Category Archives: Neuropathology

Neuropathology

UW study links past military service to Alzheimer’s disease – University of Wisconsin School of Medicine and Public Health

The brains of deceased military veterans had higher levels of two abnormal proteins considered hallmarks of Alzheimers disease, suggesting that military veterans face a greater risk for developing Alzheimers, according to a new study from the University of Wisconsin School of Medicine and Public Health.

The study was recently published in Alzheimers & Dementia: The Journal of the Alzheimers Association led byRyan Powell, PhD, MA, assistant professor of medicine, UW School of Medicine and Public Health.

Emily Greendonner 608-516-9154 egreendonner@uwhealth.org

The study found that military veterans who had donated their brains to Alzheimers disease research centers had 26% greater odds of having amyloid plaques in their brains than nonveterans and 10% greater odds of having neurofibrillary tangles made of abnormal tau proteins, according to Powell. The findings, as well as prior research showing higher frequency of Alzheimers disease risk factors among veterans, support a rationale for greater support in disease prevention and treatment interventions for this population.

To our knowledge, this is the first study to link a history of military service to Alzheimers disease neuropathology, the gold standard for diagnosing Alzheimers, said Powell, who is data science director of the UW Center for Health Disparities Research. This has important implications for the Veterans Health Administration since it indicates an urgent need to screen veterans and to target therapies to those at greatest risk.

Powell and his research collaborators looked at brain biopsy data from 597 males who died between 1986 and 2018 and donated their brains to Alzheimers disease research centers at the UW School of Medicine and Public Health and the University of California San Diego.

Genealogical archivists used genealogy databases, census and military records to determine that about 60% of the males had served in the military most likely during World War II, Korean War and Vietnam War eras. The rate of military service was consistent between those who donated brains in San Diego and in Madison, Powell said.

The group of 358 male veterans had higher levels of both amyloid plaques and tau tangles in their brains, both biomarkers of Alzheimers disease. Researching female veteran risk is a key next step but researchers were unable to conduct this analysis given the small number of them represented in the current study, Powell said.

This study is shining new light on data thats been collected over decades some donations date all the way back to the mid-1980s so the donations of these veterans are still yielding valuable new insights after all these years, he said. We identified the who and the what in this study, but we need to narrow in on the why and the when.

Veterans are exposed to many known risks for brain disorders, including chronic stress from physical and psychological pain, physical trauma including traumatic brain injuries and environmental hazards such as Agent Orange, a tactical defoliating agent used in Vietnam. In addition, veterans have higher rates of cardiovascular disease, depression and PTSD, all of which are known risk factors for dementia, Powell said.

Exposures during military service and differences in life both before and after service likely all contribute to the brain disease, he explained. Researchers hope to expand the study to other brain banks to gain a deeper understanding and include younger generations of veterans to unlock the root causes of these brain changes in veterans, he said.

We might be able to uncover other factors and learn where risks can be reduced, Powell said. And with new Alzheimers therapies coming online, theres a need for scientific-based health equity policies to get them to those who might benefit most. Its exciting that this ongoing line of research can inform policy changes that improve the health of veterans.

The study was supported by funding from the National Institutes of Health - National Institute on Aging (grants R21AG079277, R01AG070883, P30AG062715, R01AG079303, and P30AG066530).

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UW study links past military service to Alzheimer's disease - University of Wisconsin School of Medicine and Public Health

Neuropathology

Study reveals no neuroinflammation in long COVID patients with … – News-Medical.Net

In a recent study published in JAMA Network Open, researchers examined cerebrospinal fluid (CSF) markers of neuroinflammation in individuals with post-coronavirus disease 2019 (COVID-19) condition (PCC) and neuropsychiatric symptoms.

PCC, also known as long COVID, represents a diverse group of symptoms that last for months post-acute COVID-19. Some individuals with PCC have neuropsychiatric symptoms (neuro-PCC), and the underlying mechanisms are poorly understood. CSF provides a means to evaluate neuropathology, given that it circulates the central nervous system (CNS) and serves as a window to the brain.

Research Letter: Self-Reported Neuropsychiatric PostCOVID-19 Condition and CSF Markers of Neuroinflammation. Image Credit:Donkeyworx/ Shutterstock

In the present study, researchers assessed CSF markers of neuroinflammation in people with neuro-PCC and COVID-19-nave individuals. Neuro-PCC subjects were recruited to the COVID Mind Study if they reported neuropsychiatric symptoms three months after COVID-19. Asymptomatic individuals recruited before 2020 (pre-COVID-19) served as controls.

The control group also included a COVID-19-nave participant recruited in 2022, with laboratory evidence supporting the seronegative status. Individuals with a history of immunocompromising conditions and psychiatric or neurologic illness and those taking immunosuppressive medications were excluded.

Data on COVID-19 test dates/results and vaccination were obtained from medical records and interviews. Participants provided consent for blood sampling and lumbar puncture. CSF and plasma were evaluated using a multiplex cytokine laser bead assay. Enzyme-linked immunosorbent assay (ELISA) was used to measure neopterin (microglia activation marker).

Ethnicity and race were self-reported by participants. Group comparisons for clinical and demographic data were performed using t-tests, while a two-proportion z-test was used for comparisons of race. Mann-Whitney tests were used to compare cytokine data between controls and neuro-PCC subjects, controlling for false discovery rates.

The study included 37 individuals with neuro-PCC and 22 controls. Neuro-PCC subjects tested positive for COVID-19 from March 2020 to July 2022. Most individuals with neuro-PCC were White (78.4%) and female (73%). Only four participants (11%) in the neuro-PCC group were vaccinated at the time of infection, while 89% remained non-vaccinated. However, 46% were partially or fully vaccinated at the PCC study visit.

