bluuebunny/crossref_metadata_2025_split huggingface dataset:
Social engagement and the risk of incident dementia: the Atherosclerosis Risk in Communities study
Authors: Groechel Renée C. , Liu Albert C. , Lutsey Pamela L. , Palta Priya , Kucharska‐Newton Anna M. , Koton Silvia , Sharrett A. Richey , Gross Alden L. , Walker Keenan A. , Gottesman Rebecca F. 
Published: December 2023

AbstractBackgroundStrong psychosocial health has been linked to preserved cognition and functional independence in older adults. Associations between late‐life psychosocial health and dementia risk have been established in older adults, but it remains less clear how one’s social interactions in mid‐life may relate to dementia risk in late life. We hypothesized that social engagement in mid‐life will be negatively associated with the risk of dementia in late‐life.MethodWe included data from 13,216 dementia‐free participants at midlife (mean age: 57.0 years, SD: 5.7 years, 54.9% female, 23.8% Black) from the Atherosclerosis Risk in Communities (ARIC) cohort study. Social support and isolation were assessed via interviewer‐administered questionnaires (visit 2: 1990‐1992). Based upon categorization of both factors, participants were classified as having high, intermediate, or low mid‐life social engagement. Incident dementia cases were identified from visit 2 through December 31, 2019 with ongoing surveillance (e.g., in‐person neurocognitive testing, informant interviews, and hospitalization codes). Primary analyses used Cox proportional hazards regression models and were adjusted for demographics, APOE ε4, occupational/marital status, depressive symptoms, and vascular risk factors measured at visit 2. Secondary analyses examined whether sex and/or race modified the association between mid‐life social engagement and dementia risk with formal tests for interaction.ResultAmong 13,261 participants, 2,555 developed dementia (median follow‐up: 23.7 years). Participants with high (hazard ratio (HR): 0.77, 95% CI: 0.68 ‐ 0.86) or intermediate social engagement (HR: 0.84, 95% CI: 0.74 – 0.95) in mid‐life had a lower risk for developing dementia, compared to participants with low social engagement in mid‐life (Figure 1, Table 1). Sex modified this effect (p‐value for interaction = 0.042) whereas race did not. In males, only those with high social engagement in mid‐life had a lower risk of dementia; the association between males with intermediate social engagement in mid‐life and dementia risk was not significant (Table 2).ConclusionGreater social engagement in mid‐life is associated with a lower risk of dementia. This finding provides further evidence that mid‐life may be a critical time window for dementia prevention. Longitudinal studies evaluating the mechanisms by which psychosocial factors modify the likelihood of incident dementia are needed.
ApoE and immune system in the pathogenesis of tau‐mediated neurodegeneration
Authors: Chen Xiaoying 
Published: December 2023

AbstractBackgroundExtracellular amyloid‐β (Aβ) deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles (NFT) are two of the characteristic hallmarks in Alzheimer’s disease (AD). The regional progression of brain atrophy in AD highly correlates with tau accumulation but not amyloid deposition and the mechanisms of tau‐mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. To date, little is known about the extent or role of the adaptive immune response and their interaction with innate immune response in the presence of Aβ or tau pathology.MethodWe systematically compared the immunological milieus in the brain with amyloid deposition or tau aggregation and neurodegeneration.ModelsThree AD mouse models, including Aβ models with amyloid deposition in both parenchyma and along the vessels and tau pathology models; as well as human brain samples with different Braak scores.ResultWe found that mice with tauopathy but not amyloid, developed a unique innate and adaptive immune response and that depletion of microglia or T‐cells blocked tau‐mediated neurodegeneration. T cells, especially cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the AD brain. T cell numbers correlated with the extent of neuronal loss, and dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of IFN‐γ and PD‐1signaling both significantly ameliorated brain atrophy.ConclusionOur results thus reveal a tauopathy and neurodegeneration‐related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in AD and primary tauopathies.
Dissection of alpha‐synuclein specific synaptic functions by gene editing
Authors: Madhivanan Kayalvizhi , Parra‐Rivas Leonardo A , Joensuu Merja , Sanders Shanley , Caballero‐Florán René , Bingham Dominic , Sharma Rohan , Jenkins Paul M , Leterrier Christophe , Meunier Frederic A , Roy Subhojit 
Published: December 2023

