bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using an integrated multi‐omics approach to predict dementia: Explainable variational autoencoder (E‐VAE) classifier model
Authors: Vivek Sithara 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) and AD related dementias (ADRD) are complex multifactorial neurodegenerative diseases. Application of deep learning methods to analyze large scale whole genome‐wide SNP data and transcriptomic data may be a powerful approach to utilize early molecular changes for early detection of ADRD and elucidate the biological mechanisms in AD/ADRD.MethodWe harmonized the definition of dementia in the Health and Retirement Study (HRS) and an external study Religious Orders Study/Memory and Aging Project (ROSMAP) using a diagnostic algorithm previously validated in the HRS based on cognitive tests. The cognitive tests included immediate and delayed word recall, and backward counting that measure working memory and episodic memory. We developed an explainable variational autoencoder (E‐VAE) classifier model using genetic variants (genome‐wide SNP data, 5474 SNPs) and RNAseq data (592 differentially expresses genes in ADRD) from 204 study participants (102 participants with dementia and 102 controls) in the HRS to predict dementia. We validated the prediction performance in a test set of the HRS participants (26 participants with dementia and 26 controls), and further assessed the generalizability of the multi‐omics‐based VAE classifier model in the ROSMAP data (12 participants with dementia and 222 controls).ResultOur results showed a predictive accuracy of 0.73 (95% CI [0.61, 0.85]) with an AUC of 0.80 in the HRS validation data and an accuracy of 0.58 (95% CI [0.51, 0.64]) with an AUC of 0.66 in the ROSMAP study data. The E‐VAE model outperformed a penalized logistic regression model (Figure in supplementary file). We identified genes that involved in the apoptotic process, neuron and nervous system development were highly weighted in the multi‐omics‐based VAE model and found that genes in ‘Butyrophilin interactions pathway’ were over represented in ADRD (FDR adjusted p <0.05).ConclusionThis is the first study showing the generalizability of a deep learning prediction model for dementia in an independent dataset using an integrated multi‐omics approach. The more precise and definitive latent variables identified using E‐VAE can help us understand the complex biology in ADRD and characterize the disease status.
Motor Sequence Learning in Mild Cognitive Impairment and Alzheimer’s Disease and its Relationship to Biomarkers
Authors: Ruitenberg Marit F. L. , Duff Kevin , Koppelmans Vincent 
Published: December 2023

AbstractBackgroundWhile mild cognitive impairment (MCI) and Alzheimer’s disease (AD) are primarily associated with cognitive impairments, studies have also demonstrated that individuals may experience motor impairments that can precede cognitive symptoms by several years. Here, we examine potential differences in motor sequence learning abilities in individuals with MCI and AD compared to cognitively normal individuals (CNI). Moreover, we investigate whether motor sequence learning impairments could be an early behavioral biomarker. To that end, we evaluated associations between motor learning ability and existing AD biomarkers.MethodTo date, 26 individuals with AD, 27 with MCI, and 47 CNI performed a serial reaction time task that allowed us to assess the amount of sequence‐specific learning at the end of the task and the rate of such learning across the task. Additionally, participants underwent APOE genotyping to determine the presence of e4 alleles, amyloid PET imaging to quantify amyloid deposition, and structural MRI scanning to obtain hippocampal volume.ResultWhile motor responses of individuals with AD and MCI were generally slower than those of CNI, motor sequence learning occurred regardless of cognitive status and did not significantly differ among the three groups. Results of correlational analyses showed no significant associations between motor learning scores and AD biomarkers.ConclusionOur findings suggest that motor sequence learning abilities are relatively preserved in MCI and AD, which could have implications for the design of rehabilitation programs. However, its observed independence of existing biomarkers indicates that sequence learning may not be suitable as an early disease maker. Our ongoing work focuses on measuring general motor proficiency via a broad assessment spanning multiple motor domains, and evaluating whether such proficiency can serve as a predictor of disease status and progression.
Increased worry associated with self‐reported, but not informant‐reported, subjective cognitive decline predicts risk of incident dementia
Authors: Numbers Katya T. 
Published: December 2023

