bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lack of TREM2 and TYROBP effects on microglial homeostasis, activation and disease
Authors: Quipildor Gabriela E. Farias 
Published: December 2023

AbstractBackgroundMicroglia, the primary immune cell in the brain, have multiple activation phenotypes involved in broad functions in the brain, playing roles in neurotoxicity/neuroprotection – and in release of inflammatory and anti‐inflammatory cytokines – as well as roles in cell survival, proliferation, and phagocytosis. TREM2 and TYROBP form a transmembrane complex in microglia that leads to intracellular signaling networks, and these proteins are important regulators of the transition from homeostatic microglia to its activation states. Recent findings have proposed a TYROBP‐dependent and TREM2‐independent molecular signature that is involved in the early transition step from homeostatic to disease‐associated microglia (DAM). Interestingly, the sequential step of DAM activation is TREM2‐dependent. However, the underlying mechanisms that determine how TREM2 or TYROBP regulate these downstream phenotypes are largely unknown.MethodWe have isolated primary microglia from C57BL/6 wild‐type (WT) controls, Trem2 knock‐out (KO) and Tyrobp KO mice at post‐natal day 0‐3. Cells were stimulated with Alzheimer’s disease (AD)‐relevant provocations, such as amyloid beta (Aβ) oligomers, or ‘inflammatory’ stimuli, such as lipopolysaccharides (LPS). We explored protein and gene expression in the presence or absence of inhibitors within the TREM2/TYROBP downstream signaling pathway. We also performed immunofluorescence and functional assays.ResultOur results show that absence of either TREM2 or TYROBP is associated with increased basal levels of the phosphorylation state of ERK in primary microglia, when compared to WT controls. In addition, TREM2 KO and TYROBP KO cells show a less ramified cell morphology at baseline, as compared to WT microglia. Moreover, stimulating primary microglia with either Ab oligomers or LPS leads to differential protein as well as gene expression outcomes in cells that lack either TREM2 or TYROBP.ConclusionThe dysregulated downstream signal transduction and morphology in the absence of TREM2 or TYROBP suggests their important roles not only in microglial homeostasis but also in the activation processes in response to different stimuli. Future goals include the investigation of the roles that these proteins play in the mechanisms underlying microglial activation in different contexts. We ultimately aim to identify potential therapeutic targets that could contribute to the delay or treatment of AD pathology.
Racial Differences in Inpatient Hospital Services Utilization and Expenditure between American Indian and Alaska Native and non‐Hispanic White Older Adults with Dementia
Authors: Abdulsalam Ruqoyat , O'Connell Joan , Jiang Luohua 
Published: December 2023

AbstractBackgroundWhile American Indian and Alaska Native (AI/AN) and non‐Hispanic white (White) adults are at high risks for dementia, little is known about hospital utilization and expenditures among AI/ANs and Whites with dementia. The goal of this study is to examine characteristics associated with inpatient hospital services utilization and expenditures among AI/AN and White older adults with dementia, to understand what factors contribute to differences in utilization and expenditures between the two populations.MethodWe analyzed data on demographic characteristics, health coverage, chronic disease status, hospital utilization and expenditures from the CMS 2019 Medicare Master Beneficiary Summary File for all AI/AN (n = 16,324) and a 5% random sample of White (n = 139,335) adults aged ≥65 who had dementia in 2019. To examine associations between patient characteristics with utilization and expenditures, we employed Poisson and negative binomial models for utilization measures (1+ hospitalizations and number of inpatient hospital days) and a two‐part model (a gamma distribution with a log‐link function) for expenditures, while stratifying by race.ResultAI/AN adults were younger than White adults; a larger percentage were dually enrolled in Medicaid, had diabetes and ESRD, and lived in a rural county (p<0.01). Medicaid coverage is associated with higher inpatient hospital days and expenditures among AI/ANs (Incidence Rate Ratio (IRR) = 1.079; Marginal Effect (ME) = $3,313, p<0.01) but is associated with lower days and expenditures among Whites (IRR = 0.874; ME = ‐$1,438, p<0.01). The association between living in a rural county with expenditures followed a pattern similar to that of Medicaid coverage. Unadjusted mean hospital days and expenditures were 4.84 and $27,559 (AI/ANs) and 3.86 and $23,009 (Whites), respectively. When data for AI/ANs and Whites were combined, the average marginal expenditure for AI/ANs, compared to Whites was $4,550 in unadjusted model, but reduced to $2,772 when we adjusted for age, gender, comorbidities, and social determinants of health.ConclusionUnderstanding and addressing characteristics associated with racial differences in hospital use and expenditures among dementia patients may be helpful for health care resource planning and efficient use. In‐depth research is required to understand the contrasting differences in the impact of Medicaid on expenditures between AI/AN and White adults with dementia.
