Researcher finds help for Alzheimer's-associated agitation with new FDA-approved treatment

by Bridjes O'Neil, Saint Louis University

Graphical Abstract. Credit: JAMA Neurology (2023). DOI: 10.1001/jamaneurol.2023.3810

A Saint Louis University researcher was instrumental in developing the first and only Food and Drug Administration (FDA) approved treatment for agitation associated with Alzheimer's dementia.

29 jan 2024--In a paper published in JAMA Neurology, senior author and the inaugural Henry & Amelia Nasrallah Endowed Professor and Director of Geriatric Psychiatry at Saint Louis University George T. Grossberg, M.D., and colleagues shared the results of a national clinical trial. They discovered that REXULTI, also called brexpiprazole, significantly reduced agitation in patients with Alzheimer's disease and was well tolerated with few side effects.

Earlier this year, brexpiprazole became the first FDA-approved treatment of agitation-associated Alzheimer's dementia.

Of the 6.7 million people 65 and older in the US with Alzheimer's dementia, multiple studies show that about half or more develop agitation.

Agitation associated with Alzheimer's dementia may include activities like restlessness or more aggressive behavior, like screaming, destroying objects, or fighting. Frequent and severe behavioral symptoms can be extremely distressing to the person with Alzheimer's disease, as well as their families and caregivers.

Antipsychotic drugs are commonly prescribed "off-label" to treat symptoms like aggression and agitation. While these antipsychotics seem to show a modest benefit in treating aggression in the short term, they have adverse effects and other health risks that limit their use over more extended periods.

"When patients with Alzheimer's dementia develop agitation symptoms, they can become increasingly difficult to manage," said Grossberg, who is also director of geriatric psychiatry at SLU. "I'm encouraged by the findings of this study which show that brexpiprazole is an effective and well-tolerated medication that can treat the often-debilitating symptoms of agitation associated with dementia due to Alzheimer's disease."

In the multicenter Phase 3 clinical trial, researchers evaluated the efficacy and safety of brexpiprazole, a medication used for the treatment of major depressive disorder and schizophrenia, for patients with agitation associated with Alzheimer's.

The clinical trial was a 12-week, double-blind, placebo-controlled, fixed-dose, parallel-arm trial that enrolled 345 participants at 123 clinical trial sites in Europe and the United States.

Investigators enrolled participants between the ages of 55 and 90 with a diagnosis of probable Alzheimer's disease and clinically significant symptoms of agitation who lived in a care facility or community-based setting.

Participants were randomly assigned to receive the study drug or a placebo. To participate in the clinical trial, participants had to be stable and have a caregiver who could comply with the study procedures.

"It can be extremely challenging to care for patients with Alzheimer's disease," said Grossberg. "Having new medications to help patients who are suffering will enormously benefit patients, health care providers, and those caring for their loved ones."

More information: Daniel Lee et al, Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia, JAMA Neurology (2023). DOI: 10.1001/jamaneurol.2023.3810

 

Battle of the AIs in medical research: ChatGPT vs Elicit

by Osaka Metropolitan University

Accuracy and efficiency levels differ depending on the AI used. Credit: Osaka Metropolitan University

Can AI save us from the arduous and time-consuming task of academic research collection? An international team of researchers investigated the credibility and efficiency of generative AI as an information-gathering tool in the medical field.

29 jan 2024--The research team, led by Professor Masaru Enomoto of the Graduate School of Medicine at Osaka Metropolitan University, fed identical clinical questions and literature selection criteria to two generative AIs; ChatGPT and Elicit. Their findings were published in Hepatology Communications.

The results showed that while ChatGPT suggested fictitious articles, Elicit was efficient, suggesting multiple references within a few minutes with the same level of accuracy as the researchers.

"This research was conceived out of our experience with managing vast amounts of medical literature over long periods of time. Access to information using generative AI is still in its infancy, so we need to exercise caution as the current information is not accurate or up-to-date," said Dr. Enomoto. "However, ChatGPT and other generative AIs are constantly evolving and are expected to revolutionize the field of medical research in the future."

More information: Masaru Enomoto et al, Collaborating with AI in literature search—An important frontier, Hepatology Communications (2023). DOI: 10.1097/HC9.0000000000000336

 

A substantial number of Parkinson's disease cases can be attributed to preventable risk factors, researcher says

by Savannah Koplon, University of Alabama at Birmingham

Haydeh Payami, Ph.D. Credit: Steve Wood

New research published by neurology researchers from the University of Alabama at Birmingham in npj Parkinson's Disease found that preventable risk factors play a significant role in a person's potential of developing Parkinson's disease.