AbstractBackgroundSubjective cognitive decline (SCD), in the absence of impaired testing, may be an indicator of early Alzheimer’s disease (AD) and other dementias. However, not all individuals with SCD have cognitive decline. ‘SCD plus’ criteria were proposed in an effort to increase the likelihood of identifying preclinical dementia in individuals with SCD. Two of these criteria include the expression of concern (worry) about the SCD and confirmation of the SCD by an observer (informant). This study investigates whether longitudinal changes in self‐ and informant‐reported SCD‐worry are associated with increased risk of incident dementia over time.MethodParticipants were 873 older adults (M = 78.65‐years; 55% female) and 849 informants from the Sydney Memory and Ageing Study. SCD‐worry was defined as responding “Yes” to the following: “Have you noticed growing difficulties with your/their memory?” and “Have you been concerned about your/their memory getting worse?”. Changes in SCD‐worry over time were modelled using latent growth curve analyses with logit transformation. Participants’ and informants’ propensity to report SCD‐worry at baseline and change over time were analysed using Cox regressions to determine associations with incident dementia risk over 10‐years.Results32% of participants who reported noticing memory difficulties at baseline also reported worry associated with this, where only 19% of informants reported worry associated with SCD at baseline. Controlling for demographics, APOE4, mood and personality, participants’ initial level (p < .001) and change in SCD‐worry over time (p = .002), were associated with dementia risk. Controlling for the same covariates, informants’ initial SCD‐worry (p < .001) was associated with dementia risk, though SCD‐worry change was not (p = .862). When modelled together, participants’ initial level of, and longitudinal change in, SCD‐worry were still independently associated with increased dementia risk (p’s < .001); informants’ initial SCD‐worry remained significant (see Table 1).ConclusionOur findings highlight the need to factor in concerns held by individuals that go beyond just recognising cognitive changes have occurred, as the latter is a common phenomenon in older adults. Our results suggest that worries about perceived cognitive changes may characterise individuals at greater dementia risk.
Predicting progression within the cognitive decline continuum using self‐ and partner‐reported cognitive complaints, and depressive symptomatology in Cognitively Unimpaired (CU) and Subjective Cognitive Decline (SCD) participants: Evidence from the CompAS longitudinal study
Authors: Pérez‐Blanco Lucía , Felpete Alba , Nieto‐Vieites Ana , Mallo Sabela Carme , Campos‐Magdaleno Maria , Lojo‐Seoane Cristina , Juncos‐Rabadán Onésimo , Pereiro Arturo X 
Published: December 2023

AbstractBackgroundSelf‐, informant reports and also depressive symptoms can predict the risk of cognitive decline. Our aim was to study the joint contribution of complaint reporting and depression to progression along the cognitive decline continuum to dementia.MethodA total of 246 participants [Cognitively Unimpaired (CU): n = 144; Subjective Cognitive Decline (SCD): n = 102] over 50 years from the Compostela Aging Study (CompAS) were assessed at baseline and at three follow‐ups (intervals 18‐24 months). A short version of the QAM was administered to assess severity of complaints. At each follow‐up assessment participants were reclassified according to stability or progression. Logistic regressions were performed to predict stable and progressing CU and SCD participants at 3rd follow‐up by using self‐, informant‐ reports, agreement, and depressive symptomatology as predictive variable at baseline, 1st and 2nd follow‐ups s.ResultsFor CU participants, (a) complaints at baseline predicted progression to SCD by the informant‐report, and to MCI by the self‐informant agreement; (b) complaints at 1st follow‐up predicted progression to SCD or MCI by the self‐report; (c) complaints at 2nd follow‐up predicted progression to SCD by the self‐report and the depressive symptomatology. For SCD participants, progression to MCI and/or dementia was only predicted by the informant‐report at 2nd follow‐up.ConclusionsFor CU participants, self‐report was the best predictor of progression to SCD and/or MCI from the 1st follow‐up. Regards SCD participants, only informant´s report was able to predict the progression to MCI and/or dementia by the end of the follow‐up.
EEG microstates as a “real time” feedback for rTMS treatment efficacy in MCI subjects
Authors: Glik Amir , Beninger Felix , Kleinmann Michal , Zarfati Hadar , Globerman Matan , keret Ophir , Ramot Yair , Furst Miriam 
Published: December 2023