A majority of neuro-PCC participants had acute disease when severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Alpha was the predominant variant. Cognitive impairment, brain fog, and excess fatigue were the most common PCC symptoms. The neuro-PCC group did not exhibit elevated protein levels and white blood cell counts. Moreover, the CSF-to-blood albumin ratio, which changes during the breakdown of the blood-brain barrier, was not elevated in the neuro-PCC group.

There was no evidence of intrathecal production of immunoglobulins. However, interleukin-6 (IL-6) and monocyte chemoattractant protein-1 were reduced, while tumor necrosis factor-alpha levels were elevated in the CSF of neuro-PCC subjects relative to controls, albeit not statistically significant when accounted for multiple comparisons. Besides, other chemokines and cytokines in the plasma or CSF were not significantly different. Furthermore, neopterin levels were not elevated in neuro-PCC subjects.

Taken together, the study did not find evidence of neuroinflammation and blood-brain barrier dysfunction in participants with neuro-PCC relative to control participants. The findings suggest persistent CNS immune activation does not drive neurologic long COVID. The studys limitations were the small sample size, increased rates of alcohol use and smoking, reduced rates of antidepressants among controls, and discrepancies in the race and gender of neuro-PCC subjects relative to controls.

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Study reveals no neuroinflammation in long COVID patients with ... - News-Medical.Net

Neuropathology

Work complexity linked to better cognitive aging | National Institute … – National Institute on Aging

Higher occupational work complexity is associated with better cognition later in life, according to two recent NIA-funded studies published in Alzheimers & Dementia.

Previous research has indicated that people with complex jobs have better cognitive function as they age and a lower risk of dementia. Both of the two new studies built on these findings by exploring multiple forms of occupational complexity and cognitive outcomes. Occupational complexity with data, people, and things was classified using the Dictionary of Occupational Titles, which catalogs the type of work activities involved in different occupations. Examples of jobs with high complexity in each of these areas include a data analyst, a social worker, and a watch repairman, respectively. Education, self-reported as the highest level of education completed, was statistically accounted for as it could indicate prior cognitive abilities before entering the workforce.

In the first study, researchers from Indiana University and collaborating institutions analyzed data from 355 older adults enrolled in the Social Networks in Alzheimers Disease study. The scientists examined participants neuropsychological test results, neuroimaging data, employment history, and mild cognitive impairment (MCI) or dementia diagnoses. Most participants, age 70 on average, were retired and no longer working in their longest-held job. The researchers found complex work with people was associated with better memory, a decreased risk of MCI or dementia, and greater brain reserve the gap between brain atrophy and poor cognitive function. After accounting for education, complexity with data or things was not associated with any cognitive outcome. These findings suggest that exposure to cognitive enrichment at work, especially via social interaction, may improve cognitive outcomes and increase cognitive resilience to neuropathology. However, a limitation of the study is that the participants were not a diverse sample.

In the other study, researchers from Kaiser Permanente Northern California; University of California, San Francisco; and collaborative institutions also looked at occupational complexity and cognition, specifically in a racially and ethnically diverse sample. Researchers interviewed 1,536 participants, average age of 76 years, in the Kaiser Healthy Aging and Diverse Life Experiences study, which consists of approximately equal numbers of Asian, Black, Latino, and White older adults. Three interview cycles were completed over an average of about two and a half years to measure initial cognition and change over time.

In line with the first study, higher occupational complexity with people was associated with better performance on cognitive measures. However, contrary to that study, higher occupational complexity with data was also found to be associated with better cognitive outcomes and a slower annual rate of cognitive decline. Differences in the methodologies between the two studies may contribute to this inconsistency, but further research is needed. Of note, a greater proportion of Black and Latino participants were categorized in jobs with lowest complexity for working with data and people.

These two studies add to an increasing body of research demonstrating that intellectually stimulating activities during midlife, such as complex work environments, may be associated with better cognitive outcomes among older adults. Its important to note that the Dictionary of Occupational Titles assigns scores according to job titles and does not capture individual variability within the same title. Further research to better understand the pathways through which different types of occupational complexity affect cognition in later life could help to create work environments that promote cognitive health and health equity.

This research was supported in part by NIA grants R01AG057739, R01AG070931, P30AG010133, P30AG072976, R01AG066132, R01AG052132, and R00AG073457.

These activities relate to NIHs Alzheimers and Related Dementias Research Implementation Milestones:

References:

Coleman ME, et al. Social enrichment on the job: Complex work with people improves episodic memory, promotes brain reserve, and reduces the risk of dementia. Alzheimers & Dementia. 2023;19(6):2655-2665. doi: 10.1002/alz.13035.

Soh Y, et al. Association of primary lifetime occupational cognitive complexity and cognitive decline in a diverse cohort: Results from the KHANDLE study. Alzheimers & Dementia. 2023;19(9):3926-3935. doi: 10.1002/alz.13038.

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Work complexity linked to better cognitive aging | National Institute ... - National Institute on Aging

Neuropathology

Hussman Institute Celebrates Banner Year at Global Human … – University of Miami

By: Lisette Hilton | November 14, 2023 | 9 min. read| Share

Miller School-led studies on neurodegenerative disease chosen for platform presentations, poster awards and abstracts at American Society of Human Genetics annual meeting.

Many of the more than 8,000 international scientists attending the American Society of Human Genetics (ASHG) annual meeting learned about the latest neurodegenerative research at the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine.

This has been a banner year for genetics research at the Hussman Institute and Miller School. We had three platform presentations, three poster awards and contributed to more than 60 featured abstracts. Were covering the gamut of human genetics, said Director Margaret Pericak-Vance, Ph.D.This acknowledges the work that were doing and the progress were making not only in neurodegenerative diseases like Alzheimers disease but in a number of different disorders, both rare and common in the population.

