bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi‐omics analyses reveal unexpected effects of PLCg2 deficiency in the brain
Authors: Palavicini Juan Pablo , Miller Henry E. , Smith Sabrina , Campos Gabriela , Hopp Sarah C. 
Published: December 2022

AbstractBackground
Plcg2 polymorphisms are associated with both reduced (P522R) and increased (M28L) risk of Alzheimer’s disease (AD). The normal function of phospholipase C‐gamma‐2 (PLCg2) protein is to catalyze the hydrolysis of the membrane phosphatidylinositol‐4,5‐bisphosphate (PIP2) to form diacylglycerol (DAG) and inositol trisphosphate (IP3), which subsequently feed into downstream signaling pathways involving protein kinase C (PKC) activation, lipid homeostasis, and calcium regulation. In the brain, Plcg2 is primarily expressed by microglia. The Plcg2 P522R protective variant is a functional hypermorph, while it is predicted that M28L is a loss‐of‐function variant. The specific consequences of PLCg2 loss of function in the brain are unknown. We predicted that reduction of PLCg2 would lead to disrupted PIP2 and DAG metabolism, and that these changes would be associated with decreased PKC and calcium signaling resulting in changes in microglia phenotype.MethodsAt 3 months of age, PLCg2 knockout (KO), PLCg2 heterozygous, and wild‐type (WT) littermate mice were euthanized. We analyzed their brains using, shotgun lipidomics, proteomics, gene expression analysis by a Nanostring Glia Profiling panel, and immunohistochemistry (IHC).ResultsLipidomic analyses revealed expected but sex‐specific changes in total brain PIP2 and DAG content in KOs compared to WTs. Surprisingly, significant decreases in myelin‐specific lipids (e.g., cerebrosides) were identified in both sexes. Unexpectedly, Nanostring gene expression analysis revealed sex‐specific changes in myelin‐related genes, as well as subtle effects on microglia phenotype in KOs compared to WTs, suggestive of reduced microglia . Surprisingly, exploratory proteomics analyses revealed subtle changes in KO females compared to WTs, primarily related to amino acid metabolism. IHC for microglial markers confirmed subtle differences in microglia (Iba1 density and area) in KOs compared to WTs.ConclusionsOur data demonstrate that loss of PLCg2 in the brain generally leads to subtle differences in microglia phenotype in the absence of inflammatory stimuli (suggestive of reduced microglial reactivity) and a surprising potential role for PLCg2 in myelin and amino acid homeostasis that requires further investigation. Overall, our data indicate that loss of PLCg2 function has subtle effects on brain homeostasis that may underlie enhanced vulnerability to AD pathology via microglia and myelin dysfunction.
Affective and ergogenic effects of beat‐accented synchronous music on acute exercise training in older adults with mild cognitive impairment or mild dementia
Authors: Park Kyoung Shin , Hong Jiyeong , Etnier Jennifer L 
Published: December 2022

AbstractBackgroundGiven the increasing dementia population and that no cure for dementia is available, exercise may be important for older adults in the early stages of cognitive decline (ESCD) to delay the progression of cognitive deterioration. However, functional limitations are prevalent in older adults, which often hinder their exercise participation. Exercising with music is a novel approach to facilitate exercise and maximize health benefits because humans like to move in synchrony with music and because both music and exercise can help improve cognitive health. As part of a proof‐of‐concept study, we tested the acute effects of beat‐accented synchronous music (BSM) on affective and psychophysiological responses to exercise in older adults with ESCD.MethodWe developed a chair‐based group exercise program consisting of 30 min of aerobic, strength, and balance training for older adults with functional limitations. A BSM playlist at 85 beats/min was created by imposing 4/4 drumbeats on top of instrumental country music that matched participants’ exercise pace and music preference. Nine older adults with ESCD (M
age = 80.9±15.1 years; 2 females; Montreal Cognitive Assessment scores ranged 11‐24) exercised with and without BSM (twice each, counterbalanced) and provided their ratings of feelings (FS) and perceived exertion (RPE) immediately before, midway through, and immediately after each exercise session. Data were analyzed by Friedman tests.ResultWe found significant effects of BSM on FS [χ
2(1) = 4, p<0.05] and RPE [χ
2(1) = 4.5, p<0.05] during exercise. Participants reported more positive feelings (9.78±0.22 > 8.56±0.56) and higher exertion (6±0.96 > 3.94±0.49) during BSM‐based exercise compared with no‐BSM exercise. No effects of BSM on FS and RPE were found before or after exercise (p’s>0.5).ConclusionCognitive and functional decline restrains exercise participation in older adults, which exacerbates the cognitive and functional decline, creating a vicious cycle. Our findings suggest that BSM can make exercise more pleasurable while increasing perceived exercise intensity from ‘somewhat hard’ to above ‘hard’ in older adults with ESCD. These are important findings because positive affect during an acute bout of exercise is associated with future exercise participation. Future research needs to test the efficacy of a long‐term BSM‐based exercise intervention for older adults.
Cell type specific gene expression profiles of the candidate genes for Alzheimer’s disease
Authors: Sandhu Sumiti , Kong Sek Won 
Published: December 2022