AbstractBackgroundNew treatments for the Alzheimer’s disease (AD) are evolving. There is a need for cheap, immediate and available treatment feedback biomarker which can demonstrate rapidly treatment success/failure. We used EEG microstates for this purpose while using repetitive Trans Magnetic stimulation (rTMS) treatment. Four types of microstates are identified according to EEG topography. They are characterized by their duration, frequent appearance and the transitions among the different microstates. The possibility of using microstates properties as a biomarker for rTMS treatment efficacy in mild cognitive impairment (MCI) subjects was explored.MethodsWe recruited 14 MCI subject to receive 16 rTMS sessions. EEG microstates were analyzed immediately before and after each treatment. We used 3 rTMS predefined protocols. The preferred protocol, for each patient, was selected using microstates duration. All patients performed a comprehensive neuro‐cognitive evaluation before rTMS treatment. 11 subjects completed a second neuro‐cognitive evaluation after treatment period ended.ResultsMicrostates duration change was noticed before and after each rTMS treatment. Duration variation aided deciding which rTMS protocol is preferred in all participants. Moreover, new rTMS protocol was designed, for 3 patients, using microstates parameters. Cognitive performance was associated with microstate duration (p<0.05).ConclusionsMicrostates duration may serve as a “real time” treatment efficacy biomarker for MCI subjects. Further work should be done in order to validate this method.
2.Cerebrovascular neuropathology in the brains of people with Down syndrome
Authors: Aguilar Lisi Flores , Head Elizabeth 
Published: December 2023

AbstractBackgroundPeople with Down syndrome (DS) are at genetic risk of developing early‐onset Alzheimer’s disease (AD). By age 40 years, virtually all people with DS develop beta amyloid plaques and tau neurofibrillary tangles, typically followed by the development of AD dementia over a decade later. Despite having a low frequency of vascular risk factors (i.e., hypertension, atherosclerosis), people with DS show an age‐related progression of cerebral amyloid angiopathy (CAA), white matter hyperintensities, microbleeds, micro infarcts, and enlarged perivascular spaces by neuroimaging. Interestingly, the incidence of CAA at autopsy is significantly higher in people with DS than patients with late onset AD. Our main objective is to investigate the cerebrovascular pathology in DS autopsy cases.MethodFree floating 30 µm thick sections from the occipital cortex of DS cases with or without AD pathology (DSAD and DS, respectively, n = 5/group) were compared to age matched cognitively normal controls (n = 5). Sections were immunostained for collagen IV (basement membranes) and for fibrinogen (protein extravasation).ResultPreliminary results show that compared to controls, DSAD brains have impaired vascular integrity, observed as reduced collagen IV basement membrane labeling and evidence of protein extravasation which may reflect microbleeds observed using in vivo neuroimaging.ConclusionOur preliminary data suggest a disruption of blood vessel basement membranes observed as losses in collagen IV immunostaining in DSAD brains. Moreover, fibrinogen extravasation was consistently observed in DSAD brains. We are currently characterizing the age of onset of collagen IV disruption/losses and fibrinogen leakage into the brain parenchyma in the context of an AT(N) framework to understand when in AD progression, cerebrovascular pathology evolves in DS.
3. Neuropathological differences between Down syndrome and familial Alzheimer’s disease with APP duplication: role of endothelial cells in cerebral amyloid angiopathy.
Authors: Potier Marie‐Claude 
Published: December 2023

AbstractBackgroundWhile amyloid plaques are common in all AD cases, CAA is mainly found in familial AD with duplications of the APP gene (DUP‐APP), Down Syndrome (DS), and specific APP mutations. Mechanisms leading to these differences are not yet understood. We investigated the diversity of neuropathological phenotypes and the composition of brain Aß peptides in sporadic AD (sAD), DUP‐APP, APP mutations, DS with or without dementia (D), and control cases. In addition, we analysed endothelial cells derived from iPSC lines (iPSC‐d‐ECs) of patients to model the vessel wall forming the blood‐brain barrier.MethodWe analyzed Aβ and Tau pathologies in post‐mortem human brain tissues by immunohistochemistry on paraffin‐embedded sections (12 sAD, 7 DUP‐APP, 3 DS, 10 DS‐D and 9 APP mutations cases). Using immunoprecipitation and mass spectrometry, we characterized Aß species in brain homogentes from the same cases. We analysed the morphology of iPSCs‐d‐ECs, measured their levels of Aβ secretion and junctional proteins and analysed their transcriptomes.ResultAβ deposits in the parenchyma were found in sAD, DS‐D and APP mutations, and less abundant in DUP‐APP. Conversely, Aβ deposits in the blood vessels (arteries and arterioles) were prominent in DUP‐APP, less abundant in DS‐D and even less frequent in sAD and APP mutations. Only DUP‐APP cases showed Aβ deposits in the capillaries. Despite striking differences in Aβ pathologies, all cases with dementia had high Tau pathology. Aß peptides signatures were different in cases with CAA, with higher levels of shorter Aß peptides and truncated species at position 2 at the N‐terminus. iPSC‐d‐ECs secreted substantial amounts of Aβ peptides. We identified changes in the morphology and tight junctions of iPSC‐d‐ECs with DUP‐APP as well as specific gene expression dysregulations, suggesting intrinsic remodelling of ECs of the blood‐brain barrier in DUP‐APP.ConclusionOur study reveals new pathophysiological mechanisms involved in specific Aβ production and deposition in the blood vessel wall of patients carrying DUP‐APP involving EC. Differences between DUP‐APP and DS suggest the presence in the DS population of protective factors against CAA.
Hippocampal administration of astrocyte‐derived extracellular vesicles (AEVs) exacerbates motor deficits and impairs spatial memory in a mouse model of Alzheimer’s Disease
Authors: Winston Charisse N. , Rissman Robert A 
Published: December 2023