Moderate to Vigorous Physical Activity Protects Deep Learning Derived Brain Volumes in 9637 Individuals
Authors: Raji Cyrus A. , Meysami Somayeh , Hashemi Sam , Garg Saurabh , Akbari Nasrin , Nguyen Thanh Duc , Gouda Ahmed , Chodakiewitz Yosef Gavriel , London Sean , Merrill David A. , Attariwala Raj 
Published: December 2023

AbstractBackgroundRegular physical activity has been linked to a reduced risk of dementia, while loss of brain volume as measured by MRI is a marker of neurodegeneration. However, it remains unclear whether engaging in moderate or vigorous physical activity has any positive impact on brain structure and potential neuroprotective effects.MethodA total of 9637 healthy participants were scanned across four 1.5T MRI machines with a whole‐body MR imaging protocol. Brain sequences included isotropic MP‐RAGE. An ensemble of three Deep learning models corresponding to each axial, sagittal, and coronal views with FastSurfer architecture was trained on 134 participants aged 27‐66 segmented 96 brain regions. Partial correlations modeled moderate to vigorous physical activity, defined as sports, fitness and recreational activities that increased respiration and pulse rate for at least 10 continuous minutes, with brain volumes. Analyses controlled for age, sex, and total intracranial volume. Benjamini‐Hochberg False Discovery Rate of 5% accounted for multiple comparisons.ResultAverage age was 52.98 ± 13.06 years ranging from 11‐97 years with 52.5% biologically male. Overall, 7215 individuals (74.8%) reported moderate or vigorous physical activity on average 4.03 ± 3.48 days per week. Persons with vigorous activity were slightly older (mean age 54.3 versus 52.5 years) for non‐vigorous physical activity (p < .00001) and 54.8% men versus 45.2% women undertook moderate to vigorous physical activity compared to 45.4% men and 54.6% women. Fewer women engaged in moderate to vigorous physical activity compared to men (p = 9.92e‐16). Accounting for age, sex, and intracranial volume co‐variates and multiple comparisons, moderate to vigorous physical activity predicted larger volumes in multiple regions including: total gray matter volume (Partial R = 0.09, p = 2.59e‐18), total white matter volume (Partial R = 0.09, p = 4.21e‐19), hippocampus (Partial R = .098, p = 1.4e‐21), frontal cortex (Partial R = 0.08, p = 1.06e‐15), parietal lobes (Partial R = 0.055, p = 9.01e‐8), occipital lobe (Partial R = 0.071, p = 5.27e‐12). Whole brain volumes of gray matter and white matter were also larger with an increasing number of days engaged in moderate to vigorous physical activity (Partial R = 0.105, p = 6.31e‐25).ConclusionEngagement in moderate to vigorous physical activity was found to be associated with increased brain volumes, a metric of neural health.
Longitudinal genome wide association studies in Alzheimer’s disease
Authors: Zhuang Xiaowei , Xu Gang , Amei Amei , Oh Edwin 
Published: December 2023

AbstractBackgroundA large number of subjects are generally required for the genome wide association studies (GWAS) in complex traits such as Alzheimer’s disease (AD)1,2. Here we incorporated longitudinal data in AD‐GWAS to improve the statistical power for the identification of AD‐associated genetic variants with a limited sample‐size. Time‐varying genetic contributions towards AD could also be modeled and captured in this longitudinal GWAS.Method1,877 subjects from the ADNI database3 with genotyping data available were included in this analysis. Subjects’ genotype data were imputed to the Haplotype Reference Consortium using the Michigan Imputation Server4, with 9,573,130 single nucleotide polymorphisms (SNPs) remaining after the quality control step. Subjects’ longitudinal diagnosis at each visit were obtained from ADNI, providing 10,832 phenotypes for 1,877 subjects. Subjects’ diagnoses were further binarized into the normal and diseased groups. We applied the retrospective varying coefficient mixed model association test (RVMMAT) to detect time‐varying genetic effect on this longitudinal binary phenotype5. Briefly, dynamic genetic effect was modeled using smoothing splines and estimated by maximizing a double penalized quasi‐likelihood function via a retrospective approach. Subjects’ sex, age at each diagnosis, and the first 5 principal components of whole genome were included as covariates. A categorical variable for genotyping platforms was included as an additional covariate.ResultRVMMAT showed no evidence of inflation in the quantile‐quantile (Q‐Q) plot, with an inflation factor (lambda) of 0.99 (Fig. 1A). 45 SNPs reached genome‐wide significance after false discovery rate correction for multiple comparisons (Fig. 1(B)). Among these genetic variants, 35 SNPs were clustered at the APOE, APOC1, TOMM40, and NECTIN2 genes on chromosome 19, and 6 SNPs were associated with SLAIN2 gene on chromosome 4.ConclusionWe demonstrate that RVMMAT could boost the statistical power in AD‐GWAS with a limited sample‐size. We expect this method to benefit the identification of genetic variants associated with pathological or clinical biomarker‐based longitudinal phenotypes in AD.
