bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association Between HSV‐1 and Risk of Alzheimer’s Disease Detected by a Propensity‐Score Matched Case Design
Authors: Tejeda Marlene , Farrell John , Zhu Congcong , Wetzler Lee , Lunetta Kathryn L. , Bush William S. , Martin Eden R. , Wang Li‐San , Schellenberg Gerald D. , Pericak‐Vance Margaret A. , Haines Jonathan L. , Farrer Lindsay A. , Sherva Richard 
Published: December 2023

AbstractBackgroundHerpes simplex virus 1 (HSV‐1) is a neurotropic and neuroinvasive species that can enter the brain triggering inflammation and an immune response, increasing the risk of Alzheimer disease (AD). Previously, we found a significant association between HSV‐1 and AD in whole‐exome sequencing (WES) data (OR = 3.69, P = 6.71×10−4) but not whole‐genome sequenced (WGS) data (OR = 0.92, P = 0.27) from the AD Sequencing Project (ADSP).MethodTo understand this discrepancy, and to better control for the numerous covariates and technical differences that influenced viral quantity, we created a novel algorithm using propensity score analysis (PSA) which permits analysis of observational study data comparable to a randomized controlled trial. WGS reads from 6,541 AD cases and 6,855 controls from the ADSP (including 7,395 non‐Hispanic Whites, 2,961 African Americans, and 3,040 Caribbean Hispanics) that did not align to the human genome were mapped to viral reference sequences and quantified. Propensity scores were derived for 7,619 individuals with at least one HSV‐1 read and 5,777 individuals lacking any HSV‐1 reads using a binary treatment indicator for HSV‐1 status. We applied forward stepwise regression including known confounders (APOE ε4 status, sex, age, tissue source (blood or brain), population ancestry, sequencing center, and PCR amplification) to identify other potential confounders and/or interactions and quadratic terms for creating propensity scores. We tried several matching algorithms to generate matched sets of individuals with and without HSV‐1. Utilizing the best quality matched set, we evaluated the association of AD with HSV‐1 status using a weighted generalized linear model.ResultThe final regression model included terms for the covariates mentioned above that were available for most of the original sample (5828 AD cases and 6487 controls). We found a significant association between HSV‐1 and AD (OR = 1.10, P = 0.02).ConclusionResults from WGS data confirm our previous findings obtained from WES data and support the hypothesis that HSV‐1 is associated with an increased AD risk, highlighting the utility of PSA for analyzing association of risk factors with complex disorders like AD. Further studies are needed to replicate this finding in other ancestral populations and explain the lack of association in WGS data.
Atypical Alzheimer’s disease: new insights into an overlapping spectrum between the language and visual variants
Authors: Singh Neha Atulkumar , Graff‐Radford Jonathan , Machulda Mary M. , Carlos Arenn Faye , Schwarz Christopher G. , Senjem Matthew L. , Jack Clifford R. , Lowe Val J. , Josephs Keith A , Whitwell Jennifer L 
Published: December 2023

AbstractBackgroundThe language and visual variants are two common clinical phenotypes of atypical Alzheimer’s disease (AD). There are reports of overlap between these clinical phenotypes, however, the extent and frequency of overlap, and its neuroanatomical underpinnings remain unclear.MethodEighty‐two patients with biomarker‐confirmed AD who presented with either predominant language (n = 34) or visuospatial/perceptual (n = 48) deficits were recruited by the Neurodegenerative Research Group and underwent neurological and neuropsychological testing, MRI and [18F]flortaucipir‐PET. The clinical examination included testing for simultanagnosia, Gerstmann’s syndrome, ideomotor apraxia, visuospatial‐visuoperceptual function, confrontational naming, sentence repetition and letter and animal fluency. Cut‐points for abnormality were defined for each test and used to classify the following groups: language‐pure (no visual‐function deficit), language‐plus (impaired on one visual‐function), language‐mixed (impaired on two visual‐functions), visual‐pure (no language‐function deficit), visual‐plus (impaired on one language‐function) and visual‐mixed (impaired on two language‐functions). Patterns of relative volume loss and flortaucipir uptake were assessed using SPM12.ResultOf the 82 patients, 11 (13%) were language‐pure, 