bluuebunny/crossref_metadata_2025_split huggingface dataset:
A transcriptomic signature of late‐life depression
Authors: Matan‐Lithwick Stuart A , Bennett David A , Wang Yanling , Tripathy Shreejoy , Felsky Daniel 
Published: December 2022

AbstractBackgroundLate‐onset Alzheimer’s disease (AD) is commonly accompanied by symptoms of depression. While genes associated with pathological AD diagnosis and mid‐life depression have been identified, the transcriptomic signature of late‐life depression has not been described. We hypothesized that neocortical gene expression would be associated with symptoms of late‐life depression proximal to death, independent of pathologic AD diagnosis and medication status.MethodBulk tissue RNA sequencing data from frontal cortex of 1,001 elderly brain donors were analyzed (mean age at death: 89.7yrs [range: 67‐108]). All donors had genotype, demographic, and clinical assessments within one year prior to autopsy, as well as detailed postmortem neuropathological characterization. Differential expression analysis was performed with robust linear modeling including technical and demographic covariates, cell type proportions, educational attainment, APOE e4 genotype, and medication status for AD‐ and depression‐prescribed drugs. We then included main effects of depressive symptom burden proximal to death (CESD‐sum) and pathologic diagnosis of AD (NIA‐Reagan criteria).ResultAfter false discovery rate correction (FDR q<0.05), only one gene, Prader Willi/Angelman region RNA1 (PWAR1), was associated with depressive symptoms (t=5.2, q=0.005); greater PWAR1 abundance was linked to higher symptom burden. At q<0.1, 14 genes showed association. Strikingly, a majority of these genes (e.g. CTDSPL2, ACR2B‐AS1, ADGRE2, MRM1, IRF8, COL19A1) have been previously implicated in unipolar depression or bipolar disorder. Gene Set Enrichment Analysis revealed upregulation of processes related to energy metabolism (top: “oxidative phosphorylation”, p=2.1x10‐8) and downregulation of DNA modifying processes (top: “DNA conformation change”, p=2.0x10‐7), among others. Results were not changed when controlling for smoking and alcohol consumption, and no significant associations were observed for depression medication status (top q>0.23).ConclusionHere we describe a cortical transcriptomic signature of late‐life depressive symptoms. Among our top signals are genes with known links to mid‐life depression, as well as biological processes relevant to energy metabolism, synaptic plasticity, DNA modification, antigen presentation, and response to pH. Our work provides a depression‐specific expression signature for elderly frontal cortex and lays the foundation for investigation of specific mechanisms toward precision therapeutics.
The association of 25(OH)D levels and hippocampal morphology in a clinically mixed sample
Authors: Dogan Melike Karacam , Karakaşlı Ahmet Alp , Özkan Esra , Türkoğlu Özge , Yalcinkaya Oguz Kaan , Oytun Merve Güner , Zengin Hatice Yağmur , Doğu Burcu Balam , Karaosmanoğlu Ayça , Karahan Sevilay , Topçuoğlu Esen Saka , Ayhan Yavuz 
Published: December 2022