ASHG 2023, held November 1-4 in Washington, D.C., is the largest international human genetics conference, according to Stephan Zchner, M.D., Ph.D., professor, Dr. John T. Macdonald Foundation Department of Human Genetics and member of the Hussman Institute.

ASHG annual meetings get a lot of attention from a broad range of academic centers, National Institutes of Health leadership, industry, renowned international researchersThey all make it a point to be at the event, Dr. Zchner said.

Miller School researchers stand out globally for their work in studying diverse populations and pioneering work in long-read whole genome sequencing, which was among the highlights of this years meeting.

We are at the cusp of exploring with unprecedented precision the so-called noncoding space of the genome, Dr. Zchner said. Protein-coded segments make up less than 2% of the human genome. Researchers always had trouble interpreting the other 98%. The Hussman Institute is one of the first centers in the world to have acquired a new technology called long-read whole genome sequencing to better interpret the impact of the other 98%, or the noncoding space.

Dr. Zchners lab authored several abstracts on novel uses of the technology in neurodegenerative diseases. One example is a major, new type of ataxiaa brain disorder that can cause poor coordinationwhich lab researchers discovered as a noncoding element.

Three Hussman Institute studies on Alzheimers disease were featured as platform talks at ASHG:

Study: Assessing the functional effect of the Presenilin-1 G206A variant on age of onset of Alzheimer Disease in the Puerto Rican population

Presenilin is a known Alzheimers gene. It has several variants and is associated with early onset Alzheimersusually from 30- to 50-years-of-age, according to principal investigator Dr. Pericak-Vance.

We studied a variant pretty much found solely in the Puerto Rican population. Unlike some of forms of variants that you see with presenilin, this variant has a wide variety in the age of onset, from 30- to 90-years-of-age, Dr. Pericak-Vance said. We set out to better understand why this was.

Researchers screened 182 families for the presenilin mutation and identified 43 carriers of the mutation, called the G206A variant.

This mutation is unique, according to presenting author Katrina Celis, M.D., assistant scientist at the Hussman Institute.

There are other mutations that are in the same position as this mutation, but those other mutations are in Chinese, Korean or Swedish families, and they are all early onsetages 30- to 35-years-of-age, Dr. Celis said.

The Puerto Rican population is admixed, and their genomes have a combination of African, European and Amerindian ancestry. Dr. Celis and colleagues discovered the G206A variant falls in the African ancestry and has a founder effect, meaning the mutation arose in Puerto Rico, possible when an influx of people from Africa and Europe colonized the island.

We looked at individuals that primarily have African ancestry in their genome, like those from Nigeria and African Americans in the U.S., and none of them carried the mutation. That means the new mutation happened in Puerto Rico and only individuals that share that genetic background from Puerto Rico have it, Dr. Celis said.

The information could pave the way to better understand the protective phenomenon that some people with this variant seem to have and harness it to delay onset in the larger population, according to Dr. Pericak-Vance.

Study: Haplotype characterization using short- and long-read sequencing data of a protective region of segmental duplication for Alzheimer disease in African carriers of APOE 4

This study helps to characterize a protective locus for Alzheimers APOE 4 carriers, which Miller School researchers discovered and published in 2022. The APOE-4 variant, discovered by Dr. Pericak-Vance, is the strongest known genetic risk factor for Alzheimers disease.

APOE 4 carriers are at an especially high risk of developing Alzheimers disease, according to study PI Jeffery M. Vance, M.D., Ph.D., professor and founding chair of the Dr. John T. Macdonald Foundation Department of Human Genetics and professor of neurology, Hussman Institute.

This protective locus is found only in people of African ancestry, and its very strong. Having the locus drops APOE 4 carriers risk of getting Alzheimers by 75%, according to Dr. Vance.

Basically, what weve seen is that lowering APOE 4 is good and increasing APOE 4 is bad, Dr. Vance said.

Presenting author Luciana Bertholim Nasciben, postdoctoral associate at the Hussman Institute, and coauthors studied data on 36,000 people from the Alzheimers Disease Sequencing Project. They analyzed the protective region, or haplotypes, in the nearly 2,000 people found to have the protective locus. The researchers further studied the locus in 16 brains from African American Alzheimers patients used for research at the Miller School with long-read sequencing to determine that the locus was not duplicated but rather had only one copy on the DNA.

The haplotype is found throughout African ancestry, so it has been around for a while, according to Dr. Vance. The mechanism explaining how the locus decreases APOE 4 is an important topic of future research.

There is a lot of interest in this novel finding and the clarity that weve provided in our research, Dr. Vance said.

Study: Neuropathology GWAS identifies novel genes involved in amyloid, vascular brain injury, and cerebrovascular disease from common variants

Dementia is ultimately a symptom of underlying damage to the brain.

This damage is commonly caused by Alzheimers disease, but there are other types of damage, like vascular, such as with a stroke, and Lewy bodies, which is the same damage underlying Parkinsons disease, according to study principal investigator Gary W. Beecham, Ph.D., director of research informatics in the Center for Genetic Epidemiology and Statistical Genetics at the Hussman Institute and associate professor, Dr. John T. Macdonald Foundation Department of Human Genetics.

There is increasing recognition that these diseases commonly co-occur, Dr. Beecham said.

This research presented at ASHG is one of the largest studies to date aimed at identifying genetic factors associated with Alzheimers disease neuropathology.

We analyzed brain autopsy data from over 10,000 participants from national and international collaborators. We identified new genetic factors that are linked to specific types of damage. We began looking at multiple types of damage simultaneously, which shows that genetics and differing types of damage interact to impact disease, Dr. Beecham said. We need to acknowledge the complex causes of dementia by studying different genetic factors and different pathological lesions that can impact the brain in unique and complex ways to affect disease.

Three Miller School abstracts were singled out for awards among thousands of abstracts at ASHG:

The awards give the abstracts additional visibility, according to Dr. Vance.