16 (20%) language‐plus, 7 (8%) language‐mixed, 10 (12%) visual‐pure, 17 (21%) visual‐plus and 21 (26%) visual‐mixed, with no difference in disease duration across groups. Visual deficits in the language‐plus group consisted of mild simultanagnosia in 29%, Gerstmann’s syndrome in 24%, and mild visuospatial deficits. In the language‐mixed group 86% had simultanagnosia and 43% had Gerstmann’s syndrome, with visuospatial‐visuoperceptual deficits comparable to the visual‐pure group. Language deficits in the visual‐plus group consisted of mild anomia and reduced letter and animal fluency. The visual‐mixed group reported naming and repetition deficits, and reduced fluency, comparable to the language‐predominant groups. All three language groups showed left temporal volume loss and flortaucipir uptake, with greater involvement of the parieto‐occipital and frontal lobes in language‐plus and language‐mixed groups. All three visual groups showed occipital volume loss and flortaucipir uptake, with greater involvement of the parieto‐temporal and frontal lobes in visual‐plus and visual‐mixed groups.ConclusionOnly 25% of our cohort showed a pure language or visual presentation, highlighting the high frequency of syndromic overlap in atypical AD and the diagnostic challenge of categorical phenotyping. Syndromic overlap was associated with neuroanatomical overlap and more widespread patterns of atrophy and tau deposition.
Evaluation of biomarker, behavioral, and immunostimulatory profiles following treatment with Class C CpG ODN in a non‐human primate model of sporadic CAA
Authors: Patel Akash G , Karimi Sohail , Nehete Pramod N , Nehete Bharti P , Murray Sean , Debure Ludovic , Soliman Muhammad T , Szabo Jakub , Levine Dafna T , Williams Lawrence E , Gray Stanton B , Hopkins William D , Wisniewski Thomas , Scholtzova Henrieta 
Published: December 2023

AbstractBackgroundInnate immunomodulation has shown potential to be an effective therapeutic approach in ameliorating pathological features of Alzheimer’s Disease (AD). Our recently published study showed a reduction in cognitive deficits and AD‐related pathology in a squirrel monkey model (SQM) of sporadic cerebral amyloid angiopathy (CAA) following treatment with TLR9 agonist, Class B CpG ODN. Subsequently, we commenced a chronic treatment study evaluating the efficacy and safety of Class C CpG ODN in geriatric SQMs. Here, we further explore the efficacy of Class C CpG ODN by evaluating fluid biomarkers and implementing automated cognitive tests. Moreover, we assess the immunostimulatory profiles induced by Class B and Class C CpG ODNs using RNA‐Seq genome‐wide transcriptome analysis of SQM PBMCs.MethodGeriatric SQMs received monthly injections of CpG ODN‐C or saline (VEH) over three years. Fluid biomarkers for cerebrovascular dysfunction, neurodegeneration, and neuroinflammation were assessed by Luminex and SIMOA. Touchscreen‐based Automated Cognitive Testing System (ACTS) was applied among socially living SQMs to assess behavioral changes. RNA‐Seq analyses were performed using PBMCs isolated 24hrs following CpG ODN‐B and ‐C administrations in a separate cohort of elderly SQMs.ResultOur initial experiments confirmed the utility of SQMs for investigating plasma age‐associated neurodegeneration biomarkers, including NfL, GFAP, and neurogranin. Preliminary evaluation of cerebrovascular dysfunction‐related plasma biomarkers, such as MMPs, albumin index, bFGF, and VCAM, revealed no differences between our treatment groups at earlier time points. Although not significant, higher levels of plasma sTREM2 and YKL‐40 were observed in VEH monkeys compared to CpG ODN‐treated group. Concluding assessments will be performed in plasma collected at the end of the treatment period. Characterization of additional plasma/CSF biomarkers related to AD/neurodegeneration is underway. ACTS‐based two‐choice discrimination learning task revealed that CpG ODN‐treated group performed with a greater correct response rate than the VEH group. As expected, RNA‐Seq analyses of SQM PBMCs revealed significantly altered pathways, including Th1/Th2, TLR signaling, phagocytosis, chemokine signaling, interferon signaling, and senescence pathways, in addition to pathways involved in infiltration, activation, and recruitment of various immune cells.ConclusionThe study highlights the potential of the SQM model for future translational research on CAA/AD and for advancing innovative therapeutic interventions.
