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‘Doesn’t Fit Anything I Trained for’: Committee Examines Treatment for Chronic Illness After Lyme Disease
WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.
The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.
It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.
“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”
Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.
Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.
“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
Incidence and Potential Mechanisms
Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)
His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”
PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.
In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.
The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.
The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.
One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”
Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.
“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.
Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.
The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.
At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.
And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.
Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.
Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
Need for Patient-Centered Outcomes
Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.
Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.
Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.
Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.
Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.
“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”
A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.
The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
A version of this article appeared on Medscape.com.
WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.
The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.
It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.
“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”
Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.
Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.
“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
Incidence and Potential Mechanisms
Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)
His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”
PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.
In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.
The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.
The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.
One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”
Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.
“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.
Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.
The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.
At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.
And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.
Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.
Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
Need for Patient-Centered Outcomes
Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.
Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.
Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.
Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.
Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.
“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”
A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.
The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
A version of this article appeared on Medscape.com.
WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.
The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.
It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.
“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”
Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.
Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.
“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
Incidence and Potential Mechanisms
Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)
His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”
PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.
In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.
The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.
The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.
One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”
Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.
“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.
Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.
The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.
At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.
And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.
Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.
Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
Need for Patient-Centered Outcomes
Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.
Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.
Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.
Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.
Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.
“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”
A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.
The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
A version of this article appeared on Medscape.com.
High Blood Sugar May Drive Dementia, German Researchers Warn
On World Brain Day (July 22, 2024), the German Society of Neurology (DGN) and the German Brain Foundation pointed out that too much sugar can harm the brain. The current results of the Global Burden of Diseases study shows that stroke and dementia are among the top 10 causes of death. A healthy, active lifestyle with sufficient exercise and sleep, along with the avoidance of harmful substances like alcohol, nicotine, or excessive sugar, protects the brain.
“Of course, the dose makes the poison as the brain, being the body’s powerhouse, needs glucose to function,” said Frank Erbguth, MD, PhD, president of the German Brain Foundation, in a press release from DGN and the German Brain Foundation. “However, with a permanent increase in blood sugar levels due to too many, too lavish meals and constant snacking on the side, we overload the system and fuel the development of neurologic diseases, particularly dementia and stroke.”
The per capita consumption of sugar was 33.2 kg in 2021/2022, which is almost twice the recommended amount. The German Nutrition Society recommends that no more than 10% of energy come from sugar. With a goal of 2000 kilocalories, that’s 50 g per day, or 18 kg per year. This total includes not only added sugar but also naturally occurring sugar, such as in fruits, honey, or juices.
What’s the Mechanism?
In Germany, around 250,000 people are diagnosed with dementia annually, and 15%-25% have vascular dementia. That proportion represents between 40,000 and 60,000 new cases each year.
In addition, glycosaminoglycans, which are complex sugar molecules, can directly impair cognition. They affect the function of synapses between nerve cells and, thus, affect neuronal plasticity. Experimental data presented at the 2023 American Chemical Society Congress have shown this phenomenon.
Twenty years ago, a study provided evidence that a diet high in fat and sugar disrupts neuronal plasticity and can impair the function of the hippocampus in the long term. A recent meta-analysis confirms these findings: Although mental performance improves at 2-12 hours after sugar consumption, sustained sugar intake can permanently damage cognitive function.
Diabetes mellitus can indirectly cause brain damage. Since the 1990s, it has been known that patients with type 2 diabetes have a significantly higher risk for dementia. It is suspected that glucose metabolism is also disrupted in neurons, thus contributing to the development of Alzheimer’s disease. Insulin also plays a role in the formation of Alzheimer’s plaques.
The Max Planck Institute for Metabolism Research demonstrated in 2023 that regular consumption of high-sugar and high-fat foods can change the brain. This leads to an increased craving for high-sugar and high-fat foods, which in turn promotes the development of obesity and type 2 diabetes.
Reduce Sugar Consumption
DGN and the German Brain Foundation advise minimizing sugar consumption. This process is often challenging, as even a small dose of sugar can trigger the gut to send signals to the brain via the vagus nerve, thus causing a strong craving for more sugar. “This could be the reason why some people quickly eat a whole chocolate bar after just one piece,” said Dr. Erbguth. In addition, dopamine, a “feel-good hormone,” is released in the brain when consuming sugar, thus leading to a desire for more.
“It is wise to break free from this cycle by largely avoiding sugar,” said Peter Berlit, MD, secretary general and spokesperson for DGN. “The effort is worth it, as 40% of all dementia cases and 90% of all strokes are preventable, with many of them linked to industrial sugar,” said Dr. Berlit. DGN and the German Brain Foundation support the call for a tax on particularly sugary beverages. They also pointed out that foods like yogurt or tomato ketchup contain sugar, and alcohol can also significantly raise blood sugar levels.
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
On World Brain Day (July 22, 2024), the German Society of Neurology (DGN) and the German Brain Foundation pointed out that too much sugar can harm the brain. The current results of the Global Burden of Diseases study shows that stroke and dementia are among the top 10 causes of death. A healthy, active lifestyle with sufficient exercise and sleep, along with the avoidance of harmful substances like alcohol, nicotine, or excessive sugar, protects the brain.
“Of course, the dose makes the poison as the brain, being the body’s powerhouse, needs glucose to function,” said Frank Erbguth, MD, PhD, president of the German Brain Foundation, in a press release from DGN and the German Brain Foundation. “However, with a permanent increase in blood sugar levels due to too many, too lavish meals and constant snacking on the side, we overload the system and fuel the development of neurologic diseases, particularly dementia and stroke.”
The per capita consumption of sugar was 33.2 kg in 2021/2022, which is almost twice the recommended amount. The German Nutrition Society recommends that no more than 10% of energy come from sugar. With a goal of 2000 kilocalories, that’s 50 g per day, or 18 kg per year. This total includes not only added sugar but also naturally occurring sugar, such as in fruits, honey, or juices.
What’s the Mechanism?
In Germany, around 250,000 people are diagnosed with dementia annually, and 15%-25% have vascular dementia. That proportion represents between 40,000 and 60,000 new cases each year.
In addition, glycosaminoglycans, which are complex sugar molecules, can directly impair cognition. They affect the function of synapses between nerve cells and, thus, affect neuronal plasticity. Experimental data presented at the 2023 American Chemical Society Congress have shown this phenomenon.
Twenty years ago, a study provided evidence that a diet high in fat and sugar disrupts neuronal plasticity and can impair the function of the hippocampus in the long term. A recent meta-analysis confirms these findings: Although mental performance improves at 2-12 hours after sugar consumption, sustained sugar intake can permanently damage cognitive function.
Diabetes mellitus can indirectly cause brain damage. Since the 1990s, it has been known that patients with type 2 diabetes have a significantly higher risk for dementia. It is suspected that glucose metabolism is also disrupted in neurons, thus contributing to the development of Alzheimer’s disease. Insulin also plays a role in the formation of Alzheimer’s plaques.
The Max Planck Institute for Metabolism Research demonstrated in 2023 that regular consumption of high-sugar and high-fat foods can change the brain. This leads to an increased craving for high-sugar and high-fat foods, which in turn promotes the development of obesity and type 2 diabetes.
Reduce Sugar Consumption
DGN and the German Brain Foundation advise minimizing sugar consumption. This process is often challenging, as even a small dose of sugar can trigger the gut to send signals to the brain via the vagus nerve, thus causing a strong craving for more sugar. “This could be the reason why some people quickly eat a whole chocolate bar after just one piece,” said Dr. Erbguth. In addition, dopamine, a “feel-good hormone,” is released in the brain when consuming sugar, thus leading to a desire for more.
“It is wise to break free from this cycle by largely avoiding sugar,” said Peter Berlit, MD, secretary general and spokesperson for DGN. “The effort is worth it, as 40% of all dementia cases and 90% of all strokes are preventable, with many of them linked to industrial sugar,” said Dr. Berlit. DGN and the German Brain Foundation support the call for a tax on particularly sugary beverages. They also pointed out that foods like yogurt or tomato ketchup contain sugar, and alcohol can also significantly raise blood sugar levels.
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
On World Brain Day (July 22, 2024), the German Society of Neurology (DGN) and the German Brain Foundation pointed out that too much sugar can harm the brain. The current results of the Global Burden of Diseases study shows that stroke and dementia are among the top 10 causes of death. A healthy, active lifestyle with sufficient exercise and sleep, along with the avoidance of harmful substances like alcohol, nicotine, or excessive sugar, protects the brain.
“Of course, the dose makes the poison as the brain, being the body’s powerhouse, needs glucose to function,” said Frank Erbguth, MD, PhD, president of the German Brain Foundation, in a press release from DGN and the German Brain Foundation. “However, with a permanent increase in blood sugar levels due to too many, too lavish meals and constant snacking on the side, we overload the system and fuel the development of neurologic diseases, particularly dementia and stroke.”
The per capita consumption of sugar was 33.2 kg in 2021/2022, which is almost twice the recommended amount. The German Nutrition Society recommends that no more than 10% of energy come from sugar. With a goal of 2000 kilocalories, that’s 50 g per day, or 18 kg per year. This total includes not only added sugar but also naturally occurring sugar, such as in fruits, honey, or juices.
What’s the Mechanism?
In Germany, around 250,000 people are diagnosed with dementia annually, and 15%-25% have vascular dementia. That proportion represents between 40,000 and 60,000 new cases each year.
In addition, glycosaminoglycans, which are complex sugar molecules, can directly impair cognition. They affect the function of synapses between nerve cells and, thus, affect neuronal plasticity. Experimental data presented at the 2023 American Chemical Society Congress have shown this phenomenon.
Twenty years ago, a study provided evidence that a diet high in fat and sugar disrupts neuronal plasticity and can impair the function of the hippocampus in the long term. A recent meta-analysis confirms these findings: Although mental performance improves at 2-12 hours after sugar consumption, sustained sugar intake can permanently damage cognitive function.
Diabetes mellitus can indirectly cause brain damage. Since the 1990s, it has been known that patients with type 2 diabetes have a significantly higher risk for dementia. It is suspected that glucose metabolism is also disrupted in neurons, thus contributing to the development of Alzheimer’s disease. Insulin also plays a role in the formation of Alzheimer’s plaques.
The Max Planck Institute for Metabolism Research demonstrated in 2023 that regular consumption of high-sugar and high-fat foods can change the brain. This leads to an increased craving for high-sugar and high-fat foods, which in turn promotes the development of obesity and type 2 diabetes.
Reduce Sugar Consumption
DGN and the German Brain Foundation advise minimizing sugar consumption. This process is often challenging, as even a small dose of sugar can trigger the gut to send signals to the brain via the vagus nerve, thus causing a strong craving for more sugar. “This could be the reason why some people quickly eat a whole chocolate bar after just one piece,” said Dr. Erbguth. In addition, dopamine, a “feel-good hormone,” is released in the brain when consuming sugar, thus leading to a desire for more.
“It is wise to break free from this cycle by largely avoiding sugar,” said Peter Berlit, MD, secretary general and spokesperson for DGN. “The effort is worth it, as 40% of all dementia cases and 90% of all strokes are preventable, with many of them linked to industrial sugar,” said Dr. Berlit. DGN and the German Brain Foundation support the call for a tax on particularly sugary beverages. They also pointed out that foods like yogurt or tomato ketchup contain sugar, and alcohol can also significantly raise blood sugar levels.
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Two Diets Linked to Improved Cognition, Slowed Brain Aging
An intermittent fasting (IF) diet and a standard healthy living (HL) diet focused on healthy foods both lead to weight loss, reduced insulin resistance (IR), and slowed brain aging in older overweight adults with IR, new research showed. However, neither diet has an effect on Alzheimer’s disease (AD) biomarkers.
Although investigators found both diets were beneficial, some outcomes were more robust with the IF diet.
“The study provides a blueprint for assessing brain effects of dietary interventions and motivates further research on intermittent fasting and continuous diets for brain health optimization,” wrote the investigators, led by Dimitrios Kapogiannis, MD, chief, human neuroscience section, National Institute on Aging, and adjunct associate professor of neurology, the Johns Hopkins University School of Medicine.
The findings were published online in Cell Metabolism.
Cognitive Outcomes
The prevalence of IR — reduced cellular sensitivity to insulin that’s a hallmark of type 2 diabetes — increases with age and obesity, adding to an increased risk for accelerated brain aging as well as AD and related dementias (ADRD) in older adults who have overweight.
Studies reported healthy diets promote overall health, but it’s unclear whether, and to what extent, they improve brain health beyond general health enhancement.
Researchers used multiple brain and cognitive measures to assess dietary effects on brain health, including peripherally harvested neuron-derived extracellular vesicles (NDEVs) to probe neuronal insulin signaling; MRI to investigate the pace of brain aging; magnetic resonance spectroscopy (MRS) to measure brain glucose, metabolites, and neurotransmitters; and NDEVs and cerebrospinal fluid to derive biomarkers for AD/ADRD.
The study included 40 cognitively intact overweight participants with IR, mean age 63.2 years, 60% women, and 62.5% White. Their mean body weight was 97.1 kg and mean body mass index (BMI) was 34.4.
Participants were randomly assigned to 8 weeks of an IF diet or a HL diet that emphasizes fruits, vegetables, whole grains, lean proteins, and low-fat dairy and limits added sugars, saturated fats, and sodium.
The IF diet involved following the HL diet for 5 days per week and restricting calories to a quarter of the recommended daily intake for 2 consecutive days.
Both diets reduced neuronal IR and had comparable effects in improving insulin signaling biomarkers in NDEVs, reducing brain glucose on MRS, and improving blood biomarkers of carbohydrate and lipid metabolism.
Using MRI, researchers also assessed brain age, an indication of whether the brain appears older or younger than an individual’s chronological age. There was a decrease of 2.63 years with the IF diet (P = .05) and 2.42 years with the HL diet (P < .001) in the anterior cingulate and ventromedial prefrontal cortex.
Both diets improved executive function and memory, with those following the IF diet benefiting more in strategic planning, switching between two cognitively demanding tasks, cued recall, and other areas.
Hypothesis-Generating Research
AD biomarkers including amyloid beta 42 (Aß42), Aß40, and plasma phosphorylated-tau181 did not change with either diet, a finding that investigators speculated may be due to the short duration of the study. Light-chain neurofilaments increased across groups with no differences between the diets.
In other findings, BMI decreased by 1.41 with the IF diet and by 0.80 with the HL diet, and a similar pattern was observed for weight. Waist circumference decreased in both groups with no significant differences between diets.
An exploratory analysis showed executive function improved with the IF diet but not with the HL diet in women, whereas it improved with both diets in men. BMI and apolipoprotein E and SLC16A7 genotypes also modulated diet effects.
Both diets were well tolerated. The most frequent adverse events were gastrointestinal and occurred only with the IF diet.
The authors noted the findings are preliminary and results are hypothesis generating. Study limitations included the study’s short duration and its power to detect anything other than large to moderate effect size changes and differences between the diets. Researchers also didn’t acquire data on dietary intake, so lapses in adherence can’t be excluded. However, the large decreases in BMI, weight, and waist circumference with both diets indicated high adherence.
The study was supported by the National Institutes of Health’s National Institute on Aging. The authors reported no competing interests.
A version of this article first appeared on Medscape.com.
An intermittent fasting (IF) diet and a standard healthy living (HL) diet focused on healthy foods both lead to weight loss, reduced insulin resistance (IR), and slowed brain aging in older overweight adults with IR, new research showed. However, neither diet has an effect on Alzheimer’s disease (AD) biomarkers.
Although investigators found both diets were beneficial, some outcomes were more robust with the IF diet.
“The study provides a blueprint for assessing brain effects of dietary interventions and motivates further research on intermittent fasting and continuous diets for brain health optimization,” wrote the investigators, led by Dimitrios Kapogiannis, MD, chief, human neuroscience section, National Institute on Aging, and adjunct associate professor of neurology, the Johns Hopkins University School of Medicine.
The findings were published online in Cell Metabolism.
Cognitive Outcomes
The prevalence of IR — reduced cellular sensitivity to insulin that’s a hallmark of type 2 diabetes — increases with age and obesity, adding to an increased risk for accelerated brain aging as well as AD and related dementias (ADRD) in older adults who have overweight.
Studies reported healthy diets promote overall health, but it’s unclear whether, and to what extent, they improve brain health beyond general health enhancement.
Researchers used multiple brain and cognitive measures to assess dietary effects on brain health, including peripherally harvested neuron-derived extracellular vesicles (NDEVs) to probe neuronal insulin signaling; MRI to investigate the pace of brain aging; magnetic resonance spectroscopy (MRS) to measure brain glucose, metabolites, and neurotransmitters; and NDEVs and cerebrospinal fluid to derive biomarkers for AD/ADRD.
The study included 40 cognitively intact overweight participants with IR, mean age 63.2 years, 60% women, and 62.5% White. Their mean body weight was 97.1 kg and mean body mass index (BMI) was 34.4.
Participants were randomly assigned to 8 weeks of an IF diet or a HL diet that emphasizes fruits, vegetables, whole grains, lean proteins, and low-fat dairy and limits added sugars, saturated fats, and sodium.
The IF diet involved following the HL diet for 5 days per week and restricting calories to a quarter of the recommended daily intake for 2 consecutive days.
Both diets reduced neuronal IR and had comparable effects in improving insulin signaling biomarkers in NDEVs, reducing brain glucose on MRS, and improving blood biomarkers of carbohydrate and lipid metabolism.
Using MRI, researchers also assessed brain age, an indication of whether the brain appears older or younger than an individual’s chronological age. There was a decrease of 2.63 years with the IF diet (P = .05) and 2.42 years with the HL diet (P < .001) in the anterior cingulate and ventromedial prefrontal cortex.
Both diets improved executive function and memory, with those following the IF diet benefiting more in strategic planning, switching between two cognitively demanding tasks, cued recall, and other areas.
Hypothesis-Generating Research
AD biomarkers including amyloid beta 42 (Aß42), Aß40, and plasma phosphorylated-tau181 did not change with either diet, a finding that investigators speculated may be due to the short duration of the study. Light-chain neurofilaments increased across groups with no differences between the diets.
