Risk Of Neurodegenerative Diseases Research Articles

Effects of obstructive sleep apnea treatment on neurodegenerative biomarker neurofilament light chain and cognitive performance.

Obstructive sleep apnea is associated with cognitive impairment and increased risk for neurodegenerative diseases. Obstructive sleep apnea treatment with positive airway pressure therapy helps to improve cognitive symptoms and reduces long-term dementia risk. To test whether these treatment effects are due to a reduction in neuronal damage, we examined longitudinal changes in the neurodegenerative serum neurofilament light chain and cognitive performance of patients with obstructive sleep apnea. In this study, 17 patients with obstructive sleep apnea completed baseline and follow-up (9 month after starting PAP treatment) investigation of sleep, daytime symptoms, cognitive testing and serum neurofilament light chain measurements. Depending on treatment adherence and efficacy, participants were assigned either to the effective treatment (n = 10) or non-effective treatment group (n = 7). As results at baseline lower mean oxygen saturation during sleep was associated with higher serum neurofilament light chain. Patients in the non-effective treatment group showed a significant increase of age-adjusted percentile of serum neurofilament light chain levels at follow-up, whereas serum neurofilament light chain values remained constant in the effective treatment group. At a functional level, effective treatment leads to an improvement in processing speed, which was not the case in the non-effective treatment group. Longitudinal changes of age-adjusted serum neurofilament light chain levels were associated with changes in cognitive performance. To conclude, this longitudinal observational study showed that effective obstructive sleep apnea treatment positively affects the amount of neuronal damage as well as working memory performance. As cognitive symptoms might not only be attributed to obstructive sleep apnea-related sleep deficiency, but also neurodegeneration, our results underline the importance of treatment adherence and efficacy for the prevention of neuronal damage and cognitive consequences.

Bacteriophages-Dangerous Viruses Acting Incognito or Underestimated Saviors in the Fight against Bacteria?

The steadily increasing number of drug-resistant bacterial species has prompted the search for alternative treatments, resulting in a growing interest in bacteriophages. Although they are viruses infecting bacterial cells, bacteriophages are an extremely important part of the human microbiota. By interacting with eukaryotic cells, they are able to modulate the functioning of many systems, including the immune and nervous systems, affecting not only the homeostasis of the organism, but potentially also the regulation of pathological processes. Therefore, the aim of this review is to answer the questions of (i) how animal/human immune systems respond to bacteriophages under physiological conditions and under conditions of reduced immunity, especially during bacterial infection; (ii) whether bacteriophages can induce negative changes in brain functioning after crossing the blood-brain barrier, which could result in various disorders or in an increase in the risk of neurodegenerative diseases; and (iii) how bacteriophages can modify gut microbiota. The crucial dilemma is whether administration of bacteriophages is always beneficial or rather if it may involve any risks.

Immunological Profile and Markers of Endothelial Dysfunction in Elderly Patients with Cognitive Impairments.

The process of aging is accompanied by a dynamic restructuring of the immune response, a phenomenon known as immunosenescence. Further, damage to the endothelium can be both a cause and a consequence of many diseases, especially in elderly people. The purpose of this study was to carry out immunological and biochemical profiling of elderly people with acute ischemic stroke (AIS), chronic cerebral circulation insufficiency (CCCI), prediabetes or newly diagnosed type II diabetes mellitus (DM), and subcortical ischemic vascular dementia (SIVD). Socio-demographic, lifestyle, and cognitive data were obtained. Biochemical, hematological, and immunological analyses were carried out, and extracellular vesicles (EVs) with endothelial CD markers were assessed. The greatest number of significant deviations from conditionally healthy donors (HDs) of the same age were registered in the SIVD group, a total of 20, of which 12 were specific and six were non-specific but with maximal differences (as compared to the other three groups) from the HDs group. The non-specific deviations were for the MOCA (Montreal Cognitive Impairment Scale), the MMSE (Mini Mental State Examination) and life satisfaction self-assessment scores, a decrease of albumin levels, and ADAMTS13 (a Disintegrin and Metalloproteinase with a Thrombospondin Type 1 motif, member 13) activity, and an increase of the VWF (von Willebrand factor) level. Considering the significant changes in immunological parameters (mostly Th17-like cells) and endothelial CD markers (CD144 and CD34), vascular repair was impaired to the greatest extent in the DM group. The AIS patients showed 12 significant deviations from the HD controls, including three specific to this group. These were high NEFAs (non-esterified fatty acids) and CD31 and CD147 markers of EVs. The lowest number of deviations were registered in the CCCI group, nine in total. There were significant changes from the HD controls with no specifics to this group, and just one non-specific with a maximal difference from the control parameters, which was α1-AGP (alpha 1 acid glycoprotein, orosomucoid). Besides the DM patients, impairments of vascular repair were also registered in the CCCI and AIS patients, with a complete absence of such in patients with dementia (SIVD group). On the other hand, microvascular damage seemed to be maximal in the latter group, considering the biochemical indicators VWF and ADAMTS13. In the DM patients, a maximum immune response was registered, mainly with Th17-like cells. In the CCCI group, the reaction was not as pronounced compared to other groups of patients, which may indicate the initial stages and/or compensatory nature of organic changes (remodeling). At the same time, immunological and biochemical deviations in SIVD patients indicated a persistent remodeling in microvessels, chronic inflammation, and a significant decrease in the anabolic function of the liver and other tissues. The data obtained support two interrelated assumptions. Taking into account the primary biochemical factors that trigger the pathological processes associated with vascular pathology and related diseases, the first assumption is that purine degradation in skeletal muscle may be a major factor in the production of uric acid, followed by its production by non-muscle cells, the main of which are endothelial cells. Another assumption is that therapeutic factors that increase the levels of endothelial progenitor cells may have a therapeutic effect in reducing the risk of cerebrovascular disease and related neurodegenerative diseases.