More people notice the work and realize whats going on at a center like the Hussman Institute, he said.

Participating in and attending the ASHG annual meeting is an important career event for faculty and students alike. Nasciben said she feels honored to present her work and represent the Hussman Institute at a meeting as important as ASHG.

As a postdoctoral research associate, the ASHG meeting is an excellent opportunity to show my most recent results and interact with the world community of geneticists, she said. This research theme is particularly inspiring for me because it contributes to finding mechanisms of the disease and potential cures for patients threatened by this devastating disease. The work also illustrates the importance of including diverse populations in genetic studies.

Tags: Alzheimer's & Dementia, Dr. Anthony Griswold, Dr. Derek Dykxhoorn, Dr. Gary Beecham, Dr. Jeffrey Vance, Dr. John T. Macdonald Foundation Department of Human Genetics, Dr. Karen Nuytemans, Dr. Katrina Celis, Dr. Margaret Pericak-Vance, Dr. Stephan Zuchner, Hussman Institute for Human Genomics, neurodegenerative diseases

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Hussman Institute Celebrates Banner Year at Global Human ... - University of Miami

Neuropathology

What happens in your brain when your head gets hit? – Cosmos

When you hit your head or when something hits it your brain is going to feel it.

While that thud might trigger a pain response (we all know what its like to stand up and suddenly strike your head against something), inside your skull, your brain is probably rattling around.

But it isnt just a strike to the cranium that causes your grey matter to rock back and forth: concussions occur when the body anywhere on the body is impacted such that the head, and the brain within it, suddenly moves.

If the effect of this biomechanical force is enough to cause the brain to hit against the skull, or twist, physical and chemical damage may occur to the neurons brain cells that are essential to its normal, healthy function. Thats when a concussion or mild traumatic brain injury is likely.

Everyone talks about concussion in sport, but theres more to it than that

Even if theres no clinical diagnosis of concussion, the potential for subtle, silent, mild TBI remains.

We know from accelerometer data that the head undergoes quite a lot of significant acceleration/deceleration events [in sport], says Dr Michael Buckland, the head of the neuropathology department at the Royal Prince Alfred Hospital and Executive Director of the Australian Sports Brain Bank at Sydney Universitys Brain and Mind Centre.

Only a small minority of those lead to clinical signs and symptoms that would be diagnosed as concussion the vast majority appear to be clinically silent.

But there is evidence, if you look at circulating biomarkersimaging, [and] advanced MRI studies after a game of sport, that there is actually a subtle traumatic brain injury or settled damage to the brain from those events, even though you feel completely fine.

Its all about how much exposure your brain is getting to these acceleration and rotational forces over short periods of time.

A concussion or mild TBI might be accompanied by a range of symptoms, from headaches, nausea and sensitivity to sound or light, to memory problems, brain fog, sleep problems and heightened emotions.

Sometimes theres a loss of consciousness, sometimes there isnt.

Perhaps the greatest diagnostic challenge for both clinicians and patients is that symptoms vary between people.

Diagnosing concussion isnt as straightforward as you might think, says Dr Sarah Hellewell, a neurotrauma researcher from the Peron Institute and Curtin University, in Perth.

There are various guidelines, but mostly diagnosis is based on reports from patients themselves or people around them at the time of injury. Most guidelines or tests include criteria such as presence of symptoms, alterations in mental state, the time of loss of consciousness or amnesia, if any.

In the simplest terms, neurodegeneration occurs when neurons in the brain deteriorate. Repeated concussions without adequate recovery might play a major role in this process.

Too much cell death and dysfunction could lead to any of several pathologies, including Alzheimers, Parkinsons, Huntingtons, motor neurone diseases, and amyotrophic lateral sclerosis (ALS).

CTE or chronic traumatic encephalopathy is in there too, and that has captured the concerns of the sporting community in recent years.

Mostly diagnosis is based on reports from patients themselves or people around them at the time of injury.

CTE is remarkably like Alzheimers. Both show shrinkage in the hippocampus, which plays a crucial role in learning and processing information as part of short and long-term memory formation. Change to the hippocampus is associated with a range of neurodegenerative and psychiatric disorders.

Both CTE and Alzheimers appear to share a common problem: toxic tau. Tau proteins play an important structural role in stabilising microtubules in brain axons the long cable-like structures of neurons that extend away from the cell body, ending in the synapses used to communicate with other brain cells.

Trauma to the brain causes tau proteins to clump together in tangled masses and alter normal brain functioning.

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At a molecular level, tau tangles appear in different layers of the brain and may have different folded structures between CTE and Alzheimers.

But while Alzheimers might be triggered by several age, genetic, environmental and lifestyle factors, CTE is found in those with histories of repeated impacts to the head.

Tau is actually a normal, cellular protein. Its found in all neurons in the brain and it serves to stabilise their long outward projections called axons, says Buckland.

Its all about how much exposure your brain is getting to these acceleration and rotational forces over short periods of time.

Within those axons is whats called microtubule associated protein tau or MAPT [pronounced Map-Tee], and the tau stabilises the microtubules to give structural integrity to that axon.

In CTE, as in Alzheimers disease, the tau takes on an abnormal shape, gets abnormally modified chemically a lot of phosphorylation is added to it and it tends to move out of the axon and clump in the nerve cell body.

Buckland explains that many neurodegenerative diseases appear to be characterised by this abnormal accumulation of wrongly folded proteins.

Its not unlike a blood clot obstructing blood flow, except we have neural proteins crammed together in nerve cells.

Technically, both CTE and Alzheimers can only be conclusively diagnosed after death, that is, via a post-mortem examination of a persons brain (although Alzheimers has many clinical symptoms which enables a pre-death diagnosis).