In other findings, BMI decreased by 1.41 with the IF diet and by 0.80 with the HL diet, and a similar pattern was observed for weight. Waist circumference decreased in both groups with no significant differences between diets.
An exploratory analysis showed executive function improved with the IF diet but not with the HL diet in women, whereas it improved with both diets in men. BMI and apolipoprotein E and SLC16A7 genotypes also modulated diet effects.
Both diets were well tolerated. The most frequent adverse events were gastrointestinal and occurred only with the IF diet.
The authors noted the findings are preliminary and results are hypothesis generating. Study limitations included the study’s short duration and its power to detect anything other than large to moderate effect size changes and differences between the diets. Researchers also didn’t acquire data on dietary intake, so lapses in adherence can’t be excluded. However, the large decreases in BMI, weight, and waist circumference with both diets indicated high adherence.
The study was supported by the National Institutes of Health’s National Institute on Aging. The authors reported no competing interests.
A version of this article first appeared on Medscape.com.
An intermittent fasting (IF) diet and a standard healthy living (HL) diet focused on healthy foods both lead to weight loss, reduced insulin resistance (IR), and slowed brain aging in older overweight adults with IR, new research showed. However, neither diet has an effect on Alzheimer’s disease (AD) biomarkers.
Although investigators found both diets were beneficial, some outcomes were more robust with the IF diet.
“The study provides a blueprint for assessing brain effects of dietary interventions and motivates further research on intermittent fasting and continuous diets for brain health optimization,” wrote the investigators, led by Dimitrios Kapogiannis, MD, chief, human neuroscience section, National Institute on Aging, and adjunct associate professor of neurology, the Johns Hopkins University School of Medicine.
The findings were published online in Cell Metabolism.
Cognitive Outcomes
The prevalence of IR — reduced cellular sensitivity to insulin that’s a hallmark of type 2 diabetes — increases with age and obesity, adding to an increased risk for accelerated brain aging as well as AD and related dementias (ADRD) in older adults who have overweight.
Studies reported healthy diets promote overall health, but it’s unclear whether, and to what extent, they improve brain health beyond general health enhancement.
Researchers used multiple brain and cognitive measures to assess dietary effects on brain health, including peripherally harvested neuron-derived extracellular vesicles (NDEVs) to probe neuronal insulin signaling; MRI to investigate the pace of brain aging; magnetic resonance spectroscopy (MRS) to measure brain glucose, metabolites, and neurotransmitters; and NDEVs and cerebrospinal fluid to derive biomarkers for AD/ADRD.
The study included 40 cognitively intact overweight participants with IR, mean age 63.2 years, 60% women, and 62.5% White. Their mean body weight was 97.1 kg and mean body mass index (BMI) was 34.4.
Participants were randomly assigned to 8 weeks of an IF diet or a HL diet that emphasizes fruits, vegetables, whole grains, lean proteins, and low-fat dairy and limits added sugars, saturated fats, and sodium.
The IF diet involved following the HL diet for 5 days per week and restricting calories to a quarter of the recommended daily intake for 2 consecutive days.
Both diets reduced neuronal IR and had comparable effects in improving insulin signaling biomarkers in NDEVs, reducing brain glucose on MRS, and improving blood biomarkers of carbohydrate and lipid metabolism.
Using MRI, researchers also assessed brain age, an indication of whether the brain appears older or younger than an individual’s chronological age. There was a decrease of 2.63 years with the IF diet (P = .05) and 2.42 years with the HL diet (P < .001) in the anterior cingulate and ventromedial prefrontal cortex.
Both diets improved executive function and memory, with those following the IF diet benefiting more in strategic planning, switching between two cognitively demanding tasks, cued recall, and other areas.
Hypothesis-Generating Research
AD biomarkers including amyloid beta 42 (Aß42), Aß40, and plasma phosphorylated-tau181 did not change with either diet, a finding that investigators speculated may be due to the short duration of the study. Light-chain neurofilaments increased across groups with no differences between the diets.
In other findings, BMI decreased by 1.41 with the IF diet and by 0.80 with the HL diet, and a similar pattern was observed for weight. Waist circumference decreased in both groups with no significant differences between diets.
An exploratory analysis showed executive function improved with the IF diet but not with the HL diet in women, whereas it improved with both diets in men. BMI and apolipoprotein E and SLC16A7 genotypes also modulated diet effects.
Both diets were well tolerated. The most frequent adverse events were gastrointestinal and occurred only with the IF diet.
The authors noted the findings are preliminary and results are hypothesis generating. Study limitations included the study’s short duration and its power to detect anything other than large to moderate effect size changes and differences between the diets. Researchers also didn’t acquire data on dietary intake, so lapses in adherence can’t be excluded. However, the large decreases in BMI, weight, and waist circumference with both diets indicated high adherence.
The study was supported by the National Institutes of Health’s National Institute on Aging. The authors reported no competing interests.
A version of this article first appeared on Medscape.com.
FROM CELL METABOLISM
Study Links Newer Shingles Vaccine to Delayed Dementia Diagnosis
The study builds on previous observations of a reduction in dementia risk with the older live shingles vaccine and reports a delay in dementia diagnosis of 164 days with the newer recombinant version, compared with the live vaccine.
“Given the prevalence of dementia, a delay of 164 days in diagnosis would not be a trivial effect at the public health level. It’s a big enough effect that if there is a causality it feels meaningful,” said senior author Paul Harrison, DM, FRCPsych, professor of psychiatry at the University of Oxford, Oxford, England.
But Dr. Harrison stressed that the study had not proven that the shingles vaccine reduced dementia risk.
“The design of the study allows us to do away with many of the confounding effects we usually see in observational studies, but this is still an observational study, and as such it cannot prove a definite causal effect,” he said.
The study was published online on July 25 in Nature Medicine.
‘Natural Experiment’
Given the risk for deleterious consequences of shingles, vaccination is now recommended for older adults in many countries. The previously used live shingles vaccine (Zostavax) is being replaced in most countries with the new recombinant shingles vaccine (Shingrix), which is more effective at preventing shingles infection.
The current study made use of a “natural experiment” in the United States, which switched over from use of the live vaccine to the recombinant vaccine in October 2017.
Researchers used electronic heath records to compare the incidence of a dementia diagnosis in individuals who received the live shingles vaccine prior to October 2017 with those who received the recombinant version after the United States made the switch.
They also used propensity score matching to further control for confounding factors, comparing 103,837 individuals who received a first dose of the live shingles vaccine between October 2014 and September 2017 with the same number of matched people who received the recombinant vaccine between November 2017 and October 2020.
Results showed that within the 6 years after vaccination, the recombinant vaccine was associated with a delay in the diagnosis of dementia, compared with the live vaccine. Specifically, receiving the recombinant vaccine was associated with a 17% increase in diagnosis-free time, translating to 164 additional days lived without a diagnosis of dementia in those subsequently affected.
As an additional control, the researchers also found significantly lower risks for dementia in individuals receiving the new recombinant shingles vaccine vs two other vaccines commonly used in older people: influenza and tetanus/diphtheria/pertussis vaccines, with increases in diagnosis-free time of 14%-27%.
Reduced Risk or Delayed Diagnosis?
Speaking at a Science Media Centre press conference on the study, lead author Maxime Taquet, PhD, FRCPsych, clinical lecturer in psychiatry at the University of Oxford, noted that the total number of dementia cases were similar in the two shingles vaccine groups by the end of the 6-year follow-up period but there was a difference in the time at which they received a diagnosis of dementia.
“The study suggests that rather than actually reducing dementia risk, the recombinant vaccine delays the onset of dementia compared to the live vaccine in patients who go on to develop the condition,” he explained.
But when comparing the recombinant vaccine with the influenza and tetanus/diphtheria/pertussis vaccines there was a clear reduction in dementia risk itself, Dr. Taquet reported.
“It might well be that the live vaccine has a potential effect on the risk of dementia itself and therefore the recombinant vaccine only shows a delay in dementia compared to the live vaccine, but both of them might decrease the overall risk of dementia,” he suggested.
But the researchers cautioned that this study could not prove causality.
“While the two groups were very carefully matched in terms of factors that might influence the development of dementia, we still have to be cautious before assuming that the vaccine is indeed causally reducing the risk of onset of dementia,” Dr. Harrison warned.
The researchers say the results would need to be confirmed in a randomized trial, which may have to be conducted in a slightly younger age group, as currently shingles vaccine is recommended for all older individuals in the United Kingdom.
Vaccine recommendations vary from country to country, Dr. Harrison added. In the United States, the Centers for Disease Control and Prevention recommends the recombinant shingles vaccine for all adults aged 50 years or older.
In the meantime, it would be interesting to see whether further observational studies in other countries find similar results as this US study, Dr. Harrison said.
Mechanism Uncertain
Speculating on a possible mechanism behind the findings, Dr. Harrison suggested two plausible explanations.
“First, it is thought that the herpes virus could be one of many factors that could promote dementia, so a vaccine that stops reactivation of this virus might therefore be delaying that process,” he noted.
The other possibility is that adjuvants included in the recombinant vaccine to stimulate the immune system might have played a role.
“We don’t have any data on the mechanism, and thus study did not address that, so further studies are needed to look into this,” Dr. Harrison said.
Stronger Effect in Women
Another intriguing finding is that the association with the recombinant vaccine and delayed dementia diagnosis seemed to be stronger in women vs men.
In the original study of the live shingles vaccine, a protective effect against dementia was shown only in women.
In the current study, the delay in dementia diagnosis was seen in both sexes but was stronger in women, showing a 22% increased time without dementia in women versus a 13% increased time in men with the recombinant versus the live vaccine.
As expected, the recombinant vaccine was associated with a lower risk for shingles disease vs the live vaccine (2.5% versus 3.5%), but women did not have a better response than men did in this respect.
“The better protection against shingles with the recombinant vaccine was similar in men and women, an observation that might be one reason to question the possible mechanism behind the dementia effect being better suppression of the herpes zoster virus by the recombinant vaccine,” Dr. Harrison commented.
Though these findings are not likely to lead to any immediate changes in policy regarding the shingles vaccine, Dr. Harrison said it would be interesting to see whether uptake of the vaccine increased after this study.
He estimated that, currently in the United Kingdom, about 60% of older adults choose to have the shingles vaccine. A 2020 study in the United States found that only about one-third of US adults over 60 had received the vaccine.
“It will be interesting to see if that figure increases after these data are publicized, but I am not recommending that people have the vaccine specifically to lower their risk of dementia because of the caveats about the study that we have discussed,” he commented.
Outside Experts Positive
Outside experts, providing comment to the Science Media Centre, welcomed the new research.
“ The study is very well-conducted and adds to previous data indicating that vaccination against shingles is associated with lower dementia risk. More research is needed in future to determine why this vaccine is associated with lower dementia risk,” said Tara Spires-Jones, FMedSci, president of the British Neuroscience Association.
The high number of patients in the study and the adjustments for potential confounders are also strong points, noted Andrew Doig, PhD, professor of biochemistry, University of Manchester, Manchester, England.
“This is a significant result, comparable in effectiveness to the recent antibody drugs for Alzheimer’s disease,” Dr. Doig said. “Administering the recombinant shingles vaccine could well be a simple and cheap way to lower the risk of Alzheimer’s disease.”
Dr. Doig noted that a link between herpes zoster infection and the onset of dementia has been suspected for some time, and a trial of the antiviral drug valacyclovir against Alzheimer’s disease is currently underway.
In regard to the shingles vaccine, he said a placebo-controlled trial would be needed to prove causality.
“We also need to see how many years the effect might last and whether we should vaccinate people at a younger age. We know that the path to Alzheimer’s can start decades before any symptoms are apparent, so the vaccine might be even more effective if given to people in their 40s or 50s,” he said.
Dr. Harrison and Dr. Taquet reported no disclosures. Dr. Doig is a founder, director, and consultant for PharmaKure, which works on Alzheimer’s drugs and diagnostics. Other commentators declared no disclosures.
A version of this article first appeared on Medscape.com.
The study builds on previous observations of a reduction in dementia risk with the older live shingles vaccine and reports a delay in dementia diagnosis of 164 days with the newer recombinant version, compared with the live vaccine.
“Given the prevalence of dementia, a delay of 164 days in diagnosis would not be a trivial effect at the public health level. It’s a big enough effect that if there is a causality it feels meaningful,” said senior author Paul Harrison, DM, FRCPsych, professor of psychiatry at the University of Oxford, Oxford, England.
But Dr. Harrison stressed that the study had not proven that the shingles vaccine reduced dementia risk.
“The design of the study allows us to do away with many of the confounding effects we usually see in observational studies, but this is still an observational study, and as such it cannot prove a definite causal effect,” he said.
The study was published online on July 25 in Nature Medicine.
‘Natural Experiment’
Given the risk for deleterious consequences of shingles, vaccination is now recommended for older adults in many countries. The previously used live shingles vaccine (Zostavax) is being replaced in most countries with the new recombinant shingles vaccine (Shingrix), which is more effective at preventing shingles infection.
The current study made use of a “natural experiment” in the United States, which switched over from use of the live vaccine to the recombinant vaccine in October 2017.
Researchers used electronic heath records to compare the incidence of a dementia diagnosis in individuals who received the live shingles vaccine prior to October 2017 with those who received the recombinant version after the United States made the switch.
They also used propensity score matching to further control for confounding factors, comparing 103,837 individuals who received a first dose of the live shingles vaccine between October 2014 and September 2017 with the same number of matched people who received the recombinant vaccine between November 2017 and October 2020.
Results showed that within the 6 years after vaccination, the recombinant vaccine was associated with a delay in the diagnosis of dementia, compared with the live vaccine. Specifically, receiving the recombinant vaccine was associated with a 17% increase in diagnosis-free time, translating to 164 additional days lived without a diagnosis of dementia in those subsequently affected.
As an additional control, the researchers also found significantly lower risks for dementia in individuals receiving the new recombinant shingles vaccine vs two other vaccines commonly used in older people: influenza and tetanus/diphtheria/pertussis vaccines, with increases in diagnosis-free time of 14%-27%.
Reduced Risk or Delayed Diagnosis?
Speaking at a Science Media Centre press conference on the study, lead author Maxime Taquet, PhD, FRCPsych, clinical lecturer in psychiatry at the University of Oxford, noted that the total number of dementia cases were similar in the two shingles vaccine groups by the end of the 6-year follow-up period but there was a difference in the time at which they received a diagnosis of dementia.
“The study suggests that rather than actually reducing dementia risk, the recombinant vaccine delays the onset of dementia compared to the live vaccine in patients who go on to develop the condition,” he explained.
But when comparing the recombinant vaccine with the influenza and tetanus/diphtheria/pertussis vaccines there was a clear reduction in dementia risk itself, Dr. Taquet reported.
“It might well be that the live vaccine has a potential effect on the risk of dementia itself and therefore the recombinant vaccine only shows a delay in dementia compared to the live vaccine, but both of them might decrease the overall risk of dementia,” he suggested.
But the researchers cautioned that this study could not prove causality.
“While the two groups were very carefully matched in terms of factors that might influence the development of dementia, we still have to be cautious before assuming that the vaccine is indeed causally reducing the risk of onset of dementia,” Dr. Harrison warned.
The researchers say the results would need to be confirmed in a randomized trial, which may have to be conducted in a slightly younger age group, as currently shingles vaccine is recommended for all older individuals in the United Kingdom.
Vaccine recommendations vary from country to country, Dr. Harrison added. In the United States, the Centers for Disease Control and Prevention recommends the recombinant shingles vaccine for all adults aged 50 years or older.
In the meantime, it would be interesting to see whether further observational studies in other countries find similar results as this US study, Dr. Harrison said.
Mechanism Uncertain
Speculating on a possible mechanism behind the findings, Dr. Harrison suggested two plausible explanations.
“First, it is thought that the herpes virus could be one of many factors that could promote dementia, so a vaccine that stops reactivation of this virus might therefore be delaying that process,” he noted.
The other possibility is that adjuvants included in the recombinant vaccine to stimulate the immune system might have played a role.
“We don’t have any data on the mechanism, and thus study did not address that, so further studies are needed to look into this,” Dr. Harrison said.
Stronger Effect in Women
Another intriguing finding is that the association with the recombinant vaccine and delayed dementia diagnosis seemed to be stronger in women vs men.
In the original study of the live shingles vaccine, a protective effect against dementia was shown only in women.
In the current study, the delay in dementia diagnosis was seen in both sexes but was stronger in women, showing a 22% increased time without dementia in women versus a 13% increased time in men with the recombinant versus the live vaccine.
As expected, the recombinant vaccine was associated with a lower risk for shingles disease vs the live vaccine (2.5% versus 3.5%), but women did not have a better response than men did in this respect.
“The better protection against shingles with the recombinant vaccine was similar in men and women, an observation that might be one reason to question the possible mechanism behind the dementia effect being better suppression of the herpes zoster virus by the recombinant vaccine,” Dr. Harrison commented.
Though these findings are not likely to lead to any immediate changes in policy regarding the shingles vaccine, Dr. Harrison said it would be interesting to see whether uptake of the vaccine increased after this study.
He estimated that, currently in the United Kingdom, about 60% of older adults choose to have the shingles vaccine. A 2020 study in the United States found that only about one-third of US adults over 60 had received the vaccine.
“It will be interesting to see if that figure increases after these data are publicized, but I am not recommending that people have the vaccine specifically to lower their risk of dementia because of the caveats about the study that we have discussed,” he commented.
Outside Experts Positive
Outside experts, providing comment to the Science Media Centre, welcomed the new research.
“ The study is very well-conducted and adds to previous data indicating that vaccination against shingles is associated with lower dementia risk. More research is needed in future to determine why this vaccine is associated with lower dementia risk,” said Tara Spires-Jones, FMedSci, president of the British Neuroscience Association.
The high number of patients in the study and the adjustments for potential confounders are also strong points, noted Andrew Doig, PhD, professor of biochemistry, University of Manchester, Manchester, England.
