Likely cause of Alzheimer’s identified in new study

The Centers for Disease Control and Prevention (CDC) estimate that up to 5.8 million peopleTrusted Source in the United States live with Alzheimer’s disease.

Alzheimer’s disease is a neurodegenerative condition affecting parts of the brain associated with memory, thought, and language. Its symptoms range from mild memory loss to the inability to hold conversations to environmental disorientation and mood changes.

Previous research has suggested that various factors — such as age, family history, diet, and environmental factors — combine to influence a person’s risk of Alzheimer’s disease.

However, scientists in Australia have recently discovered an additional factor that may be responsible for the development of this neurodegenerative condition.

Lead study author Dr. John Mamo, Ph.D. — distinguished professor and director of the Curtin Health Innovation Research Institute at Curtin University in Perth, Australia — explained to Medical News Today the conclusion from the new research.

He said, “To find new opportunities to prevent and treat Alzheimer’s, we need to understand what actually causes the disease, and presently that is not established.”

“This study,” he added, “shows that exaggerated abundance in blood of potentially toxic fat-protein complexes can damage microscopic brain blood vessels called capillaries and, thereafter, leak into the brain, causing inflammation and brain cell death.”

“[Changes] in dietary behaviors and certain medications could potentially reduce blood concentration of these toxic fat-protein complexes, [subsequently] reducing the risk for Alzheimer’s or [slowing] down the disease progression,” he concluded.

The findings appear in the journal PLOS Biology.

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What the results say

The researchers found that when the amyloid-beta proteins made in the liver of the test mice combined with fats and traveled to the brain, they interfered with the proper functioning of the brain’s microscopic blood vessels, or capillaries.

This dysfunction in the blood-brain barrier led to the protein-fat complexes leaking from the blood into the brain, resulting in inflammation. This inflammation occurred in both the test group and the control group, but it started at a much younger age in the test group.

Unlike in the control group, this inflammation was also associated with marked degeneration in the brain cells of the mice in the test group when examined under a microscope. The scientists only rarely saw this neurodegeneration in the control mice, and it was usually at a much older age.

The team also assessed a marker of neurodegeneration and found it to be approximately two times greater in the test mice than in control mice of the same age.

So, it was unsurprising that during the test for cognitive function, the test mice performed approximately half as well as the control group at retention of learning.

These findings suggest explanations to long standing questions about the role of amyloid-beta in Alzheimer’s disease development.

Warren Harding, board chairman of Alzheimer’s WA, revealed to MNT the significance of the study results. He said:

Article culled from MedicalNewsToday

NIH unveils new online tool to improve Alzheimer’s clinical trials recruitment

The National Institute on Aging (NIA), part of the National Institutes of Health, has launched a new online research tool to help increase participation by traditionally underrepresented populations in clinical trials(link is external) on Alzheimer’s disease and related dementias. Unveiled at the Alzheimer’s Association International Conference (AAIC), Outreach Pro enables those involved with leading clinical research to create and customize participant recruitment communications such as websites, handouts, videos, and social media posts.

“We are facing a critical and growing need for people living with Alzheimer’s and related dementia, as well as those at higher risk, and healthy people, to participate in clinical trials,” said NIA Director, Richard J. Hodes M.D. “That need is especially acute for frequently underrepresented groups such as Black and Hispanic Americans, which is why Outreach Pro includes an emphasis on helping clinical trial researchers connect with these and other important communities.”

Outreach Pro is an integral part of NIA’s efforts to implement the National Strategy for Recruitment and Participation in Alzheimer’s and Related Dementias Clinical Research. Released in 2018, the national strategy was developed in collaboration with the Alzheimer’s Association with input from government, private sector, academic, and industry stakeholders, as well as from individuals, caregivers, and study participants. The overarching goal is to engage broader segments of the public, including underrepresented populations, to participate in Alzheimer’s and related dementias clinical research.

“It is critical that clinical trials have appropriate representation to ensure we have a complete understanding of how well different therapies or approaches to dementia care work in different populations,” said Holly Massett, Ph.D., NIA senior advisor on clinical research recruitment and engagement, who oversees the implementation of the national strategy. “Outreach Pro was designed to provide well-tested and culturally appropriate outreach materials that resonate with diverse populations and encourage them to participate in clinical trials.”

To use Outreach Pro, researchers and clinicians first select desired templates with one of three communication goals in mind: 1) to educate about Alzheimer’s, related dementias, and/or brain health; 2) to increase awareness and interest in Alzheimer’s and related dementias clinical trials; or, 3) to provide information about a specific Alzheimer’s or related dementia clinical trial currently enrolling participants. Each template can then be tailored using a central library of messages, headlines, photos, and text that have been extensively tested among individuals representing diverse and underserved populations.