AbstractBackgroundDespite almost two decades of research, the physiologic role of α‐synuclein remains unclear. Mice lacking α‐syn only show mild phenotypes, and most mechanistic studies have been done either in α‐syn over‐expressing systems, or in mice lacking all three synuclein genes (α/β/γ). However, over‐expression of proteins can induce unwanted phenotypes, and ‘triple‐knockout’ synuclein mice have structural and physiologic changes that are not specific to α‐syn – complicating interpretations.MethodsWe used CRISPR technology to systematically inactivate or activate each synuclein gene in cultured mouse hippocampal neurons, ensuring that our manipulations did not lead to compensatory changes in the non‐targeted synucleins. Gene‐editing was followed by unbiased evaluation of physiology and ultrastructure using optical synaptic vesicle (SV) recycling assays, electrophysiologic recordings, single‐molecule trafficking assays, super‐resolution imaging, and electron microscopy.ResultsNeurotransmission is maintained at a range of different activity patterns, motivating us to evaluate the role of α‐syn under basal states as well as conditions involving trains of action potentials. Elimination of α‐syn led to substantial increases in basal exocytosis. Single‐molecule trafficking of SVs in these neurons indicated an increase in mobility of reserve pool vesicles when α‐syn was absent. Increasing endogenous α‐syn levels by CRISPRa had largely reciprocal effects. Recent studies in our lab found that phosphorylation of α‐syn at the Ser129‐site is a trigger for α‐syn function at the synapse. Augmenting α‐syn functionality by constitutive phosphorylation of the α‐syn Ser129‐site also triggered clustering of distal SV‐pools, consistent with a role for α‐syn in physiologic clustering of reserve pool vesicles. However, when neuronal activity was augmented by trains of action potentials, loss of α‐syn selectively attenuated endocytosis, with no effect on exocytosis. Super‐resolution imaging revealed that α‐syn was translocated to peri‐active zones upon stimulation, suggesting that the altered localization of α‐syn under these conditions resulted in facilitation of endocytosis. Finally, mass‐spectrometry data also indicate that α‐syn binds to an endocytosis‐enriched proteome under conditions that favor neuronal activity.ConclusionOur data provide clarity of the repertoire of a‐syn specific functions under different physiologic conditions.
Automated analysis of letter fluency data produced by Korean and American patients with AD and MCI
Authors: Kim Jin‐Seo , Kim Seohee , Irwin David J. , Nevler Naomi , Baek Min Seok , Cho Sunghye 
Published: December 2023

AbstractBackgroundLetter fluency task measures executive functioning and working memory in clinical settings. Previous studies have shown that both the total number of correct responses and lexical characteristics of produced words are informative in explaining patients’ performance. Yet, many previous studies analyzed fluency data in one language using manual assessments, lacking crosslinguistic validity and feasibility. We developed automated pipelines for digitized letter fluency data in Korean and English to compare patients with Alzheimer’s disease (AD) or mild cognitive impairment (MCI) and healthy controls (HC) across the two languages.MethodWe analyzed letter fluency data (English: ‘F’, Korean: ‘G’) produced by 47 Koreans (mean age = 74.1±8years, 25 females) and 40 Americans (mean age = 63.8±8.6years, 16 females) with AD (11 Koreans, 20 Americans) or MCI (16 Koreans, 7 Americans) and HCs (20 Koreans, 13 Americans) using our automated pipeline for each language. The pipelines counted the number of correct responses, rated words for frequency and length, and measured phonetic and semantic distances and pause duration between two consecutive correct responses. Linear regression models compared groups in scores and language variables, respectively, where score or speech variable was included as a dependent variable and diagnostic group as an independent variable. Education level, age, and language were co‐varied in all models. The same models were built for each language without language as a covariate.ResultAD patients produced fewer correct responses with higher word frequency compared to HC (score: β = ‐4, p = 0.001, frequency: β = 0.63, p = 0.001) and MCI (score: β = ‐2.9, p = 0.017, frequency: β = 0.55, p = 0.008). AD patients also produced longer pauses between words and words that were less phonetically similar to its antecedent compared to HC (pause: β = 4.99, p = 0.002, phonetic similarity: β = 11.33, p = 0.011) and/or MCI patients (pause: β = 3.6, p = 0.039). The results remained similar when separate models were built for each language.ConclusionWe demonstrated the feasibility of automated analyses of letter fluency data in different languages and validated that word frequency, pause duration and phonetic similarity were important speech characteristics in both languages. These pipelines can be adopted in other languages, which will enable large‐scale, automated crosslinguistic analyses of letter fluency data in clinical settings.
Comparison of subjective cognitive decline and polygenic risk score in the prediction of all‐cause dementia, Alzheimer’s disease and vascular dementia
Authors: Trares Kira , Stocker Hannah , Perna Laura , Beyreuther Konrad , Schöttker Ben , Brenner Hermann 
Published: December 2023