The term mild is attached to TBIs and concussions, but its deceptive no brain injury is truly mild and there is need for close monitoring of the individual athlete.

A tennis player enduring their first nausea-inducing head hit might be fit and firing after two weeks, but a footballer placed on their fifth concussion stretcher might need much, much longer to heal properly. The brain can recover, but subsequent trauma which occurs before that process has been completed is what worries scientists: does repeat injury before recovery compound the problem?

If you subject your head to repeated concussion, you increase the chances that you might have a long-term brain disease. Thats not rocket science, says Emeritus Professor Robert Vink, a neuroscientist from UniSA.

Risk reduction in the immediate aftermath of a mild TBI or concussion is, therefore, crucial not just for short-term recovery but to reduce long-term risk.

For example, Vink warns about post-concussion drug and alcohol consumption.

Drugs worsen the CTE pathways. So, lets say youve initiated CTE by some event take alcohol, that worsens the pathway the chances of developing CTE go up, its another insult to the brain on top of the head knock, Vink says.

48 hours abstaining from drug and alcohol consumption, rest and monitored sleep, and avoiding strenuous activities like reading, television and screen use are among the current best practice care recommendations from Connectivity, a leading brain injury awareness organisation in Australia.

Understanding the physical and chemical changes that take place within the brain is crucial in the quest to provide clarity and information to communities around mild TBI and concussion: what it is, how to manage it, and when a person can return to participate in the activities they love.

When it comes to the sudden impact of biomechanical force on the brain, few, if any, sports are spared. Now science is revealing the potential extent of repeat head injury, codes are mobilising to respond.

But athletes, and the communities around them, also need definitive diagnosis of brain injuries, their seriousness, and to be given clearer management plans to ensure safe recovery.

To achieve this, neuroscientists are chasing elusive but hugely powerful biomarkers that could make the diagnosis and management much, much more effective.

Next week: The hunt for brain injury biomarkers

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What happens in your brain when your head gets hit? - Cosmos

Neuropathology

Bioengineered Protein May Prevent COVID Infections and Improve … – Feinberg News Center

A novel ACE2 protein developed by Northwestern Medicine investigators improved survival and prevented brain infection in mice infected with SARS-CoV-2 when administered intranasally, according to a recent study published in the journal Life Science Alliance.

SARS-CoV-2, the virus that causes COVID-19, uses the angiotensin converting enzyme 2 (ACE2) protein as a main receptor to infect healthy cells. Since the discovery of this mechanism in early 2020, the use of soluble ACE2 proteins to neutralize SAR-CoV-2 infection has been investigated as a novel therapeutic approach.

Over the last three years, investigators led by Daniel Batlle, MD, the Earle, del Greco, Levin Professor of Nephrology/Hypertension, developed a bioengineered soluble ACE2 protein and have been studying its therapeutic potential in reducing infection first in human organoids and later in mice infected with SARS-CoV-2.

The soluble protein, called ACE2 618-DDC-ABD, intercepts the spike of the SARS-CoV-2 virus before it can attach to the ACE2 receptor, preventing SARS-CoV-2 from entering and infecting healthy cells.

The natural ACE2 protein circulates in a small amount and cannot do much to really prevent the virus from attaching to the cell membrane receptor, so the cell membrane ACE2 receptor always wins. If you provide, however, enough amounts of an adequate soluble ACE2 protein at the right time, you can intercept the virus from attaching to the cell membrane receptor and getting inside the cells; this is whats known as the decoy action of soluble ACE2, Batlle said.

In previous work published in the Journal of the American Society of Nephrology, Batlles team found that when their decoy protein was administered both intranasally and intraperitoneally to mice inoculated with a lethal dose of SARS-CoV-2 virus, the mice experienced near 100 percent survival and reduced lung damage.

Our protein has the property of increased duration of action. That alone is an advantage because the virus is not going to take a holiday break and you want something that stays around for days. Moreover, we modified it further so that the binding power for the virus is enhanced, Batlle said.

In the current study, Batlles team studied the efficacy of this treatment approach by administering their decoy protein, comparing intranasal administration to intraperitoneal (by injection) administration to mice, either before or after infection with SARS-COV-2.

Overall, five-day survival rates were zero percent in the untreated mice, 40 percent in the mice treated intraperitoneally before SARS-COV-2 inoculation, and 90 percent in the mice treated intranasally before SARS-COV-2. Additionally, in the mice treated intranasally, the investigators found the mice had undetectable viral presence in the brain and reduced viral presence and pathology in the lungs.

We expected a difference between intranasal and systemic administration, better by the nasal route, but perhaps not of the magnitude observed, Batlle said.

In the future, Batlle said that ideally their protein could be developed into an anti-viral nasal spray that could be used by patients and healthcare providers the moment they test positive for SARS-CoV-2 or after exposure to infected individuals.

This study demonstrates that soluble ACE2 protein is most effective against the SARS-CoV-2 virus when administered by the intranasal route. We envision that intranasal inhalation of soluble ACE2 could become a new anti-viral strategy, especially when given topatients at risk and medical personnel in hospitals who are constantly exposed to the virus or to people recently infected, said Jan Wysocki, MD, PhD, research associate professor of Medicine in the Division of Nephrology and Hypertension and a co-author of the study.

Luise Hassler, a former research scholar in the Division of Nephrology and Hypertension, was the lead author of the study. Jared Ahrendsen, MD, PhD, assistant professor of Pathology in the Division of Neuropathology, was also a co-author.

This work was supported by the National Institutes of Health grant 1R21 AI166940-01, a gift from the Joseph and Bessie Feinberg Foundation, and the Biomedical Education Program.

