Category Archives: Neuropathology

Neuropathology

Senolytics show promise in combating brain aging and COVID-19 … – News-Medical.Net

In a recent study published in the journal Nature Aging, an international team of researchers observed that senolytics can alleviate physiologic brain aging and coronavirus disease 2019 (COVID-19) neuropathology.Senolytics are a class of drugs that selectively target and eliminate senescent cells, which are cells that have stopped dividing and contribute to aging and age-related diseases.

Most COVID-19 patients often experience diverse neurologic complications. Further, autopsied brain tissue transcriptomic data suggest associations between severe COVID patients' cognitive decline and brain aging signatures. While recent reports implicate senescent cells in neurodegeneration and cognitive decline in aged mice and in vivo neuropathology models, their contribution to human brain tissue aging and COVID-19 pathology in the central nervous system remains unknown.

Study: Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology. Image Credit:Jose Luis Calvo/ Shutterstock

In the present study, researchers tested the effects of senolytics on physiological brain aging and COVID-19 neuropathology. First, they generated human brain organoids (BOs) from embryonic stem cells and physiologically aged them for eight months. Subsequently, the BOs were treated with two doses of senolytics, such as the dasatinib-quercetin (D+Q) combination, ABT-737, and navitoclax, for one month at a two-week interval.

Senolytic interventions significantly reduced senescence-associated -galactosidase (SA--gal) activity, indicating the elimination of senescent cells. This was further confirmed by significantly higher levels of lamin B1 (a nuclear marker downregulated in senescence) in treated BOs. Next, the team investigated the cell types involved in senescence phenotypes by co-immunolabeling with a senescence marker (p16).

Over three-fourths of p16-positive cells coimmunostained with astrocytes (positive for glial fibrillary acidic protein), while approximately 15% co-localized with mature neurons (positive for neuronal nuclei antigen). These two brain cell populations represented a majority (> 90%) of p16-positive cells. The team found a significant reduction in senescent astrocyte populations following treatment, with the D+Q combination being the most potent. However, the effect of senolytics in reducing senescent neurons was less apparent.

RNA sequencing revealed the upregulation of lamin B1 messenger RNA (mRNA) levels across all senolytic treatments. Additionally, 81 senescence-related mRNAs were consistently suppressed with senolytic treatments. Further, aging clock predictions were performed based on whole-transcriptome sequencing. D+Q treatment of nine-month-old organoids returned their gene expression age to levels of eight-month-old organoids.

This phenotype was not observed with other tested senolytic interventions. D+Q treatment-induced changes in gene expression correlated with mammalian signatures of pro-longevity interventions, such as rapamycin administration and caloric restriction. Next, the team estimated the prevalence of senescent cells in the autopsied frontal cortex from the brains of age-matched patients who died due to severe COVID-19 or non-neurologic and non-infectious causes.

Brains of COVID-19 decedents showed over seven-fold increase in p16-positive cells than those from non-COVID-19 controls. Next, human BOs were exposed to different viral pathogens to examine how (neurotropic) viruses contribute to aging-induced neuropathology. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was mainly detected in neurons, microglia, and neural progenitors.

Seven SARS-CoV-2 variants were also tested, and their senescence phenotypes were ranked by SA--gal activity. Most variants significantly increased SA--gal, but the Delta variant exhibited the most potent induction. Moreover, there was a distinctive colocalization of viral spike and SA--gal in Delta-infected BOs. Besides, a statistically higher induction of senescence was evident between organoids infected for five and 10 days.

Increased senescence observed at 10 days post-infection (dpi) relative to 5 dpi suggested that SARS-CoV-2 infection may have triggered secondary senescence. Interestingly, non-infected senescent cells were enriched within 150 m of infected senescent cells, supporting the putative bystander effect of infected cells in triggering secondary senescence. Senescence was also triggered by infection of BOs with Japanese encephalitis virus (JEV), Zika virus (ZIKV), or Rocio virus (ROCV).

The researchers examined the associations of transcriptomic changes between COVID-19 patients and SARS-CoV-2-infected BOs. Among nearly 1,600 genes with differential expression between infected and non-infected BOs, there were 485 differentially expressed genes in COVID-19 patients' brain samples. Notably, known senescence and aging pathways were enriched in this common gene set.

Long-term senolytic treatment prevents selective accumulation of senescent cells in physiologically aged human BOs.af, BOs were generated and grown in vitro for 8months and subsequently exposed to two doses (one every 2weeks) of either navitoclax (2.5M), ABT-737 (10M) or D+Q (D, 10M; Q, 25M) within the following month, after which organoids (n=814) were collected for in situ analysis.a, SA--gal assay was performed on organoid sections. Each data point in the bar graph represents a single organoid analyzed. Data presented as means.d.; at least eight individual organoids were analyzed per condition; one-way analysis of variance (ANOVA) with Tukeys multiple-comparison post hoc corrections.b, Lamin B1 staining was performed on organoid sections. Each data point in the scatter plot represents the integrated intensity of each cell within organoid sections. At least eight individual organoids were analyzed per condition; one-way ANOVA with Tukeys multiple-comparison post hoc corrections.c,d, Representative images from quantifications shown ina,b, respectively. Scale bar, 0.3mm.e, Representative immunofluorescent images of regions from organoids treated with the indicated senolytics and vehicle control. Samples were individually immunolabeled with antibodies against GFAP, Sox2 and NeuN and co-stained for p16. Arrows indicate coimmunoreactivity of NeuN and p16. Scale bar, 50m.f, Bar graphs showing colocalization quantification performed on organoid sections. Data presented as means.d.; three individual organoids were analyzed per condition; one-way ANOVA with Tukeys multiple-comparison post hoc corrections. a.u., arbitrary units.