AbstractBackground25(OH)D may play role in differentiation and development of the hippocampus(1).25(OH)D deficiency was associated with reduced hippocampal volume in mild cognitive impairment(MCI)(2).We previously have shown that 25(OH)D levels were independently associated with reduced cognition independent from disease and AD‐related morphological changes(3),however the association with hippocampal subfields was not studied.We aimed to study the possible association between hippocampal subvolumes and 25(OH)D levels in our middle‐old age research participants.MethodThe participants were collected from a cognitive disorders research clinic at Hacettepe University.Those who use 25(OH)D supplements at the evaluation,have renal failure or diseases that could affect 25(OH)D metabolism were excluded.Concurrent serum 25(OH)D levels,Modified Mini Mental Test(3MS) scores and brain MRI data were retrospectively analyzed.FreeSurfer v.6.0 was used for automated structural neuroimaging analysis.Desikan‐Killiany atlas was utilized and in addition to the total volumes,the volumes of 12 distinct subfields of right and left hippocampi were analysed.Volumes were normalized to total intracranial volumes.Linear regression was used to determine the factors associated with the hippocampal volumes and the hippocampal subfields.Age, gender, education(years),3MS scores,syndromic diagnoses and 25(OH)D levels were used as the independent variables.Funded by TUBITAK 214S048,Hacettepe University THD2018‐17363 and Psychiatric Association of Turkey.Result208 patients(54 AD,83 subjective and mild CI,71 cognitively intact)were evaluated.Mean age was 70±9. 58.7% of the sample was female.19.7% had not finished primary school.Mean 25(OH) level was 20.5±12.16 ng/ml,57% of the sample had clinical vitamin D deficiency.25(OH)D levels were not different among diagnostic groups.Cognitive scores and age were the most consistent predictors of hippocampal subfields.In the multivariate analyses there was no association between hippocampal subunits and 25(OH)D levels regardless of the diagnoses(F=0.207, df=2, p=0.813).ConclusionHippocampal volumes were not associated with 25(OH)D levels in line with our previous findings.This finding further support the hypothesis that vitamin D might be an independent factor for cognitive impairment.However our results differed from studies reporting positive correlation between hippocampal atrophy and 25(OH)D deficiency.This may be due to the heterogenous and limited nature of our sample,cross‐sectional nature of the study (those with previous vitamin D use were not eliminated) and the limited low range of 25(OH)D levels in our sample,consistent with the Turkish population.Further studies are needed to assess the role of 25(OH)D in neurodegeneration and cognitive decline.
The cross‐sectional association between APOE ε4 and cognition in midlife: Baseline data analysis of the Physical Activity and Alzheimer’s Disease study ‐ II
Authors: Park Kyoung Shin , Slutsky‐Ganesh Alexis B , Anderson Travis , Holder Hadassah , Vance Jarod C , DuBois Samantha L , Kibildis Samuel , Labban Jeffrey D , Wahlheim Christopher N , Wideman Laurie , Etnier Jennifer L 
Published: December 2022

AbstractBackgroundCarrying at least one ε4 allele of Apolipoprotein E (APOE ε4) is a strong genetic risk factor for cognitive decline in late life. However, how APOE ε4 is associated with cognition in midlife (to what extent and in which domains) remains unspecified. We investigated the association between APOE ε4 carrier status and various domains of memory and executive function in healthy, sedentary adults in midlife.MethodA subset of 91 participants (M
age = 57±6 years; 86.8% females; 33 carriers and 58 non‐carriers of APOE ε4) from a larger study (PAAD‐II, NCT03876314) were included for analyses. At baseline, participants provided a passive drool saliva sample to determine APOE ε4 carrier status and completed a comprehensive cognitive assessment. Composite scores for auditory verbal learning, visuospatial memory, associative memory, story memory, mnemonic discrimination, working memory, inhibitory control, and fluid intelligence were computed. Analyses of covariance tested the effects of APOE ε4 on the composite scores with demographic factors as covariates.ResultSignificant effects of APOE ε4 on auditory verbal learning [F(1, 82) = 4.8, p<0.05] and fluid intelligence [F(1, 73) = 5.155, p<0.05] were found after controlling for the effects of age, race, education, and gender. APOE ε4 carriers’ z‐scores for auditory verbal learning (‐0.202±0.208) were lower than non‐carriers (0.164±0.104), and the same was found for fluid intelligence (carriers: ‐0.218±0.183; non‐carriers: 0.145±0.139). APOE ε4 was unrelated to other composite scores of memory and executive function (p’s>0.5).ConclusionEvidence from longitudinal studies suggests that negative effects of APOE ε4 on cognition are evident at 65–75 years old. We conducted a comprehensive assessment of multiple cognitive domains and demonstrated that APOE ε4 is negatively associated with some cognitive domains in midlife. These findings imply that, although APOE ε4 is a strong risk factor for cognitive decline in late life, its effects on cognitive aging could gradually start in midlife. The small but notable effects of APOE ε4 on comparably intact cognitive function in midlife suggests the potential importance of early preventive interventions (e.g., physical activity, healthy diet) for cognitive preservation in late life, especially in people with higher genetic risk for cognitive decline.
L‐Type calcium channel antagonist isradipine decreases area of plaque associated dystrophic neurites in 5XFAD mouse model
Authors: Wickline Jessica L , Smith Sabrina , Odfalk Kristian F , Shin Riley , Sanchez Jesus J , Cundey Rachael , Javors Martin , Ginsburg Brett , Hopp Sarah C. 
Published: December 2022