Abstract TP298: Cellular Senescence and Microglial Dysfunction are Linked to Progressive Cognitive Deficits in the Chronic Phase of Ischemic Stroke

Improvements in acute stroke treatment, including endovascular thrombectomy and critical care management, have increased survival rates after stroke. However, many survivors have significant neurological deficits, as stroke remains one of the leading causes of long-term disability. Despite this, the chronic progression and long-term sequelae of ischemic stroke pathology remains woefully understudied. This study examined long-term progressive deficits in young adult male C57Bl/6 mice at 3 and 6 months after a 60-minute transient middle cerebral artery occlusion (MCAO) or sham surgery to identify secondary injury processes, and neuropathology of chronic stroke human brains. Depressive-like behavior persisted for 6 months post-stroke (PS) (p= <0.0001). Cognitive function progressively worsened from 3 to 6 months as seen by a continual reduction in the discrimination index in the novel object recognition task (p=.0063). Deficits in memory retention in mice 6-months PS were observed using the fear-conditioning test (p=.0084). Brain atrophy was evident by MicroCT imaging. Histopathological assessment revealed increased microglial activation in the hippocampus and frontal cortex in both mouse and human brains chronically after stroke. Interestingly, we also observed microglia activation proximal to apoptotic neurons in the brains of stroke mice, as shown by TUNEL assay. TUNEL co-labeling with a neuronal marker showed the same neuronal apoptosis in human samples from patients with chronic stroke, in both the hippocampus and thalamus. Disease-associated microglial (DAM) phenotypes were marked by both increased proliferative status and senescent-like phenotypes, including elevated production of cytokines and other proinflammatory molecules. Our findings demonstrate that experimental stroke accelerates inflammaging in the brain, which induces premature senescence within the chronic infarct microenvironment. Cellular senescence and chronic neurodegenerative signatures likely contribute to progressive cognitive impairment following stroke. The chronic and evolving neurological consequences of stroke may offer viable targets for delayed treatment strategies to reduce risk of vascular dementia and neurodegenerative disease.

Retinal optical coherence tomography biomarkers and their association with cognitive functions : Clinical and artificial intelligence approaches. German version

Retinal optical coherence tomography (OCT) biomarkers have the potential to serve as early, noninvasive, and cost-effective markers for identifying individuals at risk for cognitive impairments and neurodegenerative diseases. They may also aid in monitoring disease progression and evaluating the effectiveness of interventions targeting cognitive decline. The association between retinal OCT biomarkers and cognitive performance has been demonstrated in several studies, and their importance in cognitive assessment is increasingly being recognized. Machine learning (ML) is abranch of artificial intelligence (AI) with an exponential number of applications in the medical field, particularly its deep learning (DL) subset, which is widely used for the analysis of medical images. These techniques efficiently deal with novel biomarkers when their outcome for the applications of interest are unclear, e.g., for the diagnosis, prognosis prediction and disease staging. However, using AI-based tools for medical purposes must be approached with caution, despite the many efforts to address the black-box nature of such approaches, especially due to the general underperformance in datasets other than those used for their development. Retinal OCT biomarkers are promising as potential indicators for decline in cognitive function. The underlying mechanisms are currently being explored to gain deeper insights into this relationship linking retinal health and cognitive function. Insights from neurovascular coupling and retinal microvascular changes play an important role. Further research is needed to establish the validity and utility of retinal OCT biomarkers as early indicators of cognitive decline and neurodegenerative diseases in routine clinical practice. Retinal OCT biomarkers could then provide anew avenue for early detection, monitoring and intervention in cognitive impairment with the potential to improve patient care and outcomes.