29 jan 2024--The 1,223 persons studied at UAB hailing from the Southern region of the United States included 808 with PD and 415 neurologically healthy controls. Researchers came away with two significant findings that indicated that preventable risks affect the risk of Parkinson's disease: Repeated blows to the head sustained in activities like football and exposure to herbicides and pesticides.

First, the study found that repeated blows to the head in sports or military combat that seem harmless and may not even cause concussion doubled a person's risk of developing PD later in life. Second, 23% of cases of PD in both men and women were associated with exposure to pesticides, herbicides or military-related chemical exposures. Together, head injury and exposure to environmental toxins may account for nearly 1 in 3 cases of PD in men, and 1 in 4 in women.

"Parkinson's disease is rising fast globally, and there is an unspoken assumption that there is no prevention—but there is," said Haydeh Payami, Ph.D., professor and John T. & Juanelle D. Strain Endowed Chair in the UAB Department of Neurology, faculty in the Center for Neurodegeneration and Experimental Therapeutics, and the study's lead author.

"Our research demonstrated that a substantial fraction of PD in the Deep South is attributable to risk factors that can be reduced or avoided. Our paper puts a number on how many cases of PD could potentially be prevented if toxic chemicals were eliminated and if we made contact sports like football safer."While genes play an important part in a person's exposure to PD cases, with about 5% of cases caused by genetic mutations that are hereditary, the other 95% of PD cases are thought to be caused by various external factors that cause disease in individuals who are genetically susceptible to their damaging effect.

As the research for this study was conducted at UAB and research participants were all from the Deep South, Payami shared that findings indicate that incidence of disease will likely vary by population depending on how prevalent the risk factors are.

For instance, in Europe, where many of the toxic chemicals that are commonly found in American products are banned, a lower fraction of Parkinson's disease could be attributed to those specific chemicals. Furthermore, numbers could change with time for better or worse, depending on actions taken now to clean the environment and improve health and safety standards.

More information: Haydeh Payami et al, Population fraction of Parkinson's disease attributable to preventable risk factors, npj Parkinson's Disease (2023). DOI: 10.1038/s41531-023-00603-z

 

Super-aging: Defining exceptional cognitive ability in late-life

by Heidi Douglass, University of New South Wales

Credit: Unsplash/CC0 Public Domain

Research led by UNSW Sydney's Center for Healthy Brain Aging (CHeBA) has highlighted the need for clarity when defining late-life cognitively high performers, which could ultimately inform strategies to help prevent the development of dementia.

29 jan 2024--Super-aging refers to the elite group of individuals who manage to maintain varying degrees of midlife levels of capability and activity into very late life. A "cognitive super-ager" is deemed to demonstrate higher levels of intellectual activity than their more cognitively average peers.

Super-agers have been shown to have healthier lifestyles, less diabetes, and, from a genetic standpoint, have lower rates of the protein associated with Alzheimer's disease. Imaging studies of the brains of super-agers also show less brain atrophy, greater white matter integrity and differences in functional connectivity.

However, how super-aging is best defined and how exactly it differs from usual or normal aging remain unanswered.

Currently, there isn't a consistent approach to measuring cognitive super-aging. Most studies consider super-aging based on memory performance that is equivalent or comparable to that of a younger adult range, but very few examine other aspects of cognition or the maintenance of high-level abilities over time.

The review, published in the International Journal of Geriatric Psychiatry, comprises a systematic literature search of 44 studies across five major research databases from their inception until July 2023. It aimed to evaluate the literature identifying older adults with exceptional cognitive performance with emphasis on how super-aging is defined, and the key clinical features that distinguish this group from the general older adult population.

A major goal of aging research is to identify factors associated with a delay in the emergence of age-related disease and a lower burden of disease to promote healthy life expectancy.

Differences in definitions of super-aging across the research were extensive and included variations in the ages of the super-aging groups and comparator groups, cognitive domains and neuropsychological tests being used as well as the cut-off scores.

The review showed that maintenance of cognitive abilities over time was inconsistently required and there was a limited focus on superior cognitive performance in domains other than verbal memory.

"Understanding and identifying exceptional cognition is extremely powerful for research," said lead author Dr. Alice Powell. "It would allow us to increase the value of research insights gained from studying this extraordinary population—both in terms of aging well and preventing and treating neurodegenerative conditions such as Alzheimer's disease."