AbstractBackgroundDecades of genetic studies discovered candidate genes for Alzheimer’s disease (AD). Molecular mechanistic insights, however, are available for few candidate genes. This lack of understanding on gene function has been a challenge to translate the role of candidate genes to discovering treatment and diagnostic biomarkers. Recent advances in single cell profiling provide an opportunity to understand functional significance of candidate genes and their products for the cell types implicated in AD.MethodWe performed an integrative analysis of single cell gene expression profiling datasets (i.e., scRNA‐seq and snRNA‐seq) comprising 11 datasets generated from animal models (0.3 million cells) and 15 datasets prepared with human brain tissues (3.1 million cells) that were retrieved from AD Knowledge Portal and the other public repositories. All human and mouse datasets were merged using Harmony to discover cell subpopulations that were unique to conditions compared to controls and/or wild type. For AD candidate genes, cell types were ranked according to their relative expression levels and correlation structure.ResultClustering of brain cell types such as excitatory and inhibitory neurons, glial and vascular endothelial cells was similar across datasets and species; however, we found that transcriptional signature of microglia at different stage of human AD was distinct from disease‐associated microglia (DAM) observed in the mouse AD models. Of note, several homeostatic microglial genes known to be downregulated in mouse DAM were upregulated in human AD samples. Moreover, microglia were the only cell type that expressed all reported AD candidate genes. Nonetheless, the cell type specific expression pattern of AD candidate genes was different between species and across datasets suggesting biological and technical biases.ConclusionUsing an unbiased approach, we highlight the (dis)similarity between human and mouse AD datasets and potential molecular pathways for AD risk genes within microglia and the other cell types implicated in AD.
A novel mouse model of SARS‐CoV‐2 induced neuroinflammation
Authors: Biose Ifechukwude Joachim , Narayanappa Amruta , Gressett Timothy E , Leist Sarah R , Srivastava Akhilesh , Ismael Saifudeen , Kolls Jay , Baric Ralph S , Bix Gregory J 
Published: December 2022

AbstractBackgroundSevere acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection may impact neurological function acutely or chronically, even in the absence of severe respiratory illness. Developing clinically relevant laboratory models to understand the neuropathogenesis of SARS‐CoV‐2 infection is an important step towards unravelling this neurologic consequence. We hypothesize that mouse adapted SARS‐CoV‐2 viral infection will induce neuroinflammation in immuno‐competent C57BL/6J (10 weeks old male) as well as immunodeficient RAG2−/‐ (10 weeks old male) and BALB/c (1 year old female) mice.MethodAll three mouse strains were inoculated intranasally with a dose of 1×103 PFU/mouse (50 µL) of either mock or the mouse‐adapted (MA)10 strain of SARS‐CoV‐2 (BEI resource, NR‐55329). Mice were euthanized on day 2, 3, 7, 15 or 30 post infection and brain samples processed for qRT‐PCR, immunofluorescence, and H&E analysis.ResultSARS‐CoV‐2 MA10 resulted in a significantly higher (p < 0.05) mRNA expression for chemokine ligand 2 (CCL2) and lower (p < 0.05) mRNA expression for the blood‐brain barrier component Claudin‐5 in RAG2−/‐ and WT mice when compared to mock infection. Also, SARS‐CoV‐2 MA10 infection increased microglial expression in 1 year old female BALB/c mice after 2 days of infection, compared to mock infected group. At 30 days post infection, MA10 infected BALB/c mice had a higher perivascular lymphocyte cuffing in the brain.ConclusionThis study demonstrates that the mouse‐adapted MA10 strain of SARS‐CoV‐2 can induce a neuroinflammatory state in the brain and more so in immunodeficient and aging mouse models. These mouse models will enable the investigation of the long‐term neurological effects of SARS‐CoV‐2 infection.
Testing the Association Between Neighborhood Disadvantage and White Matter Hyperintensities
Authors: Merkel Emily X. , Ennis Gilda E. , Cadman Robert V. , Koscik Rebecca Langhough , Ma Yue , Asthana Sanjay , Johnson Sterling C. , Kind Amy J. , Bendlin Barbara B. 
Published: December 2022