Retracted: Meta-Analysis of Matrix Metalloproteinases in the Risk of Cardiovascular and Neurodegenerative Diseases.

[This retracts the article DOI: 10.1155/2022/3360316.].

Hyperthyroidism-Induced Upregulation of Neurodegeneration-Related Gene Expression in Metaplasticity-Induced Hippocampus

Introduction: Thyroid hormones, which produce critical changes in our bodies even when their physiological levels alter slightly, are crucial hormones that influence gene transcription. Neuronal plasticity, on the other hand, requires both the activation of local proteins as well as protein translation and transcription in response to external signals. So far, no study has examined metaplastic long-term potentiation (LTP) and related gene expression levels in a hyperthyroid experimental model. Methods: The Wistar male rats were administered 0.2 mg/kg/day of <sc>l</sc>-thyroxine for 21 days to induce hyperthyroidism. Perforant path was primed with 1-Hz low-frequency stimuli (LFS) for 900 s to investigate metaplasticity responses. The LFS was followed by high-frequency stimuli (HFS, 100 Hz) after 5 min. Excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude were recorded from the granule cell layer of the dentate gyrus. The mRNA levels of genes related to neurodegeneration (Gsk-3β, Cdk5, Akt1, Mapt, p35, Capn1, Bace1, and Psen2) were measured using the RT-PCR method for the stimulated hippocampus. Results: Similar to euthyroid rats, hyperthyroid animals had a lower EPSP slope and PS after LFS. Depression of EPSP prevented subsequently induced EPSP-LTP, although HFS was able to elicit PS-LTP despite depression of PS amplitude in both groups. Despite similarities in metaplastic LTP responses, these electrophysiological findings were accompanied by increased Akt, Bace1, Cdk5, and p35-mRNA expressions and decreased Gsk-3β mRNA expression in hyperthyroid rats’ hippocampus. Conclusion: These data support the view that in thyroid hormone excess, the mechanism that keeps synaptic efficacy within a dynamic range occurs concurrently with increased mRNA expression of neurodegeneration-related genes. Our study encourages further examination of the increased risk of neurodegenerative disease in hyperthyroidism.

Exploring the role of underrepresented populations in polygenic risk scores for neurodegenerative disease risk prediction.

Exploring the role of underrepresented populations in polygenic risk scores for neurodegenerative disease risk prediction.

Effects of dietary soy content on cerebral artery function and behavior in ovariectomized female mice.

As females age, they transition through menopause, experiencing a decrease in estrogen and an increase in cardiovascular and neurodegenerative disease risk. Most standard rodent chows contain phytoestrogen-rich soybean meal, which can mimic the effects of estrogen. Understanding the impact of this soybean meal on vascular outcomes is crucial to proper experimental design. Thus, this study aimed to compare the effects of standard and soy-free chows on cerebral artery endothelial function and cognitive function in ovariectomized mice. Young female C57Bl/6J mice (n = 43; ∼6 mo) were randomly assigned to three groups: sham, ovariectomy (OVX), or ovariectomy on a diet containing soy (OVX + Soy). In posterior cerebral arteries, the OVX mice had a 27% lower maximal response to insulin compared with the sham mice. The OVX + Soy mice had a 27% greater maximal vasodilation to insulin compared with the OVX mice and there were no differences in vasodilation between the OVX + Soy and sham groups. The group differences in vasodilation were mediated by differences in nitric oxide bioavailability. The OVX + Soy mice also had greater insulin receptor gene expression in cerebral arteries compared with the OVX mice. However, no differences in aortic or cerebral artery stiffness were observed between groups. Interestingly, the OVX + Soy group scored better on nesting behavior compared with both sham and OVX groups. In summary, we found that ovariectomy impairs insulin-mediated vasodilation in cerebral arteries, but a diet containing soy mitigates these effects. These findings highlight the importance of considering dietary soy when performing vascular and behavioral tests in mice, particularly in females.NEW & NOTEWORTHY To properly design experiments, we must consider how variables like diet impact our outcomes, particularly the effects of soy on females. We found that cerebral artery vasodilation in response to insulin was impaired in ovariectomized female mice compared with intact shams. However, ovariectomized mice fed a soy diet had a preserved cerebral artery insulin-mediated vasodilation. These results highlight that the effects of diet on vascular function may explain inconsistencies found between studies.

