conducted,” “clear and consistent,” and “clinically meaningful.”
In the active treatment group, there was a higher incidence of amyloid-related imaging abnormalities (ARIAs), which can be serious and life-threatening but are usually asymptomatic. In this study, most ARIAs had resolved by 3 months.
Deaths occurred in 0.8% of the placebo and 0.7% of the treatment group. Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., noted that the numbers of deaths and serious adverse events were “quite similar” in the two groups.
“And for serious ARIA, there was an imbalance favoring placebo, but overall, these were pretty rare,” he said.
Subgroup concerns
Committee members discussed the risk/benefit profile for three subgroups of patients – those with apolipoprotein E4 (apo E4) allele, patients taking an anticoagulant, and those with cerebral amyloid angiopathy (CAA).
In the apo E4 group, the study’s primary endpoint did not favor the drug, but secondary endpoints did.
“I think the general feeling [for apo E4 status] is that the risk/benefit still remains favorable, especially when looking across multiple endpoints,” said Dr. Alexander.
However, some members supported recommending genetic testing before initiating the drug.
The views were more diverse for the use of lecanemab in the presence of an anticoagulant, which may increase the risk for cerebral hemorrhage. Some committee members strongly recommended that these patients not receive lecanemab, while others highlighted the need for more information, owing to uncertainties about the risks.
With respect to CAA, most members supported the idea of considering use of the drug in the presence of this condition, but only after discussing the risks with patients and their families and in the presence of a robust reporting system.
An Alzheimer’s Association representative was in attendance during the public hearing portion of the meeting to express support for traditional approval of lecanemab for people with early AD.
The association strongly favors full Medicare coverage for FDA-approved AD treatments. The Centers for Medicare & Medicaid Services has determined that AD treatments receiving traditional FDA approval will be covered if clinicians register and enter data in a registry.
“While this is an important signal that CMS wants to improve access to FDA-approved treatments, registry as a condition of coverage is an unnecessary and potentially harmful barrier,” said the Alzheimer’s Association in a press release following the meeting.
A version of this article first appeared on Medscape.com.
“Overall, the study demonstrated clearly that this is an effective treatment,” said acting chair Robert C. Alexander, MD, chief scientific officer, Alzheimer’s Prevention Initiative, Banner Alzheimer’s Institute, and research professor, department of psychiatry, University of Arizona, Phoenix, during the meeting.
An intravenous infusion targeting amyloid-beta, lecanemab received accelerated FDA approved earlier in 2023 for the treatment of early Alzheimer’s disease (AD). The company was required to complete a confirmatory study to verify and describe the product’s clinical benefit.
The Peripheral and Central Nervous System Drugs Advisory Committee met to discuss this phase 3 study (CLARITY-AD). The multicenter, double-blind study included 1,795 patients (mean age, 71 years) who had mild cognitive impairment caused by AD or mild AD dementia.
Delayed progression
Study participants had a broad range of comorbidities, and many were concomitantly receiving other medications. Black people were underrepresented in the study at just 3% of the total cohort.
Patients were randomly assigned to receive placebo or lecanemab 10 mg/kg biweekly. In addition to a placebo-controlled period and safety follow-up, the study has an ongoing extension phase of up to 4 years.
The study met its primary endpoint, showing a highly statistically significant 27% less decline on the Clinical Dementia Rating-Sum of Boxes at 18 months (difference in adjusted mean, –0.45; 95% CI, –0.67 to –0.23; P = .00005).
This was supported by a significant 26% difference on the AD Assessment Scale–Cognitive Subscale with 14 tasks (ADAS-Cog 14).
The drug also affected function, with a 37% decrease, compared with placebo, on the AD Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment.
Committee members heard that the results signal delays in disease progression by about 5 months, giving patients more time to live independently and participate in hobbies and interests.
Patients who received the active drug also experienced quality of life benefits. Compared with patients who received placebo, those who took lecanemab had 49% less decline as measured with the European Quality of Life–5 Dimensions scale and 56% less decline as measured by the Quality of Life in AD scale, and caregivers reported less burden.
Lecanemab also affected biomarkers of amyloid, tau, and neurodegeneration, providing a biological basis for the treatment effects consistent with slowing of disease progression.
Unanimous support
All six committee members agreed by vote that the study provides evidence of clinical benefit. They variously descried the study and results as “robust,” “compelling,” “well conducted,” “clear and consistent,” and “clinically meaningful.”
In the active treatment group, there was a higher incidence of amyloid-related imaging abnormalities (ARIAs), which can be serious and life-threatening but are usually asymptomatic. In this study, most ARIAs had resolved by 3 months.
Deaths occurred in 0.8% of the placebo and 0.7% of the treatment group. Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., noted that the numbers of deaths and serious adverse events were “quite similar” in the two groups.
“And for serious ARIA, there was an imbalance favoring placebo, but overall, these were pretty rare,” he said.
Subgroup concerns
Committee members discussed the risk/benefit profile for three subgroups of patients – those with apolipoprotein E4 (apo E4) allele, patients taking an anticoagulant, and those with cerebral amyloid angiopathy (CAA).
In the apo E4 group, the study’s primary endpoint did not favor the drug, but secondary endpoints did.
“I think the general feeling [for apo E4 status] is that the risk/benefit still remains favorable, especially when looking across multiple endpoints,” said Dr. Alexander.
However, some members supported recommending genetic testing before initiating the drug.
The views were more diverse for the use of lecanemab in the presence of an anticoagulant, which may increase the risk for cerebral hemorrhage. Some committee members strongly recommended that these patients not receive lecanemab, while others highlighted the need for more information, owing to uncertainties about the risks.
With respect to CAA, most members supported the idea of considering use of the drug in the presence of this condition, but only after discussing the risks with patients and their families and in the presence of a robust reporting system.
An Alzheimer’s Association representative was in attendance during the public hearing portion of the meeting to express support for traditional approval of lecanemab for people with early AD.
The association strongly favors full Medicare coverage for FDA-approved AD treatments. The Centers for Medicare & Medicaid Services has determined that AD treatments receiving traditional FDA approval will be covered if clinicians register and enter data in a registry.
“While this is an important signal that CMS wants to improve access to FDA-approved treatments, registry as a condition of coverage is an unnecessary and potentially harmful barrier,” said the Alzheimer’s Association in a press release following the meeting.
A version of this article first appeared on Medscape.com.
“Overall, the study demonstrated clearly that this is an effective treatment,” said acting chair Robert C. Alexander, MD, chief scientific officer, Alzheimer’s Prevention Initiative, Banner Alzheimer’s Institute, and research professor, department of psychiatry, University of Arizona, Phoenix, during the meeting.
An intravenous infusion targeting amyloid-beta, lecanemab received accelerated FDA approved earlier in 2023 for the treatment of early Alzheimer’s disease (AD). The company was required to complete a confirmatory study to verify and describe the product’s clinical benefit.
The Peripheral and Central Nervous System Drugs Advisory Committee met to discuss this phase 3 study (CLARITY-AD). The multicenter, double-blind study included 1,795 patients (mean age, 71 years) who had mild cognitive impairment caused by AD or mild AD dementia.
Delayed progression
Study participants had a broad range of comorbidities, and many were concomitantly receiving other medications. Black people were underrepresented in the study at just 3% of the total cohort.
Patients were randomly assigned to receive placebo or lecanemab 10 mg/kg biweekly. In addition to a placebo-controlled period and safety follow-up, the study has an ongoing extension phase of up to 4 years.
The study met its primary endpoint, showing a highly statistically significant 27% less decline on the Clinical Dementia Rating-Sum of Boxes at 18 months (difference in adjusted mean, –0.45; 95% CI, –0.67 to –0.23; P = .00005).
This was supported by a significant 26% difference on the AD Assessment Scale–Cognitive Subscale with 14 tasks (ADAS-Cog 14).
The drug also affected function, with a 37% decrease, compared with placebo, on the AD Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment.
Committee members heard that the results signal delays in disease progression by about 5 months, giving patients more time to live independently and participate in hobbies and interests.
Patients who received the active drug also experienced quality of life benefits. Compared with patients who received placebo, those who took lecanemab had 49% less decline as measured with the European Quality of Life–5 Dimensions scale and 56% less decline as measured by the Quality of Life in AD scale, and caregivers reported less burden.
Lecanemab also affected biomarkers of amyloid, tau, and neurodegeneration, providing a biological basis for the treatment effects consistent with slowing of disease progression.
Unanimous support
All six committee members agreed by vote that the study provides evidence of clinical benefit. They variously descried the study and results as “robust,” “compelling,” “well conducted,” “clear and consistent,” and “clinically meaningful.”
In the active treatment group, there was a higher incidence of amyloid-related imaging abnormalities (ARIAs), which can be serious and life-threatening but are usually asymptomatic. In this study, most ARIAs had resolved by 3 months.
Deaths occurred in 0.8% of the placebo and 0.7% of the treatment group. Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., noted that the numbers of deaths and serious adverse events were “quite similar” in the two groups.
“And for serious ARIA, there was an imbalance favoring placebo, but overall, these were pretty rare,” he said.
Subgroup concerns
Committee members discussed the risk/benefit profile for three subgroups of patients – those with apolipoprotein E4 (apo E4) allele, patients taking an anticoagulant, and those with cerebral amyloid angiopathy (CAA).
In the apo E4 group, the study’s primary endpoint did not favor the drug, but secondary endpoints did.
“I think the general feeling [for apo E4 status] is that the risk/benefit still remains favorable, especially when looking across multiple endpoints,” said Dr. Alexander.
However, some members supported recommending genetic testing before initiating the drug.
The views were more diverse for the use of lecanemab in the presence of an anticoagulant, which may increase the risk for cerebral hemorrhage. Some committee members strongly recommended that these patients not receive lecanemab, while others highlighted the need for more information, owing to uncertainties about the risks.
With respect to CAA, most members supported the idea of considering use of the drug in the presence of this condition, but only after discussing the risks with patients and their families and in the presence of a robust reporting system.
An Alzheimer’s Association representative was in attendance during the public hearing portion of the meeting to express support for traditional approval of lecanemab for people with early AD.
The association strongly favors full Medicare coverage for FDA-approved AD treatments. The Centers for Medicare & Medicaid Services has determined that AD treatments receiving traditional FDA approval will be covered if clinicians register and enter data in a registry.
“While this is an important signal that CMS wants to improve access to FDA-approved treatments, registry as a condition of coverage is an unnecessary and potentially harmful barrier,” said the Alzheimer’s Association in a press release following the meeting.
A version of this article first appeared on Medscape.com.
Cognitive decline risk in adult childhood cancer survivors
Among more than 2,300 adult survivors of childhood cancer and their siblings, who served as controls, new-onset memory impairment emerged more often in survivors decades later.
The increased risk was associated with the cancer treatment that was provided as well as modifiable health behaviors and chronic health conditions.
Even 35 years after being diagnosed, cancer survivors who never received chemotherapies or radiation therapies known to damage the brain reported far greater memory impairment than did their siblings, first author Nicholas Phillips, MD, told this news organization.
What the findings suggest is that “we need to educate oncologists and primary care providers on the risks our survivors face long after completion of therapy,” said Dr. Phillips, of the epidemiology and cancer control department at St. Jude Children’s Research Hospital, Memphis, Tenn.
The study was published online in JAMA Network Open.
Cancer survivors face an elevated risk for severe neurocognitive effects that can emerge 5-10 years following their diagnosis and treatment. However, it’s unclear whether new-onset neurocognitive problems can still develop a decade or more following diagnosis.
Over a long-term follow-up, Dr. Phillips and colleagues explored this question in 2,375 adult survivors of childhood cancer from the Childhood Cancer Survivor Study and 232 of their siblings.
Among the cancer cohort, 1,316 patients were survivors of acute lymphoblastic leukemia (ALL), 488 were survivors of central nervous system (CNS) tumors, and 571 had survived Hodgkin lymphoma.
The researchers determined the prevalence of new-onset neurocognitive impairment between baseline (23 years after diagnosis) and follow-up (35 years after diagnosis). New-onset neurocognitive impairment – present at follow-up but not at baseline – was defined as having a score in the worst 10% of the sibling cohort.
A higher proportion of survivors had new-onset memory impairment at follow-up compared with siblings. Specifically, about 8% of siblings had new-onset memory trouble, compared with 14% of ALL survivors treated with chemotherapy only, 26% of ALL survivors treated with cranial radiation, 35% of CNS tumor survivors, and 17% of Hodgkin lymphoma survivors.
New-onset memory impairment was associated with cranial radiation among CNS tumor survivors (relative risk [RR], 1.97) and alkylator chemotherapy at or above 8,000 mg/m2 among survivors of ALL who were treated without cranial radiation (RR, 2.80). The authors also found that smoking, low educational attainment, and low physical activity were associated with an elevated risk for new-onset memory impairment.
Dr. Phillips noted that current guidelines emphasize the importance of short-term monitoring of a survivor’s neurocognitive status on the basis of that person’s chemotherapy and radiation exposures.
