bluuebunny/crossref_metadata_2025_split huggingface dataset:
Speech for Intelligent cognition change tracking and DEtection of AD (SIDE‐AD) Research Program: SIDE‐AD
Authors: Haider Fasih , Saunders Stina , Muniz‐Terrera Graciela , Ritchie Craig W , Luz Saturnino 
Published: December 2023

AbstractBackgroundThere is emerging evidence that speech could be a potential indicator and manifestation of early Alzheimer’s disease (AD) pathology. Symptomatic AD may change an individual’s language, especially certain elements in speech such as elaboration and attribution. Therefore, the University of Edinburgh and Sony Group Corporation are collaborating within the Sony Research Award Program to create the SIDE‐AD study which aims to develop digital speech‐based biomarkers technology for AD. The study is designed to assess disease status in the pre‐dementia stages in a real‐world at‐risk population in Brain Health Services.MethodSIDE‐AD is an observational longitudinal study developing speech biomarkers for use in neurodegenerative disease. Participants are recruited from Brain Health Services in Scotland with data collection starting in spring 2023. In the context of the SIDE‐AD study, we have developed a secured online data collection infrastructure for collecting voice data by prompting individuals to record a voice sample talking about their brain health. Individuals are asked to rate their mood, anxiety and apathy. The baseline speech biomarkers will be compared to the follow‐up visit’s speech recordings as well as to other variables from routinely collected health care data. The SIDE‐AD study will employ signal processing and machine learning technologies to automate the assessment of the respondents’ speech.ResultThe objective of the SIDE‐AD study is to recruit participants (n = 150) across the AD spectrum. The developed infrastructure will be used to collect data of participants with an objective of analysing baseline speech markers in relation to self‐reported mood, anxiety and apathy as well as clinical outcomes from patients’ health care records.ConclusionThe SIDE‐AD study is carrying out research and development of a speech‐based application recording data on individuals’ self‐perceived brain health. A secured online data collection infrastructure is developed to collect speech data with an objective to analyse speech data in combination with routinely available clinical data in Brain Health Clinics, enabling real world validation of speech‐based digital biomarkers for the early detection of AD. We plan to use automatic speech recognition and acoustic patterns for the automatic assessment of brain health status relevant to emergent AD‐specific speech biomarkers.
APP/AICD‐dependent expression of Glypican 4 mediates accumulation of tau oligomers in astrocytes and their synaptotoxic action
Authors: Piacentini Roberto , Puliatti Gulia , Puma Domenica Donatella Li , Aceto Giuseppe , Acquarone Erica , D'Adamio Luciano , Ripoli Cristian , Arancio Ottavio , Grassi Claudio 
Published: December 2023

AbstractBackgroundSeveral studies including ours reported the detrimental effects of extracellular tau oligomers (ex‐oTau) on glutamatergic synaptic transmission and plasticity. Astrocytes greatly internalize ex‐oTau thus contributing to their clearance. However, glial cell engulfment of oTau leads to alteration of neuro/gliotransmitter handling that negatively affects synaptic function. We previously reported that amyloid precursor protein (APP) is required for oTau internalization in astrocytes but the molecular mechanisms underlying this phenomenon has not been clearly identified yet. Here we investigated the role of glypican 4 (GPC4), a member of the large family of heparan sulfate proteoglycans that are membrane glycoproteins highly expressed in astrocytes playing a critical role in protein trafficking through the plasma membrane.MethodThe role of GPC4 in ex‐oTau accumulation in astrocytes and the resulting synaptotoxic action were studied in in vitro and ex‐vivo models obtained from wild‐type C57/bl6 and transgenic mice in which either APP was knocked‐out or it contained the non‐phosphorylatable amino acid alanine replacing threonine 688 (APPTA mice). In these experimental models we performed immunofluorescence analyses, Western blot and real‐time PCR experiments, confocal Ca2+ imaging, high‐pressure liquid chromatography, FM1‐43 imaging, electrophysiological recordings and Chromatin immunoprecipitation assays.ResultTreatment of cultured astrocytes with a specific anti‐GPC4 antibody significantly reduced oTau internalization in astrocytes and prevented oTau‐induced alterations of intracellular Ca2+ signaling and gliotransmitter release. As such, anti‐GPC4 treatment spared neurons from the astrocyte‐mediated synaptotoxic action of ex‐oTau. Specifically, after counteracting the interaction between ex‐oTau and GPC4 no significant decreases in synaptic vesicular release and synaptic protein expression were observed in neurons co‐cultured with astrocytes following exposure to ex‐oTau. The latter also failed to inhibit hippocampal LTP at CA3‐CA1 synapses. Of note, we found that the expression of GPC4 depended on APP and, in particular, on its C‐terminal domain, AICD, generated by γ‐secretase‐dependent cleavage of APP, that can bind Gpc4 promoter. Accordingly, GPC4 expression was significantly reduced in both APP‐KO ad APPTA mice, and ex‐oTau did not exert any significant detrimental action on synaptic function in APP‐KO mice.ConclusionCollectively, our data indicate that GPC4 expression is APP/AICD‐dependent, it mediates oTau accumulation in astrocytes and the resulting synaptotoxic effects.
Distinct pattern of tau‐induced effects in the compartments of the tripartite synapse
Authors: Arancio Ottavio , Argyrousi Elentina K , Kim Young B , Zhang Hong , Nicholls Russell E 
Published: December 2023