FoxO signaling pathway stimulation by Bacillus smithii XY1 contributes to alleviating copper-induced neurotoxicity

Increasingly copper pollution in the environment exacerbates the risk of neurodegenerative diseases. It is necessary to look for effective targets and safe methods for protecting from copper-induced neurotoxicity. Here we firstly explored the impact of copper-exposure on expression profiles in zebrafish. Copper reduced embryo hatching, increased mortality and caused embryonic developmental abnormalities and behavioral dysfunction in juveniles. Transcriptomic analysis revealed that differential genes related to neuron were highly associated with oxidative stress especially enriched to FoxO pathway. Through further validation in Caenorhabditis elegans, copper resulted in nematode neurodegenerative movement disorders and neuronal damage, along with increased levels of reactive oxygen species (ROS) as well as decreased expressions of antioxidant-related enzymes and downstream genes which was also involved in FoxO signaling pathway. Bacillus smithii XY1, a novel strain with an excellent antioxidative activity, showed a great alleviative effect on copper-induced neurotoxicity that was related to FoxO stimulation, being a potential candidate for copper pollution management. Overall, these results suggested that FoxO pathway activation can regard as a strategy for mitigating neurotoxicity caused by copper and B. smithii XY1 with excellent tolerance and outstanding antioxidation specially targeted for FoxO has a promising application in controlling copper contamination.

OLFACTORY DYSFUNCTION AND DEPRESSION TRAJECTORIES IN COMMUNITY-DWELLING OLDER ADULTS

Abstract Olfactory dysfunction has been linked with all-cause mortality and neurodegenerative disease risk, though less is known about the association between olfaction and late-life depression (LLD). We examined the relationship between baseline olfactory performance and incident significant depressive symptoms and longitudinal depression trajectories in well-functioning older adults from the Health, Aging, and Body Composition study. Older adults (n=2,125, age 71-82, 51% women, 37% Black) completed an odor identification task at Year 3 (our study baseline). Cognitive assessments and depressive symptoms were ascertained across multiple visits over 8 years. We employed discrete time complementary log-log models, group-based trajectory models and multivariable-adjusted multinomial logistic regression to assess the relationship between baseline olfaction and incident depression and longitudinal depression trajectories. Mediation analysis assessed the influence of cognition on these relationships. Individuals with lower olfaction had increased risk of developing significant depressive symptoms at follow-up (hazard ratio [HR]=1.04, 95% CI:1.00, 1.08). Of the three longitudinal depression score patterns identified (stable low, stable moderate, stable high), poorer olfaction was associated with a 6% higher risk of membership in the stable moderate (relative risk ratio [RRR]=1.06, 95% CI:1.02, 1.10) and stable high (RRR=1.06, 95% CI:1.00, 1.12) groups, compared to the stable low group. Poor cognitive status only partially mediated the relationship between olfaction and incident depression severity. Suboptimal olfaction may serve as a prognostic indicator of vulnerability for development of LLD. These findings underscore the need for a greater understanding of olfaction in LLD and the demographic, cognitive and biological factors that influence these relationships over time.

Mitochondrial DNA variability and Covid-19 in the Slovak population

Recent studies have shown that mitochondria are involved in the pathogenesis of Covid-19. Mitochondria play a role in production of reactive oxygen species and induction of an innate immune response, both important during infections. Common variability of mitochondrial DNA (mtDNA) can affect oxidative phosphorylation and the risk or lethality of cardiovascular, neurodegenerative diseases and sepsis. However, it is unclear whether susceptibility of severe Covid-19 might be affected by mtDNA variation. Thus, we have analyzed mtDNA in a sample of 446 Slovak patients hospitalized due to Covid-19 and a control population group consisting of 1874 individuals. MtDNA variants in the HVRI region have been analyzed and classified into haplogroups at various phylogenetic levels. Binary logistic regression was used to assess the risk of Covid-19. Haplogroups T1, H11, K and variants 16256C > T, 16265A > C, 16293A > G, 16311 T > C and 16399A > G were associated with an increased Covid-19 risk. On contrary, Haplogroup J1, haplogroup clusters H + U5b and T2b + U5b, and the mtDNA variant 16189 T > C were associated with decreased risk of Covid-19. Following the application of the Bonferroni correction, statistical significance was observed exclusively for the cluster of haplogroups H + U5b. Unsurprisingly, the most significant factor contributing to the mortality of patients with Covid-19 is the age of patients. Our findings suggest that mtDNA haplogroups can play a role in Covid-19 pathogenesis, thus potentially useful in identifying susceptibility to its severe form. To confirm these associations, further studies taking into account the nuclear genome or other non-biological influences are needed.