However, “our study suggests that all survivors, regardless of their therapy, should be screened regularly for new-onset neurocognitive problems. And this screening should be done regularly for decades after diagnosis,” he said in an interview.
Dr. Phillips also noted the importance of communicating lifestyle modifications, such as not smoking and maintaining an active lifestyle.
“We need to start early and use the power of repetition when communicating with our survivors and their families,” Dr. Phillips said. “When our families and survivors hear the word ‘exercise,’ they think of gym memberships, lifting weights, and running on treadmills. But what we really want our survivors to do is stay active.”
What this means is engaging for about 2.5 hours a week in a range of activities, such as ballet, basketball, volleyball, bicycling, or swimming.
“And if our kids want to quit after 3 months, let them know that this is okay. They just need to replace that activity with another activity,” said Dr. Phillips. “We want them to find a fun hobby that they will enjoy that will keep them active.”
The study was supported by the National Cancer Institute. Dr. Phillips has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Among more than 2,300 adult survivors of childhood cancer and their siblings, who served as controls, new-onset memory impairment emerged more often in survivors decades later.
The increased risk was associated with the cancer treatment that was provided as well as modifiable health behaviors and chronic health conditions.
Even 35 years after being diagnosed, cancer survivors who never received chemotherapies or radiation therapies known to damage the brain reported far greater memory impairment than did their siblings, first author Nicholas Phillips, MD, told this news organization.
What the findings suggest is that “we need to educate oncologists and primary care providers on the risks our survivors face long after completion of therapy,” said Dr. Phillips, of the epidemiology and cancer control department at St. Jude Children’s Research Hospital, Memphis, Tenn.
The study was published online in JAMA Network Open.
Cancer survivors face an elevated risk for severe neurocognitive effects that can emerge 5-10 years following their diagnosis and treatment. However, it’s unclear whether new-onset neurocognitive problems can still develop a decade or more following diagnosis.
Over a long-term follow-up, Dr. Phillips and colleagues explored this question in 2,375 adult survivors of childhood cancer from the Childhood Cancer Survivor Study and 232 of their siblings.
Among the cancer cohort, 1,316 patients were survivors of acute lymphoblastic leukemia (ALL), 488 were survivors of central nervous system (CNS) tumors, and 571 had survived Hodgkin lymphoma.
The researchers determined the prevalence of new-onset neurocognitive impairment between baseline (23 years after diagnosis) and follow-up (35 years after diagnosis). New-onset neurocognitive impairment – present at follow-up but not at baseline – was defined as having a score in the worst 10% of the sibling cohort.
A higher proportion of survivors had new-onset memory impairment at follow-up compared with siblings. Specifically, about 8% of siblings had new-onset memory trouble, compared with 14% of ALL survivors treated with chemotherapy only, 26% of ALL survivors treated with cranial radiation, 35% of CNS tumor survivors, and 17% of Hodgkin lymphoma survivors.
New-onset memory impairment was associated with cranial radiation among CNS tumor survivors (relative risk [RR], 1.97) and alkylator chemotherapy at or above 8,000 mg/m2 among survivors of ALL who were treated without cranial radiation (RR, 2.80). The authors also found that smoking, low educational attainment, and low physical activity were associated with an elevated risk for new-onset memory impairment.
Dr. Phillips noted that current guidelines emphasize the importance of short-term monitoring of a survivor’s neurocognitive status on the basis of that person’s chemotherapy and radiation exposures.
However, “our study suggests that all survivors, regardless of their therapy, should be screened regularly for new-onset neurocognitive problems. And this screening should be done regularly for decades after diagnosis,” he said in an interview.
Dr. Phillips also noted the importance of communicating lifestyle modifications, such as not smoking and maintaining an active lifestyle.
“We need to start early and use the power of repetition when communicating with our survivors and their families,” Dr. Phillips said. “When our families and survivors hear the word ‘exercise,’ they think of gym memberships, lifting weights, and running on treadmills. But what we really want our survivors to do is stay active.”
What this means is engaging for about 2.5 hours a week in a range of activities, such as ballet, basketball, volleyball, bicycling, or swimming.
“And if our kids want to quit after 3 months, let them know that this is okay. They just need to replace that activity with another activity,” said Dr. Phillips. “We want them to find a fun hobby that they will enjoy that will keep them active.”
The study was supported by the National Cancer Institute. Dr. Phillips has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Among more than 2,300 adult survivors of childhood cancer and their siblings, who served as controls, new-onset memory impairment emerged more often in survivors decades later.
The increased risk was associated with the cancer treatment that was provided as well as modifiable health behaviors and chronic health conditions.
Even 35 years after being diagnosed, cancer survivors who never received chemotherapies or radiation therapies known to damage the brain reported far greater memory impairment than did their siblings, first author Nicholas Phillips, MD, told this news organization.
What the findings suggest is that “we need to educate oncologists and primary care providers on the risks our survivors face long after completion of therapy,” said Dr. Phillips, of the epidemiology and cancer control department at St. Jude Children’s Research Hospital, Memphis, Tenn.
The study was published online in JAMA Network Open.
Cancer survivors face an elevated risk for severe neurocognitive effects that can emerge 5-10 years following their diagnosis and treatment. However, it’s unclear whether new-onset neurocognitive problems can still develop a decade or more following diagnosis.
Over a long-term follow-up, Dr. Phillips and colleagues explored this question in 2,375 adult survivors of childhood cancer from the Childhood Cancer Survivor Study and 232 of their siblings.
Among the cancer cohort, 1,316 patients were survivors of acute lymphoblastic leukemia (ALL), 488 were survivors of central nervous system (CNS) tumors, and 571 had survived Hodgkin lymphoma.
The researchers determined the prevalence of new-onset neurocognitive impairment between baseline (23 years after diagnosis) and follow-up (35 years after diagnosis). New-onset neurocognitive impairment – present at follow-up but not at baseline – was defined as having a score in the worst 10% of the sibling cohort.
A higher proportion of survivors had new-onset memory impairment at follow-up compared with siblings. Specifically, about 8% of siblings had new-onset memory trouble, compared with 14% of ALL survivors treated with chemotherapy only, 26% of ALL survivors treated with cranial radiation, 35% of CNS tumor survivors, and 17% of Hodgkin lymphoma survivors.
New-onset memory impairment was associated with cranial radiation among CNS tumor survivors (relative risk [RR], 1.97) and alkylator chemotherapy at or above 8,000 mg/m2 among survivors of ALL who were treated without cranial radiation (RR, 2.80). The authors also found that smoking, low educational attainment, and low physical activity were associated with an elevated risk for new-onset memory impairment.
Dr. Phillips noted that current guidelines emphasize the importance of short-term monitoring of a survivor’s neurocognitive status on the basis of that person’s chemotherapy and radiation exposures.
However, “our study suggests that all survivors, regardless of their therapy, should be screened regularly for new-onset neurocognitive problems. And this screening should be done regularly for decades after diagnosis,” he said in an interview.
Dr. Phillips also noted the importance of communicating lifestyle modifications, such as not smoking and maintaining an active lifestyle.
“We need to start early and use the power of repetition when communicating with our survivors and their families,” Dr. Phillips said. “When our families and survivors hear the word ‘exercise,’ they think of gym memberships, lifting weights, and running on treadmills. But what we really want our survivors to do is stay active.”
What this means is engaging for about 2.5 hours a week in a range of activities, such as ballet, basketball, volleyball, bicycling, or swimming.
“And if our kids want to quit after 3 months, let them know that this is okay. They just need to replace that activity with another activity,” said Dr. Phillips. “We want them to find a fun hobby that they will enjoy that will keep them active.”
The study was supported by the National Cancer Institute. Dr. Phillips has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Muscle fat: A new risk factor for cognitive decline?
Investigators assessed muscle fat in more than 1,600 adults in their 70s and evaluated their cognitive function over a 10-year period. They found that increases in muscle adiposity from year 1 to year 6 were associated with greater cognitive decline over time, independent of total weight, other fat deposits, muscle characteristics, and traditional dementia risk factors.
The findings were similar between Black and White people and between men and women.
“Increasing adiposity – or fat deposition – in skeletal muscles predicted faster cognitive decline, irrespective of demographics or other disease, and this effect was distinct from that of other types of fat or other muscle characteristics, such as strength or mass,” study investigator Caterina Rosano MD, MPH, professor of epidemiology at the University of Pittsburgh, said in an interview.
The study was published in the Journal of the American Geriatrics Society.
Biologically plausible
“There has been a growing recognition that overall adiposity and muscle measures, such as strength and mass, are individual indicators of future dementia risk and both strengthen the algorithms to predict cognitive decline,” said Dr. Rosano, associate director for clinical translation at the University of Pittsburgh’s Aging Institute. “However, adiposity in the muscle has not been examined.”
Some evidence supports a “biologically plausible link” between muscle adiposity and dementia risk. For example, muscle adiposity increases the risk for type 2 diabetes and hypertension, both of which are dementia risk factors.
Skeletal muscle adiposity increases with older age, even in older adults who lose weight, and is “highly prevalent” among older adults of African ancestry.
The researchers examined a large, biracial sample of older adults participating in the Health, Aging and Body Composition study, which enrolled men and women aged between 70 and 79 years. Participants were followed for an average of 9.0 ± 1.8 years.
During years 1 and 6, participants’ body composition was analyzed, including intermuscular adipose tissue (IMAT), visceral and subcutaneous adiposity, total fat mass, and muscle area.
In years 1, 3, 5, 8, and 10, participants’ cognition was measured using the modified Mini-Mental State (3MS) exam.
The main independent variable was 5-year change in thigh IMAT (year 6 minus year 1), and the main dependent variable was 3MS decline (from year 5 to year 10).
The researchers adjusted all the models for traditional dementia risk factors at baseline including 3MS, education, apo E4 allele, diabetes, hypertension, and physical activity and also calculated interactions between IMAT change by race or sex.
These models also accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass as well as cytokines related to adiposity.
‘Rich and engaging crosstalk’
The final sample included 1634 participants (mean age, 73.38 years at baseline; 48% female; 35% Black; mean baseline 3MS score, 91.6).
Thigh IMAT increased by 39.0% in all participants from year 1 to year 6, which corresponded to an increase of 4.85 cm2 or 0.97 cm2/year. During the same time period, muscle strength decreased by 14.0% (P < .05), although thigh muscle area remained stable, decreasing less than 0.5%.
There were decreases in both abdominal subcutaneous and visceral adiposity of 3.92% and 6.43%, respectively (P < .05). There was a decrease of 3.3% in 3MS from year 5 to year 10.
Several variables were associated with 3MS decline, independent of any change in thigh IMAT: older age, less education, and having at least one copy of the APOe4 allele. These variables were included in the model of IMAT change predicting 3MS change.
A statistically significant association of IMAT increase with 3MS decline was found. The IMAT increase of 4.85 cm2 corresponded to a 3MS decline of an additional 3.6 points (P < .0001) from year 5 to year 10, “indicating a clinically important change.”
The association between increasing thigh IMAT with declining 3MS “remained statistically significant” after adjusting for race, age, education, and apo E4 (P < .0001) and was independent of changes in thigh muscle area, muscle strength, and other adiposity measures.
In participants with increased IMAT in years 1-6, the mean 3MS score fell to approximately 87 points at year 10, compared with those without increased IMAT, with a 3MS score that dropped to approximately 89 points.
Interactions by race and sex were not statistically significant (P > .08).
“Our results suggest that adiposity in muscles can predict cognitive decline, in addition to (not instead of) other traditional dementia risk factors,” said Dr. Rosano.
There is “a rich and engaging crosstalk between muscle, adipose tissue, and the brain all throughout our lives, happening through factors released in the bloodstream that can reach the brain, however, the specific identity of the factors responsible for the crosstalk of muscle adiposity and brain in older adults has not yet been discovered,” she noted.
Although muscle adiposity is “not yet routinely measured in clinical settings, it is being measured opportunistically on clinical CT scans obtained as part of routine patient care,” she added. “These CT measurements have already been validated in many studies of older adults; thus, clinicians could have access to this novel information without additional cost, time, or radiation exposure.”
Causality not proven
In a comment, Bruce Albala, PhD, professor, department of environmental and occupational health, University of California, Irvine, noted that the 3MS assessment is scored on a 100-point scale, with a score less than 78 “generally regarded as indicating cognitive impairment or approaching a dementia condition.” In the current study, the mean 3MS score of participants with increased IMAT was still “well above the dementia cut-off.”
Moreover, “even if there is a relationship or correlation between IMAT and cognition, this does not prove or even suggest causality, especially from a biological mechanistic approach,” said Dr. Albaba, an adjunct professor of neurology, who was not involved in the study. “Clearly, more research is needed even to understand the relationship between these two factors.”
The study was supported by the National Institute on Aging. Dr. Rosano and coauthors and Dr. Albala declared no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Investigators assessed muscle fat in more than 1,600 adults in their 70s and evaluated their cognitive function over a 10-year period. They found that increases in muscle adiposity from year 1 to year 6 were associated with greater cognitive decline over time, independent of total weight, other fat deposits, muscle characteristics, and traditional dementia risk factors.
