bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Clu‐rs2279590_h2kb variant increases axonal and neuritic damage in 5xFAD mice
Authors: Milinkeviciute Giedre , Tran Katelynn , Tran Kristine M , Phan Jimmy , Da Cunha Celia , Javonillo Dominic I , Neumann Jonathan , Alcantara Joshua A , Walker Amber , Kawauchi Shimako , Tenner Andrea J , LaFerla Frank , MacGregor Grant R , Green Kim N 
Published: December 2022

AbstractBackgroundGenome‐Wide Association Studies (GWAS) implicate clusterin (CLU, also known as apolipoprotein J) as a risk factor for late‐onset Alzheimer's disease (LOAD), with elevated expression of CLU being associated with increased risk of LOAD. The rs2279590 SNP risk allele is located within a putative enhancer element in intron 7 of CLU. Indeed, deletion of a 115bp region including this SNP reduces expression of CLU and neighboring genes (EPHX2 and PTK2B) on Chromosome 8. The region surrounding rs2279590 is poorly conserved within the mouse genome. Consequently, to model the effect of the rs2279590 risk allele on development of AD‐related pathology in mice we developed mice with a partially humanized allele of Clu.MethodCRISPR was used to substitute a 2kb region of human CLU (intron 7 to exon 9) containing the enhancer region and the GWAS AD‐risk rs2279590 SNP variant for the orthologous region of Clu within the C57BL/6J mouse genome. Clu‐rs2279590_h2kb mice were crossed with 5xFAD mice and aged to 4 months to study the effects of the partially humanized Clu allele on development of AD‐related pathologies in 5xFAD mice. Coronal brain sections were immunolabeled to visualize dense‐core plaques (Thioflavin‐S), microglia (IBA1), reactive astrocytes (GFAP), axonal and neuritic damage (neurofilament light chain (NfL) and LAMP1, respectively). Confocal images of hippocampal and cortical regions were analyzed using Imaris software. In addition, Aβ and NfL levels were quantified in the brain tissue and plasma NfL measured using meso scale discovery (MSD) technology.ResultFour‐month‐old 5xFAD hemizygous, Clu‐rs2279590_h2kb homozygous mice had reduced microglial density and volume compared to 5xFAD hemizygous controls. No change was found in astrocyte density or reactivity. Despite comparable plaque load between 5xFAD and 5xFAD x Clu‐rs2279590_h2kb mice, neuritic and axonal damage was elevated in the brain of 5xFAD x Clu‐rs2279590_h2kb mice compared to 5xFAD, while plasma NfL level did not differ. Insoluble Aβ42 levels mirrored plaque density.ConclusionDespite the lack of impact on Aβ plaque deposition, and moderate influence on gliosis, four‐month‐old 5xFAD hemizygous, Clu‐rs2279590_h2kb homozygous mice display elevated axonal and neuritic damage compared to 5xFAD hemizygous controls.
Association between sub‐classified white matter hyperintensities (WMH) volume and and cognitive function in patients with Alzheimer`s disease
Authors: Na Min Chull , Yang Hyun‐ju , Park Joon Hyuk 
Published: December 2022

AbstractBackgroundWMH in MRI are common among the elderly. WMH are associated with increased cognitive impairment and risk of Alzheimer`s disease (AD). Although WMH contribute to AD pathology, their clinical implications are not fully understood. This study aimed to assess whether WMH predict AD and investigate the association between WMH (including subclassified WMH volume) and cognitive function in AD.MethodThis study enrolled 171 patients with AD. All participants underwent clinical evaluations including brain MRI study and neuropsychological tests using the CERAD‐K neuropsychological assessment battery. In addition, Charlson comorbidity index, the Korean version of the Geriatric Depression Scale short from were administered. WMH volume was calculated using automated quantification method with SPM and MATLAB image processing software. WMH were classified according to the distance from the ventricular surface. WMH located in juxtaventricular areas, within 3 mm from the ventricular surface, were classified as juxtaventricular with matter hyperintensities (JVWMH). WMH located within 3–13 mm or farther than 13 mm from the ventricular surface were classified as periventricular white matter hyperintensities (PVWMH) or deep white matter hyperintensities (DWMH), respectively. WMH volume data were right‐skewed. Consequently, WMH volume data were logarithmic transformed.ResultThe AD group had a higher mean WMH volume(20.7 ± 18.2 ml). Multivariate linear regression analysis showed that total WMH volume in AD was associated with poor performance in categorical verbal fluency test (p = 0.008) and word list memory test (p = 0.023). JVWMH volume in AD was associated with poor performance on categorical verbal fluency test (p = 0.013) and digit span test forward (p = 0.037). PVWMH volume in AD was associated with poor performance on categorical verbal fluency test (p = 0.011) and word list memory test (p = 0.021), whereas DWMH volume showed no association with cognitive dysfunction in AD.ConclusionTotal WMH, JVWMH and PVWMH were associated specifically with executive function, immediate memory, and working memory, independently of hippocampal atrophy in AD. WMH were associated with AD risk and cognitive dysfunction differentially according to the distance from the ventricular surface.