AbstractBackgroundSubjective cognitive decline (SCD) and polygenic risk scores (PRS) have both been shown to be associated with the risk of developing dementia. However, it is of interest whether they can improve the established and well‐validated cardiovascular risk factors aging and dementia (CAIDE) model and how their predictive abilities compare.MethodsSCD and PRS were assessed and determined in a large, population‐based cohort study. In this study, the CAIDE model was applied to a sub‐sample of 5,360 study participants and evaluated for the outcomes of all‐cause dementia, Alzheimer’s disease (AD) and vascular dementia (VD) by calculating Akaike’s information criterion (AIC) and the area under the curve (AUC). The improvement of the CAIDE model by SCD and PRS was further examined using the net reclassification improvement (NRI) method and integrated discrimination improvement (IDI). Besides evaluations in the total sample, predictive abilities were evaluated in the mid‐life and late‐life sub‐cohort.ResultsDuring 17 years of follow‐up, 410 participants were diagnosed with dementia, including 139 AD and 152 VD diagnoses. Overall, the CAIDE model showed high discriminative ability for all outcomes reaching AUCs of 0.785, 0.793 and 0.789 for all‐cause dementia, AD, and VD, respectively. Adding information on SCD to the CAIDE model led to a significant increase in NRI for all‐cause dementia (4.4%, p = 0.0401) and VD (7.7%, p = 0.0095). In contrast, prediction models for AD further improved when PRS was added to the model (NRI, 8.4%, p = 0.0257). The latter became more substantial when applied to the mid‐life sub‐group (50‐64 years), achieving an NRI of 19.6% (p = 0.0075). When APOE ε4 carrier status was included in CAIDE model 2, the discriminative ability of the basic CAIDE model increased, and SCD and PRS did not further improve the prediction.ConclusionWhile PRS significantly improved the prediction of the CAIDE model for AD, information on SCD increased its discriminative ability for all‐cause dementia and VD. In contrast to PRS, information on SCD can be assessed more efficiently, and thus models including SCD can be more easily transferred to the clinical setting. Nevertheless, the two variables seem negligible if APOE ε4 carrier status is available.
When One Call Isn’t Enough: A Comparison of Alzheimer’s Association Helpline Callers
Authors: Hodgson Nancy A 
Published: December 2023