The findings were similar between Black and White people and between men and women.
“Increasing adiposity – or fat deposition – in skeletal muscles predicted faster cognitive decline, irrespective of demographics or other disease, and this effect was distinct from that of other types of fat or other muscle characteristics, such as strength or mass,” study investigator Caterina Rosano MD, MPH, professor of epidemiology at the University of Pittsburgh, said in an interview.
The study was published in the Journal of the American Geriatrics Society.
Biologically plausible
“There has been a growing recognition that overall adiposity and muscle measures, such as strength and mass, are individual indicators of future dementia risk and both strengthen the algorithms to predict cognitive decline,” said Dr. Rosano, associate director for clinical translation at the University of Pittsburgh’s Aging Institute. “However, adiposity in the muscle has not been examined.”
Some evidence supports a “biologically plausible link” between muscle adiposity and dementia risk. For example, muscle adiposity increases the risk for type 2 diabetes and hypertension, both of which are dementia risk factors.
Skeletal muscle adiposity increases with older age, even in older adults who lose weight, and is “highly prevalent” among older adults of African ancestry.
The researchers examined a large, biracial sample of older adults participating in the Health, Aging and Body Composition study, which enrolled men and women aged between 70 and 79 years. Participants were followed for an average of 9.0 ± 1.8 years.
During years 1 and 6, participants’ body composition was analyzed, including intermuscular adipose tissue (IMAT), visceral and subcutaneous adiposity, total fat mass, and muscle area.
In years 1, 3, 5, 8, and 10, participants’ cognition was measured using the modified Mini-Mental State (3MS) exam.
The main independent variable was 5-year change in thigh IMAT (year 6 minus year 1), and the main dependent variable was 3MS decline (from year 5 to year 10).
The researchers adjusted all the models for traditional dementia risk factors at baseline including 3MS, education, apo E4 allele, diabetes, hypertension, and physical activity and also calculated interactions between IMAT change by race or sex.
These models also accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass as well as cytokines related to adiposity.
‘Rich and engaging crosstalk’
The final sample included 1634 participants (mean age, 73.38 years at baseline; 48% female; 35% Black; mean baseline 3MS score, 91.6).
Thigh IMAT increased by 39.0% in all participants from year 1 to year 6, which corresponded to an increase of 4.85 cm2 or 0.97 cm2/year. During the same time period, muscle strength decreased by 14.0% (P < .05), although thigh muscle area remained stable, decreasing less than 0.5%.
There were decreases in both abdominal subcutaneous and visceral adiposity of 3.92% and 6.43%, respectively (P < .05). There was a decrease of 3.3% in 3MS from year 5 to year 10.
Several variables were associated with 3MS decline, independent of any change in thigh IMAT: older age, less education, and having at least one copy of the APOe4 allele. These variables were included in the model of IMAT change predicting 3MS change.
A statistically significant association of IMAT increase with 3MS decline was found. The IMAT increase of 4.85 cm2 corresponded to a 3MS decline of an additional 3.6 points (P < .0001) from year 5 to year 10, “indicating a clinically important change.”
The association between increasing thigh IMAT with declining 3MS “remained statistically significant” after adjusting for race, age, education, and apo E4 (P < .0001) and was independent of changes in thigh muscle area, muscle strength, and other adiposity measures.
In participants with increased IMAT in years 1-6, the mean 3MS score fell to approximately 87 points at year 10, compared with those without increased IMAT, with a 3MS score that dropped to approximately 89 points.
Interactions by race and sex were not statistically significant (P > .08).
“Our results suggest that adiposity in muscles can predict cognitive decline, in addition to (not instead of) other traditional dementia risk factors,” said Dr. Rosano.
There is “a rich and engaging crosstalk between muscle, adipose tissue, and the brain all throughout our lives, happening through factors released in the bloodstream that can reach the brain, however, the specific identity of the factors responsible for the crosstalk of muscle adiposity and brain in older adults has not yet been discovered,” she noted.
Although muscle adiposity is “not yet routinely measured in clinical settings, it is being measured opportunistically on clinical CT scans obtained as part of routine patient care,” she added. “These CT measurements have already been validated in many studies of older adults; thus, clinicians could have access to this novel information without additional cost, time, or radiation exposure.”
Causality not proven
In a comment, Bruce Albala, PhD, professor, department of environmental and occupational health, University of California, Irvine, noted that the 3MS assessment is scored on a 100-point scale, with a score less than 78 “generally regarded as indicating cognitive impairment or approaching a dementia condition.” In the current study, the mean 3MS score of participants with increased IMAT was still “well above the dementia cut-off.”
Moreover, “even if there is a relationship or correlation between IMAT and cognition, this does not prove or even suggest causality, especially from a biological mechanistic approach,” said Dr. Albaba, an adjunct professor of neurology, who was not involved in the study. “Clearly, more research is needed even to understand the relationship between these two factors.”
The study was supported by the National Institute on Aging. Dr. Rosano and coauthors and Dr. Albala declared no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Investigators assessed muscle fat in more than 1,600 adults in their 70s and evaluated their cognitive function over a 10-year period. They found that increases in muscle adiposity from year 1 to year 6 were associated with greater cognitive decline over time, independent of total weight, other fat deposits, muscle characteristics, and traditional dementia risk factors.
The findings were similar between Black and White people and between men and women.
“Increasing adiposity – or fat deposition – in skeletal muscles predicted faster cognitive decline, irrespective of demographics or other disease, and this effect was distinct from that of other types of fat or other muscle characteristics, such as strength or mass,” study investigator Caterina Rosano MD, MPH, professor of epidemiology at the University of Pittsburgh, said in an interview.
The study was published in the Journal of the American Geriatrics Society.
Biologically plausible
“There has been a growing recognition that overall adiposity and muscle measures, such as strength and mass, are individual indicators of future dementia risk and both strengthen the algorithms to predict cognitive decline,” said Dr. Rosano, associate director for clinical translation at the University of Pittsburgh’s Aging Institute. “However, adiposity in the muscle has not been examined.”
Some evidence supports a “biologically plausible link” between muscle adiposity and dementia risk. For example, muscle adiposity increases the risk for type 2 diabetes and hypertension, both of which are dementia risk factors.
Skeletal muscle adiposity increases with older age, even in older adults who lose weight, and is “highly prevalent” among older adults of African ancestry.
The researchers examined a large, biracial sample of older adults participating in the Health, Aging and Body Composition study, which enrolled men and women aged between 70 and 79 years. Participants were followed for an average of 9.0 ± 1.8 years.
During years 1 and 6, participants’ body composition was analyzed, including intermuscular adipose tissue (IMAT), visceral and subcutaneous adiposity, total fat mass, and muscle area.
In years 1, 3, 5, 8, and 10, participants’ cognition was measured using the modified Mini-Mental State (3MS) exam.
The main independent variable was 5-year change in thigh IMAT (year 6 minus year 1), and the main dependent variable was 3MS decline (from year 5 to year 10).
The researchers adjusted all the models for traditional dementia risk factors at baseline including 3MS, education, apo E4 allele, diabetes, hypertension, and physical activity and also calculated interactions between IMAT change by race or sex.
These models also accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass as well as cytokines related to adiposity.
‘Rich and engaging crosstalk’
The final sample included 1634 participants (mean age, 73.38 years at baseline; 48% female; 35% Black; mean baseline 3MS score, 91.6).
Thigh IMAT increased by 39.0% in all participants from year 1 to year 6, which corresponded to an increase of 4.85 cm2 or 0.97 cm2/year. During the same time period, muscle strength decreased by 14.0% (P < .05), although thigh muscle area remained stable, decreasing less than 0.5%.
There were decreases in both abdominal subcutaneous and visceral adiposity of 3.92% and 6.43%, respectively (P < .05). There was a decrease of 3.3% in 3MS from year 5 to year 10.
Several variables were associated with 3MS decline, independent of any change in thigh IMAT: older age, less education, and having at least one copy of the APOe4 allele. These variables were included in the model of IMAT change predicting 3MS change.
A statistically significant association of IMAT increase with 3MS decline was found. The IMAT increase of 4.85 cm2 corresponded to a 3MS decline of an additional 3.6 points (P < .0001) from year 5 to year 10, “indicating a clinically important change.”
The association between increasing thigh IMAT with declining 3MS “remained statistically significant” after adjusting for race, age, education, and apo E4 (P < .0001) and was independent of changes in thigh muscle area, muscle strength, and other adiposity measures.
In participants with increased IMAT in years 1-6, the mean 3MS score fell to approximately 87 points at year 10, compared with those without increased IMAT, with a 3MS score that dropped to approximately 89 points.
Interactions by race and sex were not statistically significant (P > .08).
“Our results suggest that adiposity in muscles can predict cognitive decline, in addition to (not instead of) other traditional dementia risk factors,” said Dr. Rosano.
There is “a rich and engaging crosstalk between muscle, adipose tissue, and the brain all throughout our lives, happening through factors released in the bloodstream that can reach the brain, however, the specific identity of the factors responsible for the crosstalk of muscle adiposity and brain in older adults has not yet been discovered,” she noted.
Although muscle adiposity is “not yet routinely measured in clinical settings, it is being measured opportunistically on clinical CT scans obtained as part of routine patient care,” she added. “These CT measurements have already been validated in many studies of older adults; thus, clinicians could have access to this novel information without additional cost, time, or radiation exposure.”
Causality not proven
In a comment, Bruce Albala, PhD, professor, department of environmental and occupational health, University of California, Irvine, noted that the 3MS assessment is scored on a 100-point scale, with a score less than 78 “generally regarded as indicating cognitive impairment or approaching a dementia condition.” In the current study, the mean 3MS score of participants with increased IMAT was still “well above the dementia cut-off.”
Moreover, “even if there is a relationship or correlation between IMAT and cognition, this does not prove or even suggest causality, especially from a biological mechanistic approach,” said Dr. Albaba, an adjunct professor of neurology, who was not involved in the study. “Clearly, more research is needed even to understand the relationship between these two factors.”
The study was supported by the National Institute on Aging. Dr. Rosano and coauthors and Dr. Albala declared no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM THE JOURNAL OF THE AMERICAN GERIATRICS SOCIETY
Blood biomarker may help predict who will develop Alzheimer’s
A blood biomarker that measures astrocyte reactivity may help determine who, among cognitively unimpaired older adults with amyloid-beta, will go on to develop Alzheimer’s disease (AD), new research suggests.
Investigators tested the blood of 1,000 cognitively healthy individuals with and without amyloid-beta pathology and found that only those with a combination of amyloid-beta burden and abnormal astrocyte activation subsequently progressed to AD.
“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” senior investigator Tharick A. Pascoal, MD, PhD, associate professor of psychiatry and neurology, University of Pittsburgh, said in a release.
At this point, the biomarker is a research tool, but its application in clinical practice “is not very far away,” Dr. Pascoal told this news organization.
The study was published online in Nature Medicine.
Multicenter study
In AD, accumulation of amyloid-beta in the brain precedes tau pathology, but not everyone with amyloid-beta develops tau, and, consequently, clinical symptoms. Approximately 30% of older adults have brain amyloid but many never progress to AD, said Dr. Pascoal.
This suggests other biological processes may trigger the deleterious effects of amyloid-beta in the early stages of AD.
Finding predictive markers of early amyloid-beta–related tau pathology would help identify cognitively normal individuals who are more likely to develop AD.
Post-mortem studies show astrocyte reactivity – changes in glial cells in the brain and spinal cord because of an insult in the brain – is an early AD abnormality. Other research suggests a close link between amyloid-beta, astrocyte reactivity, and tau.
In addition, evidence suggests plasma measures of glial fibrillary acidic protein (GFAP) could be a strong proxy of astrocyte reactivity in the brain. Dr. Pascoal explained that when astrocytes are changed or become bigger, more GFAP is released.
The study included 1,016 cognitively normal individuals from three centers; some had amyloid pathology, some did not. Participants’ mean age was 69.6 years, and all were deemed negative or positive for astrocyte reactivity based on plasma GFAP levels.
Results showed amyloid-beta is associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity. In addition, analyses using PET scans showed an AD-like pattern of tau tangle accumulation as a function of amyloid-beta exclusively in those same individuals.
Early upstream event
The findings suggest abnormalities in astrocyte reactivity is an early upstream event that likely occurs prior to tau pathology, which is closely related to the development of neurodegeneration and cognitive decline.
It’s likely many types of insults or processes can lead to astrocyte reactivity, possibly including COVID, but more research in this area is needed, said Dr. Pascoal.
“Our study only looked at the consequence of having both amyloid and astrocyte reactivity; it did not elucidate what is causing either of them,” he said.
Although “we were able to have very good results” in the current study, additional studies are needed to better establish the cut-off for GFAP levels that signal progression, said Dr. Pascoal.