Cognitive functioning and simulated driving in older adults with and without cognitive impairment
Authors: Brush David M. , Persad Carol , Song Woojin , Jansohn Eva , Giordani Bruno 
Published: December 2022

AbstractBackgroundAge‐related changes in cognitive functions affect complex task engagement such as driving. Studies have demonstrated high occurrences of driving errors and crashes among older adults, particularly those with mild cognitive impairment (MCI). We have previously demonstrated that fatigue contributes to detriments in driving ability, especially among MCI, and that attention‐maintenance tasks (AMT) improve older cognitively normal (OCN) but not MCI performance. This study considers which cognitive deficits predict driving performance across AMT conditions.MethodsParticipants included 34 OCN and 21 MCI adults age 60+ years diagnosed through consensus conference, who completed tests of memory (HVLT‐R delayed recall), executive functioning (Trail Making Test B; TMB), working memory (CogState One Back Test, ONB), simple reaction time (CogState Detection Test, DET), and choice reaction time (CogState Identification Test, IDN). Computerized driving scenarios were presented on a 45” flat screen monitor, which included a 50‐minute simulated drive designed to induce fatigue, followed by four 10‐minute sessions alternating between driving with and without AMT. Lane position, velocity, lane and velocity variability, and driving errors (e.g., leaving the road, crossing midline) were compared across 10‐minute driving segments. Cognitive measures and diagnosis were used to predict driving performance.ResultsParticipants with MCI 1) maintained significantly slower average speed, 2) demonstrated higher variability in lane‐keeping, and 3) had greater velocity variability, only in the non‐AMT condition. OCN participants performed significantly better on all cognitive measures, except DET. Linear regressions showed that TMB, alone, predicted average velocity during the AMT driving condition with no significant predictors for the non‐AMT. Velocity variability during the non‐AMT driving condition was predicted by the main effect of Diagnosis, TMBxDiagnosis, and ONBxDiagnosis interactions. TMB and HVLT‐R predicted velocity variability during the AMT condition. Lane variability during both driving conditions was predicted by DETxDiagnosis and IDNxDiagnosis.ConclusionsPerformance on TMB and its interactions are predominantly important predictors for velocity‐related driving conditions. Reaction time decrements among those with MCI predict lane variability. This suggests that executive functions are particularly needed in maintaining velocity, while monitoring is critical for maintaining lane position. Our findings demonstrate that higher cognitive burden likely accentuates driving difficulty, especially in MCI.
Fluctuations in reaction time performance as a marker of incipient amyloid‐related cognitive decline in clinically unimpaired older adults.
Authors: Jutten Roos J. , Rentz Dorene M. , Amariglio Rebecca E. , Properzi Michael J , Maruff Paul , Johnson Keith A. , Sperling Reisa A. , Papp Kathryn V. 