Outreach Pro’s current library of content includes materials specifically designed for a range of audiences, including Black Americans and Hispanic/Latinos. Initially, the materials will be available in English and Spanish, and there are plans underway to add Asian American and Pacific Islander resources and languages by Fall 2021. Materials for American Indian and Alaska Native communities will be developed and added in 2022.

NIA developed Outreach Pro and its content systematically by using literature reviews, environmental scans, listening sessions with stakeholders, focus groups, national surveys, and user testing. The NIA team created tool features in a culturally responsive way, so that all stages of content development reflect the culture and languages of the communities for whom the materials are designed. NIA plans to add content and scale up the tool’s capabilities based on feedback and performance measurement.

Outreach Pro expands NIA’s resources dedicated to recruitment diversity. For example, in 2020, NIA funded four exploratory Alzheimer’s Disease Research Centers that will broaden research initiatives with underrepresented groups, including Black Americans, Native Americans, and those in rural communities. In 2019, NIA launched the Alzheimer’s and Dementia Outreach, Recruitment, and Engagement (ADORE) Resources. The ADORE repository offers the research community resources to support recruitment and retention of volunteers into clinical trials and studies.

Blood-based biomarker can detect, predict severity of traumatic brain injury

A study from the National Institutes of Health confirms that neurofilament light chain as a blood biomarker can detect brain injury and predict recovery in multiple groups, including professional hockey players with acute or chronic concussions and clinic-based patients with mild, moderate, or severe traumatic brain injury. The research was conducted by scientists at the NIH Clinical Center, Bethesda, Maryland, and published in the July 8, 2020(link is external), online issue of Neurology.

Neurofilament Light Chain on the Neuron Credit: Pashtun Shahim, M.D., Ph.DNIH Clinical Center

After a traumatic brain injury, neurofilament light chain breaks away from neurons in the brain and collects in the cerebrospinal fluid (CSF). The scientists confirmed that neurofilament light chain also collects in the blood in levels that correlate closely with the levels in the CSF. They demonstrated that neurofilament light chain in the blood can detect brain injury and predict recovery across all stages of traumatic brain injury.

“Currently, there are no validated blood-based biomarkers to provide an objective diagnosis of mild traumatic brain injury or to predict recovery,” said Leighton Chan, M.D., M.P.H., chief of the Rehabilitation Medicine Department at the NIH Clinical Center. “Our study reinforces the need and a way forward for a non-invasive test of neurofilament light chain to aid in the diagnosis of patients and athletes whose brain injuries are often unrecognized, undiagnosed or underreported. “

The study examined multiple groups including professional hockey players in Sweden with sports-related concussions, hockey players without concussions, hockey players with persistent post-concussion symptoms, non-athlete controls, and clinic-based patients at the NIH Clinical Center who were healthy or with acute, subacute, and chronic mild traumatic brain injuries. The study showed that neurofilament light chain in the blood:

• Correlated closely with CSF neurofilament light chain in hockey players with concussions and non-athlete healthy controls, suggesting that blood neurofilament light chain could be used instead of CSF neurofilament light chain.

• Demonstrated strong diagnostic ability for sports-related concussions, where it could identify hockey players with concussions from hockey players without concussions and could identify clinic-based patients with mild, moderate, and severe traumatic brain injuries from each other and controls. This is significant as there is an unmet need for an easy and accessible blood biomarker to determine at the time of injury or in the chronic phase if a person has a concussion or signs of a traumatic brain injury.
• Could distinguish with high accuracy hockey players who could return to play after 10 days from those who developed persistent post-concussion symptoms and eventually retired from the game. In the clinic-based cohort, patients with worse functional outcomes had higher blood neurofilament light chain levels. This is significant as there is an unmet need for a blood biomarker that can help clinicians to determine when athletes can safely return to play or when patients can return to work or resume daily activities.

In the clinic-based patients, the levels of blood neurofilament light chain at five years after a single mild, moderate, or severe traumatic brain injury were significantly increased compared to healthy controls. This suggests that even a single mild traumatic brain injury (without visible signs of structural damage on a standard clinical MRI) may cause long-term brain injury, and serum neurofilament light could be a sensitive biomarker to detect even that far out from initial injury.

“This study is the first to do a detailed assessment of serum neurofilament light chain and advanced brain imaging in multiple cohorts, brain injury severities, and time points after injury,” said the study’s lead author, Pashtun Shahim, M.D., Ph.D., NIH Clinical Center. “Our results suggest that serum neurofilament light chain may provide a valuable compliment to imaging by detecting underlying neuronal damage which may be responsible for the long-term symptoms experienced by a significant number of athletes with acute concussions, and patients with more severe brain injuries.”