The effect of astrocyte reactivity on the association between amyloid-beta and tau phosphorylation was greater in men than women. Dr. Pascoal noted anti-amyloid therapies, which might be modifying the amyloid-beta-astrocyte-tau pathway, tend to have a much larger effect in men than women.
Further studies that measure amyloid-beta, tau, and GFAP biomarkers at multiple timepoints, and with long follow-up, are needed, the investigators note.
The results may have implications for clinical trials, which have increasingly focused on individuals in the earliest preclinical phases of AD. Future studies should include cognitively normal patients who are positive for both amyloid pathology and astrocyte reactivity but have no overt p-tau abnormality, said Dr. Pascoal.
This may provide a time window for interventions very early in the disease process in those at increased risk for AD-related progression.
The study did not determine whether participants with both amyloid and astrocyte reactivity will inevitably develop AD, and to do so would require a longer follow up. “Our outcome was correlation to tau in the brain, which is something we know will lead to AD.”
Although the cohort represents significant socioeconomic diversity, a main limitation of the study was that subjects were mainly White, which limits the generalizability of the findings to a more diverse population.
The study received support from the National Institute of Aging; National Heart Lung and Blood Institute; Alzheimer’s Association; Fonds de Recherche du Québec-Santé; Canadian Consortium of Neurodegeneration in Aging; Weston Brain Institute; Colin Adair Charitable Foundation; Swedish Research Council; Wallenberg Scholar; BrightFocus Foundation; Swedish Alzheimer Foundation; Swedish Brain Foundation; Agneta Prytz-Folkes & Gösta Folkes Foundation; European Union; Swedish State Support for Clinical Research; Alzheimer Drug Discovery Foundation; Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden; the UK Dementia Research Institute at UCL; National Academy of Neuropsychology; Fundação de Amparo a pesquisa do Rio Grande do Sul; Instituto Serrapilheira; and Hjärnfonden.
Dr. Pascoal reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A blood biomarker that measures astrocyte reactivity may help determine who, among cognitively unimpaired older adults with amyloid-beta, will go on to develop Alzheimer’s disease (AD), new research suggests.
Investigators tested the blood of 1,000 cognitively healthy individuals with and without amyloid-beta pathology and found that only those with a combination of amyloid-beta burden and abnormal astrocyte activation subsequently progressed to AD.
“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” senior investigator Tharick A. Pascoal, MD, PhD, associate professor of psychiatry and neurology, University of Pittsburgh, said in a release.
At this point, the biomarker is a research tool, but its application in clinical practice “is not very far away,” Dr. Pascoal told this news organization.
The study was published online in Nature Medicine.
Multicenter study
In AD, accumulation of amyloid-beta in the brain precedes tau pathology, but not everyone with amyloid-beta develops tau, and, consequently, clinical symptoms. Approximately 30% of older adults have brain amyloid but many never progress to AD, said Dr. Pascoal.
This suggests other biological processes may trigger the deleterious effects of amyloid-beta in the early stages of AD.
Finding predictive markers of early amyloid-beta–related tau pathology would help identify cognitively normal individuals who are more likely to develop AD.
Post-mortem studies show astrocyte reactivity – changes in glial cells in the brain and spinal cord because of an insult in the brain – is an early AD abnormality. Other research suggests a close link between amyloid-beta, astrocyte reactivity, and tau.
In addition, evidence suggests plasma measures of glial fibrillary acidic protein (GFAP) could be a strong proxy of astrocyte reactivity in the brain. Dr. Pascoal explained that when astrocytes are changed or become bigger, more GFAP is released.
The study included 1,016 cognitively normal individuals from three centers; some had amyloid pathology, some did not. Participants’ mean age was 69.6 years, and all were deemed negative or positive for astrocyte reactivity based on plasma GFAP levels.
Results showed amyloid-beta is associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity. In addition, analyses using PET scans showed an AD-like pattern of tau tangle accumulation as a function of amyloid-beta exclusively in those same individuals.
Early upstream event
The findings suggest abnormalities in astrocyte reactivity is an early upstream event that likely occurs prior to tau pathology, which is closely related to the development of neurodegeneration and cognitive decline.
It’s likely many types of insults or processes can lead to astrocyte reactivity, possibly including COVID, but more research in this area is needed, said Dr. Pascoal.
“Our study only looked at the consequence of having both amyloid and astrocyte reactivity; it did not elucidate what is causing either of them,” he said.
Although “we were able to have very good results” in the current study, additional studies are needed to better establish the cut-off for GFAP levels that signal progression, said Dr. Pascoal.
The effect of astrocyte reactivity on the association between amyloid-beta and tau phosphorylation was greater in men than women. Dr. Pascoal noted anti-amyloid therapies, which might be modifying the amyloid-beta-astrocyte-tau pathway, tend to have a much larger effect in men than women.
Further studies that measure amyloid-beta, tau, and GFAP biomarkers at multiple timepoints, and with long follow-up, are needed, the investigators note.
The results may have implications for clinical trials, which have increasingly focused on individuals in the earliest preclinical phases of AD. Future studies should include cognitively normal patients who are positive for both amyloid pathology and astrocyte reactivity but have no overt p-tau abnormality, said Dr. Pascoal.
This may provide a time window for interventions very early in the disease process in those at increased risk for AD-related progression.
The study did not determine whether participants with both amyloid and astrocyte reactivity will inevitably develop AD, and to do so would require a longer follow up. “Our outcome was correlation to tau in the brain, which is something we know will lead to AD.”
Although the cohort represents significant socioeconomic diversity, a main limitation of the study was that subjects were mainly White, which limits the generalizability of the findings to a more diverse population.
The study received support from the National Institute of Aging; National Heart Lung and Blood Institute; Alzheimer’s Association; Fonds de Recherche du Québec-Santé; Canadian Consortium of Neurodegeneration in Aging; Weston Brain Institute; Colin Adair Charitable Foundation; Swedish Research Council; Wallenberg Scholar; BrightFocus Foundation; Swedish Alzheimer Foundation; Swedish Brain Foundation; Agneta Prytz-Folkes & Gösta Folkes Foundation; European Union; Swedish State Support for Clinical Research; Alzheimer Drug Discovery Foundation; Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden; the UK Dementia Research Institute at UCL; National Academy of Neuropsychology; Fundação de Amparo a pesquisa do Rio Grande do Sul; Instituto Serrapilheira; and Hjärnfonden.
Dr. Pascoal reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A blood biomarker that measures astrocyte reactivity may help determine who, among cognitively unimpaired older adults with amyloid-beta, will go on to develop Alzheimer’s disease (AD), new research suggests.
Investigators tested the blood of 1,000 cognitively healthy individuals with and without amyloid-beta pathology and found that only those with a combination of amyloid-beta burden and abnormal astrocyte activation subsequently progressed to AD.
“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” senior investigator Tharick A. Pascoal, MD, PhD, associate professor of psychiatry and neurology, University of Pittsburgh, said in a release.
At this point, the biomarker is a research tool, but its application in clinical practice “is not very far away,” Dr. Pascoal told this news organization.
The study was published online in Nature Medicine.
Multicenter study
In AD, accumulation of amyloid-beta in the brain precedes tau pathology, but not everyone with amyloid-beta develops tau, and, consequently, clinical symptoms. Approximately 30% of older adults have brain amyloid but many never progress to AD, said Dr. Pascoal.
This suggests other biological processes may trigger the deleterious effects of amyloid-beta in the early stages of AD.
Finding predictive markers of early amyloid-beta–related tau pathology would help identify cognitively normal individuals who are more likely to develop AD.
Post-mortem studies show astrocyte reactivity – changes in glial cells in the brain and spinal cord because of an insult in the brain – is an early AD abnormality. Other research suggests a close link between amyloid-beta, astrocyte reactivity, and tau.
In addition, evidence suggests plasma measures of glial fibrillary acidic protein (GFAP) could be a strong proxy of astrocyte reactivity in the brain. Dr. Pascoal explained that when astrocytes are changed or become bigger, more GFAP is released.
The study included 1,016 cognitively normal individuals from three centers; some had amyloid pathology, some did not. Participants’ mean age was 69.6 years, and all were deemed negative or positive for astrocyte reactivity based on plasma GFAP levels.
Results showed amyloid-beta is associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity. In addition, analyses using PET scans showed an AD-like pattern of tau tangle accumulation as a function of amyloid-beta exclusively in those same individuals.
Early upstream event
The findings suggest abnormalities in astrocyte reactivity is an early upstream event that likely occurs prior to tau pathology, which is closely related to the development of neurodegeneration and cognitive decline.
It’s likely many types of insults or processes can lead to astrocyte reactivity, possibly including COVID, but more research in this area is needed, said Dr. Pascoal.
“Our study only looked at the consequence of having both amyloid and astrocyte reactivity; it did not elucidate what is causing either of them,” he said.
Although “we were able to have very good results” in the current study, additional studies are needed to better establish the cut-off for GFAP levels that signal progression, said Dr. Pascoal.
The effect of astrocyte reactivity on the association between amyloid-beta and tau phosphorylation was greater in men than women. Dr. Pascoal noted anti-amyloid therapies, which might be modifying the amyloid-beta-astrocyte-tau pathway, tend to have a much larger effect in men than women.
Further studies that measure amyloid-beta, tau, and GFAP biomarkers at multiple timepoints, and with long follow-up, are needed, the investigators note.
The results may have implications for clinical trials, which have increasingly focused on individuals in the earliest preclinical phases of AD. Future studies should include cognitively normal patients who are positive for both amyloid pathology and astrocyte reactivity but have no overt p-tau abnormality, said Dr. Pascoal.
This may provide a time window for interventions very early in the disease process in those at increased risk for AD-related progression.
The study did not determine whether participants with both amyloid and astrocyte reactivity will inevitably develop AD, and to do so would require a longer follow up. “Our outcome was correlation to tau in the brain, which is something we know will lead to AD.”
Although the cohort represents significant socioeconomic diversity, a main limitation of the study was that subjects were mainly White, which limits the generalizability of the findings to a more diverse population.
The study received support from the National Institute of Aging; National Heart Lung and Blood Institute; Alzheimer’s Association; Fonds de Recherche du Québec-Santé; Canadian Consortium of Neurodegeneration in Aging; Weston Brain Institute; Colin Adair Charitable Foundation; Swedish Research Council; Wallenberg Scholar; BrightFocus Foundation; Swedish Alzheimer Foundation; Swedish Brain Foundation; Agneta Prytz-Folkes & Gösta Folkes Foundation; European Union; Swedish State Support for Clinical Research; Alzheimer Drug Discovery Foundation; Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden; the UK Dementia Research Institute at UCL; National Academy of Neuropsychology; Fundação de Amparo a pesquisa do Rio Grande do Sul; Instituto Serrapilheira; and Hjärnfonden.
Dr. Pascoal reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Gout linked to smaller brain volume, higher likelihood of neurodegenerative diseases
Patients with gout may have smaller brain volumes and higher brain iron markers than people without gout, and also be more likely to develop Parkinson’s disease, probable essential tremor, and dementia, researchers in the United Kingdom report.
“We were surprised about the regions of the brain affected by gout, several of which are important for motor function. The other intriguing finding was that the risk of dementia amongst gout patients was strongly time-dependent: highest in the first 3 years after their gout diagnosis,” lead study author Anya Topiwala, BMBCh, DPhil, said in an interview.
“Our combination of traditional and genetic approaches increases the confidence that gout is causing the brain findings,” said Dr. Topiwala, a clinical research fellow and consultant psychiatrist in the Nuffield Department of Population Health at the University of Oxford, England.
“We suggest that clinicians be vigilant for cognitive and motor problems after gout diagnosis, particularly in the early stages,” she added.
Links between gout and neurodegenerative diseases debated in earlier studies
Gout, the most common inflammatory arthritis, affects around 1%-4% of people, the authors wrote, with monosodium urate crystal deposits causing acute flares of pain and swelling in joints and periarticular tissues.
Whether and how gout may affect the brain has been debated in the literature. Gout and hyperuricemia have been linked with elevated stroke risk; and although observational studies have linked hyperuricemia with lower dementia risk, especially Alzheimer’s disease, Mendelian randomization studies have had conflicting results in Alzheimer’s disease.
A novel approach that analyzes brain structure and genetics
In a study published in Nature Communications, Dr. Topiwala and her colleagues combined observational and Mendelian randomization techniques to explore relationships between gout and neurodegenerative diseases. They analyzed data from over 303,000 volunteer participants between 40 and 69 years of age recruited between 2006 and 2010 to contribute their detailed genetic and health information to the U.K. Biobank, a large-scale biomedical database and research resource.
Patients with gout tended to be older and male. At baseline, all participants’ serum urate levels were measured, and 30.8% of patients with gout reported that they currently used urate-lowering therapy.
MRI shows brain changes in patients with gout
In what the authors said is the first investigation of neuroimaging markers in patients with gout, they compared differences in gray matter volumes found in the 1,165 participants with gout and the 32,202 controls without gout who had MRI data.