Does the Timing of Alzheimer’s Disease vary by Severity of Intellectual Disability in Down Syndrome?
Authors: Fleming Victoria L , Hartley Sigan , Handen Benjamin L. , Tudorascu Dana , Lee Laise , Krinsky‐McHale Sharon J , Hom Christy , Cohen Annie , Schworer Emily K , Peven Jamie C , Zammit Matthew D , Klunk William E , Laymon Charles M , Zaman Shahid , Ances Beau , Christian Bradley T. ,   the Alzheimer’s Biomarker Consortium‐Down Syndrome
Published: December 2023

AbstractBackgroundTrisomy 21 causes Down syndrome (DS) and is a recognized cause of Alzheimer’s disease (AD). The triplication of the amyloid precursor protein gene leads to an overexpression of amyloid‐beta (Aβ), which accumulates into extracellular plaques, followed by intracellular neurofibrillary tau tangles (Lott & Head, 2019). However, variability in the age of AD onset in DS spans 25+ years (Iulita et al., 2022). As the DS field moves to AD clinical trials, it is important to identify factors related to this variability, such as premorbid severity of intellectual disability (ID). We compared the age‐trajectory of the AD biomarkers Aβ and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type (full, mosaic, translocation) and APOE statusMethodAnalyses involved 361 adults with DS (M = 45.22 years, SD = 9.92) from the Alzheimer’s Biomarkers Consortium‐Down Syndrome. Participants completed measures of memory, mental status, and visuospatial ability. Premorbid ID level was recorded. PET was acquired using [11C] PiB for Aβ, and [18F] AV‐1451 for tau in 162 participants. Aβ was quantified using the centiloid method and tau was quantified as SUVR (reference: cerebellar cortex) in a composite region determined as the volume‐weighted average of select FreeSurfer 5.3, T1 MR‐based components.ResultsGeneral linear models controlling for site, age, trisomy type and APOE status indicated no significant effect of premorbid ID level by age on the cognitive outcomes (Figure 1a‐e). There was not a significant effect of premorbid ID by age on PET Aβ or on tau PET (Figure 2a‐b). There was not a significant difference in age of those with mild cognitive impairment‐DS (MCI‐DS) or dementia by premorbid ID level (Figure 3).ConclusionThis study adds to the characterization of the time course of AD pathology and clinical symptomology in DS. Findings provide robust evidence of a similar time course in AD trajectory across severity of ID, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials. Premorbid IQ may have little effect on AD biomarkers in DS in contrast to findings in neurotypical populations.