Screening of risk factors for Alzheimer’s disease in the general population in peripandemic
Authors: Brusco Luis Ignacio , Olivar Natividad , Dunovits Cynthia , Germani Sandra 
Published: December 2023

AbstractBackgroundSince the start of the Covid‐19 Pandemic in 2020, we have seen interrupted outpatient care services for long periods of time, which has generated complications related to this new scenario: appearance of disorders neuropsychiatric disorders, complication in existing pictures, etc. The group of older adults has been more vulnerable in terms of the possible consequences of exposure to the virus without counting with immunization. Configuring a prone scenario to generate the increase in prevalence of risk factors for dementia of the Alzheimer type. The lack of information and the massiveness of the problem, added to the course of the peripandemic, requires a modification approach strategies, facilitating access to diagnostic and treatment services, constituting a new strategy adapted to a changing and dynamic demand.MethodSemi‐structured interviews with epidemiological and clinical variables are carried out charge of medical personnel; and MMSE in charge of Neuropsychologists. data analysis and interweaving of variables.Result144 subjects attend, with an average age of 66.69 years, 92.37% present risk factors, the most frequent from the clinic: dyslipidemia, hypertension and diabetes; 75% presents mood, behavioral and/or cognitive disorders; 90.75% present evolution of more than a year; 20.83% of the contestants require a more complete ENC because they are below the cutoff for MMSE.ConclusionSocial isolation, lack of medical controls and affective changes were triggers of cognitive impairment
Plasma Total‐Tau is Related to Risk of Heart Failure in the Community
Authors: Aparicio Hugo J , Himali Dibya , Pase Matthew P. , McGrath Emer R , Lioutas Vasileios‐Arsenios , Beiser Alexa S. , Vasan Ramachandran S , Seshadri Sudha , Himali Jayandra Jung 
Published: December 2023

AbstractBackgroundTau is mainly expressed in the neurons of the central nervous system, with elevated cerebrospinal fluid and plasma levels noted when pathologic extracellular aggregation of tau occurs in the setting of neurodegeneration. Plasma tau and phosphorylated tau species are currently being studied as biomarkers for diagnosis, prognosis, or to measure susceptibility risk for conditions such as Alzheimer’s disease. However, the potential for circulating tau protein or other toxic entities upstream or along the tau pathway to cause cardiac dysfunction via protein misfolding or abnormal aggregation has only received limited study.MethodsWe evaluated the association of plasma total‐tau and risk of congestive heart failure in a community‐based sample from the prospective Framingham Heart Study. Adult participants free from clinical heart failure at time of blood sample (Exam 8, 2005‐2008) were included. Participants with renal failure or on dialysis were excluded. Plasma total‐tau was measured using the Simoa platform. Total‐tau plasma values were natural log‐transformed to approximate a normal distribution. Using Cox regression models, total‐tau was related to incident congestive heart failure (up to 2019), adjusting for age and sex (Model 1) and additionally adjusting for cardiovascular risk factors: systolic blood pressure, prevalent diabetes, antihypertensive medication use, smoking status, total cholesterol‐to‐high density lipoprotein ratio, and prevalent atrial fibrillation (Model 2).ResultsWe studied 2792 participants (mean age 67±9 years, 55% women) over a mean follow‐up period of 10.7±3.2 years (Table 1). There were 215 incident cases of heart failure. Each standard deviation unit increase in the log of plasma total‐tau was associated with a 42% increased risk of incident heart failure (95% confidence interval:1.26‐1.61; p<0.0001) in Model 2 (Table 2). Among individuals with plasma total‐tau values in the top quintile compared to the bottom four quintiles, risk for incident heart failure was increased by 69% (1.26‐2.28; p = 0.0005).ConclusionElevated levels of plasma total‐tau at baseline in this community‐based sample were associated with incidence of congestive heart failure. Circulating tau protein, or possibly byproducts of related neurodegenerative pathways, may represent a shared substrate of protein misfolding, in the brain and the heart, resulting in Alzheimer’s disease and heart failure.