“This is a significant result, comparable in effectiveness to the recent antibody drugs for Alzheimer’s disease,” Dr. Doig said. “Administering the recombinant shingles vaccine could well be a simple and cheap way to lower the risk of Alzheimer’s disease.”
Dr. Doig noted that a link between herpes zoster infection and the onset of dementia has been suspected for some time, and a trial of the antiviral drug valacyclovir against Alzheimer’s disease is currently underway.
In regard to the shingles vaccine, he said a placebo-controlled trial would be needed to prove causality.
“We also need to see how many years the effect might last and whether we should vaccinate people at a younger age. We know that the path to Alzheimer’s can start decades before any symptoms are apparent, so the vaccine might be even more effective if given to people in their 40s or 50s,” he said.
Dr. Harrison and Dr. Taquet reported no disclosures. Dr. Doig is a founder, director, and consultant for PharmaKure, which works on Alzheimer’s drugs and diagnostics. Other commentators declared no disclosures.
A version of this article first appeared on Medscape.com.
The study builds on previous observations of a reduction in dementia risk with the older live shingles vaccine and reports a delay in dementia diagnosis of 164 days with the newer recombinant version, compared with the live vaccine.
“Given the prevalence of dementia, a delay of 164 days in diagnosis would not be a trivial effect at the public health level. It’s a big enough effect that if there is a causality it feels meaningful,” said senior author Paul Harrison, DM, FRCPsych, professor of psychiatry at the University of Oxford, Oxford, England.
But Dr. Harrison stressed that the study had not proven that the shingles vaccine reduced dementia risk.
“The design of the study allows us to do away with many of the confounding effects we usually see in observational studies, but this is still an observational study, and as such it cannot prove a definite causal effect,” he said.
The study was published online on July 25 in Nature Medicine.
‘Natural Experiment’
Given the risk for deleterious consequences of shingles, vaccination is now recommended for older adults in many countries. The previously used live shingles vaccine (Zostavax) is being replaced in most countries with the new recombinant shingles vaccine (Shingrix), which is more effective at preventing shingles infection.
The current study made use of a “natural experiment” in the United States, which switched over from use of the live vaccine to the recombinant vaccine in October 2017.
Researchers used electronic heath records to compare the incidence of a dementia diagnosis in individuals who received the live shingles vaccine prior to October 2017 with those who received the recombinant version after the United States made the switch.
They also used propensity score matching to further control for confounding factors, comparing 103,837 individuals who received a first dose of the live shingles vaccine between October 2014 and September 2017 with the same number of matched people who received the recombinant vaccine between November 2017 and October 2020.
Results showed that within the 6 years after vaccination, the recombinant vaccine was associated with a delay in the diagnosis of dementia, compared with the live vaccine. Specifically, receiving the recombinant vaccine was associated with a 17% increase in diagnosis-free time, translating to 164 additional days lived without a diagnosis of dementia in those subsequently affected.
As an additional control, the researchers also found significantly lower risks for dementia in individuals receiving the new recombinant shingles vaccine vs two other vaccines commonly used in older people: influenza and tetanus/diphtheria/pertussis vaccines, with increases in diagnosis-free time of 14%-27%.
Reduced Risk or Delayed Diagnosis?
Speaking at a Science Media Centre press conference on the study, lead author Maxime Taquet, PhD, FRCPsych, clinical lecturer in psychiatry at the University of Oxford, noted that the total number of dementia cases were similar in the two shingles vaccine groups by the end of the 6-year follow-up period but there was a difference in the time at which they received a diagnosis of dementia.
“The study suggests that rather than actually reducing dementia risk, the recombinant vaccine delays the onset of dementia compared to the live vaccine in patients who go on to develop the condition,” he explained.
But when comparing the recombinant vaccine with the influenza and tetanus/diphtheria/pertussis vaccines there was a clear reduction in dementia risk itself, Dr. Taquet reported.
“It might well be that the live vaccine has a potential effect on the risk of dementia itself and therefore the recombinant vaccine only shows a delay in dementia compared to the live vaccine, but both of them might decrease the overall risk of dementia,” he suggested.
But the researchers cautioned that this study could not prove causality.
“While the two groups were very carefully matched in terms of factors that might influence the development of dementia, we still have to be cautious before assuming that the vaccine is indeed causally reducing the risk of onset of dementia,” Dr. Harrison warned.
The researchers say the results would need to be confirmed in a randomized trial, which may have to be conducted in a slightly younger age group, as currently shingles vaccine is recommended for all older individuals in the United Kingdom.
Vaccine recommendations vary from country to country, Dr. Harrison added. In the United States, the Centers for Disease Control and Prevention recommends the recombinant shingles vaccine for all adults aged 50 years or older.
In the meantime, it would be interesting to see whether further observational studies in other countries find similar results as this US study, Dr. Harrison said.
Mechanism Uncertain
Speculating on a possible mechanism behind the findings, Dr. Harrison suggested two plausible explanations.
“First, it is thought that the herpes virus could be one of many factors that could promote dementia, so a vaccine that stops reactivation of this virus might therefore be delaying that process,” he noted.
The other possibility is that adjuvants included in the recombinant vaccine to stimulate the immune system might have played a role.
“We don’t have any data on the mechanism, and thus study did not address that, so further studies are needed to look into this,” Dr. Harrison said.
Stronger Effect in Women
Another intriguing finding is that the association with the recombinant vaccine and delayed dementia diagnosis seemed to be stronger in women vs men.
In the original study of the live shingles vaccine, a protective effect against dementia was shown only in women.
In the current study, the delay in dementia diagnosis was seen in both sexes but was stronger in women, showing a 22% increased time without dementia in women versus a 13% increased time in men with the recombinant versus the live vaccine.
As expected, the recombinant vaccine was associated with a lower risk for shingles disease vs the live vaccine (2.5% versus 3.5%), but women did not have a better response than men did in this respect.
“The better protection against shingles with the recombinant vaccine was similar in men and women, an observation that might be one reason to question the possible mechanism behind the dementia effect being better suppression of the herpes zoster virus by the recombinant vaccine,” Dr. Harrison commented.
Though these findings are not likely to lead to any immediate changes in policy regarding the shingles vaccine, Dr. Harrison said it would be interesting to see whether uptake of the vaccine increased after this study.
He estimated that, currently in the United Kingdom, about 60% of older adults choose to have the shingles vaccine. A 2020 study in the United States found that only about one-third of US adults over 60 had received the vaccine.
“It will be interesting to see if that figure increases after these data are publicized, but I am not recommending that people have the vaccine specifically to lower their risk of dementia because of the caveats about the study that we have discussed,” he commented.
Outside Experts Positive
Outside experts, providing comment to the Science Media Centre, welcomed the new research.
“ The study is very well-conducted and adds to previous data indicating that vaccination against shingles is associated with lower dementia risk. More research is needed in future to determine why this vaccine is associated with lower dementia risk,” said Tara Spires-Jones, FMedSci, president of the British Neuroscience Association.
The high number of patients in the study and the adjustments for potential confounders are also strong points, noted Andrew Doig, PhD, professor of biochemistry, University of Manchester, Manchester, England.
“This is a significant result, comparable in effectiveness to the recent antibody drugs for Alzheimer’s disease,” Dr. Doig said. “Administering the recombinant shingles vaccine could well be a simple and cheap way to lower the risk of Alzheimer’s disease.”
Dr. Doig noted that a link between herpes zoster infection and the onset of dementia has been suspected for some time, and a trial of the antiviral drug valacyclovir against Alzheimer’s disease is currently underway.
In regard to the shingles vaccine, he said a placebo-controlled trial would be needed to prove causality.
“We also need to see how many years the effect might last and whether we should vaccinate people at a younger age. We know that the path to Alzheimer’s can start decades before any symptoms are apparent, so the vaccine might be even more effective if given to people in their 40s or 50s,” he said.
Dr. Harrison and Dr. Taquet reported no disclosures. Dr. Doig is a founder, director, and consultant for PharmaKure, which works on Alzheimer’s drugs and diagnostics. Other commentators declared no disclosures.
A version of this article first appeared on Medscape.com.
FROM NATURE MEDICINE
New Criteria Distinguish Memory Disorder Often Misdiagnosed as Alzheimer’s
Proposed clinical criteria for a memory loss disorder that is often misdiagnosed as Alzheimer’s disease (AD) have been published.
The new criteria for limbic-predominant amnestic neurodegenerative syndrome (LANS) provide a framework for neurologists and other experts to classify the condition and offer a more precise diagnosis and potential treatments.
“In our clinical work, we see patients whose memory symptoms appear to mimic Alzheimer’s disease, but when you look at their brain imaging or biomarkers, it’s clear they don’t have Alzheimer’s. Until now, there has not been a specific medical diagnosis to point to, but now we can offer them some answers,” senior investigator David T. Jones, MD, said in a release.
The proposed criteria and the research behind it were published online in Brain Communications and will be presented at the Alzheimer›s Association International Conference in Philadelphia.
Already in Use
Predominant limbic degeneration has been linked to various underlying etiologies, older age, predominant impairment of episodic memory, and slow clinical progression, the investigators noted. However, they added, the neurologic syndrome associated with predominant limbic degeneration is undefined.
Developing clinical criteria and validating them “is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying etiology, disease course, and therapeutic needs,” the investigators wrote.
The newly proposed clinical criteria apply to LANS, which is “highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities.”
The criteria incorporate core, standard, and advanced features including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of endocortical degeneration, and low likelihood of neocortical tau with highest, high, moderate, and low degrees of certainty.
“A detailed history of the clinical symptoms, which may be supported by neuropsychological testing, with the observation of disproportionate hippocampal atrophy and limbic degeneration on MRI/FDG yields a high confidence in a diagnosis of LANS, where the most likely symptom-driving proteinopathy is TDP-43 and not Alzheimer’s associated proteins,” the first author, Nick Corriveau-Lecavalier, PhD, assistant professor of neurology and psychology at Mayo Clinic, Rochester, Minnesota, told this news organization.
To validate the criteria, the investigators screened autopsied patients from Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative cohorts and applied the criteria to those with a predominant amnestic syndrome and those who had AD neuropathologic change, limbic-predominant age-related TDP-43 encephalopathy, or both pathologies at autopsy.
“The criteria effectively categorized these cases, with Alzheimer’s disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods, and patients with both pathologies having intermediate likelihoods,” the investigators reported.
“Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods,” they added.
Dr. Corriveau-Lecavalier said the team is currently analyzing longitudinal cognitive and imaging trajectories in LANS over several years. “This will help us better understand how LANS and Alzheimer’s differ in their sequence of symptoms over time.”
It is important to understand that memory symptoms in old age are not “unequivocally” driven by Alzheimer’s and that LANS progresses more slowly and has a better prognosis than AD, he noted.
In addition, in vivo markers of TDP-43 are “on the horizon and can hopefully make their way to human research settings soon. This will help better understand the underlying molecular etiologies causing LANS and associated symptoms,” he said.
Dr. Corriveau-Lecavalier said the LANS criteria are ready for clinical use by experts in neurologic care. These criteria can be used to inform not only diagnosis but also prognosis, where this syndrome is associated with slow and mild progression and a memory-dominant profile.
He added that “the new criteria are also routinely used in our practice to make decisions about anti-amyloid treatment eligibility.”
Commenting on the research for this news organization, Rebecca M. Edelmayer, PhD, Alzheimer’s Association senior director of scientific engagement, said the research “exemplifies the great need to develop objective criteria for diagnosis and staging of Alzheimer’s and all other types of dementia and to create an integrated biological and clinical staging scheme that can be used effectively by physicians.”
“Advances in biomarkers will help to differentiate all types of dementia when incorporated into the diagnostic workup, but until those tools are available, a more succinct clinical criteria for diagnosis can be used to support a more personalized medicine approach to treatment, care, and enrollment into clinical studies,” said Dr. Edelmayer, who wasn’t involved in the research.
The research was funded in part by the National Institutes of Health and by the Robert Wood Johnson Foundation, the Elsie & Marvin Dekelboum Family Foundation, the Liston Family Foundation, the Edson Family, the Gerald A. and Henrietta Rauenhorst Foundation, and the Foundation Dr Corinne Schuler. Dr. Corriveau-Lecavalier and Dr. Edelmayer had no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Proposed clinical criteria for a memory loss disorder that is often misdiagnosed as Alzheimer’s disease (AD) have been published.
The new criteria for limbic-predominant amnestic neurodegenerative syndrome (LANS) provide a framework for neurologists and other experts to classify the condition and offer a more precise diagnosis and potential treatments.
“In our clinical work, we see patients whose memory symptoms appear to mimic Alzheimer’s disease, but when you look at their brain imaging or biomarkers, it’s clear they don’t have Alzheimer’s. Until now, there has not been a specific medical diagnosis to point to, but now we can offer them some answers,” senior investigator David T. Jones, MD, said in a release.
The proposed criteria and the research behind it were published online in Brain Communications and will be presented at the Alzheimer›s Association International Conference in Philadelphia.
Already in Use
Predominant limbic degeneration has been linked to various underlying etiologies, older age, predominant impairment of episodic memory, and slow clinical progression, the investigators noted. However, they added, the neurologic syndrome associated with predominant limbic degeneration is undefined.
Developing clinical criteria and validating them “is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying etiology, disease course, and therapeutic needs,” the investigators wrote.
The newly proposed clinical criteria apply to LANS, which is “highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities.”
The criteria incorporate core, standard, and advanced features including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of endocortical degeneration, and low likelihood of neocortical tau with highest, high, moderate, and low degrees of certainty.
“A detailed history of the clinical symptoms, which may be supported by neuropsychological testing, with the observation of disproportionate hippocampal atrophy and limbic degeneration on MRI/FDG yields a high confidence in a diagnosis of LANS, where the most likely symptom-driving proteinopathy is TDP-43 and not Alzheimer’s associated proteins,” the first author, Nick Corriveau-Lecavalier, PhD, assistant professor of neurology and psychology at Mayo Clinic, Rochester, Minnesota, told this news organization.
To validate the criteria, the investigators screened autopsied patients from Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative cohorts and applied the criteria to those with a predominant amnestic syndrome and those who had AD neuropathologic change, limbic-predominant age-related TDP-43 encephalopathy, or both pathologies at autopsy.
“The criteria effectively categorized these cases, with Alzheimer’s disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods, and patients with both pathologies having intermediate likelihoods,” the investigators reported.
“Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods,” they added.
Dr. Corriveau-Lecavalier said the team is currently analyzing longitudinal cognitive and imaging trajectories in LANS over several years. “This will help us better understand how LANS and Alzheimer’s differ in their sequence of symptoms over time.”
It is important to understand that memory symptoms in old age are not “unequivocally” driven by Alzheimer’s and that LANS progresses more slowly and has a better prognosis than AD, he noted.
In addition, in vivo markers of TDP-43 are “on the horizon and can hopefully make their way to human research settings soon. This will help better understand the underlying molecular etiologies causing LANS and associated symptoms,” he said.
Dr. Corriveau-Lecavalier said the LANS criteria are ready for clinical use by experts in neurologic care. These criteria can be used to inform not only diagnosis but also prognosis, where this syndrome is associated with slow and mild progression and a memory-dominant profile.
He added that “the new criteria are also routinely used in our practice to make decisions about anti-amyloid treatment eligibility.”
Commenting on the research for this news organization, Rebecca M. Edelmayer, PhD, Alzheimer’s Association senior director of scientific engagement, said the research “exemplifies the great need to develop objective criteria for diagnosis and staging of Alzheimer’s and all other types of dementia and to create an integrated biological and clinical staging scheme that can be used effectively by physicians.”
“Advances in biomarkers will help to differentiate all types of dementia when incorporated into the diagnostic workup, but until those tools are available, a more succinct clinical criteria for diagnosis can be used to support a more personalized medicine approach to treatment, care, and enrollment into clinical studies,” said Dr. Edelmayer, who wasn’t involved in the research.
The research was funded in part by the National Institutes of Health and by the Robert Wood Johnson Foundation, the Elsie & Marvin Dekelboum Family Foundation, the Liston Family Foundation, the Edson Family, the Gerald A. and Henrietta Rauenhorst Foundation, and the Foundation Dr Corinne Schuler. Dr. Corriveau-Lecavalier and Dr. Edelmayer had no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Proposed clinical criteria for a memory loss disorder that is often misdiagnosed as Alzheimer’s disease (AD) have been published.
The new criteria for limbic-predominant amnestic neurodegenerative syndrome (LANS) provide a framework for neurologists and other experts to classify the condition and offer a more precise diagnosis and potential treatments.
“In our clinical work, we see patients whose memory symptoms appear to mimic Alzheimer’s disease, but when you look at their brain imaging or biomarkers, it’s clear they don’t have Alzheimer’s. Until now, there has not been a specific medical diagnosis to point to, but now we can offer them some answers,” senior investigator David T. Jones, MD, said in a release.
The proposed criteria and the research behind it were published online in Brain Communications and will be presented at the Alzheimer›s Association International Conference in Philadelphia.
Already in Use
Predominant limbic degeneration has been linked to various underlying etiologies, older age, predominant impairment of episodic memory, and slow clinical progression, the investigators noted. However, they added, the neurologic syndrome associated with predominant limbic degeneration is undefined.
Developing clinical criteria and validating them “is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying etiology, disease course, and therapeutic needs,” the investigators wrote.
The newly proposed clinical criteria apply to LANS, which is “highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities.”
The criteria incorporate core, standard, and advanced features including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of endocortical degeneration, and low likelihood of neocortical tau with highest, high, moderate, and low degrees of certainty.
“A detailed history of the clinical symptoms, which may be supported by neuropsychological testing, with the observation of disproportionate hippocampal atrophy and limbic degeneration on MRI/FDG yields a high confidence in a diagnosis of LANS, where the most likely symptom-driving proteinopathy is TDP-43 and not Alzheimer’s associated proteins,” the first author, Nick Corriveau-Lecavalier, PhD, assistant professor of neurology and psychology at Mayo Clinic, Rochester, Minnesota, told this news organization.