However, major discrepancies in these approaches such as the age range of super-agers and comparator groups and the choice of cognitive domains assessed need to be addressed to reach consensus in the field.

Dr. Powell said a future approach could be to apply different criteria to identify groups of super-agers from a large population sample. Examination of how cognitive super-aging relates to physical capacity, psychological well-being and degree of social engagement may also provide greater insights into aging well.

More information: Alice Powell et al, Defining exceptional cognition in older adults: A systematic review of cognitive super‐ageing, International Journal of Geriatric Psychiatry (2023). DOI: 10.1002/gps.6034

 

Researchers discover that tiredness experienced by long COVID patients has a physical cause

by Amsterdam University Medical Center

Credit: Nature Communications (2024). DOI: 10.1038/s41467-023-44432-3

Researchers from Amsterdam UMC and Vrije Universiteit Amsterdam (VU) have discovered that the persistent fatigue in patients with long COVID has a biological cause, namely mitochondria in muscle cells that produce less energy than in healthy patients. The results of the study were published in Nature Communications.

29 jan 2024--"We're seeing clear changes in the muscles in these patients," says Michèle van Vugt, Professor of Internal Medicine at Amsterdam UMC.

A total of 25 long COVID patients and 21 healthy control participants participated in the study. They were asked to cycle for 15 minutes. This cycling test caused a long-term worsening of symptoms in people with long COVID, called post-exertional malaise (PEM). Extreme fatigue occurs after physical, cognitive, or emotional exertion beyond an unknown, individual threshold. The researchers looked at the blood and muscle tissue one week before the cycling test and one day after the test.

"We saw various abnormalities in the muscle tissue of the patients. At the cellular level, we saw that the mitochondria of the muscle, also known as the energy factories of the cell, function less well and that they produce less energy," says Rob Wüst, Assistant Professor at Department of Human Movement Sciences at the VU University.

"So, the cause of the fatigue is really biological. The brain needs energy to think. Muscles need energy to move. This discovery means we can now start to research an appropriate treatment for those with long COVID," adds van Vugt.

One of the theories about long COVID is that coronavirus particles may remain in the body of people who have had the coronavirus. "We don't see any indications of this in the muscles at the moment," says Van Vugt. The researchers also saw that the heart and lungs functioned well in the patients. This means that the long-lasting effect on patient's fitness is not caused by abnormalities in the heart or lungs.

Exercising within your own limits

Exercising is not always good for patients with long COVID. "In concrete terms, we advise these patients to guard their physical limits and not to exceed them. Think of light exertion that does not lead to worsening of the complaints. Walking is good, or riding an electric bike, to maintain some physical condition. Keep in mind that every patient has a different limit," says Brent Appelman, researcher at Amsterdam UMC.

"Because symptoms can worsen after physical exertion, some classic forms of rehabilitation and physiotherapy are counterproductive for the recovery of these patients," van Vugt adds.

Long COVID symptoms

Although the majority of people infected with the SARS-CoV-2 virus recover within weeks, a subgroup, estimated to be around one in eight, will get long COVID. Symptoms in patients with long COVID, post-acute sequelae or COVID or post-COVID syndrome (PCS) include severe cognitive problems (brain fog), fatigue, exercise intolerance, autonomic dysregulation, postural orthostatic tachycardia syndrome (POTS), orthostatic intolerance, and worsening of symptoms after PEM.

More information: Muscle Abnormalities Worsen After Post-Exertional Malaise in Long COVID, Nature Communications (2024). DOI: 10.1038/s41467-023-44432-3 www.nature.com/articles/s41467-023-44432-3

 

Different biological variants discovered in Alzheimer's disease

by Amsterdam University Medical Center

Credit: Pixabay/CC0 Public Domain

Dutch scientists have discovered five biological variants of Alzheimer's disease, which may require different treatments. As a result, previously tested drugs may incorrectly appear to be ineffective or only minimally effective. This is the conclusion of researcher Betty Tijms and colleagues from Alzheimer Center Amsterdam, Amsterdam UMC and Maastricht University. Their study is published in Nature Aging.

29 jan 2029--In those with Alzheimer's disease, the amyloid and tau proteins clump in the brain. In addition to these clumps, other biological processes such as inflammation and nerve cell growth are also involved. Using new techniques, the researchers have been able to measure these other processes in the cerebrospinal fluid of patients with amyloid and tau clumps.