The study was funded by the Intramural Research Program at NIH, the Department of Defense Center for Neuroscience and Regenerative Medicine at the Uniformed Services University, and the Swedish Research Council.

Traumatic brain injury is a major leading cause of death and disability in the United States with more than 2.87 million emergency department visits, hospitalizations and deaths annually. While majority of all traumatic brain injuries are classified as mild (also known as a concussion), it remains difficult to diagnose this condition. There are a wide range of variable behavioral and observational tests to help determine a patient’s injuries but most of these tests rely on the patient to self-report signs and symptoms. Also, imaging has limitations with detecting micro-structural injuries in the brain.

Guidelines proposed for newly defined Alzheimer’s-like brain disorder

A recently recognized brain disorder that mimics clinical features of Alzheimer’s disease has for the first time been defined with recommended diagnostic criteria and other guidelines for advancing and catalyzing future research.

Limbic-predominant Age-related TDP-43 Encephalopathy, or LATE, as seen by microscope and MRI. Nelson et. al. and Brain, DOI: 10.1093/brain/awz099.

Scientists from several National Institutes of Health-funded institutions, in collaboration with international peers, described the newly-named pathway to dementia, Limbic-predominant Age-related TDP-43 Encephalopathy, or LATE, in a report published on April 30, 2019, in the journal Brain.

“While we’ve certainly been making advances in Alzheimer’s disease research — such as new biomarker and genetic discoveries—we are still at times asking, ‘When is Alzheimer’s disease not Alzheimer’s disease in older adults?’” said Richard J. Hodes, M.D., director of the National Institute on Aging (NIA), part of the NIH. “The guidance provided in this report, including the definition of LATE, is a crucial step toward increasing awareness and advancing research for both this disease and Alzheimer’s as well.”

Alzheimer’s is the most common form of dementia, which is the loss of cognitive functions — thinking, remembering, and reasoning — and every-day behavioral abilities. In the past, Alzheimer’s and dementia were often considered to be the same. Now there is rising appreciation that a variety of diseases and disease processes contribute to dementia. Each of these diseases appear differently when a brain sample is examined at autopsy. However, it has been increasingly clear that in advanced age, a large number of people had symptoms of dementia without the telltale signs in their brain at autopsy. Emerging research seems to indicate that the protein TDP-43 — though not a stand-alone explanation — contributes to that phenomenon.

What is TDP-43?

TDP-43 (transactive response DNA binding protein of 43 kDa) is a protein that normally helps to regulate gene expression in the brain and other tissues. Prior studies found that unusually misfolded TDP-43 has a causative role in most cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.  However, these are relatively uncommon diseases. A significant new development seen in recent research is that misfolded TDP-43 protein is very common in older adults. Roughly 25 percent of individuals over 85 years of age have enough misfolded TDP-43 protein to affect their memory and/or thinking abilities.

TDP-43 pathology is also commonly associated with hippocampal sclerosis, the severe shrinkage of the hippocampal region of the brain—the part of the brain that deals with learning and memory. Hippocampal sclerosis and its clinical symptoms of cognitive impairment can be very similar to the effects of Alzheimer’s.

“Recent research and clinical trials in Alzheimer’s disease have taught us two things: First, not all of the people we thought had Alzheimer’s have it; second, it is very important to understand the other contributors to dementia,” said Nina Silverberg, Ph.D., director of the Alzheimer’s Disease Centers Program at NIA. In the past many people who enrolled in clinical trials likely were not positive for amyloid. “Noting the trend in research implicating TDP-43 as a possible Alzheimer’s mimic, a group of experts convened a workshop to provide a starting point for further research that will advance our understanding of another contributor to late life brain changes,” Silverberg explained. In addition to U.S. scientists, experts included researchers from Australia, Austria, Sweden, Japan, and the United Kingdom with expertise in clinical diagnosis, neuropathology, genetics, neuropsychology and brain imaging.

Supported by NIA, the workshop was held Oct. 17 and 18, 2018, in Atlanta, and co-chaired by Dr. Silverberg and Peter Nelson, M.D., Ph.D., from the University of Kentucky, Lexington, the lead author on the paper. As published in the report, outcomes included classification guidelines for diagnosis and staging of LATE as well as recommendations for future research directions.

LATE: A new research priority

The authors wrote that LATE is an under-recognized condition with a very large impact on public health. They emphasized that the “oldest-old” are at greatest risk and importantly, they believe that the public health impact of LATE is at least as large as Alzheimer’s in this group.