To validate the criteria, the investigators screened autopsied patients from Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative cohorts and applied the criteria to those with a predominant amnestic syndrome and those who had AD neuropathologic change, limbic-predominant age-related TDP-43 encephalopathy, or both pathologies at autopsy.
“The criteria effectively categorized these cases, with Alzheimer’s disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods, and patients with both pathologies having intermediate likelihoods,” the investigators reported.
“Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods,” they added.
Dr. Corriveau-Lecavalier said the team is currently analyzing longitudinal cognitive and imaging trajectories in LANS over several years. “This will help us better understand how LANS and Alzheimer’s differ in their sequence of symptoms over time.”
It is important to understand that memory symptoms in old age are not “unequivocally” driven by Alzheimer’s and that LANS progresses more slowly and has a better prognosis than AD, he noted.
In addition, in vivo markers of TDP-43 are “on the horizon and can hopefully make their way to human research settings soon. This will help better understand the underlying molecular etiologies causing LANS and associated symptoms,” he said.
Dr. Corriveau-Lecavalier said the LANS criteria are ready for clinical use by experts in neurologic care. These criteria can be used to inform not only diagnosis but also prognosis, where this syndrome is associated with slow and mild progression and a memory-dominant profile.
He added that “the new criteria are also routinely used in our practice to make decisions about anti-amyloid treatment eligibility.”
Commenting on the research for this news organization, Rebecca M. Edelmayer, PhD, Alzheimer’s Association senior director of scientific engagement, said the research “exemplifies the great need to develop objective criteria for diagnosis and staging of Alzheimer’s and all other types of dementia and to create an integrated biological and clinical staging scheme that can be used effectively by physicians.”
“Advances in biomarkers will help to differentiate all types of dementia when incorporated into the diagnostic workup, but until those tools are available, a more succinct clinical criteria for diagnosis can be used to support a more personalized medicine approach to treatment, care, and enrollment into clinical studies,” said Dr. Edelmayer, who wasn’t involved in the research.
The research was funded in part by the National Institutes of Health and by the Robert Wood Johnson Foundation, the Elsie & Marvin Dekelboum Family Foundation, the Liston Family Foundation, the Edson Family, the Gerald A. and Henrietta Rauenhorst Foundation, and the Foundation Dr Corinne Schuler. Dr. Corriveau-Lecavalier and Dr. Edelmayer had no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Will Treating High Blood Pressure Curb Dementia Risk?
High blood pressure is an established risk factor for neurodegeneration and cognitive decline.
Valentin Fuster, MD, president of Mount Sinai Fuster Heart Hospital in New York City, told this news organization. “There is no question in the literature that untreated high blood pressure may lead to dementia,” he said. “The open question is whether treating blood pressure is sufficient to decrease or stop the progress of dementia.”
Studies are mixed, but recent research suggests that addressing hypertension does affect the risk for dementia. A secondary analysis of the China Rural Hypertension Control Project reported at the American Heart Association (AHA) Scientific Sessions in 2023 but not yet published showed that the 4-year blood pressure–lowering program in adults aged 40 or older significantly reduced the risk for all-cause dementia and cognitive impairment.
Similarly, a post hoc analysis of the SPRINT MIND trial found that participants aged 50 or older who underwent intensive (< 120 mm Hg) vs standard (< 140 mm Hg) blood pressure lowering had a lower rate of probable dementia or mild cognitive impairment.
Other studies pointing to a benefit included a pooled individual participant analysis of five randomized controlled trials, which found class I evidence to support antihypertensive treatment to reduce the risk for incident dementia, and an earlier systematic review and meta-analysis of the association of blood pressure lowering with newly diagnosed dementia or cognitive impairment.
How It Might Work
Some possible mechanisms underlying the connection have emerged.
“Vascular disease caused by hypertension is clearly implicated in one form of dementia, called vascular cognitive impairment and dementia,” Andrew Moran, MD, PhD, associate professor of medicine at Columbia University Vagelos College of Physicians and Surgeons in New York City, told this news organization. “This category includes dementia following a stroke caused by uncontrolled hypertension.”
“At the same time, we now know that hypertension and other vascular risk factors can also contribute, along with other factors, to developing Alzheimer dementia,” he said. “Even without causing clinically evident stroke, vascular disease from hypertension can lead to subtle damage to the brain via ischemia, microhemorrhage, and atrophy.”
“It is well known that hypertension affects the vasculature, and the vasculature of the brain is not spared,” agreed Eileen Handberg, PhD, ARNP, a member of the Hypertension Workgroup at the American College of Cardiology (ACC) and a professor of medicine and director of the Cardiovascular Clinical Trials Program in the University of Florida, Gainesville, Florida. “Combine this with other mechanisms like inflammation and endothelial dysfunction, and add amyloid accumulation, and there is a deterioration in vascular beds leading to decreased cerebral blood flow,” she said.
Treating hypertension likely helps lower dementia risk through “a combination of reduced risk of stroke and also benefits on blood flow, blood vessel health, and reduction in neurodegeneration,” suggested Mitchell S.V. Elkind, MD, chief clinical science officer and past president of the AHA and a professor of neurology and epidemiology at Columbia University Irving Medical Center in New York City. “Midlife blood pressure elevations are associated with deposition of amyloid in the brain, so controlling blood pressure may reduce amyloid deposits and neurodegeneration.”
Time in Range or Treat to Target?
With respect to dementia risk, does treating hypertension to a specific target make a difference, or is it the time spent in a healthy blood pressure range?
“Observational studies and a post hoc analysis of the SPRINT MIND trial suggest that more time spent in a healthy blood pressure range or more stable blood pressure are associated with lower dementia risk,” Dr. Moran said. Citing results of the CHRC program and SPRINT MIND trial, he suggested that while a dose-response effect (the lower the blood pressure, the lower the dementia risk) hasn’t been definitively demonstrated, it is likely the case.
In his practice, Dr. Moran follows ACC/AHA guidelines and prescribes antihypertensives to get blood pressure below 130/80 mm Hg in individuals with hypertension who have other high-risk factors (cardiovascular disease, diabetes, chronic kidney disease, or high risk for these conditions). “The treatment rule for people with hypertension without these other risk factors is less clear — lowering blood pressure below 140/90 mm Hg is a must; I will discuss with patients whether to go lower than that.”
“The relative contributions of time in range versus treating to a target for blood pressure require further study,” said Dr. Elkind. “It is likely that the cumulative effect of blood pressure over time has a big role to play — and it does seem clear that midlife blood pressure is even more important than blood pressure late in life.”
That said, he added, “In general and all things being equal, I would treat to a blood pressure of < 120/80 mmHg,” given the SPRINT trial findings of greater benefits when treating to this systolic blood pressure goal. “Of course, if patients have side effects such as lightheadedness or dizziness or other medical conditions that require a higher target, then one would need to adjust the treatment targets.”
According to Dr. Fuster, targets should not be the focus because they vary. For example, the ACC/AHA guidelines use < 130/80 mm Hg, whereas the European Society of Hypertension guidelines and those of the American Academy of Family Physicians specify < 140/90 mm Hg and include age-based criteria. Because there are no studies comparing the outcomes of one set of guidelines vs another, Dr. Fuster thinks the focus should be on starting treatment as early as possible to prevent hypertension leading to dementia.
He pointed to the ongoing PESA trial, which uses brain MRI and other tests to characterize longitudinal associations among cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in asymptomatic individuals aged 40-54. Most did not have hypertension at baseline.
A recently published analysis of a subcohort of 370 PESA participants found that those with persistent high cardiovascular risk and subclinical carotid atherosclerosis already had signs of brain metabolic decline, “suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life,” wrote the investigators.
Is It Ever Too Late?
If starting hypertension treatment in midlife can help reduce the risk for cognitive impairment later, can treating later in life also help? “It’s theoretically possible, but it has to be proven,” Dr. Fuster said. “There are no data on whether there’s less chance to prevent the development of dementia if you start treating hypertension at age 70, for example. And we have no idea whether hypertension treatment will prevent progression in those who already have dementia.”
“Treating high blood pressure in older adults could affect the course of further progressive cognitive decline by improving vascular health and preventing strokes, which likely exacerbate nonvascular dementia,” Dr. Elkind suggested. “Most people with dementia have a combination of vascular and nonvascular dementia, so treating reversible causes wherever possible makes a difference.”
Dr. Elkind treats older patients with this in mind, he said, “even though most of the evidence points to the fact that it is blood pressure in middle age, not older age, that seems to have the biggest impact on later-life cognitive decline and dementia.” Like Dr. Fuster, he said, “the best strategy is to identify and treat blood pressure in midlife, before damage to the brain has advanced.”
Dr. Moran noted, “The latest science on dementia causes suggests it is difficult to draw a border between vascular and nonvascular dementia. So, as a practical matter, healthcare providers should consider that hypertension treatment is one of the best ways to prevent any category of dementia. This dementia prevention is added to the well-known benefits of hypertension treatment to prevent heart attacks, strokes, and kidney disease: ‘Healthy heart, healthy brain.’ ”
“Our BP [blood pressure] control rates overall are still abysmal,” Dr. Handberg added. Currently around one in four US adults with hypertension have it under control. Studies have shown that blood pressure control rates of 70%-80% are achievable, she said. “We can’t let patient or provider inertia continue.”
Dr. Handberg, Dr. Elkind, Dr. Moran, and Dr. Fuster declared no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
High blood pressure is an established risk factor for neurodegeneration and cognitive decline.
Valentin Fuster, MD, president of Mount Sinai Fuster Heart Hospital in New York City, told this news organization. “There is no question in the literature that untreated high blood pressure may lead to dementia,” he said. “The open question is whether treating blood pressure is sufficient to decrease or stop the progress of dementia.”
Studies are mixed, but recent research suggests that addressing hypertension does affect the risk for dementia. A secondary analysis of the China Rural Hypertension Control Project reported at the American Heart Association (AHA) Scientific Sessions in 2023 but not yet published showed that the 4-year blood pressure–lowering program in adults aged 40 or older significantly reduced the risk for all-cause dementia and cognitive impairment.
Similarly, a post hoc analysis of the SPRINT MIND trial found that participants aged 50 or older who underwent intensive (< 120 mm Hg) vs standard (< 140 mm Hg) blood pressure lowering had a lower rate of probable dementia or mild cognitive impairment.
Other studies pointing to a benefit included a pooled individual participant analysis of five randomized controlled trials, which found class I evidence to support antihypertensive treatment to reduce the risk for incident dementia, and an earlier systematic review and meta-analysis of the association of blood pressure lowering with newly diagnosed dementia or cognitive impairment.
How It Might Work
Some possible mechanisms underlying the connection have emerged.
“Vascular disease caused by hypertension is clearly implicated in one form of dementia, called vascular cognitive impairment and dementia,” Andrew Moran, MD, PhD, associate professor of medicine at Columbia University Vagelos College of Physicians and Surgeons in New York City, told this news organization. “This category includes dementia following a stroke caused by uncontrolled hypertension.”
“At the same time, we now know that hypertension and other vascular risk factors can also contribute, along with other factors, to developing Alzheimer dementia,” he said. “Even without causing clinically evident stroke, vascular disease from hypertension can lead to subtle damage to the brain via ischemia, microhemorrhage, and atrophy.”
“It is well known that hypertension affects the vasculature, and the vasculature of the brain is not spared,” agreed Eileen Handberg, PhD, ARNP, a member of the Hypertension Workgroup at the American College of Cardiology (ACC) and a professor of medicine and director of the Cardiovascular Clinical Trials Program in the University of Florida, Gainesville, Florida. “Combine this with other mechanisms like inflammation and endothelial dysfunction, and add amyloid accumulation, and there is a deterioration in vascular beds leading to decreased cerebral blood flow,” she said.
Treating hypertension likely helps lower dementia risk through “a combination of reduced risk of stroke and also benefits on blood flow, blood vessel health, and reduction in neurodegeneration,” suggested Mitchell S.V. Elkind, MD, chief clinical science officer and past president of the AHA and a professor of neurology and epidemiology at Columbia University Irving Medical Center in New York City. “Midlife blood pressure elevations are associated with deposition of amyloid in the brain, so controlling blood pressure may reduce amyloid deposits and neurodegeneration.”
Time in Range or Treat to Target?
With respect to dementia risk, does treating hypertension to a specific target make a difference, or is it the time spent in a healthy blood pressure range?
“Observational studies and a post hoc analysis of the SPRINT MIND trial suggest that more time spent in a healthy blood pressure range or more stable blood pressure are associated with lower dementia risk,” Dr. Moran said. Citing results of the CHRC program and SPRINT MIND trial, he suggested that while a dose-response effect (the lower the blood pressure, the lower the dementia risk) hasn’t been definitively demonstrated, it is likely the case.
In his practice, Dr. Moran follows ACC/AHA guidelines and prescribes antihypertensives to get blood pressure below 130/80 mm Hg in individuals with hypertension who have other high-risk factors (cardiovascular disease, diabetes, chronic kidney disease, or high risk for these conditions). “The treatment rule for people with hypertension without these other risk factors is less clear — lowering blood pressure below 140/90 mm Hg is a must; I will discuss with patients whether to go lower than that.”
“The relative contributions of time in range versus treating to a target for blood pressure require further study,” said Dr. Elkind. “It is likely that the cumulative effect of blood pressure over time has a big role to play — and it does seem clear that midlife blood pressure is even more important than blood pressure late in life.”
That said, he added, “In general and all things being equal, I would treat to a blood pressure of < 120/80 mmHg,” given the SPRINT trial findings of greater benefits when treating to this systolic blood pressure goal. “Of course, if patients have side effects such as lightheadedness or dizziness or other medical conditions that require a higher target, then one would need to adjust the treatment targets.”
According to Dr. Fuster, targets should not be the focus because they vary. For example, the ACC/AHA guidelines use < 130/80 mm Hg, whereas the European Society of Hypertension guidelines and those of the American Academy of Family Physicians specify < 140/90 mm Hg and include age-based criteria. Because there are no studies comparing the outcomes of one set of guidelines vs another, Dr. Fuster thinks the focus should be on starting treatment as early as possible to prevent hypertension leading to dementia.
He pointed to the ongoing PESA trial, which uses brain MRI and other tests to characterize longitudinal associations among cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in asymptomatic individuals aged 40-54. Most did not have hypertension at baseline.
A recently published analysis of a subcohort of 370 PESA participants found that those with persistent high cardiovascular risk and subclinical carotid atherosclerosis already had signs of brain metabolic decline, “suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life,” wrote the investigators.
Is It Ever Too Late?
If starting hypertension treatment in midlife can help reduce the risk for cognitive impairment later, can treating later in life also help? “It’s theoretically possible, but it has to be proven,” Dr. Fuster said. “There are no data on whether there’s less chance to prevent the development of dementia if you start treating hypertension at age 70, for example. And we have no idea whether hypertension treatment will prevent progression in those who already have dementia.”
“Treating high blood pressure in older adults could affect the course of further progressive cognitive decline by improving vascular health and preventing strokes, which likely exacerbate nonvascular dementia,” Dr. Elkind suggested. “Most people with dementia have a combination of vascular and nonvascular dementia, so treating reversible causes wherever possible makes a difference.”
Dr. Elkind treats older patients with this in mind, he said, “even though most of the evidence points to the fact that it is blood pressure in middle age, not older age, that seems to have the biggest impact on later-life cognitive decline and dementia.” Like Dr. Fuster, he said, “the best strategy is to identify and treat blood pressure in midlife, before damage to the brain has advanced.”
Dr. Moran noted, “The latest science on dementia causes suggests it is difficult to draw a border between vascular and nonvascular dementia. So, as a practical matter, healthcare providers should consider that hypertension treatment is one of the best ways to prevent any category of dementia. This dementia prevention is added to the well-known benefits of hypertension treatment to prevent heart attacks, strokes, and kidney disease: ‘Healthy heart, healthy brain.’ ”
“Our BP [blood pressure] control rates overall are still abysmal,” Dr. Handberg added. Currently around one in four US adults with hypertension have it under control. Studies have shown that blood pressure control rates of 70%-80% are achievable, she said. “We can’t let patient or provider inertia continue.”
Dr. Handberg, Dr. Elkind, Dr. Moran, and Dr. Fuster declared no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
High blood pressure is an established risk factor for neurodegeneration and cognitive decline.
Valentin Fuster, MD, president of Mount Sinai Fuster Heart Hospital in New York City, told this news organization. “There is no question in the literature that untreated high blood pressure may lead to dementia,” he said. “The open question is whether treating blood pressure is sufficient to decrease or stop the progress of dementia.”
Studies are mixed, but recent research suggests that addressing hypertension does affect the risk for dementia. A secondary analysis of the China Rural Hypertension Control Project reported at the American Heart Association (AHA) Scientific Sessions in 2023 but not yet published showed that the 4-year blood pressure–lowering program in adults aged 40 or older significantly reduced the risk for all-cause dementia and cognitive impairment.
Similarly, a post hoc analysis of the SPRINT MIND trial found that participants aged 50 or older who underwent intensive (< 120 mm Hg) vs standard (< 140 mm Hg) blood pressure lowering had a lower rate of probable dementia or mild cognitive impairment.
Other studies pointing to a benefit included a pooled individual participant analysis of five randomized controlled trials, which found class I evidence to support antihypertensive treatment to reduce the risk for incident dementia, and an earlier systematic review and meta-analysis of the association of blood pressure lowering with newly diagnosed dementia or cognitive impairment.
How It Might Work
Some possible mechanisms underlying the connection have emerged.
“Vascular disease caused by hypertension is clearly implicated in one form of dementia, called vascular cognitive impairment and dementia,” Andrew Moran, MD, PhD, associate professor of medicine at Columbia University Vagelos College of Physicians and Surgeons in New York City, told this news organization. “This category includes dementia following a stroke caused by uncontrolled hypertension.”