Next, the team evaluated the impact of the selective elimination of senescent cells with senolytic interventions. Senolytics significantly reduced the number of BO cells with SA--gal activity five days after SARS-CoV-2 infection. Of note, the impact of senolytics was more prominent in BOs infected with the Delta variant, and senolytics reverted Delta variant-induced lamin B1 loss and p21 upregulation.

Pretreating BOs with senolytics before infection resulted in a significant reduction of virus-induced senescence. Layer 6 corticothalamic neurons and gamma-aminobutyric acid (GABA)ergic ganglionic eminence neurons were the two populations with significantly higher incidence of senescence following infection, and senolytic interventions prevented cellular senescence in these populations.

Finally, the researchers infected K18-hACE2 mice (that express the human angiotensin-converting enzyme 2 [hACE2] under the regulation of keratin 18 [K18] promoter) with SARS-CoV-2 Delta. Senolytics with blood-brain barrier permeability, such as D+Q, navitoclax, and fisetin, were administered 24 hours post-infection, with subsequent treatments every two days. Infected mice had shortened life spans, with a median survival of five days.

However, fisetin or D+Q treatment significantly improved survival. All control animals died by 10 dpi, whereas 13% of navitoclax-, 38% of D+Q-, and 22% of fisetin-treated mice were alive at 12 dpi (experimental endpoint). Senolytics, especially D+Q, caused a profound decrease in COVID-19-related features and significantly reduced viral gene expression in mice brains.

The brains of infected mice exhibited an increase in inflammatory senescence-associated secretory phenotype (SASP) and p16 senescence markers, and (all) senolytic treatments normalized senescence and SASP gene expression of infected animals to the levels observed in non-infected brains. Delta infection also caused a loss of dopaminergic neurons in the brainstem, with a concomitant increase in astrogliosis. However, recurrent administration of senolytics partially prevented the loss of dopaminergic neurons and abrogated the onset of astrogliosis.

Taken together, the study demonstrated that senescent cells accumulate in physiologically aged human BOs, with long-term senolytic intervention(s) substantially reducing cellular senescence and inflammation. Further, D+Q treatment uniquely induced anti-aging and pro-longevity gene expression changes in BOs.

Besides, COVID-19 patients' brains exhibit rapid accumulation of cellular senescence relative to age-matched controls. Neurotropic viruses (ROCV, JEV, and ZIKV) and SARS-CoV-2 can infect BOs and induce cellular senescence, and the SARS-CoV-2 Delta variant triggers the most potent induction of senescence. Short-term senolytic interventions could reduce SARS-CoV-2 gene expression in infected BOs and prevent senescence of GABAergic and corticothalamic neurons.

Notably, senolytics ameliorated COVID-19 neuropathology in infected K18-hACE2 mice, improved their survival and clinical score, and reduced SASP, senescence, and viral gene expression. Overall, the findings highlight the vital role of cellular senescence in brain aging, COVID-19, neuropathology, and the therapeutic impact of senolytics.

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Senolytics show promise in combating brain aging and COVID-19 ... - News-Medical.Net

Neuropathology

Startling discovery at Great Salt Lake could lead to damaging health … – FOX 13 News Utah

SALT LAKE CITY Scientists have revealed a startling discovery made at a lake bed of the Great Salt Lake that could potentially impact the health of many Utahns.

Samples of neurotoxins gathered from a dried up lake bed were so large they shocked scientists who have been studying them for years.

The air sample had a very large signal, one of the biggest I have seen and I was very worried, said Dr. Sandra Banack, senior scientist at Brain Chemistry Labs.

Banack said the toxins in a nonhuman primate can trigger the neuropathology of Alzheimer's disease and ALS. She and her colleagues are concerned about what an exposed lake bed means when wind picks up the toxins and people breathe them in.

What we don't want to see is the increased risk of ALS among citizens here in the Wasatch Front," explained Dr. Paul Alan Cox, Executive Director of Brain Chemistry Labs.

While the study shows an increase is possible, its hard to prove.

We're talking, you know, a disease that can take 10-20 years to manifest. It's not like you can just go out and say, 'yes, that is the cause,' said Dr. James Metcalf, a senior research fellow at Brain Chemistry Labs.

The study simply tells scientists they need to do more research.