AbstractBackgroundUnderstanding the therapeutic and/or pathogenic potential of extracellular vesicles (EVs) and their cargo has emerged as an important topic in relation to development of Alzheimer’s disease (AD) and other age‐related dementias (ADRD). Here, we tested the impact of treatment of astrocyte‐derived plasma EVs on cellular and functional recovery was explored in aged, AD (PSAPP) mice.MethodPlasma EVs derived from normal controls, mild cognitively impaired (MCI), and AD subjects (n = 7 = /group) were extracted, precipitated using a polymer‐based isolation method (ExoQuick), and enriched against an astrocyte (GLAST) source using magnetic immunocapture and fluorescence‐activated cell sorting. Pooled AEV preparations were injected unilaterally into the right hippocampus of 7m old, female, PSAPP mice. AD‐related neuropathological changes and functional deficits in spatial learning and memory (Morris Water Maze), gait stability (rotarod) and anxiety (SLMA) were assessed at 7 months post injection (mpi).ResultWe observed MCI and AD AEV injected mice took a longer time and traveled a shorter distance to reach the cued and hidden platform as compared to mice injected with AEVs from normal controls. After the platform was removed, we observed MCI and AD AEV injected mice made significantly fewer entries into the correct quadrant zone and fewer entries into the correct target zone where the platform was originally located. Motor function was significantly impaired in MCI and AD AEV injected mice as compared to control AEV injected mice. Behavioral impairments correlated with increased gliosis, as measured by Iba1 and GFAP, and increased plaque burden, as measured by 6E10 antibody, in the brains of MCI and AD AEV injected mice. Similar levels of phosphorylated tau immunoreactivity were observed in all three mice groups.ConclusionAEVs derived from cognitively impaired subjects transfer toxic proteins to hippocampal cells and exacerbate functional impairments and AD neuropathology in vivo. Cellular and functional recovery was observed in mice injected with EVs from control subjects.
MR imaging of Brain blood flow in young and older adults with Down syndrome.
Authors: Tamayo‐Elizalde Miren , Saini Fedal , Idris Mina , Dell'Acqua Flavio , Zelaya Fernando , Strydom Andre 
Published: December 2023

AbstractBackgroundThe trisomy of chromosome 21 that causes Down syndrome (DS) predisposes to Alzheimer’s disease (AD) with a lifetime risk of >90% [1]. The overexpression of the amyloid precursor protein gene leads to amyloid‐β accumulation in the brain and, by age 40, most individuals with DS show AD neuropathology [2]. Amyloid deposits in the brain affect the parenchyma and the blood vessels.While cerebral blood flow (CBF) is substantially reduced in sporadic AD [3], particularly in the temporal and parietal lobes involved in memory and language, the cerebrovascular neuropathology ubiquitous in DS from early adulthood is not well characterised, and the link between CBF and the development of dementia symptoms in adults with DS is still unclear.Here, we compare localised cerebral perfusion in young and older adults with DS, and hypothesise hypoperfusion in older adults in areas that are commonly affected in AD.MethodArterial Spin Labeling (ASL) data was acquired from a total of 33 individuals with DS with ages between 17 and 58, of which 16 were classified as young adults (YA, < = 35 years), and 17 as older adults (OA, >36 years). CBF maps were generated for each subject from ASL images using the ASAP toolbox [4].A two‐sample t‐test statistical group analysis was then conducted between CBFs from YA and OA on SPM12 [5] with age and sex as covariates.ResultGroup analyses showed significant hypoperfusion in OA relative to YA in areas that included the precuneus, prefrontal and orbitofrontal areas, and regions involved in sensory and motor integration. Some of these are known to be affected in AD and are regions where amyloid aggregations start to occur.The association of these hypoperfusion changes with cognitive scores will also be presented.ConclusionThere are significant hypoperfusion changes associated with age in individuals with DS in areas known to be affected in AD.[1] McCarron M. et al, J Intellect Disabil Res., 2017[2] Lott and Head, Nat. Rev. Neurol., 2019[3] Roher, A. E. et al, Vasc Health Risk Manag, 2012[4] Abad, V. M., et al, Magn. Reson. Imaging, 2016[5] https://www.fil.ion.ucl.ac.uk/spm/ [Accessed on 10/12/2022]
Modelling of the development and response to amyloid‐β accumulation in the context of trisomy21 in the rodent brain
Authors: Farrell Clíona , Mumford Paige , Beament Millie , Lau Gloria , Wu Yixing , Pellen Marion , Baniowska Monika Rataj , Tosh Justin , Noy Sue , Cleverley Karen , HERAULT Yann , Tybulewicz Victor , Fisher Elizabeth , Wiseman Frances K 
Published: December 2023