“At the same time, we now know that hypertension and other vascular risk factors can also contribute, along with other factors, to developing Alzheimer dementia,” he said. “Even without causing clinically evident stroke, vascular disease from hypertension can lead to subtle damage to the brain via ischemia, microhemorrhage, and atrophy.”
“It is well known that hypertension affects the vasculature, and the vasculature of the brain is not spared,” agreed Eileen Handberg, PhD, ARNP, a member of the Hypertension Workgroup at the American College of Cardiology (ACC) and a professor of medicine and director of the Cardiovascular Clinical Trials Program in the University of Florida, Gainesville, Florida. “Combine this with other mechanisms like inflammation and endothelial dysfunction, and add amyloid accumulation, and there is a deterioration in vascular beds leading to decreased cerebral blood flow,” she said.
Treating hypertension likely helps lower dementia risk through “a combination of reduced risk of stroke and also benefits on blood flow, blood vessel health, and reduction in neurodegeneration,” suggested Mitchell S.V. Elkind, MD, chief clinical science officer and past president of the AHA and a professor of neurology and epidemiology at Columbia University Irving Medical Center in New York City. “Midlife blood pressure elevations are associated with deposition of amyloid in the brain, so controlling blood pressure may reduce amyloid deposits and neurodegeneration.”
Time in Range or Treat to Target?
With respect to dementia risk, does treating hypertension to a specific target make a difference, or is it the time spent in a healthy blood pressure range?
“Observational studies and a post hoc analysis of the SPRINT MIND trial suggest that more time spent in a healthy blood pressure range or more stable blood pressure are associated with lower dementia risk,” Dr. Moran said. Citing results of the CHRC program and SPRINT MIND trial, he suggested that while a dose-response effect (the lower the blood pressure, the lower the dementia risk) hasn’t been definitively demonstrated, it is likely the case.
In his practice, Dr. Moran follows ACC/AHA guidelines and prescribes antihypertensives to get blood pressure below 130/80 mm Hg in individuals with hypertension who have other high-risk factors (cardiovascular disease, diabetes, chronic kidney disease, or high risk for these conditions). “The treatment rule for people with hypertension without these other risk factors is less clear — lowering blood pressure below 140/90 mm Hg is a must; I will discuss with patients whether to go lower than that.”
“The relative contributions of time in range versus treating to a target for blood pressure require further study,” said Dr. Elkind. “It is likely that the cumulative effect of blood pressure over time has a big role to play — and it does seem clear that midlife blood pressure is even more important than blood pressure late in life.”
That said, he added, “In general and all things being equal, I would treat to a blood pressure of < 120/80 mmHg,” given the SPRINT trial findings of greater benefits when treating to this systolic blood pressure goal. “Of course, if patients have side effects such as lightheadedness or dizziness or other medical conditions that require a higher target, then one would need to adjust the treatment targets.”
According to Dr. Fuster, targets should not be the focus because they vary. For example, the ACC/AHA guidelines use < 130/80 mm Hg, whereas the European Society of Hypertension guidelines and those of the American Academy of Family Physicians specify < 140/90 mm Hg and include age-based criteria. Because there are no studies comparing the outcomes of one set of guidelines vs another, Dr. Fuster thinks the focus should be on starting treatment as early as possible to prevent hypertension leading to dementia.
He pointed to the ongoing PESA trial, which uses brain MRI and other tests to characterize longitudinal associations among cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in asymptomatic individuals aged 40-54. Most did not have hypertension at baseline.
A recently published analysis of a subcohort of 370 PESA participants found that those with persistent high cardiovascular risk and subclinical carotid atherosclerosis already had signs of brain metabolic decline, “suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life,” wrote the investigators.
Is It Ever Too Late?
If starting hypertension treatment in midlife can help reduce the risk for cognitive impairment later, can treating later in life also help? “It’s theoretically possible, but it has to be proven,” Dr. Fuster said. “There are no data on whether there’s less chance to prevent the development of dementia if you start treating hypertension at age 70, for example. And we have no idea whether hypertension treatment will prevent progression in those who already have dementia.”
“Treating high blood pressure in older adults could affect the course of further progressive cognitive decline by improving vascular health and preventing strokes, which likely exacerbate nonvascular dementia,” Dr. Elkind suggested. “Most people with dementia have a combination of vascular and nonvascular dementia, so treating reversible causes wherever possible makes a difference.”
Dr. Elkind treats older patients with this in mind, he said, “even though most of the evidence points to the fact that it is blood pressure in middle age, not older age, that seems to have the biggest impact on later-life cognitive decline and dementia.” Like Dr. Fuster, he said, “the best strategy is to identify and treat blood pressure in midlife, before damage to the brain has advanced.”
Dr. Moran noted, “The latest science on dementia causes suggests it is difficult to draw a border between vascular and nonvascular dementia. So, as a practical matter, healthcare providers should consider that hypertension treatment is one of the best ways to prevent any category of dementia. This dementia prevention is added to the well-known benefits of hypertension treatment to prevent heart attacks, strokes, and kidney disease: ‘Healthy heart, healthy brain.’ ”
“Our BP [blood pressure] control rates overall are still abysmal,” Dr. Handberg added. Currently around one in four US adults with hypertension have it under control. Studies have shown that blood pressure control rates of 70%-80% are achievable, she said. “We can’t let patient or provider inertia continue.”
Dr. Handberg, Dr. Elkind, Dr. Moran, and Dr. Fuster declared no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Treatable Condition Misdiagnosed as Dementia in Almost 13% of Cases
, one of the main causes of the condition, new research suggests.
The study of more than 68,000 individuals in the general population diagnosed with dementia between 2009 and 2019 found that almost 13% had FIB-4 scores indicative of cirrhosis and potential hepatic encephalopathy.
The findings, recently published online in The American Journal of Medicine, corroborate and extend the researchers’ previous work, which showed that about 10% of US veterans with a dementia diagnosis may in fact have hepatic encephalopathy.
“We need to increase awareness that cirrhosis and related brain complications are common, silent, but treatable when found,” said corresponding author Jasmohan Bajaj, MD, of Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia. “Moreover, these are being increasingly diagnosed in older individuals.”
“Cirrhosis can also predispose patients to liver cancer and other complications, so diagnosing it in all patients is important, regardless of the hepatic encephalopathy-dementia connection,” he said.
FIB-4 Is Key
Dr. Bajaj and colleagues analyzed data from 72 healthcare centers on 68,807 nonveteran patients diagnosed with dementia at two or more physician visits between 2009 and 2019. Patients had no prior cirrhosis diagnosis, the mean age was 73 years, 44.7% were men, and 78% were White.
The team measured the prevalence of two high FIB-4 scores (> 2.67 and > 3.25), selected for their strong predictive value for advanced cirrhosis. Researchers also examined associations between high scores and multiple comorbidities and demographic factors.
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and platelet labs were collected up to 2 years after the index dementia diagnosis because they are used to calculate FIB-4.
The mean FIB-4 score was 1.78, mean ALT was 23.72 U/L, mean AST was 27.42 U/L, and mean platelets were 243.51 × 109/µL.
A total of 8683 participants (12.8%) had a FIB-4 score greater than 2.67 and 5185 (7.6%) had a score greater than 3.25.
In multivariable logistic regression models, FIB-4 greater than 3.25 was associated with viral hepatitis (odds ratio [OR], 2.23), congestive heart failure (OR,1.73), HIV (OR, 1.72), male gender (OR, 1.42), alcohol use disorder (OR, 1.39), and chronic kidney disease (OR, 1.38).
FIB-4 greater than 3.25 was inversely associated with White race (OR, 0.76) and diabetes (OR, 0.82).
The associations were similar when using a threshold score of greater than 2.67.
“With the aging population, including those with cirrhosis, the potential for overlap between hepatic encephalopathy and dementia has risen and should be considered in the differential diagnosis,” the authors wrote. “Undiagnosed cirrhosis and potential hepatic encephalopathy can be a treatable cause of or contributor towards cognitive impairment in patients diagnosed with dementia.”
Providers should use the FIB-4 index as a screening tool to detect cirrhosis in patients with dementia, they concluded.
The team’s next steps will include investigating barriers to the use of FIB-4 among practitioners, Dr. Bajaj said.
Incorporating use of the FIB-4 index into screening guidelines “with input from all stakeholders, including geriatricians, primary care providers, and neurologists … would greatly expand the diagnosis of cirrhosis and potentially hepatic encephalopathy in dementia patients,” Dr. Bajaj said.
The study had a few limitations, including the selected centers in the cohort database, lack of chart review to confirm diagnoses in individual cases, and the use of a modified FIB-4, with age capped at 65 years.
‘Easy to Miss’
Commenting on the research, Nancy Reau, MD, section chief of hepatology at Rush University Medical Center in Chicago, said that it is easy for physicians to miss asymptomatic liver disease that could progress and lead to cognitive decline.
“Most of my patients are already labeled with liver disease; however, it is not uncommon to receive a patient from another specialist who felt their presentation was more consistent with liver disease than the issue they were referred for,” she said.
Still, even in metabolic dysfunction–associated steatotic liver disease, which affects nearly one third of the population, the condition isn’t advanced enough in most patients to cause symptoms similar to those of dementia, said Dr. Reau, who was not associated with the study.
“It is more important for specialists in neurology to exclude liver disease and for hepatologists or gastroenterologists to be equipped with tools to exclude alternative explanations for neurocognitive presentations,” she said. “It is important to not label a patient as having HE and then miss alternative explanations.”
“Every presentation has a differential diagnosis. Using easy tools like FIB-4 can make sure you don’t miss liver disease as a contributing factor in a patient that presents with neurocognitive symptoms,” Dr. Reau said.
This work was partly supported by grants from Department of Veterans Affairs merit review program and the National Institutes of Health’s National Center for Advancing Translational Science. Dr. Bajaj and Dr. Reau reported no conflicts of interest.
A version of this article appeared on Medscape.com.
, one of the main causes of the condition, new research suggests.
The study of more than 68,000 individuals in the general population diagnosed with dementia between 2009 and 2019 found that almost 13% had FIB-4 scores indicative of cirrhosis and potential hepatic encephalopathy.
The findings, recently published online in The American Journal of Medicine, corroborate and extend the researchers’ previous work, which showed that about 10% of US veterans with a dementia diagnosis may in fact have hepatic encephalopathy.
“We need to increase awareness that cirrhosis and related brain complications are common, silent, but treatable when found,” said corresponding author Jasmohan Bajaj, MD, of Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia. “Moreover, these are being increasingly diagnosed in older individuals.”
“Cirrhosis can also predispose patients to liver cancer and other complications, so diagnosing it in all patients is important, regardless of the hepatic encephalopathy-dementia connection,” he said.
FIB-4 Is Key
Dr. Bajaj and colleagues analyzed data from 72 healthcare centers on 68,807 nonveteran patients diagnosed with dementia at two or more physician visits between 2009 and 2019. Patients had no prior cirrhosis diagnosis, the mean age was 73 years, 44.7% were men, and 78% were White.
The team measured the prevalence of two high FIB-4 scores (> 2.67 and > 3.25), selected for their strong predictive value for advanced cirrhosis. Researchers also examined associations between high scores and multiple comorbidities and demographic factors.
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and platelet labs were collected up to 2 years after the index dementia diagnosis because they are used to calculate FIB-4.
The mean FIB-4 score was 1.78, mean ALT was 23.72 U/L, mean AST was 27.42 U/L, and mean platelets were 243.51 × 109/µL.
A total of 8683 participants (12.8%) had a FIB-4 score greater than 2.67 and 5185 (7.6%) had a score greater than 3.25.
In multivariable logistic regression models, FIB-4 greater than 3.25 was associated with viral hepatitis (odds ratio [OR], 2.23), congestive heart failure (OR,1.73), HIV (OR, 1.72), male gender (OR, 1.42), alcohol use disorder (OR, 1.39), and chronic kidney disease (OR, 1.38).
FIB-4 greater than 3.25 was inversely associated with White race (OR, 0.76) and diabetes (OR, 0.82).
The associations were similar when using a threshold score of greater than 2.67.
“With the aging population, including those with cirrhosis, the potential for overlap between hepatic encephalopathy and dementia has risen and should be considered in the differential diagnosis,” the authors wrote. “Undiagnosed cirrhosis and potential hepatic encephalopathy can be a treatable cause of or contributor towards cognitive impairment in patients diagnosed with dementia.”
Providers should use the FIB-4 index as a screening tool to detect cirrhosis in patients with dementia, they concluded.
The team’s next steps will include investigating barriers to the use of FIB-4 among practitioners, Dr. Bajaj said.
Incorporating use of the FIB-4 index into screening guidelines “with input from all stakeholders, including geriatricians, primary care providers, and neurologists … would greatly expand the diagnosis of cirrhosis and potentially hepatic encephalopathy in dementia patients,” Dr. Bajaj said.
The study had a few limitations, including the selected centers in the cohort database, lack of chart review to confirm diagnoses in individual cases, and the use of a modified FIB-4, with age capped at 65 years.
‘Easy to Miss’
Commenting on the research, Nancy Reau, MD, section chief of hepatology at Rush University Medical Center in Chicago, said that it is easy for physicians to miss asymptomatic liver disease that could progress and lead to cognitive decline.
“Most of my patients are already labeled with liver disease; however, it is not uncommon to receive a patient from another specialist who felt their presentation was more consistent with liver disease than the issue they were referred for,” she said.
Still, even in metabolic dysfunction–associated steatotic liver disease, which affects nearly one third of the population, the condition isn’t advanced enough in most patients to cause symptoms similar to those of dementia, said Dr. Reau, who was not associated with the study.
“It is more important for specialists in neurology to exclude liver disease and for hepatologists or gastroenterologists to be equipped with tools to exclude alternative explanations for neurocognitive presentations,” she said. “It is important to not label a patient as having HE and then miss alternative explanations.”
“Every presentation has a differential diagnosis. Using easy tools like FIB-4 can make sure you don’t miss liver disease as a contributing factor in a patient that presents with neurocognitive symptoms,” Dr. Reau said.
This work was partly supported by grants from Department of Veterans Affairs merit review program and the National Institutes of Health’s National Center for Advancing Translational Science. Dr. Bajaj and Dr. Reau reported no conflicts of interest.
A version of this article appeared on Medscape.com.
, one of the main causes of the condition, new research suggests.
The study of more than 68,000 individuals in the general population diagnosed with dementia between 2009 and 2019 found that almost 13% had FIB-4 scores indicative of cirrhosis and potential hepatic encephalopathy.
The findings, recently published online in The American Journal of Medicine, corroborate and extend the researchers’ previous work, which showed that about 10% of US veterans with a dementia diagnosis may in fact have hepatic encephalopathy.
“We need to increase awareness that cirrhosis and related brain complications are common, silent, but treatable when found,” said corresponding author Jasmohan Bajaj, MD, of Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia. “Moreover, these are being increasingly diagnosed in older individuals.”
“Cirrhosis can also predispose patients to liver cancer and other complications, so diagnosing it in all patients is important, regardless of the hepatic encephalopathy-dementia connection,” he said.
FIB-4 Is Key
Dr. Bajaj and colleagues analyzed data from 72 healthcare centers on 68,807 nonveteran patients diagnosed with dementia at two or more physician visits between 2009 and 2019. Patients had no prior cirrhosis diagnosis, the mean age was 73 years, 44.7% were men, and 78% were White.
The team measured the prevalence of two high FIB-4 scores (> 2.67 and > 3.25), selected for their strong predictive value for advanced cirrhosis. Researchers also examined associations between high scores and multiple comorbidities and demographic factors.
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and platelet labs were collected up to 2 years after the index dementia diagnosis because they are used to calculate FIB-4.
The mean FIB-4 score was 1.78, mean ALT was 23.72 U/L, mean AST was 27.42 U/L, and mean platelets were 243.51 × 109/µL.
A total of 8683 participants (12.8%) had a FIB-4 score greater than 2.67 and 5185 (7.6%) had a score greater than 3.25.
In multivariable logistic regression models, FIB-4 greater than 3.25 was associated with viral hepatitis (odds ratio [OR], 2.23), congestive heart failure (OR,1.73), HIV (OR, 1.72), male gender (OR, 1.42), alcohol use disorder (OR, 1.39), and chronic kidney disease (OR, 1.38).
FIB-4 greater than 3.25 was inversely associated with White race (OR, 0.76) and diabetes (OR, 0.82).
The associations were similar when using a threshold score of greater than 2.67.
“With the aging population, including those with cirrhosis, the potential for overlap between hepatic encephalopathy and dementia has risen and should be considered in the differential diagnosis,” the authors wrote. “Undiagnosed cirrhosis and potential hepatic encephalopathy can be a treatable cause of or contributor towards cognitive impairment in patients diagnosed with dementia.”
Providers should use the FIB-4 index as a screening tool to detect cirrhosis in patients with dementia, they concluded.
The team’s next steps will include investigating barriers to the use of FIB-4 among practitioners, Dr. Bajaj said.
Incorporating use of the FIB-4 index into screening guidelines “with input from all stakeholders, including geriatricians, primary care providers, and neurologists … would greatly expand the diagnosis of cirrhosis and potentially hepatic encephalopathy in dementia patients,” Dr. Bajaj said.
The study had a few limitations, including the selected centers in the cohort database, lack of chart review to confirm diagnoses in individual cases, and the use of a modified FIB-4, with age capped at 65 years.
‘Easy to Miss’
Commenting on the research, Nancy Reau, MD, section chief of hepatology at Rush University Medical Center in Chicago, said that it is easy for physicians to miss asymptomatic liver disease that could progress and lead to cognitive decline.
“Most of my patients are already labeled with liver disease; however, it is not uncommon to receive a patient from another specialist who felt their presentation was more consistent with liver disease than the issue they were referred for,” she said.
Still, even in metabolic dysfunction–associated steatotic liver disease, which affects nearly one third of the population, the condition isn’t advanced enough in most patients to cause symptoms similar to those of dementia, said Dr. Reau, who was not associated with the study.
“It is more important for specialists in neurology to exclude liver disease and for hepatologists or gastroenterologists to be equipped with tools to exclude alternative explanations for neurocognitive presentations,” she said. “It is important to not label a patient as having HE and then miss alternative explanations.”