They found no marked sex differences in associations. Urate was inversely linked with global brain volume and with gray and white matter volumes, and gout appeared to age global gray matter by 2 years.
Patients with gout and higher urate showed significant differences in regional gray matter volumes, especially in the cerebellum, pons, and midbrain, as well as subcortical differences in the nucleus accumbens, putamen, and caudate. They also showed significant differences in white matter tract microstructure in the fornix.
Patients with gout were more likely to develop dementia (average hazard ratio [HR] over study = 1.60), especially in the first 3 years after gout diagnosis (HR = 7.40). They were also at higher risk for vascular dementia (average HR = 2.41), compared with all-cause dementia, but not for Alzheimer’s disease (average HR = 1.62).
In asymptomatic participants though, urate and dementia were inversely linked (HR = 0.85), with no time dependence.
Gout was linked with higher incidence of Parkinson’s disease (HR = 1.43) and probable essential tremor (HR = 6.75). In asymptomatic participants, urate and Parkinson’s disease (HR = 0.89), but not probable essential tremor, were inversely linked.
Genetic analyses reinforce MRI results
Using Mendelian randomization estimates, the authors found that genetic links generally reflected their observational findings. Both genetically predicted gout and serum urate were significantly linked with regional gray matter volumes, including cerebellar, midbrain, pons, and brainstem.
They also found significant links with higher magnetic susceptibility in the putamen and caudate, markers of higher iron. But while genetically predicted gout was significantly linked with global gray matter volume, urate was not.
In males, but not in females, urate was positively linked with alcohol intake and lower socioeconomic status.
Dr. Topiwala acknowledged several limitations to the study, writing that “the results from the volunteer participants may not apply to other populations; the cross-sectional serum urate measurements may not reflect chronic exposure; and Parkinson’s disease and essential tremor may have been diagnostically confounded.”
A novel approach that suggests further related research
Asked to comment on the study, Puja Khanna, MD, MPH, a rheumatologist and clinical associate professor of medicine at the University of Michigan, Ann Arbor, called its novel use of neuroimaging interesting.
Dr. Khanna, who was not involved in the study, said she would like to know more about the role that horizontal pleiotropy – one genetic variant having independent effects on multiple traits – plays in this disease process, and about the impact of the antioxidative properties of urate in maintaining neuroprotection.
“[The] U.K. Biobank is an excellent database to look at questions of association,” John D. FitzGerald, MD, PhD, MPH, MBA, professor and clinical chief of rheumatology at the University of California, Los Angeles, said in an interview.
“This is a fairly rigorous study,” added Dr. FitzGerald, also not involved in the study. “While it has lots of strengths,” including its large sample size and Mendelian randomization, it also has “abundant weaknesses,” he added. “It is largely cross-sectional, with single urate measurement and single brain MRI.”
“Causation is the big question,” Dr. FitzGerald noted. “Does treating gout (or urate) help prevent dementia or neurodegenerative decline?”
Early diagnosis benefits patients
Dr. Khanna and Dr. FitzGerald joined the authors in advising doctors to monitor their gout patients for cognitive and motor symptoms of neurodegenerative disease.
“It is clearly important to pay close attention to the neurologic exam and history in gout, especially because it is a disease of the aging population,” Dr. Khanna advised. “Addressing dementia when gout is diagnosed can lead to prompt mitigation strategies that can hugely impact patients.”
Dr. Topiwala and her colleagues would like to investigate why the dementia risk was time-dependent. “Is this because of the acute inflammatory response in gout, or could it just be that patients with gout visit their doctors more frequently, so any cognitive problems are picked up sooner?” she asked.
The authors, and Dr. Khanna and Dr. FitzGerald, report no relevant financial relationships. The Wellcome Trust; the U.K. Medical Research Council; the European Commission Horizon 2020 research and innovation program; the British Heart Foundation; the U.S. National Institutes of Health; the Engineering and Physical Sciences Research Council; and the National Institute for Health and Care Research funded the study.
Patients with gout may have smaller brain volumes and higher brain iron markers than people without gout, and also be more likely to develop Parkinson’s disease, probable essential tremor, and dementia, researchers in the United Kingdom report.
“We were surprised about the regions of the brain affected by gout, several of which are important for motor function. The other intriguing finding was that the risk of dementia amongst gout patients was strongly time-dependent: highest in the first 3 years after their gout diagnosis,” lead study author Anya Topiwala, BMBCh, DPhil, said in an interview.
“Our combination of traditional and genetic approaches increases the confidence that gout is causing the brain findings,” said Dr. Topiwala, a clinical research fellow and consultant psychiatrist in the Nuffield Department of Population Health at the University of Oxford, England.
“We suggest that clinicians be vigilant for cognitive and motor problems after gout diagnosis, particularly in the early stages,” she added.
Links between gout and neurodegenerative diseases debated in earlier studies
Gout, the most common inflammatory arthritis, affects around 1%-4% of people, the authors wrote, with monosodium urate crystal deposits causing acute flares of pain and swelling in joints and periarticular tissues.
Whether and how gout may affect the brain has been debated in the literature. Gout and hyperuricemia have been linked with elevated stroke risk; and although observational studies have linked hyperuricemia with lower dementia risk, especially Alzheimer’s disease, Mendelian randomization studies have had conflicting results in Alzheimer’s disease.
A novel approach that analyzes brain structure and genetics
In a study published in Nature Communications, Dr. Topiwala and her colleagues combined observational and Mendelian randomization techniques to explore relationships between gout and neurodegenerative diseases. They analyzed data from over 303,000 volunteer participants between 40 and 69 years of age recruited between 2006 and 2010 to contribute their detailed genetic and health information to the U.K. Biobank, a large-scale biomedical database and research resource.
Patients with gout tended to be older and male. At baseline, all participants’ serum urate levels were measured, and 30.8% of patients with gout reported that they currently used urate-lowering therapy.
MRI shows brain changes in patients with gout
In what the authors said is the first investigation of neuroimaging markers in patients with gout, they compared differences in gray matter volumes found in the 1,165 participants with gout and the 32,202 controls without gout who had MRI data.
They found no marked sex differences in associations. Urate was inversely linked with global brain volume and with gray and white matter volumes, and gout appeared to age global gray matter by 2 years.
Patients with gout and higher urate showed significant differences in regional gray matter volumes, especially in the cerebellum, pons, and midbrain, as well as subcortical differences in the nucleus accumbens, putamen, and caudate. They also showed significant differences in white matter tract microstructure in the fornix.
Patients with gout were more likely to develop dementia (average hazard ratio [HR] over study = 1.60), especially in the first 3 years after gout diagnosis (HR = 7.40). They were also at higher risk for vascular dementia (average HR = 2.41), compared with all-cause dementia, but not for Alzheimer’s disease (average HR = 1.62).
In asymptomatic participants though, urate and dementia were inversely linked (HR = 0.85), with no time dependence.
Gout was linked with higher incidence of Parkinson’s disease (HR = 1.43) and probable essential tremor (HR = 6.75). In asymptomatic participants, urate and Parkinson’s disease (HR = 0.89), but not probable essential tremor, were inversely linked.
Genetic analyses reinforce MRI results
Using Mendelian randomization estimates, the authors found that genetic links generally reflected their observational findings. Both genetically predicted gout and serum urate were significantly linked with regional gray matter volumes, including cerebellar, midbrain, pons, and brainstem.
They also found significant links with higher magnetic susceptibility in the putamen and caudate, markers of higher iron. But while genetically predicted gout was significantly linked with global gray matter volume, urate was not.
In males, but not in females, urate was positively linked with alcohol intake and lower socioeconomic status.
Dr. Topiwala acknowledged several limitations to the study, writing that “the results from the volunteer participants may not apply to other populations; the cross-sectional serum urate measurements may not reflect chronic exposure; and Parkinson’s disease and essential tremor may have been diagnostically confounded.”
A novel approach that suggests further related research
Asked to comment on the study, Puja Khanna, MD, MPH, a rheumatologist and clinical associate professor of medicine at the University of Michigan, Ann Arbor, called its novel use of neuroimaging interesting.
Dr. Khanna, who was not involved in the study, said she would like to know more about the role that horizontal pleiotropy – one genetic variant having independent effects on multiple traits – plays in this disease process, and about the impact of the antioxidative properties of urate in maintaining neuroprotection.
“[The] U.K. Biobank is an excellent database to look at questions of association,” John D. FitzGerald, MD, PhD, MPH, MBA, professor and clinical chief of rheumatology at the University of California, Los Angeles, said in an interview.
“This is a fairly rigorous study,” added Dr. FitzGerald, also not involved in the study. “While it has lots of strengths,” including its large sample size and Mendelian randomization, it also has “abundant weaknesses,” he added. “It is largely cross-sectional, with single urate measurement and single brain MRI.”
“Causation is the big question,” Dr. FitzGerald noted. “Does treating gout (or urate) help prevent dementia or neurodegenerative decline?”
Early diagnosis benefits patients
Dr. Khanna and Dr. FitzGerald joined the authors in advising doctors to monitor their gout patients for cognitive and motor symptoms of neurodegenerative disease.
“It is clearly important to pay close attention to the neurologic exam and history in gout, especially because it is a disease of the aging population,” Dr. Khanna advised. “Addressing dementia when gout is diagnosed can lead to prompt mitigation strategies that can hugely impact patients.”
Dr. Topiwala and her colleagues would like to investigate why the dementia risk was time-dependent. “Is this because of the acute inflammatory response in gout, or could it just be that patients with gout visit their doctors more frequently, so any cognitive problems are picked up sooner?” she asked.
The authors, and Dr. Khanna and Dr. FitzGerald, report no relevant financial relationships. The Wellcome Trust; the U.K. Medical Research Council; the European Commission Horizon 2020 research and innovation program; the British Heart Foundation; the U.S. National Institutes of Health; the Engineering and Physical Sciences Research Council; and the National Institute for Health and Care Research funded the study.
Patients with gout may have smaller brain volumes and higher brain iron markers than people without gout, and also be more likely to develop Parkinson’s disease, probable essential tremor, and dementia, researchers in the United Kingdom report.
“We were surprised about the regions of the brain affected by gout, several of which are important for motor function. The other intriguing finding was that the risk of dementia amongst gout patients was strongly time-dependent: highest in the first 3 years after their gout diagnosis,” lead study author Anya Topiwala, BMBCh, DPhil, said in an interview.
“Our combination of traditional and genetic approaches increases the confidence that gout is causing the brain findings,” said Dr. Topiwala, a clinical research fellow and consultant psychiatrist in the Nuffield Department of Population Health at the University of Oxford, England.
“We suggest that clinicians be vigilant for cognitive and motor problems after gout diagnosis, particularly in the early stages,” she added.
Links between gout and neurodegenerative diseases debated in earlier studies
Gout, the most common inflammatory arthritis, affects around 1%-4% of people, the authors wrote, with monosodium urate crystal deposits causing acute flares of pain and swelling in joints and periarticular tissues.
Whether and how gout may affect the brain has been debated in the literature. Gout and hyperuricemia have been linked with elevated stroke risk; and although observational studies have linked hyperuricemia with lower dementia risk, especially Alzheimer’s disease, Mendelian randomization studies have had conflicting results in Alzheimer’s disease.
A novel approach that analyzes brain structure and genetics
In a study published in Nature Communications, Dr. Topiwala and her colleagues combined observational and Mendelian randomization techniques to explore relationships between gout and neurodegenerative diseases. They analyzed data from over 303,000 volunteer participants between 40 and 69 years of age recruited between 2006 and 2010 to contribute their detailed genetic and health information to the U.K. Biobank, a large-scale biomedical database and research resource.
Patients with gout tended to be older and male. At baseline, all participants’ serum urate levels were measured, and 30.8% of patients with gout reported that they currently used urate-lowering therapy.
MRI shows brain changes in patients with gout
In what the authors said is the first investigation of neuroimaging markers in patients with gout, they compared differences in gray matter volumes found in the 1,165 participants with gout and the 32,202 controls without gout who had MRI data.
They found no marked sex differences in associations. Urate was inversely linked with global brain volume and with gray and white matter volumes, and gout appeared to age global gray matter by 2 years.
Patients with gout and higher urate showed significant differences in regional gray matter volumes, especially in the cerebellum, pons, and midbrain, as well as subcortical differences in the nucleus accumbens, putamen, and caudate. They also showed significant differences in white matter tract microstructure in the fornix.
Patients with gout were more likely to develop dementia (average hazard ratio [HR] over study = 1.60), especially in the first 3 years after gout diagnosis (HR = 7.40). They were also at higher risk for vascular dementia (average HR = 2.41), compared with all-cause dementia, but not for Alzheimer’s disease (average HR = 1.62).
In asymptomatic participants though, urate and dementia were inversely linked (HR = 0.85), with no time dependence.
Gout was linked with higher incidence of Parkinson’s disease (HR = 1.43) and probable essential tremor (HR = 6.75). In asymptomatic participants, urate and Parkinson’s disease (HR = 0.89), but not probable essential tremor, were inversely linked.