Assessing causal associations between neurodegenerative diseases and neurological tumors with biological aging: a bidirectional Mendelian randomization study.

Aging is a significant risk factor for many neurodegenerative diseases and neurological tumors. Previous studies indicate that the frailty index, facial aging, telomere length (TL), and epigenetic aging clock acceleration are commonly used biological aging proxy indicators. This study aims to comprehensively explore potential relationships between biological aging and neurodegenerative diseases and neurological tumors by integrating various biological aging proxy indicators, employing Mendelian randomization (MR) analysis. Two-sample bidirectional MR analyses were conducted using genome-wide association study (GWAS) data. Summary statistics for various neurodegenerative diseases and neurological tumors, along with biological aging proxy indicators, were obtained from extensive meta-analyses of GWAS. Genetic single-nucleotide polymorphisms (SNPs) associated with the exposures were used as instrumental variables, assessing causal relationships between three neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), two benign neurological tumors (vestibular schwannoma and meningioma), one malignant neurological tumor (glioma), and four biological aging indicators (frailty index, facial aging, TL, and epigenetic aging clock acceleration). Sensitivity analyses were also performed. Our analysis revealed that genetically predicted longer TL reduces the risk of Alzheimer's disease but increases the risk of vestibular schwannoma and glioma (All Glioma, GBM, non-GBM). In addition, there is a suggestive causal relationship between some diseases (PD and GBM) and DNA methylation GrimAge acceleration. Causal relationships between biological aging proxy indicators and other neurodegenerative diseases and neurological tumors were not observed. Building upon prior investigations into the causal relationships between telomeres and neurodegenerative diseases and neurological tumors, our study validates these findings using larger GWAS data and demonstrates, for the first time, that Parkinson's disease and GBM may promote epigenetic age acceleration. Our research provides new insights and evidence into the causal relationships between biological aging and the risk of neurodegenerative diseases and neurological tumors.

The role of NF-κB signaling pathway in reactive astrocytes among neurodegeneration after methamphetamine exposure by integrated bioinformatics

BackgroundMethamphetamine (METH) is a highly addictive stimulant that has become one of the top five risk substances cause deaths from substance abuse. METH exposure increases the risk of neurodegenerative disease (ND), such as Parkinson's disease (PD), leading to disability and death. Activation of reactive astrocytes is an essential factor in neurodegeneration, and their complex role in METH exposure remains unclear. This study explored the role of reactive astrocyte overactivation in neurodegeneration after METH exposure. MethodsMETH bulk RNA sequencing data (GSE107015 and GSE98793) and single-cell RNA sequencing data (GSE119861) were obtained from the GEO database. We performed immune infiltration analysis on the bulk RNA data. After cell clustering using the single-cell RNA data, astrocytes were extracted for downstream analysis. Differentially expressed genes (DEGs) were identified from the bulk and single-cell RNA sequencing datasets, and GO, KEGG, and GSEA pathway analyses were performed. The PPI network and random forest methods were performed on the overlapping genes of the DEGs to screen hub genes. To explore the common ground between METH exposure and neurodegenerative diseases, we applied a random forest algorithm to PD chip data (GSE99039 and GSE72267) to establish a diagnostic model using the hub genes in METH. New object recognition and the Morris water maze were used to examine cognitive function in mice exposed to METH for 14 days in vivo. Astrocytes were cocultured with neurons for the detection of intercellular crosstalk. ResultsDEGs in the METH group significantly enriched pathways related to NDs, inflammation, and the NF-κB signaling pathway. Immune infiltration analysis revealed significantly increased infiltration of monocytes, T cells, and NK cells and decreased infiltration of neutrophils in the METH group. An intersection of 44 hub genes was screened based on the PPI network and random forest algorithm. These genes suggest that there might be similar pathogenesis between METH exposure and PD. METH exposure resulted in learning memory impairment, hippocampal astrocyte activation, and upregulation of NF-κB expression in mice. Activation of reactive astrocytes cocultured with neurons causes neural damage. ConclusionsThis study explored the crosstalk between astrocytes and neurons in METH exposure, providing a potential pathogenesis to explore the altered immune microenvironment involving reactive astrocytes after METH exposure.