AbstractBackgroundFamily care partners of persons living with dementia (PLWD) have limited support and resources and experience high levels of stress and burden. Prior research has demonstrated that one call to the Alzheimer’s Association’s Helpline benefitted 80% of callers following a single call. However, some care partners need more support than a single call.MethodThe aim of this study was to evaluate the efficacy of offering up to two callbacks after an initial call to the Helpline. Study participants were Helpline callers who were asked if they sought additional calls due no progress towards implementing recommended action steps after a single Helpline call. Outcomes were compared at 2, 4 and 6 weeks after baseline and included PROMIS measures of self‐efficacy.ResultOf 2504 participants, 79.92% were female, 73% were white, age = 60.31 years (± 12.59), 85.06% bachelor’s degree+, 64.42% lived with PLWD. No statistical difference were noted in demographics between single vs. +1 callers. However, +1 callers scored lower on two PROMIS items: upset (p < 0.0171) and ability to bounce back (p < 0.017). After one call, those with +1 call improved on the total PROMIS (p < 0.0001), as well as the following items: negative feelings < 0.001), stress (p < 0.0009), upset (p < 0.0145), discouragement (p < 0.006), and distress (p < 0.0001). From the first call to the second call, callers improved on the total score (p < 0.0065), upset (p < 0.0349) and ability to relax (p < 0.0213) items. Following second call, participants improved on the overall survey score (p < 0.004), as well as the following items: stress (p < 0.016), upset (p < 0.03), discouragement (p < 0.04), distress (p < 0.0066), and ability to relax (p < 0.02).ConclusionFurther research is indicated to understand the support needs of care partners that can benefit from more than one call to a tele support program.
A study to determine the mechanisms underlying changes in synaptic vesicle glycoprotein 2A density in Alzheimer’s disease
Authors: Chang Ya Yin , King Declan , Holt Kristjan , Gladstein Scott , Horton Wesley A. , Bevis Amanda , Smith Daniel G , Zetterberg Henrik , Finnema Sjoerd J , Spires‐Jones Tara L ,   FNIH SV2A Project Team
Published: December 2023

AbstractBackgroundSynaptic vesicle glycoprotein 2A (SV2A) is a transmembrane synaptic vesicle protein that regulates vesicle exocytosis and neurotransmitter release. Positron emission tomography (PET) studies reveal that the levels of SV2A are decreased in the brains of patients with Alzheimer’s disease (AD) and other brain disorders. Whether changes in SV2A PET signal are caused by a loss of synapses or a loss of SV2A protein is unclear and an impediment to developing novel treatments for neurodegenerative diseases. The goal of this study is to determine the biological underpinnings of reduced SV2A signal in individuals with AD.MethodWe examined post‐mortem brain samples from the entorhinal cortex (EC) and cerebellum (CBM) in AD patients and age‐ and sex‐matched controls without neurological conditions (EC n = 19 AD, 15 controls; CBM n = 11 AD, 12 controls). We explored differences in synaptic density and synaptic ultrastructure using array tomography and electron microscopy, and analyzed data using linear mixed‐effects models (with post‐hoc Tukey comparisons) and Spearman correlations.ResultSV2A puncta density measured with array tomography in both brain regions strongly correlates with synaptophysin puncta density, the gold standard marker for synapse density in post‐mortem brain tissue (ñ = 0.87 EC, ñ = 0.72 CBM, p<0.001 both regions). We observed lower SV2A puncta density in AD cases compared to controls in EC (p = 0.001), slightly higher SV2A puncta density in AD in CBM (p = 0.02), and no difference in the proportion of synaptophysin puncta labelled with SV2A in AD vs control (p = 0.37). Electron microscopy revealed immunogold labelled SV2A protein localized specifically to presynaptic vesicles and no difference in the number of immuno‐gold labelled SV2A particles per synapse.ConclusionOur data indicate that the loss of SV2A PET signal reported in vivo in patients with AD is likely caused by a loss of synapses and not the loss of SV2A protein within remaining synapses. These findings indicate that changes in SV2A PET signal are due to synaptic loss and that strategies for reversing synaptic loss or associated neuropathophysiological effects may be important to the treatment of AD and other synaptopathies. This work is part of the SV2A PET Project, a program of the FNIH Biomarker Consortium.
阿尔茨海默病和轻度认知障碍患者的外周免疫细胞与神经心理学量表、脑18 F‐FDG、18F‐AV45 PET‐CT 之间的相关性
Authors: Zhan Yu , Zhou Huiling , Kang Jian , Zhao Li , Dong Chunbo 
Published: December 2023