Genetic analyses reinforce MRI results
Using Mendelian randomization estimates, the authors found that genetic links generally reflected their observational findings. Both genetically predicted gout and serum urate were significantly linked with regional gray matter volumes, including cerebellar, midbrain, pons, and brainstem.
They also found significant links with higher magnetic susceptibility in the putamen and caudate, markers of higher iron. But while genetically predicted gout was significantly linked with global gray matter volume, urate was not.
In males, but not in females, urate was positively linked with alcohol intake and lower socioeconomic status.
Dr. Topiwala acknowledged several limitations to the study, writing that “the results from the volunteer participants may not apply to other populations; the cross-sectional serum urate measurements may not reflect chronic exposure; and Parkinson’s disease and essential tremor may have been diagnostically confounded.”
A novel approach that suggests further related research
Asked to comment on the study, Puja Khanna, MD, MPH, a rheumatologist and clinical associate professor of medicine at the University of Michigan, Ann Arbor, called its novel use of neuroimaging interesting.
Dr. Khanna, who was not involved in the study, said she would like to know more about the role that horizontal pleiotropy – one genetic variant having independent effects on multiple traits – plays in this disease process, and about the impact of the antioxidative properties of urate in maintaining neuroprotection.
“[The] U.K. Biobank is an excellent database to look at questions of association,” John D. FitzGerald, MD, PhD, MPH, MBA, professor and clinical chief of rheumatology at the University of California, Los Angeles, said in an interview.
“This is a fairly rigorous study,” added Dr. FitzGerald, also not involved in the study. “While it has lots of strengths,” including its large sample size and Mendelian randomization, it also has “abundant weaknesses,” he added. “It is largely cross-sectional, with single urate measurement and single brain MRI.”
“Causation is the big question,” Dr. FitzGerald noted. “Does treating gout (or urate) help prevent dementia or neurodegenerative decline?”
Early diagnosis benefits patients
Dr. Khanna and Dr. FitzGerald joined the authors in advising doctors to monitor their gout patients for cognitive and motor symptoms of neurodegenerative disease.
“It is clearly important to pay close attention to the neurologic exam and history in gout, especially because it is a disease of the aging population,” Dr. Khanna advised. “Addressing dementia when gout is diagnosed can lead to prompt mitigation strategies that can hugely impact patients.”
Dr. Topiwala and her colleagues would like to investigate why the dementia risk was time-dependent. “Is this because of the acute inflammatory response in gout, or could it just be that patients with gout visit their doctors more frequently, so any cognitive problems are picked up sooner?” she asked.
The authors, and Dr. Khanna and Dr. FitzGerald, report no relevant financial relationships. The Wellcome Trust; the U.K. Medical Research Council; the European Commission Horizon 2020 research and innovation program; the British Heart Foundation; the U.S. National Institutes of Health; the Engineering and Physical Sciences Research Council; and the National Institute for Health and Care Research funded the study.
FROM NATURE COMMUNICATIONS
Game-changing Alzheimer’s research: The latest on biomarkers
The field of neurodegenerative dementias, particularly Alzheimer’s disease (AD), has been revolutionized by the development of imaging and cerebrospinal fluid biomarkers and is on the brink of a new development: emerging plasma biomarkers. Research now recognizes the relationship between the cognitive-behavioral syndromic diagnosis (that is, the illness) and the etiologic diagnosis (the disease) – and the need to consider each separately when developing a diagnostic formulation. The National Institute on Aging and Alzheimer’s Association Research Framework uses the amyloid, tau, and neurodegeneration system to define AD biologically in living patients. Here is an overview of the framework, which requires biomarker evidence of amyloid plaques (amyloid positivity) and neurofibrillary tangles (tau positivity), with evidence of neurodegeneration (neurodegeneration positivity) to support the diagnosis.
The diagnostic approach for symptomatic patients
The differential diagnosis in symptomatic patients with mild cognitive impairment (MCI), mild behavioral impairment, or dementia is broad and includes multiple neurodegenerative diseases (for example, AD, frontotemporal lobar degeneration, dementia with Lewy bodies, argyrophilic grain disease, hippocampal sclerosis); vascular ischemic brain injury (for example, stroke); tumors; infectious, inflammatory, paraneoplastic, or demyelinating diseases; trauma; hydrocephalus; toxic/metabolic insults; and other rare diseases. The patient’s clinical syndrome narrows the differential diagnosis.
Once the clinician has a prioritized differential diagnosis of the brain disease or condition that is probably causing or contributing to the patient’s signs and symptoms, they can then select appropriate assessments and tests, typically starting with a laboratory panel and brain MRI. Strong evidence backed by practice recommendations also supports the use of fluorodeoxyglucose PET as a marker of functional brain abnormalities associated with dementia. Although molecular biomarkers are typically considered at the later stage of the clinical workup, the anticipated future availability of plasma biomarkers will probably change the timing of molecular biomarker assessment in patients with suspected cognitive impairment owing to AD.
Molecular PET biomarkers
Three PET tracers approved by the U.S. Food and Drug Administration for the detection of cerebral amyloid plaques have high sensitivity (89%-98%) and specificity (88%-100%), compared with autopsy, the gold standard diagnostic tool. However, these scans are costly and are not reimbursed by Medicare and Medicaid. Because all amyloid PET scans are covered by the Veterans Administration, this test is more readily accessible for patients receiving VA benefits.
The appropriate-use criteria developed by the Amyloid Imaging Task Force recommends amyloid PET for patients with persistent or progressive MCI or dementia. In such patients, a negative amyloid PET scan would strongly weigh against AD, supporting a differential diagnosis of other etiologies. Although a positive amyloid PET scan in patients with MCI or dementia indicates the presence of amyloid plaques, it does not necessarily confirm AD as the cause. Cerebral amyloid plaques may coexist with other pathologies and increase with age, even in cognitively normal individuals.
The IDEAS study looked at the clinical utility of amyloid PET in a real-world dementia specialist setting. In the study, dementia subspecialists documented their presumed etiologic diagnosis (and level of confidence) before and after amyloid PET. Of the 11,409 patients who completed the study, the etiologic diagnosis changed from AD to non-AD in just over 25% of cases and from non-AD to AD in 10.5%. Clinical management changed in about 60% of patients with MCI and 63.5% of patients with dementia.
In May 2020, the FDA approved flortaucipir F-18, the first diagnostic tau radiotracer for use with PET to estimate the density and distribution of aggregated tau neurofibrillary tangles in adults with cognitive impairment undergoing evaluation for AD. Regulatory approval of flortaucipir F-18 was based on findings from two clinical trials of terminally ill patients who were followed to autopsy. The studies included patients with a spectrum of clinically diagnosed dementias and those with normal cognition. The primary outcome of the studies was accurate visual interpretation of the images in detecting advanced AD tau neurofibrillary tangle pathology (Braak stage V or VI tau pathology). Sensitivity of five trained readers ranged from 68% to 86%, and specificity ranged from 63% to 100%; interrater agreement was 0.87. Tau PET is not yet reimbursed and is therefore not yet readily available in the clinical setting. Moreover, appropriate use criteria have not yet been published.
Molecular fluid biomarkers
Cerebrospinal fluid (CSF) analysis is currently the most readily available and reimbursed test to aid in diagnosing AD, with appropriate-use criteria for patients with suspected AD. CSF biomarkers for AD are useful in cognitively impaired patients when the etiologic diagnosis is equivocal, there is only an intermediate level of diagnostic confidence, or there is very high confidence in the etiologic diagnosis. Testing for CSF biomarkers is also recommended for patients at very early clinical stages (for example, early MCI) or with atypical clinical presentations.
A decreased concentration of amyloid-beta 42 in CSF is a marker of amyloid neuritic plaques in the brain. An increased concentration of total tau in CSF reflects injury to neurons, and an increased concentration of specific isoforms of hyperphosphorylated tau reflects neurofibrillary tangles. Presently, the ratios of t-tau to amyloid-beta 42, amyloid-beta 42 to amyloid-beta 40, and phosphorylated-tau 181 to amyloid-beta 42 are the best-performing markers of AD neuropathologic changes and are more accurate than assessing individual biomarkers. These CSF biomarkers of AD have been validated against autopsy, and ratio values of CSF amyloid-beta 42 have been further validated against amyloid PET, with overall sensitivity and specificity of approximately 90% and 84%, respectively.
Some of the most exciting recent advances in AD center around the measurement of these proteins and others in plasma. Appropriate-use criteria for plasma biomarkers in the evaluation of patients with cognitive impairment were published in 2022. In addition to their use in clinical trials, these criteria cautiously recommend using these biomarkers in specialized memory clinics in the diagnostic workup of patients with cognitive symptoms, along with confirmatory CSF markers or PET. Additional data are needed before plasma biomarkers of AD are used as standalone diagnostic markers or considered in the primary care setting.
We have made remarkable progress toward more precise molecular diagnosis of brain diseases underlying cognitive impairment and dementia. Ongoing efforts to evaluate the utility of these measures in clinical practice include the need to increase diversity of patients and providers. Ultimately, the tremendous progress in molecular biomarkers for the diseases causing dementia will help the field work toward our common goal of early and accurate diagnosis, better management, and hope for people living with these diseases.
Bradford C. Dickerson, MD, MMSc, is a professor, department of neurology, Harvard Medical School, and director, Frontotemporal Disorders Unit, department of neurology, at Massachusetts General Hospital, both in Boston.
A version of this article first appeared on Medscape.com.
The field of neurodegenerative dementias, particularly Alzheimer’s disease (AD), has been revolutionized by the development of imaging and cerebrospinal fluid biomarkers and is on the brink of a new development: emerging plasma biomarkers. Research now recognizes the relationship between the cognitive-behavioral syndromic diagnosis (that is, the illness) and the etiologic diagnosis (the disease) – and the need to consider each separately when developing a diagnostic formulation. The National Institute on Aging and Alzheimer’s Association Research Framework uses the amyloid, tau, and neurodegeneration system to define AD biologically in living patients. Here is an overview of the framework, which requires biomarker evidence of amyloid plaques (amyloid positivity) and neurofibrillary tangles (tau positivity), with evidence of neurodegeneration (neurodegeneration positivity) to support the diagnosis.
The diagnostic approach for symptomatic patients
The differential diagnosis in symptomatic patients with mild cognitive impairment (MCI), mild behavioral impairment, or dementia is broad and includes multiple neurodegenerative diseases (for example, AD, frontotemporal lobar degeneration, dementia with Lewy bodies, argyrophilic grain disease, hippocampal sclerosis); vascular ischemic brain injury (for example, stroke); tumors; infectious, inflammatory, paraneoplastic, or demyelinating diseases; trauma; hydrocephalus; toxic/metabolic insults; and other rare diseases. The patient’s clinical syndrome narrows the differential diagnosis.
Once the clinician has a prioritized differential diagnosis of the brain disease or condition that is probably causing or contributing to the patient’s signs and symptoms, they can then select appropriate assessments and tests, typically starting with a laboratory panel and brain MRI. Strong evidence backed by practice recommendations also supports the use of fluorodeoxyglucose PET as a marker of functional brain abnormalities associated with dementia. Although molecular biomarkers are typically considered at the later stage of the clinical workup, the anticipated future availability of plasma biomarkers will probably change the timing of molecular biomarker assessment in patients with suspected cognitive impairment owing to AD.
Molecular PET biomarkers
Three PET tracers approved by the U.S. Food and Drug Administration for the detection of cerebral amyloid plaques have high sensitivity (89%-98%) and specificity (88%-100%), compared with autopsy, the gold standard diagnostic tool. However, these scans are costly and are not reimbursed by Medicare and Medicaid. Because all amyloid PET scans are covered by the Veterans Administration, this test is more readily accessible for patients receiving VA benefits.
The appropriate-use criteria developed by the Amyloid Imaging Task Force recommends amyloid PET for patients with persistent or progressive MCI or dementia. In such patients, a negative amyloid PET scan would strongly weigh against AD, supporting a differential diagnosis of other etiologies. Although a positive amyloid PET scan in patients with MCI or dementia indicates the presence of amyloid plaques, it does not necessarily confirm AD as the cause. Cerebral amyloid plaques may coexist with other pathologies and increase with age, even in cognitively normal individuals.
The IDEAS study looked at the clinical utility of amyloid PET in a real-world dementia specialist setting. In the study, dementia subspecialists documented their presumed etiologic diagnosis (and level of confidence) before and after amyloid PET. Of the 11,409 patients who completed the study, the etiologic diagnosis changed from AD to non-AD in just over 25% of cases and from non-AD to AD in 10.5%. Clinical management changed in about 60% of patients with MCI and 63.5% of patients with dementia.