AbstractBackgroundIndividuals who have Down syndrome (DS), a genetic condition caused by having three copies of chromosome 21, frequently develop early‐onset Alzheimer’s disease (AD). This is caused by the additional copy of the APP gene, located on chromosome 21, which leads to a raised abundance of amyloid‐β. However, significant evidence demonstrates that the additional copy of other genes on the chromosome modifies the accumulation and response to amyloid‐β. Here we present a series of rodent preclinical models of AD‐DS, which we use to investigate this biology and can be used to test potential therapeutic approaches.MethodsWe previously crossed mouse models of DS with the AppNL‐F model of amyloid‐β accumulation; demonstrating that three copies of a region of chromosome 21 containing 38 genes is sufficient to reduce the accumulation of amyloid‐β. Here we present new data from a cross of the Dp1Tyb DS mouse model with an App gene knock‐out (to normalise the number of copies of this gene) and novel DS‐AD rodent models in which the endogenous App gene has been partially humanized (Dup(Rno11)‐APP‐H3 and Ts68Yah) compared with DS model controls (Dup(Rno11) and Ts66Yah). Brain material from these models at a range of ages was analyzed by western blot, biochemical fractionation and MSD assay, and immunohistology to study APP processing and amyloid‐β accumulation. We used MSD assay and immunofluorescence to study the response to accumulating amyloid‐β with a focus on the response of microglia, neuroinflammation and break‐down of the blood‐brain barrier.ResultsOur data indicate that three copies of App contribute to altered microglia biology in the Dp1Tyb mouse model of DS and that partial humanization of the App gene in DS rodent models leads to alterations in the processing of APP, and results in raised levels of human amyloid‐β in the brain.ConclusionThese new model systems of DS‐AD amyloid‐β biology can be used to better understand the early development of AD in people who have DS and to test the safety and efficacy of new therapies for this important group of individuals who are at extremely high risk of developing early onset dementia.
Diffusion tensor image analysis along the perivascular space inversely correlates with age in healthy subjects
Authors: Ozsahin Ilker , Zhou Liangdong , Wang Xiuyuan Hugh , Garetti Jacob , Xi Ke , Tanzi Emily , Kuceyeski Amy , Shah Sudhin , Li Yi , Butler Tracy A 
Published: December 2023

AbstractBackgroundThe glymphatic system is a brain waste fluid clearance system. Glymphatic dysfunction of glymphatic system has been seen in normal aging in many neurological diseases. Diffusion tensor image analysis along the perivascular space (DTI‐ALPS) is a novel MRI method to assess the glymphatic function. In this study, we aim to evaluate the changes in glymphatic system by aging with DTI‐ALPS method.MethodWe investigated DTI‐ALPS indices of 49 healthy subjects underwent MRI scans. Anatomical T1w MPRAGE and multi‐shell diffusion‐weighted MRI were acquired on a 3T Siemens Prisma scanner. Diffusion MRI (dMRI) images were corrected for distortions induced by susceptibility and eddy current. To evaluate the glymphatic system activity, an index called ALPS index was calculated. Linear regression analysis was used to evaluate the correlation of age and ALPS.ResultResults showed that DTI‐ALPS index inversely correlates with age: R = ‐0.42, p<0.05, meaning glymphatic system activity inversely correlates with aging in healthy subjects.ConclusionUnderstanding the factors affecting glymphatic function might help better understanding the underlying mechanism of neurological diseases and healthy aging.