“Every presentation has a differential diagnosis. Using easy tools like FIB-4 can make sure you don’t miss liver disease as a contributing factor in a patient that presents with neurocognitive symptoms,” Dr. Reau said.
This work was partly supported by grants from Department of Veterans Affairs merit review program and the National Institutes of Health’s National Center for Advancing Translational Science. Dr. Bajaj and Dr. Reau reported no conflicts of interest.
A version of this article appeared on Medscape.com.
From the American Journal of Medicine
Scientist Aims to Unravel Long COVID’s Neurologic Impacts
Neurologic symptoms of long COVID are vast, common, hard to treat, disabling, and can mimic dozens of other syndromes, with some symptoms as serious as those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS).
Now, recent evidence has suggested long COVID is primarily an autonomic nervous system disorder.
Their lives may never be the same.
Lindsay S. McAlpine, MD, a specialist in the neurologic sequelae of COVID-19 at the Yale School of Medicine and director of the Yale NeuroCOVID Clinic, New Haven, Connecticut, treats patients who struggle with neurologic symptoms even after disease recovery.
“Some people have the brain fog and the shortness of breath; some have the palpitations and the headaches ... it’s kind of a mix and match,” she said.
Dr. McAlpine’s research has been slowly building up into what could bring about a significant breakthrough in treating some of the most misunderstood and difficult-to-treat symptoms of long COVID.
The Effect of Vascular Inflammation on Long COVID
The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”
Using advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, McAlpine hopes to unearth and better understand the pathophysiology behind neurologic issues post-COVID.
Dr. McAlpine said, “What we’re seeing is that there’s a unique signature of vascular inflammation in long COVID that is distinct from acute COVID. And it has to do with endothelial apathy and platelet dysfunction.”
She’s also looking into whether microvascular dysfunction could increase one’s risk for small vessel disease. Her research is quantitatively building an overall pathophysiology piece by piece.
“We’re quantifying cognitive dysfunction and using objective testing ... a very rigorous 3-hour protocol to really identify the patterns of weakness until we find deficits in memory working and declarative memory, deficits in executive functioning, and others. Those are the three pieces that I’m trying to piece together: The MRI, the blood work, and the cognitive testing,” she said.
Ultimately, Dr. McAlpine believes long COVID will eventually be classified as a peripheral autonomic disorder. The damage being wrought to the whole body also damages the brain’s vasculature, and Dr. McAlpine’s MRI techniques probe at this connection.
“Some of my MRI techniques are dependent on the very subtle changes in blood flow to different regions in response to demand. Brain fog has been a key symptom of POTS and ME/CFS. And it’s now a key symptom of long COVID ... what I’m looking at in some of my studies is how and in which parts of the brain are affected by this,” she said.
Dr. McAlpine’s interest in COVID’s effect on our nervous system goes back all the way to the first wave of patients with COVID, where she noticed an unusually high incidence of ischemic stroke.
“We recognized that COVID really has a huge impact on the vessels ... there’s quite a bit of vascular inflammation. In terms of neurology, we were seeing quite a bit of ischemic stroke, which is unusual,” she said.
Patients don’t normally present with stroke while infected with a virus. Seeking answers, she conducted a stroke study in patients with acute COVID and found profound endotheliopathy — damage to key cells in the lining of blood vessels — leading to a cascade of dysfunction and clotting.
A Constellation of Neuropsychiatric Symptoms
In early June, Dr. McAlpine gave a presentation of her research at the Demystifying Long COVID North American Conference 2024 in Boston. She’s been hard at work in extrapolating the causes of neuropsychiatric long COVID, a tangled web of symptoms seen in patients with long COVID that range from cognitive dysfunction to headaches, neuropathy, mental health, and the aforementioned dysautonomia.
Amid the sea of neurologic long COVID symptoms, she said “symptoms that are mixing and matching are very similar. So, I wanted to specifically look at a symptom that I could definitely isolate to the brain, and that is brain fog and cognitive dysfunction and impairment.”
In September 2021, the journal Translational Psychiatry published a study titled “Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions.”
Going back all the way to the first cases of COVID in March 2020, the initial symptoms most patients complained of during an acute viral infection were around the respiratory system. Yet delirium, confusion, and neurocognitive disorders were also reported, puzzling experts and inciting a well-founded fear among many.
Even worse, after recovery, these neuropsychiatric symptoms persisted. The study found that coronavirus was able to invade the central nervous system through blood vessels and neuronal retrograde pathways, leading to brain injury and dysfunction of the cardiorespiratory center in the brainstem.
The study concluded by reporting that neuroimaging and neurochemical evidence indicated neuroimmune dysfunction and brain injury in severe patients with COVID-19. Suggested treatments included immunosuppressive therapies, vaccines to target the coronavirus’ spike protein, and pharmacological agents to improve endothelial integrity.
But there was still much that was unknown, and the study’s authors stressed the need for multidisciplinary research going forward.
How Immune Dysfunction Plays a Role
Similarly, Dr. McAlpine and her research team are still trying to sift their way through this opaque web to see why long COVID can cause autoimmune flare-ups.
In a study published in April, Dr. McAlpine and others found that small fiber neuropathy (SFN) after COVID is autoimmune-mediated and a dysfunction of the immune system.
Notably, they found that SFN could be a key pathologic finding in long COVID. SFN before the pandemic had been linked to ME/CFS and POTS, and the basic hypothesis revolved around an inflammatory immune response during a viral illness that may lead to immune dysregulation (dysimmunity) and damage to small fiber nerves.
But much still remains to be answered.
“We’ve seen quite a bit of that, but we still haven’t figured it out,” Dr. McAlpine said. “My big question is, how is this autonomic dysfunction related to the immune dysfunction, and how is that related to the vascular inflammation? There’s quite a bit of overlap in individuals with autoimmune disease and those who go on to develop this long COVID,” she added.
Still, a large portion of patients with long COVID don’t show autoimmune dysfunction, and those patients lack common biomarkers for an autoimmune condition.
“When we look at the spinal fluid in those individuals [with multiple sclerosis or a neuroinfectious disease], there’s inflammation going on ... the white blood cell count is elevated, the protein is elevated, the antibodies, the bands are elevated. I’ve been seeing long COVID patients now for 4 years, and their presentation is so distinctly different compared to my individuals that I see my patients with MS, or a neuroinfectious disease,” she said.
The mechanisms behind how all of this is interlaced remain unclear, and there may not be a one-size-fits-all treatment or definite pathogenesis for everyone.
“It’s that intersection of the immune system and the vessel wall ... Next is to figure out what do we treat, what are the targets, all of that, but there’s so many different presentations, and everybody has kind of a unique case,” she said.
How Physician Can Treat Common Symptoms Now
Though a cure for symptoms still eludes the scientific community, recent evidence has suggested that a combination of N-acetyl cysteine (NAC) and guanfacine has been successful in easing neurologic symptoms.
In November 2023, Arman Fesharaki-Zadeh, MD, PhD, a Yale Medicine behavioral neurologist and neuropsychiatrist, published a small study in Neuroimmunology Reports with his colleague, Yale neuroscientist Amy Arnsten, PhD. The two researchers showed how among 12 patients given 600 mg NAC daily, along with 1 mg guanfacine (increased to 2 mg after a month if well-tolerated), eight demonstrated improved cognitive abilities.
In patients who stayed on guanfacine + NAC, improved working memory, concentration, and executive functions were seen.
Also, they resumed their normal work schedule. Interruption and inability to work has been a significant factor in the lower quality-of-life long COVID patients experience.
Placebo-controlled trials will be needed going forward, but their small study has established safety and could open up a larger study in the future. For the moment, NAC can be gotten over the counter, and patients could get a prescription off-label from their doctor.
Dr. McAlpine has seen this combination work well for her own patients at Yale’s NeuroCOVID clinic.
Additionally, lifestyle practices such as quitting tobacco, increased exercise, exercising the mind, lowering alcohol intake, and even vitamin D supplementation (1000-2000 IU daily) could prove beneficial in tamping down persistent brain fog.
Vitamin D supports brain and nerve function through its reduction of brain aging biomarkers, regulating genes important for brain function, activating and deactivating enzymes important for neurotransmitter synthesis, and supporting neuronal growth and survival.
A version of this article first appeared on Medscape.com.
Neurologic symptoms of long COVID are vast, common, hard to treat, disabling, and can mimic dozens of other syndromes, with some symptoms as serious as those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS).
Now, recent evidence has suggested long COVID is primarily an autonomic nervous system disorder.
Their lives may never be the same.
Lindsay S. McAlpine, MD, a specialist in the neurologic sequelae of COVID-19 at the Yale School of Medicine and director of the Yale NeuroCOVID Clinic, New Haven, Connecticut, treats patients who struggle with neurologic symptoms even after disease recovery.
“Some people have the brain fog and the shortness of breath; some have the palpitations and the headaches ... it’s kind of a mix and match,” she said.
Dr. McAlpine’s research has been slowly building up into what could bring about a significant breakthrough in treating some of the most misunderstood and difficult-to-treat symptoms of long COVID.
The Effect of Vascular Inflammation on Long COVID
The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”
Using advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, McAlpine hopes to unearth and better understand the pathophysiology behind neurologic issues post-COVID.
Dr. McAlpine said, “What we’re seeing is that there’s a unique signature of vascular inflammation in long COVID that is distinct from acute COVID. And it has to do with endothelial apathy and platelet dysfunction.”
She’s also looking into whether microvascular dysfunction could increase one’s risk for small vessel disease. Her research is quantitatively building an overall pathophysiology piece by piece.
“We’re quantifying cognitive dysfunction and using objective testing ... a very rigorous 3-hour protocol to really identify the patterns of weakness until we find deficits in memory working and declarative memory, deficits in executive functioning, and others. Those are the three pieces that I’m trying to piece together: The MRI, the blood work, and the cognitive testing,” she said.
Ultimately, Dr. McAlpine believes long COVID will eventually be classified as a peripheral autonomic disorder. The damage being wrought to the whole body also damages the brain’s vasculature, and Dr. McAlpine’s MRI techniques probe at this connection.
“Some of my MRI techniques are dependent on the very subtle changes in blood flow to different regions in response to demand. Brain fog has been a key symptom of POTS and ME/CFS. And it’s now a key symptom of long COVID ... what I’m looking at in some of my studies is how and in which parts of the brain are affected by this,” she said.
Dr. McAlpine’s interest in COVID’s effect on our nervous system goes back all the way to the first wave of patients with COVID, where she noticed an unusually high incidence of ischemic stroke.
“We recognized that COVID really has a huge impact on the vessels ... there’s quite a bit of vascular inflammation. In terms of neurology, we were seeing quite a bit of ischemic stroke, which is unusual,” she said.
Patients don’t normally present with stroke while infected with a virus. Seeking answers, she conducted a stroke study in patients with acute COVID and found profound endotheliopathy — damage to key cells in the lining of blood vessels — leading to a cascade of dysfunction and clotting.
A Constellation of Neuropsychiatric Symptoms
In early June, Dr. McAlpine gave a presentation of her research at the Demystifying Long COVID North American Conference 2024 in Boston. She’s been hard at work in extrapolating the causes of neuropsychiatric long COVID, a tangled web of symptoms seen in patients with long COVID that range from cognitive dysfunction to headaches, neuropathy, mental health, and the aforementioned dysautonomia.
Amid the sea of neurologic long COVID symptoms, she said “symptoms that are mixing and matching are very similar. So, I wanted to specifically look at a symptom that I could definitely isolate to the brain, and that is brain fog and cognitive dysfunction and impairment.”
In September 2021, the journal Translational Psychiatry published a study titled “Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions.”
Going back all the way to the first cases of COVID in March 2020, the initial symptoms most patients complained of during an acute viral infection were around the respiratory system. Yet delirium, confusion, and neurocognitive disorders were also reported, puzzling experts and inciting a well-founded fear among many.
Even worse, after recovery, these neuropsychiatric symptoms persisted. The study found that coronavirus was able to invade the central nervous system through blood vessels and neuronal retrograde pathways, leading to brain injury and dysfunction of the cardiorespiratory center in the brainstem.
The study concluded by reporting that neuroimaging and neurochemical evidence indicated neuroimmune dysfunction and brain injury in severe patients with COVID-19. Suggested treatments included immunosuppressive therapies, vaccines to target the coronavirus’ spike protein, and pharmacological agents to improve endothelial integrity.
But there was still much that was unknown, and the study’s authors stressed the need for multidisciplinary research going forward.
How Immune Dysfunction Plays a Role
Similarly, Dr. McAlpine and her research team are still trying to sift their way through this opaque web to see why long COVID can cause autoimmune flare-ups.
In a study published in April, Dr. McAlpine and others found that small fiber neuropathy (SFN) after COVID is autoimmune-mediated and a dysfunction of the immune system.
Notably, they found that SFN could be a key pathologic finding in long COVID. SFN before the pandemic had been linked to ME/CFS and POTS, and the basic hypothesis revolved around an inflammatory immune response during a viral illness that may lead to immune dysregulation (dysimmunity) and damage to small fiber nerves.
But much still remains to be answered.
“We’ve seen quite a bit of that, but we still haven’t figured it out,” Dr. McAlpine said. “My big question is, how is this autonomic dysfunction related to the immune dysfunction, and how is that related to the vascular inflammation? There’s quite a bit of overlap in individuals with autoimmune disease and those who go on to develop this long COVID,” she added.
Still, a large portion of patients with long COVID don’t show autoimmune dysfunction, and those patients lack common biomarkers for an autoimmune condition.
“When we look at the spinal fluid in those individuals [with multiple sclerosis or a neuroinfectious disease], there’s inflammation going on ... the white blood cell count is elevated, the protein is elevated, the antibodies, the bands are elevated. I’ve been seeing long COVID patients now for 4 years, and their presentation is so distinctly different compared to my individuals that I see my patients with MS, or a neuroinfectious disease,” she said.
The mechanisms behind how all of this is interlaced remain unclear, and there may not be a one-size-fits-all treatment or definite pathogenesis for everyone.
“It’s that intersection of the immune system and the vessel wall ... Next is to figure out what do we treat, what are the targets, all of that, but there’s so many different presentations, and everybody has kind of a unique case,” she said.
How Physician Can Treat Common Symptoms Now
Though a cure for symptoms still eludes the scientific community, recent evidence has suggested that a combination of N-acetyl cysteine (NAC) and guanfacine has been successful in easing neurologic symptoms.
In November 2023, Arman Fesharaki-Zadeh, MD, PhD, a Yale Medicine behavioral neurologist and neuropsychiatrist, published a small study in Neuroimmunology Reports with his colleague, Yale neuroscientist Amy Arnsten, PhD. The two researchers showed how among 12 patients given 600 mg NAC daily, along with 1 mg guanfacine (increased to 2 mg after a month if well-tolerated), eight demonstrated improved cognitive abilities.
In patients who stayed on guanfacine + NAC, improved working memory, concentration, and executive functions were seen.
Also, they resumed their normal work schedule. Interruption and inability to work has been a significant factor in the lower quality-of-life long COVID patients experience.
Placebo-controlled trials will be needed going forward, but their small study has established safety and could open up a larger study in the future. For the moment, NAC can be gotten over the counter, and patients could get a prescription off-label from their doctor.
Dr. McAlpine has seen this combination work well for her own patients at Yale’s NeuroCOVID clinic.
Additionally, lifestyle practices such as quitting tobacco, increased exercise, exercising the mind, lowering alcohol intake, and even vitamin D supplementation (1000-2000 IU daily) could prove beneficial in tamping down persistent brain fog.
Vitamin D supports brain and nerve function through its reduction of brain aging biomarkers, regulating genes important for brain function, activating and deactivating enzymes important for neurotransmitter synthesis, and supporting neuronal growth and survival.
A version of this article first appeared on Medscape.com.
Neurologic symptoms of long COVID are vast, common, hard to treat, disabling, and can mimic dozens of other syndromes, with some symptoms as serious as those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS).
Now, recent evidence has suggested long COVID is primarily an autonomic nervous system disorder.
Their lives may never be the same.
Lindsay S. McAlpine, MD, a specialist in the neurologic sequelae of COVID-19 at the Yale School of Medicine and director of the Yale NeuroCOVID Clinic, New Haven, Connecticut, treats patients who struggle with neurologic symptoms even after disease recovery.
“Some people have the brain fog and the shortness of breath; some have the palpitations and the headaches ... it’s kind of a mix and match,” she said.
Dr. McAlpine’s research has been slowly building up into what could bring about a significant breakthrough in treating some of the most misunderstood and difficult-to-treat symptoms of long COVID.
The Effect of Vascular Inflammation on Long COVID
The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”
Using advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, McAlpine hopes to unearth and better understand the pathophysiology behind neurologic issues post-COVID.
Dr. McAlpine said, “What we’re seeing is that there’s a unique signature of vascular inflammation in long COVID that is distinct from acute COVID. And it has to do with endothelial apathy and platelet dysfunction.”
She’s also looking into whether microvascular dysfunction could increase one’s risk for small vessel disease. Her research is quantitatively building an overall pathophysiology piece by piece.
“We’re quantifying cognitive dysfunction and using objective testing ... a very rigorous 3-hour protocol to really identify the patterns of weakness until we find deficits in memory working and declarative memory, deficits in executive functioning, and others. Those are the three pieces that I’m trying to piece together: The MRI, the blood work, and the cognitive testing,” she said.
Ultimately, Dr. McAlpine believes long COVID will eventually be classified as a peripheral autonomic disorder. The damage being wrought to the whole body also damages the brain’s vasculature, and Dr. McAlpine’s MRI techniques probe at this connection.
“Some of my MRI techniques are dependent on the very subtle changes in blood flow to different regions in response to demand. Brain fog has been a key symptom of POTS and ME/CFS. And it’s now a key symptom of long COVID ... what I’m looking at in some of my studies is how and in which parts of the brain are affected by this,” she said.