In May 2020, the FDA approved flortaucipir F-18, the first diagnostic tau radiotracer for use with PET to estimate the density and distribution of aggregated tau neurofibrillary tangles in adults with cognitive impairment undergoing evaluation for AD. Regulatory approval of flortaucipir F-18 was based on findings from two clinical trials of terminally ill patients who were followed to autopsy. The studies included patients with a spectrum of clinically diagnosed dementias and those with normal cognition. The primary outcome of the studies was accurate visual interpretation of the images in detecting advanced AD tau neurofibrillary tangle pathology (Braak stage V or VI tau pathology). Sensitivity of five trained readers ranged from 68% to 86%, and specificity ranged from 63% to 100%; interrater agreement was 0.87. Tau PET is not yet reimbursed and is therefore not yet readily available in the clinical setting. Moreover, appropriate use criteria have not yet been published.
Molecular fluid biomarkers
Cerebrospinal fluid (CSF) analysis is currently the most readily available and reimbursed test to aid in diagnosing AD, with appropriate-use criteria for patients with suspected AD. CSF biomarkers for AD are useful in cognitively impaired patients when the etiologic diagnosis is equivocal, there is only an intermediate level of diagnostic confidence, or there is very high confidence in the etiologic diagnosis. Testing for CSF biomarkers is also recommended for patients at very early clinical stages (for example, early MCI) or with atypical clinical presentations.
A decreased concentration of amyloid-beta 42 in CSF is a marker of amyloid neuritic plaques in the brain. An increased concentration of total tau in CSF reflects injury to neurons, and an increased concentration of specific isoforms of hyperphosphorylated tau reflects neurofibrillary tangles. Presently, the ratios of t-tau to amyloid-beta 42, amyloid-beta 42 to amyloid-beta 40, and phosphorylated-tau 181 to amyloid-beta 42 are the best-performing markers of AD neuropathologic changes and are more accurate than assessing individual biomarkers. These CSF biomarkers of AD have been validated against autopsy, and ratio values of CSF amyloid-beta 42 have been further validated against amyloid PET, with overall sensitivity and specificity of approximately 90% and 84%, respectively.
Some of the most exciting recent advances in AD center around the measurement of these proteins and others in plasma. Appropriate-use criteria for plasma biomarkers in the evaluation of patients with cognitive impairment were published in 2022. In addition to their use in clinical trials, these criteria cautiously recommend using these biomarkers in specialized memory clinics in the diagnostic workup of patients with cognitive symptoms, along with confirmatory CSF markers or PET. Additional data are needed before plasma biomarkers of AD are used as standalone diagnostic markers or considered in the primary care setting.
We have made remarkable progress toward more precise molecular diagnosis of brain diseases underlying cognitive impairment and dementia. Ongoing efforts to evaluate the utility of these measures in clinical practice include the need to increase diversity of patients and providers. Ultimately, the tremendous progress in molecular biomarkers for the diseases causing dementia will help the field work toward our common goal of early and accurate diagnosis, better management, and hope for people living with these diseases.
Bradford C. Dickerson, MD, MMSc, is a professor, department of neurology, Harvard Medical School, and director, Frontotemporal Disorders Unit, department of neurology, at Massachusetts General Hospital, both in Boston.
A version of this article first appeared on Medscape.com.
The field of neurodegenerative dementias, particularly Alzheimer’s disease (AD), has been revolutionized by the development of imaging and cerebrospinal fluid biomarkers and is on the brink of a new development: emerging plasma biomarkers. Research now recognizes the relationship between the cognitive-behavioral syndromic diagnosis (that is, the illness) and the etiologic diagnosis (the disease) – and the need to consider each separately when developing a diagnostic formulation. The National Institute on Aging and Alzheimer’s Association Research Framework uses the amyloid, tau, and neurodegeneration system to define AD biologically in living patients. Here is an overview of the framework, which requires biomarker evidence of amyloid plaques (amyloid positivity) and neurofibrillary tangles (tau positivity), with evidence of neurodegeneration (neurodegeneration positivity) to support the diagnosis.
The diagnostic approach for symptomatic patients
The differential diagnosis in symptomatic patients with mild cognitive impairment (MCI), mild behavioral impairment, or dementia is broad and includes multiple neurodegenerative diseases (for example, AD, frontotemporal lobar degeneration, dementia with Lewy bodies, argyrophilic grain disease, hippocampal sclerosis); vascular ischemic brain injury (for example, stroke); tumors; infectious, inflammatory, paraneoplastic, or demyelinating diseases; trauma; hydrocephalus; toxic/metabolic insults; and other rare diseases. The patient’s clinical syndrome narrows the differential diagnosis.
Once the clinician has a prioritized differential diagnosis of the brain disease or condition that is probably causing or contributing to the patient’s signs and symptoms, they can then select appropriate assessments and tests, typically starting with a laboratory panel and brain MRI. Strong evidence backed by practice recommendations also supports the use of fluorodeoxyglucose PET as a marker of functional brain abnormalities associated with dementia. Although molecular biomarkers are typically considered at the later stage of the clinical workup, the anticipated future availability of plasma biomarkers will probably change the timing of molecular biomarker assessment in patients with suspected cognitive impairment owing to AD.
Molecular PET biomarkers
Three PET tracers approved by the U.S. Food and Drug Administration for the detection of cerebral amyloid plaques have high sensitivity (89%-98%) and specificity (88%-100%), compared with autopsy, the gold standard diagnostic tool. However, these scans are costly and are not reimbursed by Medicare and Medicaid. Because all amyloid PET scans are covered by the Veterans Administration, this test is more readily accessible for patients receiving VA benefits.
The appropriate-use criteria developed by the Amyloid Imaging Task Force recommends amyloid PET for patients with persistent or progressive MCI or dementia. In such patients, a negative amyloid PET scan would strongly weigh against AD, supporting a differential diagnosis of other etiologies. Although a positive amyloid PET scan in patients with MCI or dementia indicates the presence of amyloid plaques, it does not necessarily confirm AD as the cause. Cerebral amyloid plaques may coexist with other pathologies and increase with age, even in cognitively normal individuals.
The IDEAS study looked at the clinical utility of amyloid PET in a real-world dementia specialist setting. In the study, dementia subspecialists documented their presumed etiologic diagnosis (and level of confidence) before and after amyloid PET. Of the 11,409 patients who completed the study, the etiologic diagnosis changed from AD to non-AD in just over 25% of cases and from non-AD to AD in 10.5%. Clinical management changed in about 60% of patients with MCI and 63.5% of patients with dementia.
In May 2020, the FDA approved flortaucipir F-18, the first diagnostic tau radiotracer for use with PET to estimate the density and distribution of aggregated tau neurofibrillary tangles in adults with cognitive impairment undergoing evaluation for AD. Regulatory approval of flortaucipir F-18 was based on findings from two clinical trials of terminally ill patients who were followed to autopsy. The studies included patients with a spectrum of clinically diagnosed dementias and those with normal cognition. The primary outcome of the studies was accurate visual interpretation of the images in detecting advanced AD tau neurofibrillary tangle pathology (Braak stage V or VI tau pathology). Sensitivity of five trained readers ranged from 68% to 86%, and specificity ranged from 63% to 100%; interrater agreement was 0.87. Tau PET is not yet reimbursed and is therefore not yet readily available in the clinical setting. Moreover, appropriate use criteria have not yet been published.
Molecular fluid biomarkers
Cerebrospinal fluid (CSF) analysis is currently the most readily available and reimbursed test to aid in diagnosing AD, with appropriate-use criteria for patients with suspected AD. CSF biomarkers for AD are useful in cognitively impaired patients when the etiologic diagnosis is equivocal, there is only an intermediate level of diagnostic confidence, or there is very high confidence in the etiologic diagnosis. Testing for CSF biomarkers is also recommended for patients at very early clinical stages (for example, early MCI) or with atypical clinical presentations.
A decreased concentration of amyloid-beta 42 in CSF is a marker of amyloid neuritic plaques in the brain. An increased concentration of total tau in CSF reflects injury to neurons, and an increased concentration of specific isoforms of hyperphosphorylated tau reflects neurofibrillary tangles. Presently, the ratios of t-tau to amyloid-beta 42, amyloid-beta 42 to amyloid-beta 40, and phosphorylated-tau 181 to amyloid-beta 42 are the best-performing markers of AD neuropathologic changes and are more accurate than assessing individual biomarkers. These CSF biomarkers of AD have been validated against autopsy, and ratio values of CSF amyloid-beta 42 have been further validated against amyloid PET, with overall sensitivity and specificity of approximately 90% and 84%, respectively.
Some of the most exciting recent advances in AD center around the measurement of these proteins and others in plasma. Appropriate-use criteria for plasma biomarkers in the evaluation of patients with cognitive impairment were published in 2022. In addition to their use in clinical trials, these criteria cautiously recommend using these biomarkers in specialized memory clinics in the diagnostic workup of patients with cognitive symptoms, along with confirmatory CSF markers or PET. Additional data are needed before plasma biomarkers of AD are used as standalone diagnostic markers or considered in the primary care setting.
We have made remarkable progress toward more precise molecular diagnosis of brain diseases underlying cognitive impairment and dementia. Ongoing efforts to evaluate the utility of these measures in clinical practice include the need to increase diversity of patients and providers. Ultimately, the tremendous progress in molecular biomarkers for the diseases causing dementia will help the field work toward our common goal of early and accurate diagnosis, better management, and hope for people living with these diseases.
Bradford C. Dickerson, MD, MMSc, is a professor, department of neurology, Harvard Medical School, and director, Frontotemporal Disorders Unit, department of neurology, at Massachusetts General Hospital, both in Boston.
A version of this article first appeared on Medscape.com.
Flavanol supplement improves memory in adults with poor diets
Taking a daily flavanol supplement improves hippocampal-dependent memory in older adults who have a relatively poor diet, results of a large new study suggest.
There’s increasing evidence that certain nutrients are important for the aging body and brain, study investigator Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Columbia University Vagelos College of Physicians and Surgeons, New York, told this news organization.
“With this new study, I think we can begin to say flavanols might be the first one that really is a nutrient for the aging brain.”
These findings, said Dr. Small, represent “the beginning of a new era” that will eventually lead to formal recommendations” related to ideal intake of flavanols to reduce cognitive aging.
The findings were published online in the Proceedings of the National Academy of Science.
Better cognitive aging
Cognitive aging refers to the decline in cognitive abilities that are not thought to be caused by neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Cognitive aging targets two areas of the brain: the hippocampus, which is related to memory function, and the prefrontal cortex, which is related to attention and executive function.
Previous research has linked flavanols, which are found in foods like apples, pears, berries, and cocoa beans, to improved cognitive aging. The evidence shows that consuming these nutrients might be associated with the hippocampal-dependent memory component of cognitive aging.
The new study, known as COcoa Supplement and Multivitamin Outcomes Study-Web (COSMOS-Web), included 3,562 generally healthy men and women, mean age 71 years, who were mostly well-educated and non-Hispanic/non-Latinx White individuals.
Participants were randomly assigned to receive oral flavanol-containing cocoa extract (500 mg of cocoa flavanols, including 80 mg of epicatechin) or a placebo daily.
The primary endpoint was hippocampal-dependent memory at year 1 as assessed with the ModRey, a neuropsychological test designed to measure hippocampal function.
Results showed participants in both groups had a typical learning (practice) effect, with similar improvements (d = 0.025; P = .42).
Researchers used other tests to measure cognition: the Color/Directional Flanker Task, a measure of prefrontal cortex function, and the ModBent, a measure that’s sensitive to dentate gyrus function. The flavanol intervention did not affect ModBent results or performance on the Flanker test after 1 year.
However, it was a different story for those with a poor diet at baseline. Researchers stratified participants into tertiles on the basis of diet quality as measured by the Healthy Eating Index (HEI) scores. Those in the lowest tertile had poorer baseline hippocampal-dependent memory performance but not memory related to the prefrontal cortex.
The flavanol intervention improved performance on the ModRey test, compared with placebo in participants in the low HEI tertile (overall effect: d = 0.086; P = .011) but not among those with a medium or high HEI at baseline.
“We confirmed that the flavanol intervention only benefits people who are relatively deficient at baseline,” said Dr. Small.
The correlation with hippocampal-dependent memory was confirmed in a subset of 1,361 study participants who provided a urine sample. Researchers measured urinary 5-(3′,4′-dihydroxyphenyl)-gamma-valerolactone metabolite (gVLM) concentrations, a validated biomarker of flavanol consumption.
After stratifying these results into tertiles, researchers found performance on the ModRey was significantly improved with the dietary flavanol intervention (overall effect: d = 0.141; P = .006) in the lowest gVLM tertile.
Memory restored
When participants in the lowest tertile consumed the supplement, “their flavanol levels went back to normal, and when that happened, their memory was restored,” said Dr. Small.
It appears that there is a sort of ceiling effect to the flavanol benefits. “It seems what you need to do is normalize your flavanol levels; if you go above normal, there was no evidence that your memory keeps on getting better,” said Dr. Small.