The Contribution of Hyperhomocysteinemia to Aβ‐Induced Endothelial Cell Apoptosis, Blood Brain Barrier Dysfunction, and Angiogenic Deficits
Authors: Carey Ashley M , Parodi‐Rullan Rebecca M , Fossati Silvia 
Published: December 2023

AbstractBackgroundCerebrovascular dysfunction has been implicated as a major contributor to Alzheimer’s Disease (AD) pathology, with particularly endothelial cell (EC) stress promoting the focal ischemia, cerebral blood flow impairments, and blood brain barrier (BBB) permeability that are pathologically characteristic in AD. Recent evidence has emerged suggesting a link between cardiovascular (CV) diseases and AD pathology, particularly showing that CV/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy), contribute to AD pathology and risk. Despite this, the underlying molecular mechanisms for this interaction remain unclear. Previously, our lab has demonstrated that amyloid beta (Aβ), particularly Aβ40‐Q22 (the vasculotropic Dutch mutant), promotes TRAIL death receptor (DR)‐mediated apoptosis, barrier permeability, and angiogenic impairment within human cerebral ECs. We tested the hypothesis that Hhcy exacerbates Aβ‐induced cerebral EC TRAIL DR‐mediated apoptosis, barrier dysfunction, and angiogenesis defects.MethodHuman cerebral microvascular ECs (HCMECs) were challenged with AβQ22 and/or homocysteine (Hcy). Apoptotic mediator expression, caspase activation, cytochrome c release, and DNA fragmentation were measured to assess apoptosis. Junction protein expression, trans‐endothelial‐electrical‐resistance (TEER), and inflammatory mediators were measured to assess EC barrier integrity. Angiogenesis inhibition and activation (cytokine expression, pVEGFR2Y1175 expression/localization, VEGF‐A ELISA) assays were utilized to measure EC angiogenic capability and wound healing and actin polymerization assays were utilized to measure EC wound healing ability.ResultCombined challenge of ECs with AβQ22 and Hcy potentiated increases in TRAIL DR‐related apoptotic mediators' expression, caspase activity, cytochrome c release, and DNA fragmentation and potentiated decreases in anti‐apoptotic mediators’ expression at differential timepoints. Treatment of ECs with AβQ22 and Hcy additively decreased TEER and, at certain timepoints, potentiated decreased junction protein expression, increased inflammatory mediator expression, and phosphorylated BBB protein expression. Combined treatment of ECs with AβQ22 and Hcy additively decreased angiogenesis progression, angiogenesis‐stimulating cytokine expression, wound healing capability, and actin polymerization levels. Additionally, Hcy decreased HCMEC soluble VEGF‐A levels.ConclusionThe presence of high Hcy exacerbates Aβ induced‐EC apoptosis, barrier dysfunction, and angiogenic impairment. This study revealed several of the specific molecular mechanism through which amyloidosis and CV risk factors may additively act to produce EC dysfunction and death in AD.
The Sustainable Personalised Interventions for Cognition, Care, and Engagement (SPICE) Program: A twelve week reablement intervention for people with dementia and carers
Authors: D'Cunha Nathan M , Bennett Michelle , Mitterfellner Rachael , Brennan Rosalie , Wiseman Lara , Isbel Stephen , Bail Kasia , Barrett Louise , Rutherford Kathleen , Huang Ian , Gibson Diane 
Published: December 2023

AbstractBackgroundThere is a need for integrated and effective reablement programs to promote the quality of life of people with dementia and their carers.MethodThe Sustainable Personalised Interventions for Cognition, Care, and Engagement (SPICE) Program is currently being evaluated in Canberra, Australia. SPICE is a multicomponent active therapeutic intervention delivered by allied health professionals over twelve weeks. The five components are: 1) cognitive stimulation therapy (CST); 2) carer education, support and capacity building; 3) physical activity; 4) Care of People with dementia in their Environments (COPE) program; and 5) dietary assessment and advice. Six people with dementia and their six carers participate in a small group twice per week for the CST, carer, and physical activity components, while COPE and dietary assessment and advice are completed as a dyad. Pre‐ and post‐intervention outcome measures on quality of life, neuropsychiatric symptoms, cognitive function, and physical function are being collected, in addition to a program evaluation interview. After four groups have completed the protocol, the SPICE waiting‐list pilot trial will finish data collection in early 2024. Here we report on the first group to complete the program.ResultAttendance to the in‐person components of the program were 94% for people with dementia and 92% for carers. All participants completed the COPE program, and compliance with the dietary appointments was 94%. Quantitative outcome measures suggest benefits, but inferences cannot be drawn due to small sample size. Both people with dementia and carers reported high program satisfaction and perceived benefits, supporting the feasibility of the intervention. The program was rewarding for all participants, and carers felt the strategies and lessons learned had immediate benefits. The social aspects, inclusiveness, and group cohesiveness were key drivers of their satisfaction with the program.ConclusionThe results from the first group to complete the SPICE program shows that an intensive, multicomponent active therapeutic program is feasible and considered valuable for people with dementia and their carers. Findings from the pilot trial are required to confirm the results from the first group to potentially support a randomised controlled trial.