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Bioengineered Protein May Prevent COVID Infections and Improve ... - Feinberg News Center

Neuropathology

My Fathers Brain: Life in the Shadow of Alzheimers – Next Big Idea Club Magazine

Sandeep Jauhar is a New York Times bestselling author and a practicing cardiologist. He writes regularly for the New York Times and has appeared on National Public Radio and MSNBC. His essays have been published in The Wall Street Journal, Time, and Slate.

Below, Sandeep shares five key insights from his new book, My Fathers Brain: Life in the Shadow of Alzheimers. Listen to the audio versionread by Sandeep himselfin the Next Big Idea App.

My father became cognitively impaired in what has been called a hypercognitive world. In this world, swirling with information, we prioritize intellect and reason as predominant virtues. If you do not possess these virtues, you are marginalized. If you cant follow or add to the endless conversation, you are rendered invisible. So, when my fathers cognition degenerated, he became largely invisible to the outside world.

This happened to my father in his own family, too. I wish I could say that we were more patient than the world outside, but we werent. The Etch-a-Sketch that was his Alzheimers mind trapped him in a perpetual present, and his children in perpetual frustration. He is helpless. He wont remember. He is like a child now. We would say those things in front of him, sometimes even to him. There was little to deter us, even as we regretted it, again and again, after the fact. We knew that our father was more than just his damaged brain, we knew it, but we struggled to believe it.

The risk of Alzheimers is twice as high in the loneliest persons as compared with those who have the most social support. Even after controlling for other factors, such as cognitive and physical activity, neuropathology is not the sole driver of clinical dementia.

Moreover, brain damage and the degree of clinical dementia are not as strongly correlated as one might expect. Patients with only a small amount of brain damage often have excess disability out of proportion to their neurological impairment. The converse is also true: Patients with an excess of brain damage may be surprisingly cognitively intact. The usual explanation for this discrepancy is cognitive reserve or higher educational levels, prior intelligence, and so on. However, what is rarely acknowledged is the vital role of psychosocial reserve, relationships, environment, and family support. Studies have shown that this may be just as important in Alzheimers disease as neuropathology.

When our parents got sick, my siblings and I joined the ranks of the 15 million or so unpaid (and untrained) family caregivers for older adults in this country. The busiest half of this largely invisible workforce spends, on average, nearly 30 hours a week providing care to relatives. Many of these relatives have dementia and it amounts to more than $400 billion worth of annual unpaid time. The work takes its toll and these relatives are at increased risk of developing depression, as well as physical and career difficulties, including loss of job productivity. Being sick and elderly in this country can be terrifying, and having a sick and elderly loved one is a full-time job.

In the U.S., government support for dementia care is largely nonexistent. Of the $200 billion in total annual costs for dementia care, Medicare pays only $11 billion. The shortfall is covered by families, to the tune of $80,000 per family per yearalmost double the outlay for cancer or heart disease. Long-term care insurance may help with this burden; however, most Americans dont own, or cannot afford such policies. Therefore, most of the burden of elder care ends up being borne by family caregivers, unless families can afford to hire private help.

When my father was declining from Alzheimers disease, one of the things my siblings and I used to argue about was how much to correct or accommodate his confusions. For example, my father, in his impaired state, expected his live-in aide to work for free and would lash out at her (and us) whenever he learned that she had been paid. My siblings tended to think that it was fine to lie to him and tell him she was receiving no money from us. More pragmatic than I, they had no reservations about employing deception to help our father (and themselves) get through one of his rancorous moods.

I fought against this practice as a matter of principle. To me, a healthy relationship with our father, even in his debilitated state, could only be based on truth and trust. Little lies, even if told with the best of intentions, would erode what little connection we had left with him.

However, while doing the hard work of caring for my father, I came to learn that truth-telling can be a double-edged sword. I came to understand that the relationship between ethics and treatment in dementia is a complicated one. The demands of truth-telling exist in tension with other moral imperatives, such as a sons obligation to do the best for his declining father. Personal ethics, I discovered, may come into conflict with the reality of caregiving.

I remember one day after my father kicked his caregiver out of the house, I took her back to him. I knew that if she left, that would surely be the end of my fathers independent living. He would undoubtedly end up in a locked memory unit like so many dementia patients.

Look, Dad, Harwinder came back, I said. He eyed her suspiciously.

She says she is sorry, I said. She told me she will work for free. No money. Just food and shelter.

His face relaxed, and I discerned a faint smile. Okay, he said, Please come in.

I remember so many details from our first year in America, nearly five decades ago, when I was just eight years old. There was a lawn mower in the backyard whose engine imprinted a coin-sized burn on my thigh. There was a small woodshed that housed shovels, gardening tools, and various rusted hulks. In the middle of the yard was a grand oak tree with a tire swing. I can still see my father sitting on a lawn chair under that tree, his fingers caked with soil, his cold beer trickling condensation, predicting how bountiful the harvest would be that fall.

But did it all really happen this way? Was the garden really visible through the kitchen window? Was that window really framed by frilly white curtains? Memory construction, psychologists say, involves a tension between two opposing principles. Correspondence tries to force our memories to agree with the original event that we experienced. It is how most of us view memory: as a true reproduction of something that occurred in the past.

The principle of coherence, on the other hand, transforms our memories to make them consistent with the way we see ourselves and the world in the present. Through coherence, our memories are reconstructed to support our current values or beliefs and these beliefs may not allow us to see things the way they really happened. Those kitchen curtains may now be white to reflect the nostalgia with which I reflect, 45 years later, on my familys first year in America. Hence, autobiographical memories involve a balance of two conflicting forces, one aiming to represent the past the way it was, the other aiming to reconstruct the past in the way that we need to see it today.

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My Fathers Brain: Life in the Shadow of Alzheimers - Next Big Idea Club Magazine

Neuropathology

Scholarship for the PhD in Medical Sciences in the field of Pathology … – Times Higher Education

The PhD in Medical Sciences:

The University of Nicosia Medical School offers the degree PhD in Medical Sciences. The degree is awarded to students who successfully complete an independent research programme leading to novel findings in the chosen field of study. The PhD programme aspires to empower students to become independent researchers, thus advancing innovation and development.