Improving dementia phenotype prediction with functional mapping of genetic data in non‐European ancestries

AbstractBackgroundMany common genetic variants have been associated with dementia, but their ability to predict dementia prospectively is unknown, especially in non‐European ancestral populations. We sought to optimize dementia risk prediction models with machine learning in individuals of diverse genetic ancestries.MethodSamples were selected from the University of California Los Angeles Health System with their electronic health records (EHRs) and linked genetic data. Dementia phenotype was defined using diagnosis codes and mapped phecodes. Polygenic risk scores (PRSs) were built using summary statistics of different population‐based genome‐wide association studies (GWASs). Independent significant and functionally mapped single nucleotide polymorphisms (SNPs) were identified using the FUMA tool. Logistic regression models were built with 1) APOE status, 2) a single PRS, or 3) multiple PRSs. The model with age and sex only was built as the baseline model. We trained LASSO models to determine dementia risk SNPs from weighted SNP‐level genetic data. We compared the predictive performance of these models after five‐fold cross‐validation with area under precision‐recall curve (AUPRC) and area under receiver operating characteristic (AUC). Finally, identified risk SNPs were mapped to genes for biological interpretation.ResultThere were 975 individuals included in the final Hispanic Latinx American ancestry sample, of which 9.44% (N = 92) were dementia cases. The model with LASSO‐selected functional mapped SNPs from multiple neurodegenerative diseases GWASs outperformed all other genetic risk score models (AUPRC: 0.39, AUROC: 0.87), resulting in a 19.6% increase in AUPRC from the best PRS model, and a 26.9% increase from the baseline model. The best‐performing LASSO model included nine SNPs, mostly located in the 19q13, 4p15, and 17q21 regions. Results of mapped genes not only revealed well‐known risk genes of dementia but identified risk genes from other neurodegenerative diseases.ConclusionWe demonstrated that building genetic risk scores with trans‐ancestry GWAS and selecting potential causal SNPs can be beneficial for dementia prediction in non‐European ancestry populations. Further training using machine learning methods with functionally mapped SNP‐level genetic data showed significant improvement in predictive power compared to PRS models. Genetic risks of multiple neurodegenerative diseases may contribute to the predisposition to dementia.

Change in life space is associated with cognitive decline and increased risk of incident Alzheimer’s and Parkinson’s disease in older men

AbstractBackgroundLife space measures the range of geospatial movement through one’s environment during daily functioning. Prior studies on the association of life space and cognitive change are mostly cross‐sectional and have mixed results. To clarify this association, we prospectively evaluated change in life space with cognitive decline and incident Alzheimer’s disease (AD) and Parkinson’s disease (PD).MethodWe studied 1,684 men enrolled in a prospective study of aging. We excluded individuals with probable dementia or PD at baseline (Study Year 7). Life space was evaluated with the self‐reported University of Alabama at Birmingham Life Space Assessment at Year 7 and Year 14. The composite life space score ranges from 0 (most restricted) to 120 (least restricted). Incident AD or PD was defined as a self‐reported physician diagnosis or medication use at Year 14. We conducted logistic regression analyses examining change in life space with the odds of our outcomes unadjusted and adjusted for age, clinic site, race, education, living arrangement, vascular risk factors, and depression. We also conducted mixed linear effects models to evaluate the association between change in life space and change in 3MS and Trails B score.ResultOf 1,684 men (mean age 77.1 +/‐ 18.7 SD) in our analytic cohort, 80 (4.8%) developed incident AD and 23 (1.4%) developed PD over 7 years. The mean (SD) life space score at baseline was 92.9 (18.7) and change over 7 years was ‐9.9 (22.3). In the fully adjusted model, each 1 SD decrement in life space was associated with increased odds of AD (OR 1.6, 95% CI 1.3, 2.0) and PD (OR 1.6, 95% CI 1.1, 2.5). For each 1 SD decline in life space, men worsened by 20.6 seconds in their Trails B score and 1.15 points in their 3MS score over 7 years (p&lt;0.001 for both).ConclusionIn this novel longitudinal analysis, decline in life space is associated with cognitive decline and incident AD and PD. Future studies should examine whether decline in life space is a sensitive and practical way to identify older individuals at risk for cognitive dysfunction and neurodegenerative disease.