AbstractBackgroundSocial determinants of health—the conditions in the places where people live, learn, work, and play—have been shown to affect a broad range of health outcomes, including risk for Alzheimer’s disease and related dementias (ADRD). However, the biological mechanisms by which socio‐contextual factors increase risk for ADRD are poorly known. Higher levels of neighborhood disadvantage have been linked with increased cardiovascular disease (CVD) risk. CVD risk has been associated with white matter lesions known as white matter hyperintensities (WMH) because they produce increased signal on fluid‐attenuated inversion recovery (FLAIR) MRI scans. WMH have been associated with increased risk for stroke, cognitive decline, and dementia. We investigated whether greater neighborhood‐level disadvantage was associated with greater WMH volume.MethodParticipants (n = 804) were enrolled in the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center Clinical Core. MRI was performed at 3 T to acquire T2‐weighted FLAIR images which were then processed using the lesion prediction algorithm from the Lesion Segmentation Toolbox to measure WMH volume. Area Deprivation Index (ADI) distributions from the state of Wisconsin were used to create a dichotomous variable that compared the highest state‐ranked quintile (most disadvantaged neighborhoods) to the lowest 4 state‐ranked quintiles (least disadvantaged neighborhoods). Multiple linear regression tested ADI as a predictor of natural log‐transformed WMH volume. Age, sex, education, intracranial volume, MRI head coil, and study cohort were controlled.ResultFour percent (n = 33) of participants were identified as living in the most disadvantaged neighborhoods (see Table 1). The association between neighborhood‐level disadvantage and log‐transformed WMH volume was not statistically significant (see Table 2 and Figure 1).ConclusionNeighborhood disadvantage was not related to WMH volume in this study. This finding contrasts with previous studies demonstrating associations between increased neighborhood disadvantage and reduced cerebral and hippocampal volume (Hunt et al., 2020) and increased odds for AD neuropathology (Powell et al., 2020). Statistical power to assess the primary effect was likely limited by the small number of participants from the most disadvantaged neighborhoods. This illustrates the need for additional research and increased population‐representative recruitment from disadvantaged contexts for ADRD research studies.
Mechanisms of Cognitive Decline due to White Matter Lesions in Cognitively Intact Older Adults
Authors: Taghvaei Mohammad , Cook Philip , Khandelwal Pulkit , Shakibajahromi Banafsheh , Sadaghiani Shokufeh , Das Sandhitsu R. , Brown Christopher , Tackett William , Dolui Sudipto , Shinohara Russell T. , Wolk David A. , Detre John A. 
Published: December 2022