AbstractBackgroundEpidemiological studies suggest that L‐type calcium channel (LTCC) antagonists may reduce the incidence of neurodegenerative diseases including Alzheimer’s disease (AD). However, the neuroprotective mechanism of LTCC antagonists is unknown. Amyloid‐β (aβ) increases intracellular calcium signaling, which regulates lysosomal processing and microglial inflammatory responses, both of which are altered in AD. Neurons near aβ plaques develop dystrophic neurites, which are abnormal axonal swellings that accumulate lysosomes. Further, microglia accumulate around aβ plaques and secrete inflammatory cytokines. We hypothesized that antagonism of LTCCs with isradipine would reduce aβ plaque associated dystrophic neurites and inflammatory microglia in the 5XFAD mouse model of AD by restoring normal intracellular calcium regulation.MethodWe treated 6‐ and 9‐month‐old 5XFAD mice with isradipine (3 mg/kg/day) or vehicle via subcutaneous pellets for 30 days. Following three weeks of treatment we tested locomotion and cognitive behavior via open field, novel object recognition and Morris water maze. We measured gene expression of inflammatory mediators (IL1β, TNF, CD68) and LTCC subunits (Cav1.2, Cav1.3) using qPCR. Using immunohistochemistry (IHC), we examined aβ plaque number and area (D54D2 and ThioS), microglia area (Iba1), dystrophic neurites area and particle number (LAMP1) normalized to total brain area.ResultIHC revealed that isradipine treatment in 9‐month‐old 5XFADs decreased the total area of LAMP1 positive dystrophic neurites (p = 0.0310) compared to vehicle‐treated 5XFADs; this change was not observed in the 6‐month‐old group. Isradipine treatment in the 9‐month‐old 5XFADs also led to a decreasing trend (p = 0.0552) in plaque load compared to vehicle‐treated 5xFADs as measured by IHC. Isradipine treatment did not modulate plaque associated microglia as measured by IHC or inflammatory gene expression as measured by qPCR, regardless of age. There was no treatment effect on behavior or expression of LTCC subunits.ConclusionOur data show that isradipine reduces aβ plaque associated dystrophic neurite pathology in 9‐month‐old 5XFAD mice, potentially showing LTCC play a role in mediating this specific phenotype. Our future studies will focus on understanding why antagonizing LTCCs leads to a decrease in LAMP1 and whether this is due to changes in lysosomal development and processing or other possible mechanisms.
Mild behavioral impairment is associated with sleep apnea, insomnia and brain white matter hyperintensity burden
Authors: Sanderlin Ashley H. , Lockhart Samuel N. , Hayden Kathleen M. , Craft Suzanne , Yang Mia , Sachs Bonnie C. , Cleveland Maryjo , Williams Benjamin J. , Williamson Jeff D. , Bateman James R. 
Published: December 2022

AbstractBackgroundMild behavioral impairment (MBI) is a neurobehavioral syndrome associated with increased risk for Alzheimer’s disease (AD) and other neurodegenerative disorders. White matter hyperintensities (WMH) are brain lesions associated with cerebrovascular insult and contribute to cognitive decline across the cognitive spectrum (normal cognition, mild cognitive impairment (MCI) and dementia). Sleep disturbance is common among older adults with cognitive impairment and like MBI, is a modifiable AD risk factor that can affect brain structure including WMH. We sought to examine the prevalence of MBI and its relationship with sleep and WMH in a community cohort of older adults.MethodParticipants enrolled in the Wake Forest AD Research Center (ADRC) Clinical Core cohort (N = 633, mean age = 70.4 years) provided history of sleep apnea and insomnia, underwent neuropsychological assessment and neuropsychiatric symptom assessment, as reported by an informant on the Neuropsychiatric Inventory Questionnaire (NPI‐Q). MBI scores were derived from the NPI‐Q severity and included 10 symptoms reflecting affective dysregulation, impulse control, decreased motivation, social inappropriateness and abnormal perception or thought content, and excluded NPI‐Q questions on sleep and appetite. T1 and T2 FLAIR MRI were obtained; T1 and FLAIR were segmented to quantify WMH volume, which was scaled by head size and log transformed. Global cognitive status was assessed using the clinical dementia rating (CDR) global score.ResultIn our sample, 24% of participants had MBI. Normal cognition (CDR = 0) participants had significantly lower rates of MBI compared to both MCI (CDR = 0.5) and dementia (CDR ≥ 1, Figure 1, p<.001). MBI scores were also significantly higher in participants with than without sleep apnea (Fig. 2, p = 0.003) and insomnia (Figure 3, p = 0.043). Further, WMH volume was higher in participants with MBI (Figure 4, p<.001).ConclusionMBI increased in prevalence with cognitive impairment. Sleep disturbances and greater WMH burden in our MBI participants may increase their risk of cognitive decline for normal cognition and MCI groups and relate to poor behavioral and health outcomes in participants with dementia. Future studies will assess interactions of sleep, MBI and WMH across cognitive groups and their association with risk of conversion to MCI or AD.
Distinct cerebrospinal fluid immune perturbations in healthy brain aging and cognitive impairment
Authors: Piehl Natalie , Ramakrishnan Abhirami , Wyss‐Coray Tony , Gate David 
Published: December 2022