Alzheimer’s disease induces pathological changes in the lungs of humans and the AppNL‐G‐F mouse model
Authors: Sahu Bijayani , Nookala Suba , Floden Angela M , Ambhore Nilesh , Venkatachalem Sathish , Combs Colin K 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is an age‐related neurodegenerative disorder characterized by brain accumulation of amyloid beta (Aβ) plaques, neurofibrillary tangles, neuron death, robust gliosis, and neuroinflammation, affecting around 35 million individuals worldwide. It is well known that brain immune changes are a component of the disease, but immune dysfunction in secondary organs has also been reported. To assess peripheral immune changes in AD, we asked whether lung dysfunction and inflammatory change are present during the disease.MethodMale and female C57BL/6 wild type and AppNL‐G‐F mice (8‐9 months old) were sacrificed, and broncho‐alveolar lavage fluid (BALF) and lungs were collected. BALF was used to quantify immune cell phenotype by flow cytometry, and the BALF supernatant was used to determine Aβ and cytokine concentrations and total protein content. Lungs were sectioned and stained with hematoxylin and eosin, Alcian blue and Masson’s trichrome. In addition, lung sections from wild‐type and AppNL‐G‐F mice and human AD patient and healthy controls were immunostained for APP, Aβ and claudin 4.ResultAD mice showed significantly increased pulmonary airway thickening and mucus and collagen production as indicated by hematoxylin and eosin, Alcian blue and Masson’s trichrome staining, respectively, compared to the wild‐type controls. Female but not male AppNL‐G‐F
mice also demonstrated reduced B cell and neutrophil numbers and elevated IL‐1β in their BALF compared to controls. Although there were no differences in BALF supernatant total protein content between wild‐type and AppNL‐G‐F
mice, lungs from both sexes of AppNL‐G‐F
mice had decreased claudin‐4 immunoreactivity suggesting altered epithelial permeability. BALF supernatant from male and female AppNL‐G‐F
mice also contained soluble Aβ1‐40 and Aβ1‐42 correlating with lung APP immunoreactivity. Human AD male and female lungs had reduced claudin‐4 immunoreactivity and increased APP and Aβ staining compared to controls verifying lung changes are also present in human disease.ConclusionThese data demonstrate disease‐associated changes in the lungs of both human AD patients and the AppNL‐G‐F
mouse model. Further characterization of lung dysfunction and its contribution to brain changes may define a novel lung‐to‐brain contribution to disease.