Regulation of tau‐phosphorylation and other Alzheimer’s disease‐associated phenotypes in REST conditional knockout mice
Authors: Tomás Mariana Santos Vidal , Benestad Johan Lafond , Keime Céline , Buckley Noel , Beglopoulos Vassilios 
Published: December 2023

AbstractBackgroundThe RE1‐silencing transcription factor (REST) has been strongly implicated in Alzheimer’s disease (AD), healthy ageing and longevity, and there is a clear need to understand better the exact mechanisms that mediate that role. Here we study the role of REST in a series of AD‐related phenotypes in the mouse brain.MethodWe have previously generated a conditional knockout (cKO) mouse model, lacking Rest in the postnatal forebrain. Immunohistochemistry and Western blot were used to evaluate the effect of REST on neuronal, synaptic and astrocytic markers and key proteins involved in tau phosphorylation. Furthermore, RNA‐Seq (including gene ontology, gene set enrichment and protein‐protein interaction analyses) was used to study the effect of REST inactivation at the transcriptome.ResultQuantification of labelled neuronal nuclei on brain sections revealed no major neurodegeneration in Rest cKO mice. However, mild phenotypes of dendritic degeneration and as astrocytic activation were suggested. The levels of an important postsynaptic protein, PSD‐95, appeared reduced in the brain of Rest cKO mice. Interestingly, levels of proteins involved in the phosphorylation of tau, such as glycogen synthase kinase‐3beta (GSK‐3β) and p35/p25 (activators of CDK5), as well as the levels of phosphorylated tau, were found increased in the brain of Rest cKO mice. RNA‐seq results suggest that postnatal inactivation of REST down‐regulates synaptic activity and neuronal pathways, while triggering an immune response.ConclusionOur results suggest dysregulation of one of the biochemical hallmarks of Alzheimer’s disease, tau phosphorylation, and of synaptic and neuronal pathways, as well as an immune response, when REST is inactivated in the adult mouse brain.
Psychometric Characteristics of the Novel Subjective Cognitive Changes Questionnaire (SCC‐Q) in Older Adults at Risk of Dementia
Authors: Zuntychová Terezie , Vyhnalek Martin , Matuskova Veronika , Krejčová Svatava , Laczó Jan , Hort Jakub , Markova Hana 
Published: December 2023

AbstractBackgroundSubjective cognitive complaints (SCC) in the elderly may represent an early cognitive marker of Alzheimer’s disease (AD). Currently, there is no recommended gold standard for evaluating SCC. In addition, available questionnaires were originally developed to identify individuals at later stages of AD. Based on previous research, we constructed the Subjective Cognitive Changes Questionnaire (SCC‐Q), which includes items potentially sensitive to early cognitive decline. The study aimed to analyse reliability of the individual items and construct and convergent validity of the SCC‐Q.MethodA total of 211 non‐demented participants over the age of 55 from the Czech Brain Aging Study (CBAS) underwent a comprehensive neuropsychological examination, based on which they were classified into two groups: patients with amnestic mild cognitive impairment (n = 88) and those with subjective cognitive decline (SCD) (n = 88). Further, we included cognitively healthy volunteers without SCC (n = 35). All participants completed the novel 26‐item SCC‐Q in which they evaluated change in specific cognitive abilities during the last 5 years on a 5‐point Likert scale. The structure of the SCC‐Q was explored using the principal component analysis (PCA) with varimax rotation. To analyse associations between the components and cognitive performance (convergent validity), non‐parametric partial rank correlations controlled for sex, age and education were performed. Cognitive performance was expressed as composite z‐scores representing memory, attention and working memory, language, executive, and visuospatial function.ResultItem analysis showed that all included items were highly reliable (McDonald’s Ω > 0.9, Cronbach’s α > 0.9). Using the PCA, four components explaining 57.6% of the variance were identified. Two of them were significantly associated with memory, attention and working memory, and executive or visuospatial function, respectively (all ps ≤ 0.048). The component more closely associated with cognitive domains includes items related to spatial orientation changes.ConclusionThe SCC‐Q has the potential to become a valuable method for clinical practice in identifying individuals at risk of developing cognitive deficits. Further analyses are needed to confirm its validity.