Proteomics identifies immunological drivers of post‐infection brain atrophy and cognitive decline

AbstractBackgroundPrior infections can modify the risk for dementia and neurodegenerative disease, yet the mechanisms by which infections contribute to neurodegeneration remain unclear.MethodWe examined how infection diagnoses documented in the Baltimore Longitudinal Study of Aging (BLSA) are associated with rates of change in brain volumes over time, and how these same infections relate to dementia risk using hospital records from UK Biobank and a Finnish multicohort sample (the Finnish Public Sector study, the Health and Social Support study, and the Still Working study). After determining how infections differentially relate to an immunological plasma proteome (942 proteins) in BLSA participants, we then identified a subset of infection‐related proteins that also predict changes in brain regions vulnerable to infection‐specific atrophy (candidate proteins). In addition to evaluating their associations with longitudinal cognitive performance as well as Alzheimer’s disease and related dementias (ADRD) plasma biomarkers (Aβ42/40, GFAP, NfL, pTau‐181), we also investigated the causal link between candidate proteins and longitudinal brain volume loss using Mendelian randomization. Study design is illustrated in Figure 1.ResultA total of 982 cognitively normal participants (age: 65.4 [SD 14.9]); 55.2% female; 66.9% white) were included in the primary MRI analysis. Of the 15 infections examined, we identified six diagnoses related to accelerated brain volume loss, including influenza, viral, respiratory, and skin/subcutaneous infections, with atrophy commonly observed in the temporal lobe. Each infection linked to brain volume loss in the BLSA was associated with increased risk of dementia in the UK Biobank (n = 495,896), with many also associated with increased risk in the Finnish multicohort sample (n = 273,132). From a set of 260 infection‐related proteins, we identified 35 candidate proteins that also predicted changes in brain regions vulnerable to infection‐specific atrophy (Figure 2A‐F). Many candidate proteins were related to cognitive decline, plasma ADRD biomarkers or mechanistically implicated in longitudinal brain volume loss in Mendelian randomization analyses (Figure 2G‐H; Figure 3A).ConclusionWe demonstrate that infections are linked to accelerated regional brain atrophy and dementia risk. Additionally, we identify molecular mediators by which infections may contribute to neurodegeneration (Figure 3B).

TREM2 Burden associates solely with Alzheimer’s Disease, and decreases the Chance to become a Centenarian

AbstractBackgroundRare TREM2 variants are major risk factors for Alzheimer’s disease (AD), but TREM2 variants may also confer a higher risk for other neurodegenerative diseases and a lower probability for cognitively healthy aging. We studied the TREM2 burden associated with different types of dementia and cognitively healthy centenarians (CHCs).MethodWe included participants of the 100‐Plus Study, Amsterdam Dementia Cohort, Longitudinal Aging Study Amsterdam and various Dutch memory clinics. TREM2 variants (R47H, R62H, Q33X, R62C, T96K) were genotyped with a high density array or imputed using standard methods (TOPMED reference panel). To avoid family bias and ethnic differences, related individuals and those of non‐European ancestry were excluded. Frequencies of individual variants and the burden of TREM2 variants were compared in AD dementia, dementia with Lewy Bodies (DLB), frontotemporal dementia (FTD), cognitively normal controls and CHCs (correcting for 5 principal components).ResultWe identified 242 carriers of TREM2 mutations and 6,683 controls without a TREM2 mutation with a mean age of 69 years (SD ±14 years), 50% female (Table 1). TREM2 variants were significantly associated with AD dementia (OR 1.4, 95%CI 1.1‐1.8, p = 0.01) (Table 2). R47H conferred the highest risk for AD (OR 2.8, 95%CI 1.4‐5.6, p = 0.004), compared to 1.3‐fold increased risk of R62H (95%CI 0.9‐1.7, p = 0.11). The carrier frequency was not increased in DLB (OR 1.4, 95%CI 0.7‐2.6, p = 0.34) and was not increased in FTD compared to controls (OR 0.59, 95%CI 0.3‐1.3, p = 0.18). Of interest, the allele frequency of TREM2 variants in centenarians is half of the expected frequency (OR = 0.46, 95%CI 0.1‐1.1, p = 0.10), and only concerns R62H.ConclusionWe replicate the association of TREM2 with increased risk of AD. In contrast to previous reports no association was observed with DLB or FTD. Cognitively healthy centenarians show a negative trend for TREM2 allele frequency suggesting that carrying a TREM2 variant decreases chances of survival to extreme age.