Dr. McAlpine’s interest in COVID’s effect on our nervous system goes back all the way to the first wave of patients with COVID, where she noticed an unusually high incidence of ischemic stroke.
“We recognized that COVID really has a huge impact on the vessels ... there’s quite a bit of vascular inflammation. In terms of neurology, we were seeing quite a bit of ischemic stroke, which is unusual,” she said.
Patients don’t normally present with stroke while infected with a virus. Seeking answers, she conducted a stroke study in patients with acute COVID and found profound endotheliopathy — damage to key cells in the lining of blood vessels — leading to a cascade of dysfunction and clotting.
A Constellation of Neuropsychiatric Symptoms
In early June, Dr. McAlpine gave a presentation of her research at the Demystifying Long COVID North American Conference 2024 in Boston. She’s been hard at work in extrapolating the causes of neuropsychiatric long COVID, a tangled web of symptoms seen in patients with long COVID that range from cognitive dysfunction to headaches, neuropathy, mental health, and the aforementioned dysautonomia.
Amid the sea of neurologic long COVID symptoms, she said “symptoms that are mixing and matching are very similar. So, I wanted to specifically look at a symptom that I could definitely isolate to the brain, and that is brain fog and cognitive dysfunction and impairment.”
In September 2021, the journal Translational Psychiatry published a study titled “Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions.”
Going back all the way to the first cases of COVID in March 2020, the initial symptoms most patients complained of during an acute viral infection were around the respiratory system. Yet delirium, confusion, and neurocognitive disorders were also reported, puzzling experts and inciting a well-founded fear among many.
Even worse, after recovery, these neuropsychiatric symptoms persisted. The study found that coronavirus was able to invade the central nervous system through blood vessels and neuronal retrograde pathways, leading to brain injury and dysfunction of the cardiorespiratory center in the brainstem.
The study concluded by reporting that neuroimaging and neurochemical evidence indicated neuroimmune dysfunction and brain injury in severe patients with COVID-19. Suggested treatments included immunosuppressive therapies, vaccines to target the coronavirus’ spike protein, and pharmacological agents to improve endothelial integrity.
But there was still much that was unknown, and the study’s authors stressed the need for multidisciplinary research going forward.
How Immune Dysfunction Plays a Role
Similarly, Dr. McAlpine and her research team are still trying to sift their way through this opaque web to see why long COVID can cause autoimmune flare-ups.
In a study published in April, Dr. McAlpine and others found that small fiber neuropathy (SFN) after COVID is autoimmune-mediated and a dysfunction of the immune system.
Notably, they found that SFN could be a key pathologic finding in long COVID. SFN before the pandemic had been linked to ME/CFS and POTS, and the basic hypothesis revolved around an inflammatory immune response during a viral illness that may lead to immune dysregulation (dysimmunity) and damage to small fiber nerves.
But much still remains to be answered.
“We’ve seen quite a bit of that, but we still haven’t figured it out,” Dr. McAlpine said. “My big question is, how is this autonomic dysfunction related to the immune dysfunction, and how is that related to the vascular inflammation? There’s quite a bit of overlap in individuals with autoimmune disease and those who go on to develop this long COVID,” she added.
Still, a large portion of patients with long COVID don’t show autoimmune dysfunction, and those patients lack common biomarkers for an autoimmune condition.
“When we look at the spinal fluid in those individuals [with multiple sclerosis or a neuroinfectious disease], there’s inflammation going on ... the white blood cell count is elevated, the protein is elevated, the antibodies, the bands are elevated. I’ve been seeing long COVID patients now for 4 years, and their presentation is so distinctly different compared to my individuals that I see my patients with MS, or a neuroinfectious disease,” she said.
The mechanisms behind how all of this is interlaced remain unclear, and there may not be a one-size-fits-all treatment or definite pathogenesis for everyone.
“It’s that intersection of the immune system and the vessel wall ... Next is to figure out what do we treat, what are the targets, all of that, but there’s so many different presentations, and everybody has kind of a unique case,” she said.
How Physician Can Treat Common Symptoms Now
Though a cure for symptoms still eludes the scientific community, recent evidence has suggested that a combination of N-acetyl cysteine (NAC) and guanfacine has been successful in easing neurologic symptoms.
In November 2023, Arman Fesharaki-Zadeh, MD, PhD, a Yale Medicine behavioral neurologist and neuropsychiatrist, published a small study in Neuroimmunology Reports with his colleague, Yale neuroscientist Amy Arnsten, PhD. The two researchers showed how among 12 patients given 600 mg NAC daily, along with 1 mg guanfacine (increased to 2 mg after a month if well-tolerated), eight demonstrated improved cognitive abilities.
In patients who stayed on guanfacine + NAC, improved working memory, concentration, and executive functions were seen.
Also, they resumed their normal work schedule. Interruption and inability to work has been a significant factor in the lower quality-of-life long COVID patients experience.
Placebo-controlled trials will be needed going forward, but their small study has established safety and could open up a larger study in the future. For the moment, NAC can be gotten over the counter, and patients could get a prescription off-label from their doctor.
Dr. McAlpine has seen this combination work well for her own patients at Yale’s NeuroCOVID clinic.
Additionally, lifestyle practices such as quitting tobacco, increased exercise, exercising the mind, lowering alcohol intake, and even vitamin D supplementation (1000-2000 IU daily) could prove beneficial in tamping down persistent brain fog.
Vitamin D supports brain and nerve function through its reduction of brain aging biomarkers, regulating genes important for brain function, activating and deactivating enzymes important for neurotransmitter synthesis, and supporting neuronal growth and survival.
A version of this article first appeared on Medscape.com.
Night Owl or Lark? The Answer May Affect Cognition
new research suggests.
“Rather than just being personal preferences, these chronotypes could impact our cognitive function,” said study investigator, Raha West, MBChB, with Imperial College London, London, England, in a statement.
But the researchers also urged caution when interpreting the findings.
“It’s important to note that this doesn’t mean all morning people have worse cognitive performance. The findings reflect an overall trend where the majority might lean toward better cognition in the evening types,” Dr. West added.
In addition, across the board, getting the recommended 7-9 hours of nightly sleep was best for cognitive function, and sleeping for less than 7 or more than 9 hours had detrimental effects on brain function regardless of whether an individual was a night owl or lark.
The study was published online in BMJ Public Health.
A UK Biobank Cohort Study
The findings are based on a cross-sectional analysis of 26,820 adults aged 53-86 years from the UK Biobank database, who were categorized into two cohorts.
Cohort 1 had 10,067 participants (56% women) who completed four cognitive tests measuring fluid intelligence/reasoning, pairs matching, reaction time, and prospective memory. Cohort 2 had 16,753 participants (56% women) who completed two cognitive assessments (pairs matching and reaction time).
Participants self-reported sleep duration, chronotype, and quality. Cognitive test scores were evaluated against sleep parameters and health and lifestyle factors including sex, age, vascular and cardiac conditions, diabetes,alcohol use, smoking habits, and body mass index.
The results revealed a positive association between normal sleep duration (7-9 hours) and cognitive scores in Cohort 1 (beta, 0.0567), while extended sleep duration negatively impacted scores across in Cohort 1 and 2 (beta, –0.188 and beta, –0.2619, respectively).
An individual’s preference for evening or morning activity correlated strongly with their test scores. In particular, night owls consistently performed better on cognitive tests than early birds.
“While understanding and working with your natural sleep tendencies is essential, it’s equally important to remember to get just enough sleep, not too long or too short,” Dr. West noted. “This is crucial for keeping your brain healthy and functioning at its best.”
Contrary to some previous findings, the study did not find a significant relationship between sleep, sleepiness/insomnia, and cognitive performance. This may be because specific aspects of insomnia, such as severity and chronicity, as well as comorbid conditions need to be considered, the investigators wrote.
They added that age and diabetes consistently emerged as negative predictors of cognitive functioning across both cohorts, in line with previous research.
Limitations of the study include the cross-sectional design, which limits causal inferences; the possibility of residual confounding; and reliance on self-reported sleep data.
Also, the study did not adjust for educational attainment, a factor potentially influential on cognitive performance and sleep patterns, because of incomplete data. The study also did not factor in depression and social isolation, which have been shown to increase the risk for cognitive decline.
No Real-World Implications
Several outside experts offered their perspective on the study in a statement from the UK nonprofit Science Media Centre.
The study provides “interesting insights” into the difference in memory and thinking in people who identify themselves as a “morning” or “evening” person, Jacqui Hanley, PhD, with Alzheimer’s Research UK, said in the statement.
However, without a detailed picture of what is going on in the brain, it’s not clear whether being a morning or evening person affects memory and thinking or whether a decline in cognition is causing changes to sleeping patterns, Dr. Hanley added.
Roi Cohen Kadosh, PhD, CPsychol, professor of cognitive neuroscience, University of Surrey, Guildford, England, cautioned that there are “multiple potential reasons” for these associations.
“Therefore, there are no implications in my view for the real world. I fear that the general public will not be able to understand that and will change their sleep pattern, while this study does not give any evidence that this will lead to any benefit,” Dr. Cohen Kadosh said.
Jessica Chelekis, PhD, MBA, a sleep expert from Brunel University London, Uxbridge, England, said that the “main takeaway should be that the cultural belief that early risers are more productive than ‘night owls’ does not hold up to scientific scrutiny.”
“While everyone should aim to get good-quality sleep each night, we should also try to be aware of what time of day we are at our (cognitive) best and work in ways that suit us. Night owls, in particular, should not be shamed into fitting a stereotype that favors an ‘early to bed, early to rise’ practice,” Dr. Chelekis said.
Funding for the study was provided by the Korea Institute of Oriental Medicine in collaboration with Imperial College London. Dr. Hanley, Dr. Cohen Kadosh, and Dr. Chelekis have no relevant disclosures.
A version of this article first appeared on Medscape.com.
new research suggests.
“Rather than just being personal preferences, these chronotypes could impact our cognitive function,” said study investigator, Raha West, MBChB, with Imperial College London, London, England, in a statement.
But the researchers also urged caution when interpreting the findings.
“It’s important to note that this doesn’t mean all morning people have worse cognitive performance. The findings reflect an overall trend where the majority might lean toward better cognition in the evening types,” Dr. West added.
In addition, across the board, getting the recommended 7-9 hours of nightly sleep was best for cognitive function, and sleeping for less than 7 or more than 9 hours had detrimental effects on brain function regardless of whether an individual was a night owl or lark.
The study was published online in BMJ Public Health.
A UK Biobank Cohort Study
The findings are based on a cross-sectional analysis of 26,820 adults aged 53-86 years from the UK Biobank database, who were categorized into two cohorts.
Cohort 1 had 10,067 participants (56% women) who completed four cognitive tests measuring fluid intelligence/reasoning, pairs matching, reaction time, and prospective memory. Cohort 2 had 16,753 participants (56% women) who completed two cognitive assessments (pairs matching and reaction time).
Participants self-reported sleep duration, chronotype, and quality. Cognitive test scores were evaluated against sleep parameters and health and lifestyle factors including sex, age, vascular and cardiac conditions, diabetes,alcohol use, smoking habits, and body mass index.
The results revealed a positive association between normal sleep duration (7-9 hours) and cognitive scores in Cohort 1 (beta, 0.0567), while extended sleep duration negatively impacted scores across in Cohort 1 and 2 (beta, –0.188 and beta, –0.2619, respectively).
An individual’s preference for evening or morning activity correlated strongly with their test scores. In particular, night owls consistently performed better on cognitive tests than early birds.
“While understanding and working with your natural sleep tendencies is essential, it’s equally important to remember to get just enough sleep, not too long or too short,” Dr. West noted. “This is crucial for keeping your brain healthy and functioning at its best.”
Contrary to some previous findings, the study did not find a significant relationship between sleep, sleepiness/insomnia, and cognitive performance. This may be because specific aspects of insomnia, such as severity and chronicity, as well as comorbid conditions need to be considered, the investigators wrote.
They added that age and diabetes consistently emerged as negative predictors of cognitive functioning across both cohorts, in line with previous research.
Limitations of the study include the cross-sectional design, which limits causal inferences; the possibility of residual confounding; and reliance on self-reported sleep data.
Also, the study did not adjust for educational attainment, a factor potentially influential on cognitive performance and sleep patterns, because of incomplete data. The study also did not factor in depression and social isolation, which have been shown to increase the risk for cognitive decline.
No Real-World Implications
Several outside experts offered their perspective on the study in a statement from the UK nonprofit Science Media Centre.
The study provides “interesting insights” into the difference in memory and thinking in people who identify themselves as a “morning” or “evening” person, Jacqui Hanley, PhD, with Alzheimer’s Research UK, said in the statement.
However, without a detailed picture of what is going on in the brain, it’s not clear whether being a morning or evening person affects memory and thinking or whether a decline in cognition is causing changes to sleeping patterns, Dr. Hanley added.
Roi Cohen Kadosh, PhD, CPsychol, professor of cognitive neuroscience, University of Surrey, Guildford, England, cautioned that there are “multiple potential reasons” for these associations.
“Therefore, there are no implications in my view for the real world. I fear that the general public will not be able to understand that and will change their sleep pattern, while this study does not give any evidence that this will lead to any benefit,” Dr. Cohen Kadosh said.
Jessica Chelekis, PhD, MBA, a sleep expert from Brunel University London, Uxbridge, England, said that the “main takeaway should be that the cultural belief that early risers are more productive than ‘night owls’ does not hold up to scientific scrutiny.”
“While everyone should aim to get good-quality sleep each night, we should also try to be aware of what time of day we are at our (cognitive) best and work in ways that suit us. Night owls, in particular, should not be shamed into fitting a stereotype that favors an ‘early to bed, early to rise’ practice,” Dr. Chelekis said.
Funding for the study was provided by the Korea Institute of Oriental Medicine in collaboration with Imperial College London. Dr. Hanley, Dr. Cohen Kadosh, and Dr. Chelekis have no relevant disclosures.
A version of this article first appeared on Medscape.com.
new research suggests.
“Rather than just being personal preferences, these chronotypes could impact our cognitive function,” said study investigator, Raha West, MBChB, with Imperial College London, London, England, in a statement.
But the researchers also urged caution when interpreting the findings.
“It’s important to note that this doesn’t mean all morning people have worse cognitive performance. The findings reflect an overall trend where the majority might lean toward better cognition in the evening types,” Dr. West added.
In addition, across the board, getting the recommended 7-9 hours of nightly sleep was best for cognitive function, and sleeping for less than 7 or more than 9 hours had detrimental effects on brain function regardless of whether an individual was a night owl or lark.
The study was published online in BMJ Public Health.
A UK Biobank Cohort Study
The findings are based on a cross-sectional analysis of 26,820 adults aged 53-86 years from the UK Biobank database, who were categorized into two cohorts.
Cohort 1 had 10,067 participants (56% women) who completed four cognitive tests measuring fluid intelligence/reasoning, pairs matching, reaction time, and prospective memory. Cohort 2 had 16,753 participants (56% women) who completed two cognitive assessments (pairs matching and reaction time).
Participants self-reported sleep duration, chronotype, and quality. Cognitive test scores were evaluated against sleep parameters and health and lifestyle factors including sex, age, vascular and cardiac conditions, diabetes,alcohol use, smoking habits, and body mass index.
The results revealed a positive association between normal sleep duration (7-9 hours) and cognitive scores in Cohort 1 (beta, 0.0567), while extended sleep duration negatively impacted scores across in Cohort 1 and 2 (beta, –0.188 and beta, –0.2619, respectively).
An individual’s preference for evening or morning activity correlated strongly with their test scores. In particular, night owls consistently performed better on cognitive tests than early birds.
“While understanding and working with your natural sleep tendencies is essential, it’s equally important to remember to get just enough sleep, not too long or too short,” Dr. West noted. “This is crucial for keeping your brain healthy and functioning at its best.”
Contrary to some previous findings, the study did not find a significant relationship between sleep, sleepiness/insomnia, and cognitive performance. This may be because specific aspects of insomnia, such as severity and chronicity, as well as comorbid conditions need to be considered, the investigators wrote.
They added that age and diabetes consistently emerged as negative predictors of cognitive functioning across both cohorts, in line with previous research.
Limitations of the study include the cross-sectional design, which limits causal inferences; the possibility of residual confounding; and reliance on self-reported sleep data.
Also, the study did not adjust for educational attainment, a factor potentially influential on cognitive performance and sleep patterns, because of incomplete data. The study also did not factor in depression and social isolation, which have been shown to increase the risk for cognitive decline.
No Real-World Implications
Several outside experts offered their perspective on the study in a statement from the UK nonprofit Science Media Centre.
The study provides “interesting insights” into the difference in memory and thinking in people who identify themselves as a “morning” or “evening” person, Jacqui Hanley, PhD, with Alzheimer’s Research UK, said in the statement.
However, without a detailed picture of what is going on in the brain, it’s not clear whether being a morning or evening person affects memory and thinking or whether a decline in cognition is causing changes to sleeping patterns, Dr. Hanley added.
Roi Cohen Kadosh, PhD, CPsychol, professor of cognitive neuroscience, University of Surrey, Guildford, England, cautioned that there are “multiple potential reasons” for these associations.
“Therefore, there are no implications in my view for the real world. I fear that the general public will not be able to understand that and will change their sleep pattern, while this study does not give any evidence that this will lead to any benefit,” Dr. Cohen Kadosh said.
Jessica Chelekis, PhD, MBA, a sleep expert from Brunel University London, Uxbridge, England, said that the “main takeaway should be that the cultural belief that early risers are more productive than ‘night owls’ does not hold up to scientific scrutiny.”
“While everyone should aim to get good-quality sleep each night, we should also try to be aware of what time of day we are at our (cognitive) best and work in ways that suit us. Night owls, in particular, should not be shamed into fitting a stereotype that favors an ‘early to bed, early to rise’ practice,” Dr. Chelekis said.