SEX EFFECTS ON THE QUALITY OF SLEEP IN DOWN SYNDROME
Authors: Giménez Sandra , Clos Susana , Bejanin Alexandre , Carmona‐Iragui Maria , Arranz Javier , Benejam Bessy , Videla Laura , Fernandez Susana , Rodríguez‐Baz Íñigo , Barroeta Isabel , Lleo Alberto , Fortea Juan 
Published: December 2023

AbstractBackgroundSex differences in biological factors, such as sleep, might contribute to sex differences in dementia risk. Down’s syndrome (DS) is a genetically determined form of Alzheimer’s disease (AD), with disrupted sleep and a high prevalence of obstructive sleep apnea (OSA). However, sex differences in nocturnal sleep in adults with DS have not been yet investigated. Thus, we aimed to evaluate the sex effect on polysomnographic sleep measures in adults with DS.MethodCross‐sectional study of 187 adults with DS from the Down‐Alzheimer Barcelona Neuroimaging Initiative (DABNI) that underwent a nocturnal polysomnography study. Sleep macrostructure parameters of i)sleep continuity [Total sleep time(TST), Sleep efficiency(SE), Wake after sleep onset(WASO), Sleep latency and latency to REM sleep], ii) NREM (phase N1, N2, N3) and REM stages, in minutes and percentages, and iii) respiratory parameters to determine the presence of OSA were evaluated. Chi‐squared and Mann‐Whitney tests were used to test differences between categorical data, and continuous variables, respectively. To evaluate the sex effects on sleep parameters, we performed ANCOVAs using sleep measurements as dependent variables, the sex, presence of dementia, and OSA as fixed effects, and age as a covariate. Interactions between subjects effects were aso calculatedResultOur cohort includes 187 adults with DS (57,2% females and 42.8% males). OSA was present in 76,2% of the subjects, and 22% of the subjects had symptomatic AD (prodomal/demented) without significant differences in both prevalences between sexes(p = 0.23, p = 0.08 respectively) (table 1). Females presented significant longer TST, WASO, NREM (m), N2(m), N3(m), with higher SE and N3(%), and decreased N1(%) compare to males. These sex differences were maintained after age correction. Results remain essentially similar when including dementia and OSA in the statistical models. No significant interactions between sex and OSA and sex and dementia were observed(Table2).ConclusionAs in general euploid population, females with DS presented a better objective sleep quality with more deep sleep than men. Further work is needed to investigate how sex differences in sleep parameters can influence clinical and biomarker profiles of AD in adults with Down syndrome.
Interactions of synaptic and inflammatory biomarkers in Alzheimer’s Disease
Authors: Rahmouni Nesrine , Tissot Cécile , Servaes Stijn , Therriault Joseph , Macedo Arthur C. , Stevenson Jenna , Lussier Firoza Z , Machado Luiza Santos , Arias Jaime Fernandez , Wang Yi‐Ting , Stevenson Alyssa , Socualaya Kely Quispialaya , Kunach Peter , Nazneen Tahnia , Hosseini Seyyed Ali , Gauthier Serge , Karikari Thomas K , Benedet Andrea Lessa , Ashton Nicholas J. , Zetterberg Henrik , Pascoal Tharick A. , Blennow Kaj , Zimmer Eduardo R , Rosa‐Neto Pedro 
Published: December 2023

AbstractBackgroundThe sequential model predicts synaptic depletion as a downstream of amyloid, tau and neuroinflammation. However, synaptic toxicity might be consequence of toxic forms of amyloid in the absence of tau. In this study we explore the role of synaptic depletion and neuroinflammation as determinants of tau pathology. GAP‐43 and neurogranin are pre‐ and post‐synaptic biomarkers known to be detected at elevated levels in cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD).MethodWe included 126 individuals from TRIAD cohort. Brain inflammation, tau tangle and amyloid‐β (Aβ) deposition were assessed via [11C]PBR28‐PET, [18F]MK6240‐PET and [18F]AZD4694‐PET, respectively. All patients had plasma GFAP quantified, and a subset of 78 individuals had CSF GFAP, CSF Neurogranin and CSF GAP‐43 quantifications available. Voxel and region of interest regression models evaluated the relationship between PET tracers and the fluid biomarkers. Models with [18F]AZD4694‐PET as the outcome were adjusted for [18F]MK6240‐PET voxel‐wise and vice‐versa. A linear regression interaction model evaluated the interaction between CSF GFAP and both synaptic biomarkers with Aβ‐ and tau‐PET as the outcome.ResultPositive associations were found between CSF neurogranin and Aβ‐, tau‐ and brain inflammation‐PET in AD related regions; the strongest associations were found with tau‐pet and CSF neurogranin in the medial temporal lobe. GAP‐43 was also positively associated with tau‐ and TSPO‐PET, but no associations were found with Aβ‐PET. Both plasma and CSF GFAP were associated with Aβ‐, tau‐ and TSPO‐PET in AD related regions, with the strongest t‐values in the model including plasma GFAP and amyloid‐PET. A negative interaction was found between CSF GFAP and both synaptic biomarkers with amyloid‐ and tau‐PET as the outcomes. These associations were stronger with tau‐PET and were found in the temporal, occipital and parietal areas.ConclusionThis study supports the role of synaptic dysfunction and neuroinflammation on tau load. As both synaptic biomarkers and GFAP increase as a function of tangles load, tau accumulation is linked to the relationship between synaptic abnormalities and inflammation in early stages of the disease. Our results suggest that synaptic depletion is a phenomenon that might start prior to tau tangles.