Betty Tijms and Pieter Jelle Visser examined 1,058 proteins in the cerebrospinal fluid of 419 people with Alzheimer's disease. They found that there are five biological variants within this group. The first variant is characterized by increased amyloid production. In a second type, the blood-brain barrier is disrupted, and there is reduced amyloid production and less nerve cell growth.

Furthermore, the variants differ in the degree of protein synthesis, the functioning of the immune system, and the functioning of the organ that produces cerebrospinal fluid. Patients with different Alzheimer's variants also showed differences in other aspects of the disease. For example, the researchers found a faster course of the disease in certain subgroups.

The findings are of great importance for drug research. They could mean that a certain drug might only work in one variant of Alzheimer's disease. For example, medication that inhibits amyloid production may work in the variant with increased amyloid production, but may be harmful in the variant with decreased amyloid production. It is also possible that patients with one variant would have a higher risk of side effects, while that risk would be much lower with other variants.

The next step for the research team is to show that the Alzheimer's variants do indeed react differently to medicines, in order to treat all patients with appropriate medicines in the future.

More information: Cerebrospinal fluid proteomics in Alzheimer's disease patients reveals five molecular subtypes with distinct genetic risk profiles, Nature Aging (2024). DOI: 10.1038/s43587-023-00550-7 , www.nature.com/articles/s43587-023-00550-7

 

Strong links found between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome

by University of Otago

Differentially regulated proteins in long COVID patients clustered into three groups. Credit: Scientific Reports (2023). DOI: 10.1038/s41598-023-49402-9

People suffering from long COVID or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) could benefit from a coordinated treatment strategy, a new University of Otago study has found.

29 jan 2029--The pilot study, published in Scientific Reports, has confirmed what researchers have suspected for some time: the two conditions are closely related.

Senior author Emeritus Professor Warren Tate says the research—the first comparative molecular study of the immune cell proteins of both conditions—"strongly affirms" the link between the two.

"This means information from study of the pathophysiology of ME/CFS and therapeutic opportunities that have slowly accumulated over the last 30 years can be transferred to understanding and treating the now estimated 100 million cases of long COVID world-wide.

"But equally important, the immense resources put into long COVID research currently in the rich nations, while yet to produce major breakthroughs, can also benefit the many millions of 'hidden' ME/CFS patients whose numbers have increased steadily over time in the absence of their recovery from the illness."

Study results showed the immune system activity of six long COVID patients one year after a COVID-19 infection was dramatically different from five healthy controlled-group study participants, reflecting a chronic dysfunctional state.

Data gathered from those patients was found to be similar to data gathered from a group of nine diagnosed ME/CFS patients, who had suffered the condition for 16 years on average.

The study reinforces the researchers' previously published model in Frontiers of Neurology to explain the complex dysfunctional physiology for both ME/CFS and long COVID: In susceptible people (determined by their health history and genetic background), the normal transitory immune/inflammatory response of the peripheral nervous system to infection or stress does not resolve quickly as in most people.

Instead, it becomes chronic and leads to a cascade effect involving the brain, immune system and central nervous system, which in turn results in multiple neurological symptoms and poor brain regulation of body physiology.

Emeritus Professor Tate says long COVID from the pandemic SARS-CoV-2 virus is a specific example of ME/CFS, that has occurred in susceptible people from endemic viruses like glandular fever, and from small historical viral outbreaks geographically contained like the SARS-CoV-1 virus outbreak in 2003.

"It highlights within our community there are significant numbers of people debilitated now with disrupted immune systems, dysfunctional energy production, and disturbed brain regulation of their overall physiology that severely disrupts their family lives, ability to work and participate in their communities long-term, and that these people need support from all levels of society."

Therapeutic targeting of the immune response/inflammatory pathways could be effective, Emeritus Professor Tate says.

"Currently, patients with ME/CFS and long COVID will understandably clutch at any potential treatment suggested to find a better quality of life in the absence of defined treatments.

"That means often multiple drugs, nutraceuticals, cognitive therapies and relaxation strategies with possible crossover adverse effects are being tried at the same time, without resulting benefit to the patient in most cases."

While potential compounds are available that target different points of the cellular energy production pathway, no systematic studies have been carried out to determine whether they show real benefit.

Investment in combined clinical trials to treat both conditions is desperately needed, he says.

"Immunotherapy for treating specific features of a disturbed immune system for many diseases is in a revolutionary phase of development and should have potential for application to ME/CFS and long COVID patients now the specific changes in their dysfunctional immune systems are being carefully documented."

Emeritus Professor Tate is calling for national guidelines with best practice disease management plans for clinicians so both patient groups have a good chance of a more fulfilling life no matter the stage of their illness, although he points out this must be accompanied by specialist clinics with a range of practitioners to support the patient's needs.