The clinical and neurocognitive features of LATE affect multiple areas of cognition, ultimately impairing activities of daily life. Additionally, based on existing research, the authors suggested that LATE progresses more gradually than Alzheimer’s. However, LATE combined with Alzheimer’s—which is common for these two highly prevalent brain diseases—appears to cause a more rapid decline than either would alone.

“It is important to note that the disease itself is not new. LATE has been there all along, but we hope this report will enable more rapid advancement in research to help us better understand the causes and open new opportunities for treatment,” said Dr. Silverberg.

Want to learn a new skill? Take some short breaks

NIH study suggests our brains may use short rest periods to strengthen memories.

In a study of healthy volunteers, National Institutes of Health researchers found that our brains may solidify the memories of new skills we just practiced a few seconds earlier by taking a short rest. The results highlight the critically important role rest may play in learning.

In a study of healthy volunteers, NIH researchers found that taking short breaks, early and often, may help our brains learn new skills.Cohen lab, NIH/NINDS

“Everyone thinks you need to ‘practice, practice, practice’ when learning something new. Instead, we found that resting, early and often, may be just as critical to learning as practice,” said Leonardo G. Cohen, M.D., Ph.D., senior investigator at NIH’s National Institute of Neurological Disorders and Stroke and a senior author of the paper published in the journal Current Biology. “Our ultimate hope is that the results of our experiments will help patients recover from the paralyzing effects caused by strokes and other neurological injuries by informing the strategies they use to ‘relearn’ lost skills.”

The study was led by Marlene Bönstrup, M.D., a postdoctoral fellow in Dr. Cohen’s lab. Like many scientists, she held the general belief that our brains needed long periods of rest, such as a good night’s sleep, to strengthen the memories formed while practicing a newly learned skill. But after looking at brain waves recorded from healthy volunteers in learning and memory experiments at the NIH Clinical Center, she started to question the idea.

The waves were recorded from right-handed volunteers with a highly sensitive scanning technique called magnetoencephalography. The subjects sat in a chair facing a computer screen and under a long cone-shaped brain scanning cap. The experiment began when they were shown a series of numbers on a screen and asked to type the numbers as many times as possible with their left hands for 10 seconds; take a 10 second break; and then repeat this trial cycle of alternating practice and rest 35 more times. This strategy is typically used to reduce any complications that could arise from fatigue or other factors.

As expected, the volunteers’ speed at which they correctly typed the numbers improved dramatically during the first few trials and then leveled off around the 11th cycle. When Dr. Bönstrup looked at the volunteers’ brain waves she observed something interesting.

“I noticed that participants’ brain waves seemed to change much more during the rest periods than during the typing sessions,” said Dr. Bönstrup. “This gave me the idea to look much more closely for when learning was actually happening. Was it during practice or rest?”

By reanalyzing the data, she and her colleagues made two key findings. First, they found that the volunteers’ performance improved primarily during the short rests, and not during typing. The improvements made during the rest periods added up to the overall gains the volunteers made that day. Moreover, these gains were much greater than the ones seen after the volunteers returned the next day to try again, suggesting that the early breaks played as critical a role in learning as the practicing itself.

Second, by looking at the brain waves, Dr. Bönstrup found activity patterns that suggested the volunteers’ brains were consolidating, or solidifying, memories during the rest periods. Specifically, they found that the changes in the size of brain waves, called beta rhythms, correlated with the improvements the volunteers made during the rests.

Further analysis suggested that the changes in beta oscillations primarily happened in the right hemispheres of the volunteers’ brains and along neural networks connecting the frontal and parietal lobes that are known to help control the planning of movements. These changes only happened during the breaks and were the only brain wave patterns that correlated with performance. 

“Our results suggest that it may be important to optimize the timing and configuration of rest intervals when implementing rehabilitative treatments in stroke patients or when learning to play the piano in normal volunteers,” said Dr. Cohen. “Whether these results apply to other forms of learning and memory formation remains an open question.”

Dr. Cohen’s team plans to explore, in greater detail, the role of these early resting periods in learning and memory.

NIH study reveals differences in brain activity in children with anhedonia

Using fMRI, researchers uncover the neural underpinnings, which could aid development of potential treatments.

Image showing differences in fMRI activation between children with and without anhedonia during reward-anticipation. JAMA Network

Researchers have identified changes in brain connectivity and brain activity during rest and reward anticipation in children with anhedonia, a condition where people lose interest and pleasure in activities they used to enjoy.

The study, by scientists at the National Institute of Mental Health (NIMH), part of the National Institutes of Health, sheds light on brain function associated with anhedonia and helps differentiate anhedonia from other related aspects of psychopathology. The findings appear in the journal JAMA Psychiatry. 