Published: December 2022

AbstractBackgroundAccumulating evidence suggests that fluctuations in reaction time (RT) performance across assessments, usually defined by intraindividual variability in RT (IIV‐RT), are associated with cognitive impairment and decreased neurobiological integrity. Computerized cognitive testing facilitates the study of IIV‐RT, allowing for precise and frequent RT measurements in remote settings. We investigated whether quantifying IIV‐RT over months on various remotely administered computerized RT tasks could aid in the detection of emerging cognitively decline in initially clinically unimpaired (CU) older adults with elevated Alzheimer’s disease (AD) biomarkers.MethodN = 114 CU individuals (age 77.6±5.1, 61% female, MMSE 29±1.2, n = 33 amyloid‐positive as measured using PiB‐PET imaging) from the Harvard Aging Brain Study (HABS) completed the self‐administered Computerized Cognitive Composite (C3) monthly at‐home on an iPad for up to one year (11.7±3.2 C3 assessments). Baseline C3 assessment coincided with participants’ HABS in‐clinic visit including Preclinical Alzheimer’s Cognitive Composite (PACC) testing, and participants had 1.8±1.2 subsequent years follow‐up PACC testing available. The C3 includes two basic RT tasks (Detection [DET]; Identification [IDN]), and two complex RT tasks (One Card Learning [OCL]; One Back [ONB]) that also require working memory skills. IIV‐RT measures were derived for each task by computing the intraindividual standard deviation between mean RTs across all monthly visits for each participant. Subsequently, IDN and DET IIV‐RT were combined into a basic IIV‐RT composite, and OCL and ONB IIV‐RT into a complex IIV‐RT composite. Linear mixed models were used to investigate the association between both IIV‐RT composites and PACC decline adjusting for covariates (age, sex, education, amyloid status (+/‐)) and their interaction with time.ResultGreater IIV‐RT on complex RT tasks was associated with steeper decline on the PACC (Time*IIV‐RT ß = ‐1.3, 95%CI[‐2.57 – ‐0.03],p = .04) (Figure 1), which was driven by amyloid‐positive individuals (Time*Amyloid[+]*IIV‐RT ß = ‐3.52, 95%CI[‐6.43 – ‐0.61],p = .02) (Figure 2). In contrast, greater IIV‐RT on basic RT tasks was only associated with baseline PACC performance (IIV‐RT ß = ‐4.29, 95%CI[‐7.32 – ‐1.26],p = .007) but not with PACC change over time.ConclusionOur findings suggest that fluctuations in RT performance over monthly‐repeated complex RT tasks may reflect evidence of early amyloid‐related neurodegeneration and provide a marker of incipient cognitive decline in preclinical AD.
Transcriptome and Translatome Regulation of Pathogenesis in Alzheimer's Disease Model Mice
Authors: Eastman Guillermo , Sharlow Elizabeth R , Lazo John S , Sotelo‐Silveira José R , Bloom George S 
Published: December 2022

AbstractBackgroundDefining cellular mechanisms that drive Alzheimer's disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre‐symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD.MethodTo identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2‐/‐) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA‐Seq and Ribo‐Seq (ribosome profiling). Identical starting pools of bulk RNA were used for RNA‐Seq and Ribo‐Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels to disentangle genes specifically regulated at the translation level. Regulated genes were functionally evaluated by gene ontology tools.ResultCompared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to APP metabolism associated with neurotoxicity and neuroprotection.ConclusionThis work represents the first genome‐wide study of brain translatome regulation in animal models of AD, and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain.
Network medicine‐based multimodal omics analytic framework identifies immunometabolism endophenotypes underlying sex difference of Alzheimer’s disease
Authors: Cheng Feixiong , Hou Yuan , Zhou Yadi , Xu Jielin , Bekris Lynn M. , Lathia Justin D. , Pieper Andrew A. , Leverenz James B. , Cummings Jeffrey 
Published: December 2022