More information: Katie Peppercorn et al, A pilot study on the immune cell proteome of long COVID patients shows changes to physiological pathways similar to those in myalgic encephalomyelitis/chronic fatigue syndrome, Scientific Reports (2023). DOI: 10.1038/s41598-023-49402-9

 

Thinning of brain region may signal dementia risk 5–10 years before symptoms

by Will Sansom, University of Texas Health Science Center at San Antonio

Strengths of significant association (regression t values) for gray matter thickness in Alzheimer's disease (AD) dementia cases versus cognitively healthy controls after accounting for multiple comparisons. Cluster masks significantly associated with AD versus normal cognition were computed separately for thresholds of t values from 3 to 6.5, in increments of 0.5. This highlights areas of differing but significant association strengths. However, gray matter density means over the t ≥ 3 cluster were used for the analyses. Credit: Alzheimer's & Dementia (2023). DOI: 10.1002/alz.13600

A ribbon of brain tissue called cortical gray matter grows thinner in people who go on to develop dementia, and this appears to be an accurate biomarker of the disease five to 10 years before symptoms appear, researchers from The University of Texas Health Science Center at San Antonio (also called UT Health San Antonio) report.

29 jan 2024--The researchers, working with colleagues from The University of California, Davis, and Boston University, conducted an MRI brain imaging study published in Alzheimer's & Dementia. They studied 1,000 Massachusetts participants in the Framingham Heart Study and 500 people from a California cohort. The California volunteers included 44% representation of Black and Hispanic participants, whereas the Massachusetts cohort was predominantly non-Hispanic white. Both cohorts were 70 to 74 years of age on average at the time of MRI studies.

"The big interest in this paper is that if we can replicate it in additional samples, cortical gray matter thickness will be a marker we can use to identify people at high risk of dementia," said study lead author Claudia Satizabal, Ph.D., of UT Health San Antonio's Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases. "By detecting the disease early, we are in a better time window for therapeutic interventions and lifestyle modifications, and to do better tracking of brain health to decrease individuals' progression to dementia."

Repeating the Framingham findings in the more-diverse California cohort "gives us confidence that our results are robust," Satizabal said.

Sifting MRIs for a pattern

While dementias can affect different brain regions, Alzheimer's disease and frontotemporal dementia impact the cortex, and Alzheimer's is the most common type of dementia.

The study compared participants with and without dementia at the time of MRI. "We went back and examined the brain MRIs done 10 years earlier, and then we mixed them up to see if we could discern a pattern that reliably distinguished those who later developed dementia from those who did not," said co-author Sudha Seshadri, MD, director of the Glenn Biggs Institute at UT Health San Antonio and senior investigator with the Framingham Heart Study.

"This kind of study is only possible when you have longitudinal follow-up over many years as we did at Framingham, and as we are building in San Antonio," Seshadri said. "The people who had the research MRI scans while they were well and kept coming back to be studied are the selfless heroes who make such valuable discoveries, such prediction tools, possible."

The results were consistent across populations. Thicker ribbons correlated with better outcomes and thinner ribbons with worse, in general. "Although more studies are needed to validate this biomarker, we're off to a good start," Satizabal said. "The relationship between thinning and dementia risk behaved the same way in different races and ethnic groups."

Clinical trial researchers could use the thinning biomarker to minimize cost by selecting participants who haven't yet developed any disease but are on track for it, Seshadri said. They would be at greatest need to try investigational medications, she said.

The biomarker would also be useful to develop and evaluate therapeutics, Seshadri noted.

Future directions

Satizabal said the team plans to explore risk factors that may be related to the thinning. These include cardiovascular risk factors, diet, genetics and exposure to environmental pollutants, she said.

"We looked at APOE4, which is a main genetic factor related to dementia, and it was not related to gray matter thickness at all," Satizabal said. "We think this is good, because if thickness is not genetically determined, then there are modifiable factors such as diet and exercise that can influence it."

Could the MRI gray matter biomarker be used widely someday?

"A high proportion of people going to the neurologist get their MRI done, so this thickness value might be something that a neuroradiologist derives," Seshadri said. "A person's gray matter thickness might be analyzed as a percentile of the thickness of healthy people for that age."

More information: Claudia L. Satizabal et al, A novel neuroimaging signature for ADRD risk stratification in the community, Alzheimer's & Dementia (2023). DOI: 10.1002/alz.13600