Anhedonia is a risk factor for, and a symptom of, certain mental disorders and is predictive of illness severity, resistance to treatment, and suicide risk. While researchers have sought to understand the brain mechanisms that contribute to anhedonia, investigations on this condition have more commonly focused on adults rather than children. Importantly, previous studies often did not separate anhedonia from other related psychopathologies, such as low mood, anxiety, or attention-deficit/hyperactivity disorder.

“Understanding the neural mechanisms of anhedonia that are distinguishable from other psychiatric concerns is important for clinicians to develop on-target treatments,” said lead study author Narun Pornpattananangkul, Ph.D., a postdoctoral fellow in the Emotion and Development Branch, part of NIMH’s Division of Intramural Research Programs. “Yet, disentangling shared characteristics from unique neural mechanisms of anhedonia is challenging because it often co-occurs with other psychiatric conditions.”

To learn more about the neurological underpinnings of anhedonia in children, researchers from the NIMH Division of Intramural Research Programs examined fMRI data collected from more than 2,800 children (9-10 years old) as part of the Adolescent Brain Cognitive Development (ABCD) Study(link is external). Some of the children included in the sample were identified as having anhedonia, low mood, anxiety, or attention-deficit/hyperactivity disorder (ADHD). fMRI data were collected while the children were at rest and while they completed tasks assessing reward anticipation and working memory.

Analysis of brain connectivity at rest revealed significant differences in children with anhedonia compared to children without anhedonia. Many of these differences were related to the connectivity between the arousal-related cingulo-opercular network and the reward-related ventral striatum area. These findings suggest that children with anhedonia have altered integration of reward and arousal compared to children without anhedonia. 

When the researchers examined brain activity during the tasks, they found that children with anhedonia showed hypoactivation of brain regions involved in integrating reward and arousal during the reward anticipation task — but not the working memory task. This hypoactivation was not seen in children with low mood, anxiety, or ADHD. In fact, children with ADHD showed the opposite pattern: abnormalities in brain activation during the working memory task — but the not the reward anticipation task.

The study suggests that children with anhedonia have differences in the way their brain integrates reward and arousal and in the way their brain activates when anticipating rewards.

“We found anhedonia-specific alterations, such that youth with anhedonia, but not youth with low mood, anxiety, or ADHD, showed differences in the way they integrated reward and arousal and also showed diminished activity in reward-anticipation contexts,” said Dr. Pornpattananangkul. “This finding may start to provide the specific neural targets for treating anhedonia in youth.”

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Article published courtesy of the NIH

NIH study implicates hyperactive immune system in aging brain disorders

Results suggest a breakdown in brain cell waste system triggers a destructive immune reaction.

In a study of flies, NIH scientists showed how the immune system may be a culprit in the damage caused by aging brain disorders.Giniger Lab, NIH/NINDS

In a study of fruit flies, NIH scientists suggested that the body’s immune system may play a critical role in the damage caused by aging brain disorders.

The results are based on experiments in which the researchers altered the activity of Cdk5, a gene that preclinical studies have suggested is important for early brain development and may be involved in neurodegenerative diseases, such as ALS, Alzheimer’s and Parkinson’s disease. 

Previously, they found that altering Cdk5 sped up the genetic aging process, causing the flies to die earlier than normal and have problems with walking or flying late in life and greater signs of neurodegenerative brain damage.

In this study, published in Cell Reports, they suggested that altering Cdk5 resulted in the death of dopamine releasing neurons, especially in the brains of older flies. Typically, Parkinson’s disease damages the same types of cells in humans.

Further experiments in flies suggested the neuron loss happened because altering Cdk5 slowed autophagy, or a cell’s waste disposal system that rids the body of damaged cells in a contained, controlled fashion, which in turn triggered the immune system to attack the animal’s own neurons. This immune system attack is a much “messier” and more diffuse process than autophagy. 

Genetically restoring the waste system or blocking the immune system’s responses prevented the reduction in dopamine neurons caused by altering Cdk5. The authors concluded that this chain reaction in which a breakdown in autophagy triggers a widely destructive immune reaction may occur in human brain during several neurodegenerative disorders and that researchers may want to look to these systems for new treatment targets and strategies.

Who

Edward Giniger, Ph.D., senior scientist, NIH’s National Institute of Neurological Disorders and Stroke (NINDS)

Article

Shukla et al. Hyperactive innate immunity causes degeneration of dopamine neurons upon altering activity of Cdk5, January 2, 2019, Cell Reports

This study was supported by the Intramural Research Program at the NINDS (NS003106).