AbstractBackgroundCerebrospinal fluid (CSF) contains a tightly regulated, specialized immune system. Yet, little is known about how aging influences CSF immunity in cognitively typical versus cognitively impaired individuals.MethodHere, we performed single cell RNA sequencing (scRNAseq) on CSF collected from 45 cognitively typical subjects ranging from 54‐82 years old. We then assessed age‐related transcriptomic changes using bioinformatic approaches, including linear and local polynomial regression. We reveal pronounced changes to several CSF immune cell types, underscored by increased expression of lipid processing genes in activated monocytes with age. We then compared CSF immune systems from cognitively typical subjects to 14 subjects with mild cognitive impairment or Alzheimer’s disease.ResultOur results indicate disparate age‐related CSF immune system perturbations, including the upregulation of C‐X‐C Motif Chemokine Receptor 6 in clonally expanded T cells of cognitively impaired subjects.ConclusionThese results highlight the utility of CSF immune system changes to identify therapeutic targets of neurodegenerative disease‐associated neuroinflammation.
Pathological tau activates nuclear factor‐kappa B (NF‐κB) and drives neuroinflammation
Authors: Bhaskar Kiran , Jiang Shanya , Dadras Somayeh , Hulse Jonathan P , Tangavelou Karthikeyan , Chisholm Devon C , Mandell Michael 
Published: December 2022

AbstractBackgroundHyperphosphorylation and aggregation of tau is a pathological hallmark of Alzheimer’s disease and related tauopathies. Pathologically modified tau (pTau) displays varying degree of gain‐of‐toxic functions, in addition to loss of its normal homeostatic function in neurons. Several prior studies have suggested occurrence of innate immune activation in brain regions that spatio‐temporally overlap with pTau burden in brains of various tauopathies. Recent studies have suggested that once tau is hyperphosphorylated and misfolded, the neurons tend to expel pTau to the extracellular space, which is taken up by other neurons and results in trans‐neuronal propagation of pTau. We made a compelling discovery that en route to other neurons, pTau can also interact with and serve as an initial trigger to lead to microglial activation and neuroinflammation (Cell Reports 2021). However, it is not unclear if pTau driven innate immune activation involve canonical NF‐κB pathway.MethodsFirst, we determined the levels of NF‐κB activation in autopsy brains of different tauopathies via Western blot analyses for markers of NF‐κB. Second, we performed bulk‐RNA sequence analyses of human primary microglia treated with paired‐helical filaments (PHFs) purified from human tauopathy brains. Third, we crossed PS19 mouse model of tauopathy to NF‐κB‐GFP‐Luciferase reporter mice (Luc) to generate PS19/Luc+ mice and performed IVIS® live image analyses at different time points. Finally, we treated Luc expressing BV2 cells, primary microglia, and bone marrow derived macrophages (BMDMs) with pTau and validated nuclear localization of NF‐κB via Cellomics® high‐content microscopy.ResultsPhosphorylated NF‐κB p65 (Ser536) levels were significantly high in the autopsy brains of Corticobasal degeneration (CBD), Progressive supranuclear Palsy (PSP) and Pick’s disease (PiD) compared to healthy controls. RNA‐seq and bioluminescence analyses suggested human brain‐derived pTau induced NF‐κB activation in microglial cells and BMDMs. PS19/Luc+ mice displayed increased NF‐κB activation with age.ConclusionsTogether, these results suggest NF‐κB activation in the brains of human tauopathy and that pTau can directly activate NF‐κB in various model systems. Neutralization of pTau via immunotherapy and determining if it has any effect on NF‐κB activation is in progress.
Identification of Genetic Loci and Sex Differences Associated with Amyloid Burden Using the AD‐BXD Mouse Population
Authors: Charland Kevin , Kaur Harpreet , Hadad Niran , Ouellette Andrew R , O'Connell Kristen MS , Kaczorowski Catherine C. 
Published: December 2022