AbstractBackgroundWhite matter hyperintensities (WMH) on FLAIR MRI are highly prevalent in older adults and are linked to cognitive deficits as well as dementia. Likely mechanisms underlying associations between WMH and cognitive deficits include widespread partial disconnection due to the diffuse nature of progressive WMH and/or tract‐specific disconnection syndromes. We used a virtual lesion approach to evaluate cognitive deficits in domains associated with three tracts: left arcuate fasciculus (LAF; verbal working memory), inferior longitudinal fasciculus (ILF; visual processing), and fornix (memory).MethodWMH were semi‐automatically segmented from FLAIR MRI data in 481 ADNI controls and applied as regions of avoidance for probabilistic fiber tracking on DTI data in 46 healthy older subjects from the Human Connectome Lifespan database. Correlations between overall WMH burden or individual tract disruption and global or tract‐domain‐specific cognitive tests were assessed. Tract disconnection was also compared in subgroups with enriched disruption of specific tracts with respect to global WMH burden, Amyloid beta deposition status, and best (>Mean+1SD) versus worst (<Mean‐1SD) test performance.ResultAll three tracts showed disconnections due to WMH and the mean tract disconnection increased significantly with overall WMH burden (ILF; p<0.001, LAF: p<0.001, Fornix; p=0.025) (Figure 1A). Also, both overall WMH burden and percent disconnection in ILF were associated with prolonged Trail A and Trail B times after correction for age and education (Table 1). In subgroup analyses, Amyloid beta positive status significantly moderated correlation of Trail B times with overall WMH burden (p=0.007) and ILF disconnection (p=0.020) (Figure 2). Subjects with enriched ILF disconnection (Figure 1B) also had prolonged Trail A times than the average group (34.3 vs 30.2, p=0.003). Based on cognitive tests performance, subjects with better scores on verbal category fluency or verbal logical memory tests had lower LAF (p=0.035) and fornix (Test I; p=0.003, Test II; 0.025) disconnection.ConclusionWhile overall WMH burden correlates with cognitive deficits in ADNI controls, significant correlations between specific tract disconnection and tract‐domain‐specific cognitive tests are also observed. Both mechanisms likely contribute to age‐associated cognitive decline. Furthermore, amyloid beta accumulation strengthens these relationships.
Combining quantitative and survival trait analyses identifies novel general and sex‐specific genes for age‐at‐onset of Alzheimer’s disease
Authors: Li Yi‐Ju , Nuytemans Karen , La Jong ok , Jiang Rong , Slifer Susan H. , Naj Adam C. , Gao Xiaoyi Raymond , Martin Eden R. 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) has high genetic heritability for both disease risk and age‐at‐onset (AAO) of AD. However, our understanding of genetics of AAO of AD lags behind AD risk. Here, we utilized two statistical approaches to identify genes modifying AAO of AD globally or in a sex‐specific manner.MethodPooled data from 9,219 AD cases and 10,345 controls from 20 cohorts from the Alzheimer Disease Genetic Consortium were analyzed using a linear mixed model (LMM) for AAO from cases only, and a Cox proportional hazard frailty model (CoxFM) from all subjects with AAO observed in cases and censored at age‐at‐exam in controls. Both methods modeled outcome on SNP, sex, APOE‐e4, and 10 principal components (PCs), and incorporated random intercept by cohort. Fisher’s method was used to combine results of LMM and CoxFM. Genome‐wide significant variants were determined based on p < 5×10−8 in individual or combined tests. Multiple secondary analyses were performed including sex‐specific association tests for top SNPs (p< 10−6). Two gene‐expression datasets of prefrontal cortex tissues from NCBI/GEO were analyzed by sex to evaluate the sex‐specific AAO genes.ResultWe identified 34 genome‐wide significant loci. We confirmed 6 known AD risk genes (APOE, CR1, BIN1, TREM2, PICALM, and FERMT2) also regulating AAO as AD. Twenty‐eight potential novel loci were identified including ARFGEF2, MAPK9, and the MLX region harboring functional related genes for AD. Sex‐specific analyses showed the effects of PICALM, MLX, and CDH2 on AAO were solely from females, and ATP2C1 from males. Particularly, the MLX region harboring 10 genes in strong LD, including variants in COASY and HSD17B1 previously reported to associate with earlier AAO of AD in female AD patients with Down Syndrome. Gene expression further supported higher differential expression of AD over controls for HSD17B1, COASY, PLEKHH3, and MLX in females than males.ConclusionUsing two statistical methods to model AAO of AD, we identified six known AD risk genes and 28 novel loci associated with AAO of AD, and further narrowed down four loci with sex‐specific effects. Notably, HSD17B1, involved in estrogen activation, has strong functional implications warrant for further investigation.
Alzheimer’s pathology disrupts cortical processing of repeated stimuli in cognitively intact older adults
Authors: Giorgio Joseph , Adams Jenna N. , Maass Anne , Jagust William J. , Breakspear Michael 
Published: December 2022