The study included only older adults, so it’s unclear what the impact of flavanol supplementation is in younger adults. But cognitive aging “begins its slippery side” in the 40s, said Dr. Small. “If this is truly a nutrient that is taken to prevent that slide from happening, it might be beneficial to start in our 40s.”
He recognized that the effect size is not large but said this is “very dependent” on baseline factors and most study participants had a rather healthy diet. “None of our participants were really highly deficient” in flavanols, he said.
“To see a stronger effect size, we need to do another study where we recruit people who are very low, truly deficient, in flavanols, and then see what happens.”
Showing that flavanols are linked to the hippocampal and not to the prefrontal component of cognitive aging “speaks to the mechanism,” said Dr. Small.
Though the exact mechanism linking flavanols with enhanced memory isn’t clear, there are some clues; for example, research suggests cognitive aging affects the dentate gyrus, a subregion of the hippocampus.
The flavanol supplements were well tolerated. “I can say with close to certainty that this is very safe,” said Dr. Small, adding the flavanols have now been used in numerous studies.
The findings suggest flavanol consumption might be part of future dietary guidelines. “I suspect that once there is sufficient evidence, flavanols will be part of the dietary recommendations for healthy aging,” said Dr. Small.
A word of caution
Heather M. Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, said that though science suggests a balanced diet is good for overall brain health, no single food, beverage, ingredient, vitamin, or supplement has yet been proven to prevent dementia, treat or cure Alzheimer’s, or benefit cognitive function or brain health.
Experts agree the best source of vitamins and other nutrients is from whole foods as part of a balanced diet. “We recognize that, for a variety of reasons, this may not always be possible,” said Dr. Snyder.
However, she noted, dietary supplements are not subject to the same rigorous review and regulation process as medications.
“The Alzheimer’s Association strongly encourages individuals to have conversations with their physicians about all medications and dietary supplements they are currently taking or interested in starting.”
COSMOS is supported by an investigator-initiated grant from Mars Edge, a segment of Mars, company engaged in flavanol research and flavanol-related commercial activities, which included infrastructure support and the donation of study pills and packaging. Small reports receiving an unrestricted research grant from Mars.
A version of this article first appeared on Medscape.com.
Taking a daily flavanol supplement improves hippocampal-dependent memory in older adults who have a relatively poor diet, results of a large new study suggest.
There’s increasing evidence that certain nutrients are important for the aging body and brain, study investigator Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Columbia University Vagelos College of Physicians and Surgeons, New York, told this news organization.
“With this new study, I think we can begin to say flavanols might be the first one that really is a nutrient for the aging brain.”
These findings, said Dr. Small, represent “the beginning of a new era” that will eventually lead to formal recommendations” related to ideal intake of flavanols to reduce cognitive aging.
The findings were published online in the Proceedings of the National Academy of Science.
Better cognitive aging
Cognitive aging refers to the decline in cognitive abilities that are not thought to be caused by neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Cognitive aging targets two areas of the brain: the hippocampus, which is related to memory function, and the prefrontal cortex, which is related to attention and executive function.
Previous research has linked flavanols, which are found in foods like apples, pears, berries, and cocoa beans, to improved cognitive aging. The evidence shows that consuming these nutrients might be associated with the hippocampal-dependent memory component of cognitive aging.
The new study, known as COcoa Supplement and Multivitamin Outcomes Study-Web (COSMOS-Web), included 3,562 generally healthy men and women, mean age 71 years, who were mostly well-educated and non-Hispanic/non-Latinx White individuals.
Participants were randomly assigned to receive oral flavanol-containing cocoa extract (500 mg of cocoa flavanols, including 80 mg of epicatechin) or a placebo daily.
The primary endpoint was hippocampal-dependent memory at year 1 as assessed with the ModRey, a neuropsychological test designed to measure hippocampal function.
Results showed participants in both groups had a typical learning (practice) effect, with similar improvements (d = 0.025; P = .42).
Researchers used other tests to measure cognition: the Color/Directional Flanker Task, a measure of prefrontal cortex function, and the ModBent, a measure that’s sensitive to dentate gyrus function. The flavanol intervention did not affect ModBent results or performance on the Flanker test after 1 year.
However, it was a different story for those with a poor diet at baseline. Researchers stratified participants into tertiles on the basis of diet quality as measured by the Healthy Eating Index (HEI) scores. Those in the lowest tertile had poorer baseline hippocampal-dependent memory performance but not memory related to the prefrontal cortex.
The flavanol intervention improved performance on the ModRey test, compared with placebo in participants in the low HEI tertile (overall effect: d = 0.086; P = .011) but not among those with a medium or high HEI at baseline.
“We confirmed that the flavanol intervention only benefits people who are relatively deficient at baseline,” said Dr. Small.
The correlation with hippocampal-dependent memory was confirmed in a subset of 1,361 study participants who provided a urine sample. Researchers measured urinary 5-(3′,4′-dihydroxyphenyl)-gamma-valerolactone metabolite (gVLM) concentrations, a validated biomarker of flavanol consumption.
After stratifying these results into tertiles, researchers found performance on the ModRey was significantly improved with the dietary flavanol intervention (overall effect: d = 0.141; P = .006) in the lowest gVLM tertile.
Memory restored
When participants in the lowest tertile consumed the supplement, “their flavanol levels went back to normal, and when that happened, their memory was restored,” said Dr. Small.
It appears that there is a sort of ceiling effect to the flavanol benefits. “It seems what you need to do is normalize your flavanol levels; if you go above normal, there was no evidence that your memory keeps on getting better,” said Dr. Small.
The study included only older adults, so it’s unclear what the impact of flavanol supplementation is in younger adults. But cognitive aging “begins its slippery side” in the 40s, said Dr. Small. “If this is truly a nutrient that is taken to prevent that slide from happening, it might be beneficial to start in our 40s.”
He recognized that the effect size is not large but said this is “very dependent” on baseline factors and most study participants had a rather healthy diet. “None of our participants were really highly deficient” in flavanols, he said.
“To see a stronger effect size, we need to do another study where we recruit people who are very low, truly deficient, in flavanols, and then see what happens.”
Showing that flavanols are linked to the hippocampal and not to the prefrontal component of cognitive aging “speaks to the mechanism,” said Dr. Small.
Though the exact mechanism linking flavanols with enhanced memory isn’t clear, there are some clues; for example, research suggests cognitive aging affects the dentate gyrus, a subregion of the hippocampus.
The flavanol supplements were well tolerated. “I can say with close to certainty that this is very safe,” said Dr. Small, adding the flavanols have now been used in numerous studies.
The findings suggest flavanol consumption might be part of future dietary guidelines. “I suspect that once there is sufficient evidence, flavanols will be part of the dietary recommendations for healthy aging,” said Dr. Small.
A word of caution
Heather M. Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, said that though science suggests a balanced diet is good for overall brain health, no single food, beverage, ingredient, vitamin, or supplement has yet been proven to prevent dementia, treat or cure Alzheimer’s, or benefit cognitive function or brain health.
Experts agree the best source of vitamins and other nutrients is from whole foods as part of a balanced diet. “We recognize that, for a variety of reasons, this may not always be possible,” said Dr. Snyder.
However, she noted, dietary supplements are not subject to the same rigorous review and regulation process as medications.
“The Alzheimer’s Association strongly encourages individuals to have conversations with their physicians about all medications and dietary supplements they are currently taking or interested in starting.”
COSMOS is supported by an investigator-initiated grant from Mars Edge, a segment of Mars, company engaged in flavanol research and flavanol-related commercial activities, which included infrastructure support and the donation of study pills and packaging. Small reports receiving an unrestricted research grant from Mars.
A version of this article first appeared on Medscape.com.
Taking a daily flavanol supplement improves hippocampal-dependent memory in older adults who have a relatively poor diet, results of a large new study suggest.
There’s increasing evidence that certain nutrients are important for the aging body and brain, study investigator Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Columbia University Vagelos College of Physicians and Surgeons, New York, told this news organization.
“With this new study, I think we can begin to say flavanols might be the first one that really is a nutrient for the aging brain.”
These findings, said Dr. Small, represent “the beginning of a new era” that will eventually lead to formal recommendations” related to ideal intake of flavanols to reduce cognitive aging.
The findings were published online in the Proceedings of the National Academy of Science.
Better cognitive aging
Cognitive aging refers to the decline in cognitive abilities that are not thought to be caused by neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Cognitive aging targets two areas of the brain: the hippocampus, which is related to memory function, and the prefrontal cortex, which is related to attention and executive function.
Previous research has linked flavanols, which are found in foods like apples, pears, berries, and cocoa beans, to improved cognitive aging. The evidence shows that consuming these nutrients might be associated with the hippocampal-dependent memory component of cognitive aging.
The new study, known as COcoa Supplement and Multivitamin Outcomes Study-Web (COSMOS-Web), included 3,562 generally healthy men and women, mean age 71 years, who were mostly well-educated and non-Hispanic/non-Latinx White individuals.
Participants were randomly assigned to receive oral flavanol-containing cocoa extract (500 mg of cocoa flavanols, including 80 mg of epicatechin) or a placebo daily.
The primary endpoint was hippocampal-dependent memory at year 1 as assessed with the ModRey, a neuropsychological test designed to measure hippocampal function.
Results showed participants in both groups had a typical learning (practice) effect, with similar improvements (d = 0.025; P = .42).
Researchers used other tests to measure cognition: the Color/Directional Flanker Task, a measure of prefrontal cortex function, and the ModBent, a measure that’s sensitive to dentate gyrus function. The flavanol intervention did not affect ModBent results or performance on the Flanker test after 1 year.
However, it was a different story for those with a poor diet at baseline. Researchers stratified participants into tertiles on the basis of diet quality as measured by the Healthy Eating Index (HEI) scores. Those in the lowest tertile had poorer baseline hippocampal-dependent memory performance but not memory related to the prefrontal cortex.
The flavanol intervention improved performance on the ModRey test, compared with placebo in participants in the low HEI tertile (overall effect: d = 0.086; P = .011) but not among those with a medium or high HEI at baseline.
“We confirmed that the flavanol intervention only benefits people who are relatively deficient at baseline,” said Dr. Small.
The correlation with hippocampal-dependent memory was confirmed in a subset of 1,361 study participants who provided a urine sample. Researchers measured urinary 5-(3′,4′-dihydroxyphenyl)-gamma-valerolactone metabolite (gVLM) concentrations, a validated biomarker of flavanol consumption.
After stratifying these results into tertiles, researchers found performance on the ModRey was significantly improved with the dietary flavanol intervention (overall effect: d = 0.141; P = .006) in the lowest gVLM tertile.
Memory restored
When participants in the lowest tertile consumed the supplement, “their flavanol levels went back to normal, and when that happened, their memory was restored,” said Dr. Small.
It appears that there is a sort of ceiling effect to the flavanol benefits. “It seems what you need to do is normalize your flavanol levels; if you go above normal, there was no evidence that your memory keeps on getting better,” said Dr. Small.
The study included only older adults, so it’s unclear what the impact of flavanol supplementation is in younger adults. But cognitive aging “begins its slippery side” in the 40s, said Dr. Small. “If this is truly a nutrient that is taken to prevent that slide from happening, it might be beneficial to start in our 40s.”
He recognized that the effect size is not large but said this is “very dependent” on baseline factors and most study participants had a rather healthy diet. “None of our participants were really highly deficient” in flavanols, he said.
“To see a stronger effect size, we need to do another study where we recruit people who are very low, truly deficient, in flavanols, and then see what happens.”
Showing that flavanols are linked to the hippocampal and not to the prefrontal component of cognitive aging “speaks to the mechanism,” said Dr. Small.
Though the exact mechanism linking flavanols with enhanced memory isn’t clear, there are some clues; for example, research suggests cognitive aging affects the dentate gyrus, a subregion of the hippocampus.
The flavanol supplements were well tolerated. “I can say with close to certainty that this is very safe,” said Dr. Small, adding the flavanols have now been used in numerous studies.
The findings suggest flavanol consumption might be part of future dietary guidelines. “I suspect that once there is sufficient evidence, flavanols will be part of the dietary recommendations for healthy aging,” said Dr. Small.
A word of caution
Heather M. Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, said that though science suggests a balanced diet is good for overall brain health, no single food, beverage, ingredient, vitamin, or supplement has yet been proven to prevent dementia, treat or cure Alzheimer’s, or benefit cognitive function or brain health.
Experts agree the best source of vitamins and other nutrients is from whole foods as part of a balanced diet. “We recognize that, for a variety of reasons, this may not always be possible,” said Dr. Snyder.
However, she noted, dietary supplements are not subject to the same rigorous review and regulation process as medications.
“The Alzheimer’s Association strongly encourages individuals to have conversations with their physicians about all medications and dietary supplements they are currently taking or interested in starting.”
COSMOS is supported by an investigator-initiated grant from Mars Edge, a segment of Mars, company engaged in flavanol research and flavanol-related commercial activities, which included infrastructure support and the donation of study pills and packaging. Small reports receiving an unrestricted research grant from Mars.
A version of this article first appeared on Medscape.com.