AbstractBackgroundIn light of the rising prevalence of both diet‐induced obesity and Alzheimer’s Disease (AD) in the developed world, the influence of a high‐fat diet (HFD) on AD progression was investigated. Beta‐amyloid 1‐42 (Aβ42), in particular, was examined as little is known about the extent to which an individual’s genetics, sex, and diet determine the onset and progression of this classic AD neuropathology.MethodAD‐BXD mice were generated by crossing female 5XFAD mice to male members of the BXD reference panel (Neuner, et al. 2019). Cortical Aβ42 levels were quantified (ELISA) from four hundred and twenty‐two mice (235 female, 187 male) across 52 AD‐BXD strains fed either a 6kcal% extruded control diet (n = 227) or 45kcal% HFD (n = 195) at 10 weeks of age until 3, 6, or 14 months old.ResultWhile a 45kcal% HFD did not alter cortical Aβ42 levels in 5XFAD mice relative to control diet, there was a main effect of genetic background (strain) and sex. Specifically, wide variation in cortical Aβ42 was observed across the AD‐BXD mouse population that was highly heritable (h2≈0.9), and females displayed greater Aβ42 levels than males. Quantitative trait locus (QTL) mapping revealed significant genetic loci associated with increased amyloid burden with aging, indicating sequence differences on chromosomes (Chr) 19 and X that may underlie the observed sex differences when age was included as covariates. Furthermore, we identified several missense mutations within our Chr 19 QTL that could explain differences in Aβ42 phenotype, and expression QTL analysis is underway to identify putative regulatory variants of cortical amyloid burden.ConclusionWe found that genetic factors, strain and sex, are key determinants of cortical amyloid burden – but not diet (environmental factor) suggesting involvement of other regulators/pathways in eliciting cognitive decline in AD‐BXD mouse population (Dunn et. al., AAIC 2021) Resolving genetic modifiers of amyloid burden located on Chr 19 and X may reveal novel targets for anti‐amyloid therapeutics and provide a possible mechanistic explanation for why females (XX) are at a higher risk for developing AD than males (XY).
Tau‐RNA complexes contribute to the pathogenesis and progression in Alzheimer’s disease and related tauopathies
Authors: Lessard Christian B , Koren John , Abisambra Jose F. F 
Published: December 2022

AbstractBackgroundRecent in vitro and in vivo data show that Tau‐RNA complexes contribute to neuronal dysfunction. However, whether these complexes appear in human tauopathy brains, and whether they are inherently toxic remains unknown. Clarifying the dynamics of tau‐RNA interactions and its relevance in disease would reveal critical and urgently needed information to determine novel therapeutic targets.MethodHuman Alzheimer’s and age‐matched non‐demented control brains were subjected to enhanced cross‐linking immunoprecipitation (eCLIP) sequencing. Amount of RNA was quantified and sequenced in each group. Cell culture experiments were used to validate eCLIP data.ResultTau associated robustly with RNA, many of which have not been previously reported. Early and late‐stage AD tau‐RNA complexes shifted from coding to non‐coding sequences. The consensus sequences that associated with tau contain numerous splice sites and start codons. RNA‐stabilizing species associated with tau in AD brains. Tau overexpression impaired RNA processing, transport, and translation in vitro.ConclusionTau‐RNA interactions, that have not been previously reported, were identified for the first time in human AD brains, and they reveal novel sequences that could be associated with disease.