AbstractBackgroundAlthough Alzheimer’s disease (AD) is sexually dimorphic in prevalence, incidence, symptomology, and neuropathology, the molecular mechanisms underlying these sex differences are not well understood.MethodWe presented a multimodal omics analytic framework to inspect sex differences in susceptibility to inflammation, cellular metabolism, and disease pathophysiology of AD. Specifically, we investigated the interplay between cellular metabolism and immune responses, termed the “immunometabolism endophenotype,” by unique integration of transcriptomics (single‐cell/nuclei RNA‐seq), proteomics (inflammatory biomarker expression), and metabolomics from the AD knowledge portal, the Alzheimer’s Disease Metabolomics Consortium, and the Cleveland Alzheimer's Disease Research Center (CADRC).ResultWe identified sex‐specific, elevated pro‐inflammatory gene/protein expression in blood (including myeloid‐derived suppressor cells [MDSCs]) and cerebrospinal fluid of phenotypically characterized subjects by AD biomarkers of Amyloid deposition, pathologic Tau, and Neurodegeneration (ATN). We also identified sex‐specific microglial gene signatures in AD patient brains from single‐cell/nuclei RNA‐seq (sc/snRNA‐seq) data analyses. We further found that women lost gene expression of innate and adaptive pathways (i.e., NF‐kappa B signaling, Toll‐like receptor signaling, and HIF signaling) in microglia compared to men with amyloid and tau neuropathology. However, women have elevated expression of innate and adaptive pathways (i.e., IL‐17 signaling and antigen processing and presentation) in excitatory neurons compared to men with tau neuropathology. Integrative sc/snRNA‐seq data analyses showed sex‐specific ligand‐receptor interactions among microglia, astrocytes, and neurons. We also found that women with AD have elevated metabolites of glycerophospholipids and sphingolipids compared to men with AD. A microglia‐specific male‐biased metabolite‐enzyme network is enriched in immune pathways of Type I and II IFN signaling and fructose, mannose, and HIF‐1 metabolic pathways. By contrast, the female‐biased metabolite‐enzyme network is significantly enriched in glycerophospholipids. These findings were further validated by the female‐biased expression of pro‐inflammatory cytokines (i.e., IFNγ, GM‐CSF, IL‐8, and IL‐15) from ATN‐characterized cohorts from our CADRC.ConclusionThis study establishes proof‐of‐concept of sex‐specific immune responses, cellular metabolism, and microglial immunometabolism underlying sex differences in AD.
Blood‐brain barrier dysfunction is associated with A/T/N biomarkers and cognition in the aging brain
Authors: Tabdili Yasmine , Belmonte Krystal Courtney D , Brathaban Nivetha , Iorio Emma , Park Ryan , VandeBunte Anna M , Casaletto Kaitlin B , Kramer Joel H. , Akassoglou Katerina , Elahi Fanny M 
Published: December 2022

AbstractBackgroundAge‐associated dysfunction of the blood‐brain barrier results in increased non‐specific permeability of the barrier and “leakage” of blood proteins into the central nervous system (CNS). Over the past decade, fibrinogen, the blood coagulation factor, has been demonstrated to be necessary and sufficient for triggering brain dysfunction and degeneration in model systems and is now serving as a robust biomarker of pathological BBB leakage. Importantly, BBB leakage may be an early pathological feature of the aging brain, instigating the development of neurodegenerative disease pathologies.MethodWe used colorimetric enzyme‐linked immunosorbent and chemiluminescence immunoassays to quantify CSF concentrations of fibrinogen and A/T/N AD biomarkers in a cohort of 84 deeply phenotyped functionally normal older adults and built linear models to test the associations of fibrinogen (BBB leakage) with A/T/N biomarkers and cognition (processing speed). The “N” biomarkers included three synaptic proteins (neurogranin, SNAP25, and GAP43). We set significance at α=0.05.ResultWe found strong, significant associations of BBB leakage (CSF fibrinogen levels) with all three synaptic proteins, as well as tau and p‐tau. With respect to Aβ, we found a significant association of BBB leakage with Aβ 1‐40, which is the peptide most strongly associated with cerebral amyloid angiopathy, an aging and AD‐related microangiopathy of the CNS. Importantly, we also found a significant association with processing speed–a highly relevant cognitive measure for the aging brain.ConclusionIn this work, we demonstrate associations between BBB leakage and levels of AD A/T/N biomarkers in the aging brain. Although correlation is not causation, prior mechanistic studies in mice have demonstrated that fibrinogen leakage into the CNS triggers and propagates degenerative brain pathologies, relevant to AD. This is the first in vivo translation and extension of these pathways to the aging brain. Our reported findings have implications for therapeutics, given great interest in development of therapies for BBB leakage in neurodegenerative disorders. This process may start early in the aging brain and therefore trials may consider the inclusion of preclinical disease stages.