AbstractBackgroundImmune dysfunction in Alzheimer’s disease (AD) was previously thought to be limited to the central nervous system, but recent studies suggest that the peripheral immune system also plays a key role. This study compared and analyzed the changes in peripheral immune cells in patients with AD and mild cognitive impairment (MCI) and their correlation with cognition, and combined 18F‐FDG PET and 18F‐AV45 PET to investigate the role of peripheral immune cells in AD pathology and the possibility as biomarkers for early clinical diagnosis and disease assessment.MethodsThe 146 participants included 70 AD patients, 26 MCI patients, and 50 controls. 34 AD patients tested with 18F‐AV45 (18F ‐Florbetapir) positron emission tomography (PET). 23 were Aβ‐positive (A+), and 11 were Aβ‐negative (A‐). All participants had a peripheral immune cell, cognitive evaluation, and detailed nervous system examination.Results(1) Significant differences in peripheral immune cells in AD compared with MCI and CG; (2) There was no significant correlation between NEU%, NLR, LY, and LY% and cognitive scale scores for patients in the AD and A+ groups, while there was a significant correlation with cognitive scale scores in the MCI and A‐ groups; and (3) Peripheral immune cells NEU%, NLR, LY, and LY% in A+ patients were correlated with FDG metabolism in several functional brain areas and Aβ load in some brain areas, but not with Aβ load in all functional brain areas in A‐ patients.ConclusionDifferences in peripheral immune cells help to distinguish AD from MCI, with NLR having better diagnostic efficacy. peripheral immune cells may have a greater impact on early cognitive dysfunction; NEU%, NLR, LY, and LY% may be associated with Aβ deposition and could serve as potential biomarkers for early clinical diagnosis and disease assessment in AD.
Longitudinal AD biomarkers in monozygotic twins: genetic contribution to AD biomarker concentrations over time
Authors: Vromen Eleonora M. , Coomans Emma M. , Verberk Inge M.W. , van der Wal Mariska , Pijnenburg Yolande A.L. , Teunissen Charlotte E. , den Braber Anouk , Tijms Betty M. , Visser Pieter Jelle 
Published: December 2023

AbstractBackgroundUnderstanding the earliest pathophysiological changes in Alzheimer’s disease (AD) is important for development of therapeutic intervention strategies. Studying genetically identical twins provides unique information on genetic and environmental influences on development of AD. Here we studied change in AD biomarkers amyloid β1‐42 (aβ42), amyloid β1‐40 (aβ40), phosphorylated tau181 (p‐tau) and total tau (t‐tau) in CSF over time in a cohort of older cognitively normal monozygotic twins and tested the genetic contribution to biomarker concentrations at baseline and to change of biomarker concentrations over time.MethodWe included 103 twins (npairs = 42) from the EMIF‐AD preclinAD study with 2‐4 repeated CSF sampling available across a time period of 4.47±2 years (mean±SD age: 68.8±7 years, 54 (52%) female). We measured aβ42, aβ40, p‐tau and t‐tau using the Lumipulse platform (Fujirebio Diagnostics, Inc.). We used linear mixed models to investigate change in biomarker concentrations over time. We used twin‐pair intraclass correlation (ICC) analysis to estimate the genetic contribution to biomarker concentrations at baseline and at repeated measurements, and to annual change in biomarker concentrations.ResultAt baseline, 25 (24%) individuals had an abnormal aβ42/aβ40 ratio, 27 (26%) abnormal p‐tau and 35 (34%) abnormal t‐tau, and at last measurement respectively 34 (33%), 38 (37%) and 45 (44%). Across the group, aβ42/aβ40 decreased (β±SE ‐0.001±0, p‐value<0.001), and p‐tau and t‐tau increased over time (respectively 1.37±0.3, p‐value<0.001; 6.58±2.3, p‐value = 0.004). Increases in p‐tau levels were most pronounced in amyloid positive individuals (2.72±0.38, p‐value<0.001) compared to amyloid negative individuals (0.65±0.24, p‐value = 0.007; p‐value interaction<0.001). At baseline, the genetic contribution to biomarker concentrations was lowest for t‐tau (ICC = 0.5, p<0.001) and highest for aβ40 (ICC = 0.79, p<0.001). ICC’s remained similar at repeated measurements (table 1). Annual changes of aβ40 and p‐tau showed significant twin‐pair correlations (resp. ICC’s: 0.58 and 0.42; p‐values <0.01; Figure 1), indicating a genetic contribution to change in these concentrations over time.ConclusionIn this sample of older cognitively normal monozygotic twins, we found that AD biomarkers became increasingly abnormal over time. Our unique twin design further indicates that these very early pathophysiological changes are under moderate to high genetic influence, which also indicates a role of environmental factors.