The Research Project:

We are currently inviting application through a competitive process for high calibre candidates to apply for one PhD Scholarship in the fields of Pathology of Neurodegenerative Diseases. The successful candidate will enrol in the PhD programme in Medical Sciences and will work under the Supervision of Professor Dimitrios Kanakis with expertise in the fields of Pathology and Neuropathology at the University of Nicosia Medical School.

Project Description:

Code and Title of research project: PHD-2023-A2: Investigating the possible association of NRG1 and tau, in the development of Alzheimer s Disease (AD).

Background and Rationale:

Neurodegenerative disorders constitute a major problem for the health care system globally. The number of newly diagnosed patients suffering from one of the known neurodegenerative diseases increases dramatically. Finding a treatment or even a preventative measure against such disorders is one of the major challenges of modern science. However, these scientific efforts, though intensive, have not yet achieved the expected result, that is the development of efficacious therapeutic schemes. The reason for this is the absence of sufficient knowledge of the pathogenesis of each of the various degenerative diseases. It is therefore of utmost importance to understand comprehensively the pathology of this category of diseases in order to focus our research explicitly.

Alzheimer s disease (AD) is the commonest age-related neurodegenerative disorder, affecting millions of people worldwide. It is a progressive neurological disorder that drives to the irreversible loss of neurons, primarily in the entorhinal cortex and hippocampus. The amyloid- plaques and the neurofibrillary tangles (NFTs) are the main histopathological hallmarks of the disease.

The amyloid hypothesis suggests that the abnormal cleavage of Amyloid Precursor Protein (APP) and the subsequent deposition of toxic amyloid peptides are a predominant step in the pathogenesis of the disease. However, tau hyperphosphorylation and neurofibrillary tangle (NFT) formation is a direct epiphenomenon of this abnormal deposition suggesting the close association of APP and MAPT (Microtubule Associated Protein Tau) genes.

Neuregulins (NRG) are a family of growth and differentiation factors involved in neuronal differentiation and migration, oligodendrocyte development, N-methyl-D-aspartate (NMDA) receptor function, myelination, neurite extension and arborization, synapse formation and neurotransmitter release.

There are four different neuregulin types: NRG1, NRG2, NRG3, and NRG4. NRG1 is the most widely studied growth factor of the neuregulin family. There are three NRG1 isoforms, namely NRG1 type I, NRG1 type II and NRG1 type III. NRG1 protein has been shown to be important in the development of the CNS, the circulatory system and accessory reproductive organs like the mammary glands. NRG1 plays a pivotal role in neurogenesis and neural differentiations (i.e. neural crest cell differentiation into Schwann cells). Its function is mediated by transmembrane tyrosine kinase receptors of the ErbB family, inducing receptor heterodimerization, which in turn initiates a signal transduction cascade.

A close association of Neuregulin-1 (NRG1), BACE1 and APP genes exists that suggest a potential link between NRG1 and Alzheimer s disease, as the last two factors (i.e. BACE and APP) have been implicated in the development of this condition. NRG1 is a major physiological substrate of -site amyloid precursor protein cleaving enzyme 1 (BACE1), which is cleaved within its ectodomain allowing the exposure of the EGF-like domain for ErbB signaling. In other words, NRG1 activation is mediated by the enzymatic cleavage of BACE1, a rate limiting enzyme for APP proteolysis and amyloid production.

Double immunofluorescence and electron microscopy analysis demonstrated that ErbB4 antibodies co-localized with hyper-phosphorylated tau inclusions and NFTs, proving the relationship between the neuregulin receptor ErbB4 and protein hyper-phosphorylated protein tau. The importance of ErbB/neuregulin signaling in AD pathogenesis, APP processing and tau hyper-phosphorylation has also been shown.

In vitro experiments demonstrated further that NRG1 eliminated the effect of amyloid beta-induced decrease in dendritic spine density in rat primary hippocampal neurons, and improved neural cell differentiation in mouse fetal neuronal stem cells. These results render Neuregulin-1 a potential therapeutic agent for Alzheimer s disease.

It is therefore evident that the exact role of NRG1 is quite enigmatic, so there is an urgent need to solve the puzzle and understand the exact role of NRG1 in AD pathogenesis. Additionally, there is a missing link between NRG1 gene and tau hyper-phosphorylation. The main aim of the study is to elucidate the possible role of NRG-1 type III gene in the pathogenesis of Alzheimer s disease, through direct or indirect MAPT interaction leading to tau hyper-phosphorylation and NFT formation.

Aims and Objectives:

The current Research Proposal has the following aims and objectives:

1. To examine the possible association of NRG1 with tau protein, tau hyper-phosphorylation and the development of toxic NFTs in AD mice.

2. To examine the potential co-localization of the NRG1 protein with the hyper-phosphorylated protein tau.

3. In a later stage, the association of NRG1 with BACE1 will be examined too, through RNAi technology. BACE1 inhibition will be performed on NRG1 transfected cells, in order to assess the possible change in NRG1 normal processing.

The Scholarship:

The Scholarship will have a duration of three to four years and will cover:

The tuition fees for the PhD programme which are 15,000 in total for the first 3 years and 2,000 for year 4.

Requirements and Qualifications:

Eligible Candidates should hold (or hold by the time that the programme is expected to commence i.e. October 2023) a recognised degree (BSc or a degree equivalent for entry to a Master s Degree) and a Master s degree (MSc) in the field(s) of Molecular Biology or a Doctor of Medicine degree (e.g. MBBS or MD degree).