Funding for the study was provided by the Korea Institute of Oriental Medicine in collaboration with Imperial College London. Dr. Hanley, Dr. Cohen Kadosh, and Dr. Chelekis have no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM BMJ PUBLIC HEALTH
Change in Clinical Definition of Parkinson’s Triggers Debate
Parkinson’s disease (PD) and dementia with Lewy bodies are currently defined by clinical features, which can be heterogeneous and do not capture the presymptomatic phase of neurodegeneration.
Recent advances have enabled the detection of misfolded and aggregated alpha-synuclein protein (synucleinopathy) — a key pathologic feature of these diseases — allowing for earlier and more accurate diagnosis. This has led two international research groups to propose a major shift from a clinical to a biological definition of the disease.
Both groups emphasized the detection of alpha-synuclein through recently developed seed amplification assays as a key diagnostic and staging tool, although they differ in their approaches and criteria.
NSD-ISS
NSD is defined by the presence during life of pathologic neuronal alpha-synuclein (S, the first biological anchor) in cerebrospinal fluid (CSF), regardless of the presence of any specific clinical syndrome. Individuals with pathologic neuronal alpha-synuclein aggregates are at a high risk for dopaminergic neuronal dysfunction (D, the second key biological anchor).
Dr. Simuni and colleagues also proposed the NSD integrated staging system (NSD-ISS) rooted in the S and D biological anchors coupled with the degree of functional impairment caused by clinical signs or symptoms.
Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B).
The presence of clinical manifestations marks the transition to stage 2 and beyond, with stage 2 characterized by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment.
“An advantage of the NSD-ISS will be to reduce heterogeneity in clinical trials by requiring biological consistency within the study cohort rather than identifying study participants on the basis of clinical criteria for Parkinson’s disease and dementia with Lewy bodies,” Dr. Simuni and colleagues pointed out in a position paper describing the NSD-ISS published online earlier this year in The Lancet Neurology.
The NSD-ISS will “evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated.”
For now, the NSD-ISS is intended for research use only and not in the clinic.
The SynNeurGe Research Diagnostic Criteria
Separately, a team led by Anthony Lang, MD, with the Krembil Brain Institute at Toronto Western Hospital, Toronto, Ontario, Canada, proposed the SynNeurGe biological classification of PD.
Described in a companion paper published online in The Lancet Neurology, their “S-N-G” classification emphasizes the important interactions between three biological factors that contribute to disease: The presence or absence of pathologic alpha-synuclein (S) in tissues or CSF, an evidence of underlying neurodegeneration (N) defined by neuroimaging procedures, and the documentation of pathogenic gene variants (G) that cause or strongly predispose to PD.
These three components link to a clinical component, defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features.
As with the NSD-ISS, the SynNeurGe model is intended for research purposes only and is not ready for immediate application in the clinic.
Both groups acknowledged the need for studies to test and validate the proposed classification systems.
Caveats, Cautionary Notes
Adopting a biological definition of PD would represent a shift as the field has prompted considerable discussion and healthy debate.
Commenting for this news organization, James Beck, PhD, chief scientific officer at the Parkinson’s Foundation, said the principle behind the proposed classifications is where “the field needs to go.”
“Right now, people with Parkinson’s take too long to get a confirmed diagnosis of their disease, and despite best efforts, clinicians can get it wrong, not diagnosing people or maybe misdiagnosing people,” Dr. Beck said. “Moving to a biological basis, where we have better certainty, is going to be really important.”
Beck noted that the NSD-ISS “goes all in on alpha-synuclein,” which does play a big role in PD, but added, “I don’t know if I want to declare a winner after the first heat. There are other biomarkers that are coming to fruition but still need validation, and alpha-synuclein may be just one of many to help determine whether someone has Parkinson’s disease or not.”
Un Kang, MD, director of translational research at the Fresco Institute for Parkinson’s & Movement Disorders at NYU Langone Health, New York City, told this news organization that alpha-synuclein has “very high diagnostic accuracy” but cautioned that the adoption of a biological definition for PD would not usurp a clinical diagnosis.
“We need both,” Dr. Kang said. “But knowing the underlying pathology is important for earlier diagnosis and testing of potential therapies to treat the molecular pathology. If a patient doesn’t have abnormal synuclein, you may be treating the wrong disease.”
The coauthors of recent JAMA Neurology perspective said the biological definitions are “exciting, but there is “wisdom” in tapping the brakes when attempting to establish a biological definition and classification system for PD.
“Although these two proposals represent significant steps forward, a sprint toward the finish line may not be wise,” wrote Njideka U. Okubadejo, MD, with University of Lagos, Nigeria; Joseph Jankovic, MD, with Baylor College of Medicine, Houston; and Michael S. Okun, MD, with University of Florida Health, Gainesville, Florida.
“A process that embraces inclusivity and weaves in evolving technological advancements will be important. Who benefits if implementation of a biologically based staging system for PD is hurried?” they continued.
The proposals rely heavily on alpha-synuclein assays, they noted, which currently require subjective interpretation and lack extensive validation. They also worry that the need for expensive and, in some regions, unattainable biological fluids (CSF) or imaging studies (dopamine transporter scan) may limit global access to both PD trials and future therapeutics.
They also worry about retiring the name Parkinson’s disease.
“Beyond the historical importance of the term Parkinson disease, any classification that proposes abandoning the two words in either clinical or research descriptions could have unintended global repercussions,” Dr. Okubadejo, Dr. Jankovic, and Dr. Okun cautioned.
Dr. Beck told this news organization he’s spoken to clinicians at meetings about this and “no one really likes the idea” of retiring the term Parkinson’s disease.
Frederick Ketchum, MD, and Nathaniel Chin, MD, with University of Wisconsin–Madison, worry about the “lived” experience of the asymptomatic patient after receiving a biological diagnosis.
“Biological diagnosis might enable effective prognostication and treatment in the future but will substantially change the experience of illness for patients now as new frameworks are slowly adopted and knowledge is gained,” they said in a correspondence in The Lancet Neurology.
“Understanding and addressing this lived experience remains a core task for health professionals and must be made central as we begin an era in which neurological diseases are redefined on a biological basis,” Dr. Ketchum and Dr. Chin advised.
A complete list of agencies that supported this work and author disclosures are available with the original articles. Dr. Beck and Dr. Kang had no relevant disclosures.
A version of this article first appeared on Medscape.com.
Parkinson’s disease (PD) and dementia with Lewy bodies are currently defined by clinical features, which can be heterogeneous and do not capture the presymptomatic phase of neurodegeneration.
Recent advances have enabled the detection of misfolded and aggregated alpha-synuclein protein (synucleinopathy) — a key pathologic feature of these diseases — allowing for earlier and more accurate diagnosis. This has led two international research groups to propose a major shift from a clinical to a biological definition of the disease.
Both groups emphasized the detection of alpha-synuclein through recently developed seed amplification assays as a key diagnostic and staging tool, although they differ in their approaches and criteria.
NSD-ISS
NSD is defined by the presence during life of pathologic neuronal alpha-synuclein (S, the first biological anchor) in cerebrospinal fluid (CSF), regardless of the presence of any specific clinical syndrome. Individuals with pathologic neuronal alpha-synuclein aggregates are at a high risk for dopaminergic neuronal dysfunction (D, the second key biological anchor).
Dr. Simuni and colleagues also proposed the NSD integrated staging system (NSD-ISS) rooted in the S and D biological anchors coupled with the degree of functional impairment caused by clinical signs or symptoms.
Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B).
The presence of clinical manifestations marks the transition to stage 2 and beyond, with stage 2 characterized by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment.
“An advantage of the NSD-ISS will be to reduce heterogeneity in clinical trials by requiring biological consistency within the study cohort rather than identifying study participants on the basis of clinical criteria for Parkinson’s disease and dementia with Lewy bodies,” Dr. Simuni and colleagues pointed out in a position paper describing the NSD-ISS published online earlier this year in The Lancet Neurology.
The NSD-ISS will “evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated.”
For now, the NSD-ISS is intended for research use only and not in the clinic.
The SynNeurGe Research Diagnostic Criteria
Separately, a team led by Anthony Lang, MD, with the Krembil Brain Institute at Toronto Western Hospital, Toronto, Ontario, Canada, proposed the SynNeurGe biological classification of PD.
Described in a companion paper published online in The Lancet Neurology, their “S-N-G” classification emphasizes the important interactions between three biological factors that contribute to disease: The presence or absence of pathologic alpha-synuclein (S) in tissues or CSF, an evidence of underlying neurodegeneration (N) defined by neuroimaging procedures, and the documentation of pathogenic gene variants (G) that cause or strongly predispose to PD.
These three components link to a clinical component, defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features.
As with the NSD-ISS, the SynNeurGe model is intended for research purposes only and is not ready for immediate application in the clinic.
Both groups acknowledged the need for studies to test and validate the proposed classification systems.
Caveats, Cautionary Notes
Adopting a biological definition of PD would represent a shift as the field has prompted considerable discussion and healthy debate.
Commenting for this news organization, James Beck, PhD, chief scientific officer at the Parkinson’s Foundation, said the principle behind the proposed classifications is where “the field needs to go.”
“Right now, people with Parkinson’s take too long to get a confirmed diagnosis of their disease, and despite best efforts, clinicians can get it wrong, not diagnosing people or maybe misdiagnosing people,” Dr. Beck said. “Moving to a biological basis, where we have better certainty, is going to be really important.”
Beck noted that the NSD-ISS “goes all in on alpha-synuclein,” which does play a big role in PD, but added, “I don’t know if I want to declare a winner after the first heat. There are other biomarkers that are coming to fruition but still need validation, and alpha-synuclein may be just one of many to help determine whether someone has Parkinson’s disease or not.”
Un Kang, MD, director of translational research at the Fresco Institute for Parkinson’s & Movement Disorders at NYU Langone Health, New York City, told this news organization that alpha-synuclein has “very high diagnostic accuracy” but cautioned that the adoption of a biological definition for PD would not usurp a clinical diagnosis.
“We need both,” Dr. Kang said. “But knowing the underlying pathology is important for earlier diagnosis and testing of potential therapies to treat the molecular pathology. If a patient doesn’t have abnormal synuclein, you may be treating the wrong disease.”
The coauthors of recent JAMA Neurology perspective said the biological definitions are “exciting, but there is “wisdom” in tapping the brakes when attempting to establish a biological definition and classification system for PD.
“Although these two proposals represent significant steps forward, a sprint toward the finish line may not be wise,” wrote Njideka U. Okubadejo, MD, with University of Lagos, Nigeria; Joseph Jankovic, MD, with Baylor College of Medicine, Houston; and Michael S. Okun, MD, with University of Florida Health, Gainesville, Florida.
“A process that embraces inclusivity and weaves in evolving technological advancements will be important. Who benefits if implementation of a biologically based staging system for PD is hurried?” they continued.
The proposals rely heavily on alpha-synuclein assays, they noted, which currently require subjective interpretation and lack extensive validation. They also worry that the need for expensive and, in some regions, unattainable biological fluids (CSF) or imaging studies (dopamine transporter scan) may limit global access to both PD trials and future therapeutics.
They also worry about retiring the name Parkinson’s disease.
“Beyond the historical importance of the term Parkinson disease, any classification that proposes abandoning the two words in either clinical or research descriptions could have unintended global repercussions,” Dr. Okubadejo, Dr. Jankovic, and Dr. Okun cautioned.
Dr. Beck told this news organization he’s spoken to clinicians at meetings about this and “no one really likes the idea” of retiring the term Parkinson’s disease.
Frederick Ketchum, MD, and Nathaniel Chin, MD, with University of Wisconsin–Madison, worry about the “lived” experience of the asymptomatic patient after receiving a biological diagnosis.
“Biological diagnosis might enable effective prognostication and treatment in the future but will substantially change the experience of illness for patients now as new frameworks are slowly adopted and knowledge is gained,” they said in a correspondence in The Lancet Neurology.
“Understanding and addressing this lived experience remains a core task for health professionals and must be made central as we begin an era in which neurological diseases are redefined on a biological basis,” Dr. Ketchum and Dr. Chin advised.
A complete list of agencies that supported this work and author disclosures are available with the original articles. Dr. Beck and Dr. Kang had no relevant disclosures.
A version of this article first appeared on Medscape.com.
Parkinson’s disease (PD) and dementia with Lewy bodies are currently defined by clinical features, which can be heterogeneous and do not capture the presymptomatic phase of neurodegeneration.
Recent advances have enabled the detection of misfolded and aggregated alpha-synuclein protein (synucleinopathy) — a key pathologic feature of these diseases — allowing for earlier and more accurate diagnosis. This has led two international research groups to propose a major shift from a clinical to a biological definition of the disease.
Both groups emphasized the detection of alpha-synuclein through recently developed seed amplification assays as a key diagnostic and staging tool, although they differ in their approaches and criteria.
NSD-ISS
NSD is defined by the presence during life of pathologic neuronal alpha-synuclein (S, the first biological anchor) in cerebrospinal fluid (CSF), regardless of the presence of any specific clinical syndrome. Individuals with pathologic neuronal alpha-synuclein aggregates are at a high risk for dopaminergic neuronal dysfunction (D, the second key biological anchor).
Dr. Simuni and colleagues also proposed the NSD integrated staging system (NSD-ISS) rooted in the S and D biological anchors coupled with the degree of functional impairment caused by clinical signs or symptoms.
Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B).
The presence of clinical manifestations marks the transition to stage 2 and beyond, with stage 2 characterized by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment.
“An advantage of the NSD-ISS will be to reduce heterogeneity in clinical trials by requiring biological consistency within the study cohort rather than identifying study participants on the basis of clinical criteria for Parkinson’s disease and dementia with Lewy bodies,” Dr. Simuni and colleagues pointed out in a position paper describing the NSD-ISS published online earlier this year in The Lancet Neurology.
The NSD-ISS will “evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated.”
For now, the NSD-ISS is intended for research use only and not in the clinic.
The SynNeurGe Research Diagnostic Criteria
Separately, a team led by Anthony Lang, MD, with the Krembil Brain Institute at Toronto Western Hospital, Toronto, Ontario, Canada, proposed the SynNeurGe biological classification of PD.
Described in a companion paper published online in The Lancet Neurology, their “S-N-G” classification emphasizes the important interactions between three biological factors that contribute to disease: The presence or absence of pathologic alpha-synuclein (S) in tissues or CSF, an evidence of underlying neurodegeneration (N) defined by neuroimaging procedures, and the documentation of pathogenic gene variants (G) that cause or strongly predispose to PD.
These three components link to a clinical component, defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features.
As with the NSD-ISS, the SynNeurGe model is intended for research purposes only and is not ready for immediate application in the clinic.
Both groups acknowledged the need for studies to test and validate the proposed classification systems.
Caveats, Cautionary Notes
Adopting a biological definition of PD would represent a shift as the field has prompted considerable discussion and healthy debate.
Commenting for this news organization, James Beck, PhD, chief scientific officer at the Parkinson’s Foundation, said the principle behind the proposed classifications is where “the field needs to go.”
“Right now, people with Parkinson’s take too long to get a confirmed diagnosis of their disease, and despite best efforts, clinicians can get it wrong, not diagnosing people or maybe misdiagnosing people,” Dr. Beck said. “Moving to a biological basis, where we have better certainty, is going to be really important.”
Beck noted that the NSD-ISS “goes all in on alpha-synuclein,” which does play a big role in PD, but added, “I don’t know if I want to declare a winner after the first heat. There are other biomarkers that are coming to fruition but still need validation, and alpha-synuclein may be just one of many to help determine whether someone has Parkinson’s disease or not.”
Un Kang, MD, director of translational research at the Fresco Institute for Parkinson’s & Movement Disorders at NYU Langone Health, New York City, told this news organization that alpha-synuclein has “very high diagnostic accuracy” but cautioned that the adoption of a biological definition for PD would not usurp a clinical diagnosis.
“We need both,” Dr. Kang said. “But knowing the underlying pathology is important for earlier diagnosis and testing of potential therapies to treat the molecular pathology. If a patient doesn’t have abnormal synuclein, you may be treating the wrong disease.”
The coauthors of recent JAMA Neurology perspective said the biological definitions are “exciting, but there is “wisdom” in tapping the brakes when attempting to establish a biological definition and classification system for PD.
“Although these two proposals represent significant steps forward, a sprint toward the finish line may not be wise,” wrote Njideka U. Okubadejo, MD, with University of Lagos, Nigeria; Joseph Jankovic, MD, with Baylor College of Medicine, Houston; and Michael S. Okun, MD, with University of Florida Health, Gainesville, Florida.
“A process that embraces inclusivity and weaves in evolving technological advancements will be important. Who benefits if implementation of a biologically based staging system for PD is hurried?” they continued.
The proposals rely heavily on alpha-synuclein assays, they noted, which currently require subjective interpretation and lack extensive validation. They also worry that the need for expensive and, in some regions, unattainable biological fluids (CSF) or imaging studies (dopamine transporter scan) may limit global access to both PD trials and future therapeutics.
They also worry about retiring the name Parkinson’s disease.
“Beyond the historical importance of the term Parkinson disease, any classification that proposes abandoning the two words in either clinical or research descriptions could have unintended global repercussions,” Dr. Okubadejo, Dr. Jankovic, and Dr. Okun cautioned.
Dr. Beck told this news organization he’s spoken to clinicians at meetings about this and “no one really likes the idea” of retiring the term Parkinson’s disease.
Frederick Ketchum, MD, and Nathaniel Chin, MD, with University of Wisconsin–Madison, worry about the “lived” experience of the asymptomatic patient after receiving a biological diagnosis.
“Biological diagnosis might enable effective prognostication and treatment in the future but will substantially change the experience of illness for patients now as new frameworks are slowly adopted and knowledge is gained,” they said in a correspondence in The Lancet Neurology.
“Understanding and addressing this lived experience remains a core task for health professionals and must be made central as we begin an era in which neurological diseases are redefined on a biological basis,” Dr. Ketchum and Dr. Chin advised.
A complete list of agencies that supported this work and author disclosures are available with the original articles. Dr. Beck and Dr. Kang had no relevant disclosures.
A version of this article first appeared on Medscape.com.