Microglial TREM2 senses TDP‐43 and protects against TDP‐43‐related neurodegeneration

AbstractBackgroundTriggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, in the central nervous system, is exclusively expressed on microglia. TREM2 variants have been linked to increased risk for neurodegenerative diseases, but the functional effects of microglial TREM2 in TAR‐DNA binding protein 43 kDa (TDP‐43)‐related neurodegeneration remain largely unknown.MethodWe investigated TDP‐43 neurodegeneration via viral‐mediated expression of hTDP‐43 protein in mice or inducible expression of hTDP43 with defective nuclear localization signals in transgenic mice. Mass cytometry analysis, mass spectrometry, surface plasmon resonance, and computational simulation were used to study the interaction between TREM2 and TDP‐43.ResultWe found that TREM2 deficiency impaired microglia phagocytic clearance of pathological TDP‐43, and enhanced neuronal damage and motor function impairments. hTDP‐43 induced a TREM2‐dependent subpopulation of microglia with high CD11c expression and higher phagocytic ability. We further demonstrated an interaction between TDP‐43 and TREM2, in vitro and in vivo, in hTDP‐43‐expressing transgenic mouse brains. We computationally identified the region within hTDP‐43 that interacts with TREM2 and observed the potential interaction in ALS patient tissues.ConclusionOur data reveal the novel interaction between TREM2 and TDP‐43, highlighting that TDP‐43 is a potential ligand for microglial TREM2 and the interaction mediates neuroprotection of microglial TREM2 in TDP‐43‐related neurodegeneration.

Temporal Profiles of P-Tau, T-Tau, and P-Tau:Tau Ratios in Cerebrospinal Fluid and Blood from Moderate-Severe Traumatic Brain Injury Patients and Relationship to 6-12 Month Global Outcomes.

Traumatic brain injury (TBI) can initiate progressive injury responses, which are linked to increased risk of neurodegenerative diseases known as "tauopathies." Increased post-TBI tau hyperphosphorylation has been reported in brain tissue and biofluids. Acute-to-chronic TBI total (T)-tau and phosphorylated (P)-tau temporal profiles in the cerebrospinal fluid (CSF) and serum and their relationship to global outcome is unknown. Our multi-site longitudinal study examines these concurrent profiles acutely (CSF and serum) and also characterizes the acute- to-chronic serum patterns. Serial serum and CSF samples from individuals with moderate-to-severe TBI were obtained from two cohorts (acute, subacute, and chronic samples from University of Pittsburgh [UPitt] [n = 286 unique subjects] and acute samples from Baylor College of Medicine [BCM] [n = 114 unique subjects]) and assayed for T-tau and P-tau using the Rolling Circle Amplification-Surround Optical Fiber ImmunoAssay platform. Biokinetic analyses described serum T-tau and P-tau temporal patterns. T-tau and P-tau levels are compared with those in healthy controls (n = 89 for both CSF and serum), and univariate/multivariable associations are made with global outcome, including the Disability Rating Scale (DRS) and the Glasgow Outcome Scale-Extended (GOS-E) scores at 3 and 6 months post-TBI (BCM cohort) and at 6 and 12 months post-TBI (UPitt cohort). For both the UPitt and BCM cohorts, temporal increases in median serum and CSF T-tau and P-tau levels occurred over the first 5 days post-injury, while the initial increases of P-tau:T-tau ratio plateaued by day 4 post-injury (UPitt: n = 99, BCM: n = 48). Biokinetic analyses with UPitt data showed novel findings that T-tau (n = 74) and P-tau (n = 87) reached delayed maximum levels at 4.5 and 5.1 days, while exhibiting long serum half-lives (152 and 123 days), respectively. The post-TBI rise in acute (days 2-6) serum P-tau (up to 276-fold) far outpaced that of T-tau (7.3-fold), leading to a P-tau:T-tau increase of up to 267-fold, suggesting a shift toward tau hyperphosphorylation. BCM analyses showed that days 0-6 mean CSF T-tau and P-tau levels and P-tau:T-tau ratios were associated with greater disability (DRS) (n = 48) and worse global outcome (GOS-E) (n = 48) 6 months post-injury. Days 0-6 mean serum T-tau, P-tau, and P-tau:T-tau ratio were not associated with outcome in either cohort (UPitt: n = 145 [DRS], n = 154 [GOS-E], BCM: n = 99 [DRS and GOS-E]). UPitt multivariate models showed that higher chronic (months 1-6) mean P-tau levels and P-tau:T-tau ratio, but not T-tau levels, are associated with greater disability (DRS: n = 119) and worse global outcomes (GOS-E: n = 117) 12 months post-injury. This work shows the potential importance of monitoring post-TBI T-tau and P-tau levels over time. This multi-site longitudinal study features concurrent acute TBI T-tau and P-tau profiles in CSF and serum, and also characterizes acute-to-chronic serum profiles. Longitudinal profiles, along with no temporal concordance between trajectory groups over time, imply a sustained post-TBI shift in tau phosphorylation dynamics that may favor tauopathy development chronically.