Loneliness predicts stronger negative associations between cerebrovascular, but not Alzheimer’s, pathology and cognition
Authors: Lao Patrick J. , Young Christina B , Andrews Ryan M , Gibbons Laura E , Kraal A.Zarina , Turney Indira C , Deters Kacie D , Trelle Alexandra N , Fox‐Fuller Joshua T. , Minto Lex , Seblova Dominika , Mukherjee Shubhabrata , Dotson Vonetta M , Manly Jennifer J , Zahodne Laura B. 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) and cerebrovascular disease are the two most common pathologies underlying dementia. Loneliness is associated with faster cognitive decline and greater AD risk independent of pathology. Risk reduction efforts would benefit from knowing whether loneliness exacerbates the cognitive impact of pathology. Our objective was to characterize the interaction between loneliness and AD or cerebrovascular pathology on cognitive performance.MethodsParticipants with neuropathological data were drawn from the Religious Orders Study, the Memory and Aging Project, and the Minority Aging Research Study (Table 1). Loneliness was assessed with a modified version of the de Jong‐Gierveld Loneliness Scale. Amyloid and tau pathology were assessed jointly with the NIA‐Reagan scale as high/intermediate likelihood or low likelihood/no AD. Chronic infarcts and chronic microinfarcts were each assessed as present or not present. Composite domain scores for episodic memory, working memory, semantic memory, perceptual speed, and perceptual orientation were obtained from the study visit proximal to death. Separate general linear models were run for each domain and each pathology, including an interaction between loneliness and pathology and adjusting for covariates.ResultsGreater loneliness was associated with older age and lower education, and loneliness was greater in men compared to women, but not different by race or APOE‐ε4 (2). Loneliness was not associated with AD or cerebrovascular pathology (Table 3). Greater loneliness was independently associated with lower cognitive scores in all domains. Greater pathology was independently associated with lower episodic memory and semantic memory scores, while cerebrovascular disease was not independently associated with cognitive scores. We additionally found that negative associations between microinfarcts and cognitive scores in working memory, semantic memory, and perceptual orientation were stronger among individuals with greater (Table 4).ConclusionsNegative associations between loneliness and cognition are apparent across domains and independent of pathology. While loneliness does not appear to be related to AD or cerebrovascular pathology directly, it may increase susceptibility to cognitive impairment due to microinfarcts. Social support‐based interventions may benefit optimal brain aging, particularly in older adults exposed to greater loneliness.
Spatial dysregulation of Rho GTPases in Alzheimer’s Disease brain in human and in transgenic mouse model
Authors: Akhtar Shayan Nik , Zhu Yi , Lu Qun 
Published: December 2022

AbstractBackgroundAlzheimer disease (AD) is histopathologically characterized by brain accumulation of amyloid plaques, neurofibrillary tangle formation, and loss of synapses. The small GTPases of Rho family such as RhoA, Rac1 and Cdc42 play an important role in neural plasticity by regulating synaptic actin and spine dynamics. However, the functions of these proteins in AD are paradoxical. To understand their contributions in AD pathogenesis, it is important to investigate the relationship between the expression of Rho GTPases and their functional states in signaling.MethodWe characterized the spatial dysregulation of Rho GTPases in human AD brains and that of aged Triple Transgenic (3xTg‐AD) mouse model carrying mutations in amyloid precursor protein, tau protein, and presenilin. For human brains, the paraffin‐embedded tissues were collected from age and gender matched AD and Non‐Dementia (ND) patients. Phosphorylated Rho GTPase antibodies were used as signaling indicators for immunofluorescence microscopyResultWe observed altered phospho‐RhoA (S188) and phospho‐Rac/Cdc42(S71) expression and distribution in human, wild type (WT), and 3xTg‐AD mouse brains. In the CA3 region and dentate gyrus (DG), pRac/Cdc42 immunostaining showed decreased punctate staining in WT compared to 3xTg‐AD mice. For CA3 pRhoA immunostaining scored a slightly higher level of expression in WT compared to 3xTg‐AD. In the CA2 region, pRac/Cdc42 immunostaining was perinuclear in WT and diffused in 3xTg‐AD, whereas the pRhoA immunostaining pattern was similar between WT and 3xTg‐AD. In the CA1 region, pRac/Cdc42 immunostaining showed perinuclear as well as dendritic localization in WT and 3xTg‐AD, while pRhoA immunostaining between WT and 3xTg‐AD was similar. In human brains,there was no significant difference in pRhoA in cortex between ND and AD whereas pRac/Cdc42 was slightly reduced in AD cortex. However, while Rac signaling was reduced, Cdc42 signaling was increased in ND compared to AD cortex. On the other hand, Rac signaling is decreased in ND DG compared to AD whereas the differences in Cdc42 signaling in DG were not significant.ConclusionSmall GTPases of Rho family are differentially dysregulated in expression, distribution, and functional states in different areas of the brain in AD patients as well as in AD mouse brains