Expertise in a variety of laboratory (e.g. immunohistochemistry and immunofluorescence in paraffin fixed mouse brain samples) and specific molecular biology methods (e.g. Western blotting, in vitro experiments with different cell lines) is a prerequisite for carrying out the experiments of the PhD project.

Application for the PhD Scholarship:

Candidates should submit an online application through this link and upload the following supporting documents:

A cover letter clearly stating that they apply for the PhD Scholarship in the field of Pathology of Neurodegenerative Diseases for the PhD Research Project PHD-2023-A2: Investigating the possible association of NRG1 and tau, in the development of Alzheimer s Disease (AD) .

Copies of the applicant s qualifications/degree(s) the application can be assessed with scanned copies, but certified true copies must be provided if the candidate is successful and prior to enrolment on the PhD programme.

Copies of the applicant s transcript(s) - the application can be assessed with scanned copies, but certified true copies must be provided if the candidate is successful and prior to enrolment on the PhD programme.

Proof of English language proficiency such as IELTS with a score of 7 overall and with a minimum score of 7 in writing or TOEFL iBT with a score of 94 overall and a minimum score of 27 in Writing. Other internationally recognized English language qualifications might be considered upon review. Students from the UK, Ireland USA, Canada (from English speaking provinces), Australia and New Zealand are exempt from the English language requirement.

Two reference letters, of which at least one should be from an academic.

A full Curriculum Vitae (CV)

Once you complete your application please send an email to admissions@med.unic.ac.cy expressing officially your interest in the PhD Research Project PHD-2023-A2: Investigating the possible association of NRG1 and tau, in the development of Alzheimer s Disease (AD) and also attaching all the required documents.

Applications should be submitted by Friday, June 2, 2023 at 5pm. Only fully completed applications, containing all necessary supporting documents will be reviewed.

Only candidates who are shortlisted will be contacted and invited to an interview.

Follow this link:

Scholarship for the PhD in Medical Sciences in the field of Pathology ... - Times Higher Education

Neuropathology

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Variation along P2RX7 interacts with early traumas on severity of ... - Nature.com

Neuropathology

How to Treat Dementia No Matter What Age You Are – DISCOVER Magazine

Search the term preventing dementia online, and a list of possible precautions pop up. One story describesa new studythat finds older Americans who used the Internet but not too much have a lower risk of dementia. Other stories suggest that taking vitamin D, getting a good nights sleep or learning a second language are key to combating dementia.

Scientists dont fully understand what causes dementia, a degenerative neurological condition that impacts memory, speech and basic functioning. But they do know thatas many as 40 percentof cases could be slowed or prevented by making certain lifestyle changes.

In 2020,The LancetCommission on Dementia identified 12 risk factors. Although some of these factors, like air pollution, are out of a persons control, there are many lifestyle changes a person can make to reduce their risk. Problematically,studies find that mostpeople arent aware of the risk factors and what they can do to protect themselves.

As more people live longer, the threat of developing this condition increases. By 2050, an estimated 135 million peoplewill be living with dementia. The bulk of these diagnoses, about 71 percent, will come from lower and middle-income countries where education and healthcare are more limited.

Scientists have learned that preventing dementia is a lifelong process that begins in childhood with access to education.The LancetCommission identified not having an educationbeyond age 12as an important risk factor.

Lack of education is a widespread problem as many people worldwide cannot read or have a limited education.About 14 percentof the worlds population aged 15 and over are illiterate, and although younger generations are becoming more literate, young girls are less educated than their male peers.

Literacy is increasing, but access to education past age 12 is not. Dropout rates were made worse during the COVID-19 pandemic whenmore older children left school, particularly girls.

Reading and engaging in intellectual challenges can reduce a persons risk for dementia later in life. Scientists believe education helps build apersons cognitive reserve, allowing the brain to endure neuropathology. A stronger cognitive reserve can mean a persons dementia is less noticeable or progresses more slowly.

Maintaining a cognitive reserve starts early in life but has to be worked at over the years. This is why studies suggest a person who challenges themselves mentally through puzzles or language learning could stave it off.

Social ties are also a way to maintain a persons cognitive reserve.The LancetCommission noted that hearing loss typically begins in middle age (after age 45) and can threaten a persons interest in socializing and, in turn, minimize their cognitive reserve but more on that later.

During the middle years, a person can also start to develop other dementia risk factors related to vascular brain damage. Having diabetes, high cholesterol, hypertension, and obesity all create the potential for vascular brain damage. Similarly, smoking and drinking alcohol excessively also risk brain damage associated with the condition.

The Lancetcategorized the above conditions asmodifiable factorsthat could be changed through interventions. Exercising, eating aMediterranean diet, getting hearing aids if needed, managing cholesterol and hypertension, drinking in moderation and not smoking can all help reduce or prevent dementia.

There were other identified risk factors. However, the commission identified that a person could likely not control, including head injury and vascular damage from air pollution.

As people enter later life (after age 65), dwindling social contact and depression can be painful risk factors for dementia. Researchers havelinked social isolationto a decline in cardiovascular health and an increase in depression and dementia.

Social isolation increases a persons risk for dementia because it limits how they engage with others and maintain their cognitive reserve. Similarly, as mentioned above, hearing loss can also stop older adults from socializing or challenging themselves mentally.About one-thirdof U.S. adults have hearing loss, which makes it difficult for them to speak on the phone, follow conversations or enjoy listening to the TV or radio.Only about one-fifthof older adults with hearing loss actually have a pair of hearing aids.

Interventions like hearing aids, exercise and community-supported social events can help older people get the socialization they need to maintain their cognitive reserve and fend off dementia. Such interventions demonstrate how managing modifiable factors is a lifelong need that follows a person from their earliest to their oldest years.

Read More: The 4 Main Types of Dementia

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How to Treat Dementia No Matter What Age You Are - DISCOVER Magazine