AbstractBackgroundWe used functional imaging (fMRI) and generative modelling to investigate effects of Alzheimer’s disease (AD) pathology (β‐amyloid/Aβ, pathological tau) on cortical mechanisms that support differentiation of novel and repeated stimuli.Method66 subjects (45 Older Adults (OA), 21 Younger Adults) underwent an fMRI task involving stimuli of novel and repeated scenes and objects (stimulus conditions; scenes and objects, context condition; repetition); 42 OA also had PIB‐PET measurement of Aβ and flortaucipir (FTP)‐PET of pathological tau. fMRI data were decomposed into functional networks using group spatial Independent Component Analysis (ICA). We used Dynamic Causal Modelling (DCM) to predict local cortical activity from the time‐course associated with stimulus‐related activity and stimulus repetition. AD pathology was defined as Entorhinal cortex FTP‐SUVR (EC‐tau) and continuous global Aβ. A hierarchical approach uncovered the optimal model that best described our data while considering subject variability due to Aβ and EC‐tau.ResultFive ICA networks were selected for DCM analysis (Figure 1), two input; related to stimulus category (LOC Objects>Scenes: t(65) = 21.64 p<0.001; PPA Scenes>Objects: t(65) = 22.4 p<0.001) and three higher order showing significant effects of repetition (DMN (t(65) = 14.04 p<0.001, MTL t(65) = 11 p<0.001, SAL ‐13.14, p<0.001). Time‐courses modelled using DCM included all possible connections (except between LOC and PPA), allowing repetition to modulate any of these connections with stimuli modelled as inputs to LOC and PPA. From this analysis we observed very strong evidence that increased Aβ removes the inhibition of the DMN by MTL leading to over stimulation when stimuli are repeated (Commonality(repeated) ‐0.38 Pp = 1; Ab(repeated) 1.99, Pp = 1). Conversely, we observed very strong evidence that increased EC‐tau removes the inhibition of the MTL by DMN when stimuli are repeated leading to over stimulation when stimuli are repeated (Commonality(repeated) ‐0.29, Pp = 1, EC‐tau(repeated) 1.7, Pp = 1).ConclusionAD pathology disrupts the normal cortical processes that subserve the ability to recognise repeated stimuli in cognitively intact OA. Critically, global Aβ disinhibits the DMN and EC‐tau disinhibits the MTL, two previously described functional phenomena linked to AD pathology. These models provide a systems‐level account of how pathology affects interactions between functional brain networks that may underlie cognitive decline.
Potential Involvement of Varicella Zoster Virus in Alzheimer’s Disease/Dementia via Reactivation of Herpes Simplex Virus Type 1
Authors: Cairns Dana M , Itzhaki Ruth F , Kaplan David L 
Published: December 2022

AbstractBackgroundInfections are associated with cognitive decline and development of AD/dementia. Epidemiological studies have revealed an increased AD/dementia risk after shingles, caused by varicella zoster virus (VZV), and/or a decreased risk after vaccination against shingles. This suggests that VZV might reside latently in brain, and on reactivation might cause direct damage in brain, as is thought to be the case with herpes simplex virus type 1 (HSV1), a virus strongly implicated in AD. Alternatively, shingles‐induced inflammation could lead to neuroinflammation and reactivation of HSV1 in brain, i.e., to an indirect consequence – a suggestion previously made to account for the risk of AD/dementia conferred by infections (Itzhaki and Dobson 2002), and for the reduction in risk after certain vaccinations ‐ by preventing occurrence of infection and consequent reactivation. Our aim was to investigate these possibilities by infecting cell cultures with VZV.MethodExperiments were carried out infecting human‐induced neural stem cells (hiNSC) cultures, and cultures quiescently infected with HSV1 with VZV. Cultures were observed for the presence of AD‐related phenotypes such as beta amyloid and P‐tau accumulation, gliosis, and neuroinflammation.ResultCells infected with VZV do not show the main AD characteristics ‐ beta amyloid and P‐tau accumulation – which HSV1 does cause ‐ but do show gliosis and increased levels of several cytokines, suggesting that VZV’s action is indirect. However, very intriguingly, we found that VZV infection of cells quiescently infected with HSV1 leads to reactivation of HSV1 and consequent AD‐like changes, including beta amyloid and P‐tau accumulation, supporting the above infection‐reactivation concept.ConclusionOur results support a role for VZV in AD/dementia via reactivation of HSV1 in brain and in combination with some current preliminary results, indicate that the risk of cognitive decline and of dementia conferred by some infectious diseases might indeed result from their causing HSV1 reactivation in brain.
Regulation of Epigenetic BET Proteins on Alzheimer’s Disease in Preclinical Models
Authors: Zhang Can , Tanzi Rudolph E. , Wang Changning 
Published: December 2022

AbstractBackgroundEpigenetic regulation plays substantial roles in human pathophysiology, which provides opportunities for intervention in human disorders through targeting epigenetic pathways. Emerging evidence from both preclinical and clinical studies suggested the potential in developing therapeutics of Alzheimer’s disease (AD) by targeting epigenetic regulatory proteins. Recently there has been keen interest in the family of bromodomain (BD)‐containing BET (bromodomain and extra terminal domain) proteins, which consists of 4 protein members. All BET proteins have two BD domains, which confer significant and complex regulatory mechanisms for AD.MethodHere, we developed domain‐specific small molecule probe targeting BD1 and evaluated expression of BET in AD transgenic animals compared to wild type animals using positron emission tomography‐based molecular imaging. We also investigated the effects of pharmacological inhibition of BET on AD cell models.ResultWe found that 5xFAD animals were characterized by increased signal in the brain in association with our BD1‐specific probe. Using BET inhibitors, AD‐related proteins were significantly changed.ConclusionOur study shows that BET protein may associate with AD by a gain of function mechanism and that inhibitors for specific domains may be utilized for AD in the presence of BET increase.