And that may then give us links as to which people are vulnerable to the action of this toxin," said Metcalf, "whether it's contributing to an increased rate of disease and ultimately protect people.

In the meantime, its the unknown risks while Wasatch Front residents keep inhaling the air that worries scientists.

As scientists, we feel very strongly that all efforts should be made to refuel the Great Salt Lake so that these water levels come up and we're not getting the dust blowing this way off the lake bottom that's dried, said Cox.

Utah political leaders and state officials tasked with helping the Great Salt Lake reacted with concern in interviews with FOX 13 News.

What can we do to protect ourselves from the already proven risks and the possibility of more found in this study?

Research on its own can't make change, explained Eliza Cowie, Policy Director at O2 Utah.

Cowie encourages people to pay attention, read up on the issues, and show up when it comes time for decisions to be made at the Utah State Capitol that impact the lake and the state's air quality.

Its really important to get people involved to take that information and produce it as a policy solution," she said. "You can't rely purely on researchers and scientists to save us. We need to kind of take the information and produce our own results.

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Startling discovery at Great Salt Lake could lead to damaging health ... - FOX 13 News Utah

Neuropathology

Senolytic therapies suppress long COVID in human organoids … – BioWorld Online

Infection

Researchers from the University of Queensland discovered that senolytic therapies can suppress long-COVID neuropathology and long-term disorders caused by viral infections by reducing senescent cells, thereby reducing inflammation. Published Nov. 13, 2023, in Nature, the study examined the use of human pluripotent stem cells to generate small mini human brain organoids to screen for antiaging interventions called senolytics that selectively eliminate senescent cells that accumulate with age, lead author Julio Aguado told BioWorld.

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Senolytic therapies suppress long COVID in human organoids ... - BioWorld Online

Neuropathology

Eight scientists among most-cited researchers in world – Mirage News

Eight scientists from the University of Freiburg are among the "Highly Cited Researchers" for 2023. A survey by Clarivate Analytics reveals that they are among the most-frequently cited authors worldwide in their fields of research over the past decade. With nine entries - one scientist is recognised for work in two areas - the University of Freiburg holds fifth place among German universities alongside Bonn and Dsseldorf.

The University of Freiburg's Faculty of Environment and Natural Resources is represented in the list by Prof. Dr. Jrgen Bauhus and Prof. Dr. Carsten Dormann. Bauhus' research focuses on the structure and dynamics of forests, nutrient and carbon cycles in forests and ecological interactions in forest ecosystems. Dormann researches and develops statistical ecology methods that are used for example for the analysis of ecological networks.

Dr. Bjrn Grning from the Department of Computer Science is also among the Highly Cited Researchers. Grning is an expert in bioinformatics and heads Freiburg's Galaxy team. Galaxy is an open source platform for the analysis of big data in the life sciences.

Bjrn Grning, Bertram Bengsch, Marco Prinz, Carsten Dormann, Jrg Meerpohl, Jrgen Bauhus, Lukas Schwingshackl and Ori Staszewski. Photos: SFB 1425, Freiburg University Medical Center, Christian Hanner, Jrgen Gocke, Angela Schuberth-Ziehmer.

Five researchers from the Medical Faculty among the most-cited scientists

From the Medical Faculty at the University of Freiburg, the Highly Cited Researchers include Prof. Dr. Bertram Bengsch, Prof. Dr. Jrg Meerpohl, Prof. Dr. Marco Prinz, Prof. Dr. Lukas Schwingshackl, and Dr. Ori Staszewski, who is now a neuropathology consultant at Klinikum Saarbrcken. With the direct involvement of patients, Bengsch, from the Department of Internal Medicine II, undertakes research into the adaptive immune system in chronic disease, specifically virus infections, tumour diseases and diseases brought about by the autoimmune system. Meerpohl is the head of the Institute for Evidence in Medicine at the Freiburg University Medical Center. Together with his team, he develops new ways of making scientific findings accessible to doctors more clearly, more quickly and more convincingly in review papers.

Prinz is the head of the Institute of Neuropathology at the Freiburg University Medical Center, and was recognised as a Highly Cited Researcher by Clarivate in two areas: in immunology and in the field of neural and behavioural sciences. Together with Staszewski, Prinz studies the role of the immune system in the healthy brain and its involvement in diseases such as multiple sclerosis, Alzheimer's and brain tumours. They are both researching among other things the influence of nutrition and epigenetics on the formation of the immune system in the brain. Schwingshackl, senior researcher at the Institute for Evidence in Medicine and at Cochrane Germany, analyses studies into the influence of nutrition on health and develops new methods for future dietary guidelines.

About the list

Clarivate Analytics identifies the Highly Cited Researchers from an analysis of the most-cited papers in the Web of Science literature database. The list ranks the authors of research papers that are among the top one percent in their field in the Web of Science citations index. For 2023, the survey looked at papers that were published and cited in the period from January 2012 to December 2022. In total, the list includes more than 6,800 researchers from more than 1,300 institutions across 67 countries and regions.

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Eight scientists among most-cited researchers in world - Mirage News

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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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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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

Continued here:

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