AbstractBackgroundTau‐induced synaptic dysfunction is thought to play a key role in the memory decline of Alzheimer’s disease (AD). Synapses are complex multicomponent structures that – in the case of glutamatergic central synapses – are made up of presynaptic, postsynaptic and astrocytic cells that interact with one another to regulate synaptic activity and plasticity. However, since the majority of studies aimed at understanding tau‐induced synaptic impairments were performed on preparations with broadly distributed mutant tau expression, the contribution of tau’s pathological actions in particular synaptic compartments to these impairments is largely unknown.MethodIn order to restrict expression of pathological tau to presynaptic, postsynaptic and astrocytic cells at Schaffer collateral synapses in the mouse hippocampus, we developed a method using a novel tau‐expressing viral vector together with Cre recombinase‐expressing transgenic mice. Electrophysiological analysis of different forms of synaptic plasticity was performed in mouse hippocampal slices 13‐14 days after intra‐hippocampal injection.ResultExpression of mutant tau in presynaptic cells of the hippocampus lead to impairment of long‐term potentiation (LTP) and long‐term depression (LTD), as well as paired‐pulse facilitation (PPF) and synaptic fatigue (SF), but not post‐tetanic potentiation (PTP). Postsynaptic expression leads to defects in LTP, PPF and PTP, while LTD and SF were unaffected. Finally, expression of pathological tau in hippocampal astrocytes had a negative impact on LTP, PPF, PTP, SF, but not LTD.ConclusionThese results suggest that tau elevation in the different cells of the tripartite synapse could lead to a compartment‐specific electrophysiological footprint. Besides extending our knowledge regarding the action of pathological tau in AD, these results are important for the development of combinatorial therapeutic approaches effective for the various synaptic impairments.
Using Natural Language Processing to identify psychiatric symptoms related to Alzheimer’s disease: a novel tool to enhance molecular brain research in Alzheimer’s disease
Authors: Vogelgsang Jonathan , Jiang Weiqian , Dan Shu , Vempati Sangeetha , Chatigny Michael , Abston Joshua , Durning Peter , McCoy Thomas , Klengel Torsten , Berretta Sabina 
Published: December 2023

AbstractBackgroundNeuropsychiatric symptoms (NPS), such as anxiety, depression, or agitation, are common across different stages of Alzheimer’s disease (AD). However, their molecular course is still poorly understood. While post‐mortem brain research provides a unique source to study brain‐specific molecular changes, clinical characterization of post‐mortem brain donors is challenging and primarily subject to case‐control designs. Here, we present a novel approach to post‐mortem brain donor characterization using natural language processing (NLP).MethodWe analyzed electronic health records (HER) of 92 brain donors (46 males, 46 females, mean age 81.9 years, B&B 0 ‐ VI) using NLP‐based NIMH Research Domain Criteria (RDoC) quantification. Individual RDoC scores were regressed to their neuropathological findings or RNAseq data from two independent brain regions, BA32 and insula.ResultNeuritic plaques (NP) in all four cortices show a high association with RDoC “cognition”, controlled for age and sex (frontal: ß = 0.38, p < 0.001; parietal: ß = 0.35, p < 0.001; temporal: ß = 0.37, p < 0.001; occipital: ß = 0.37, p < 0.001). These findings align with prior clinicopathological correlation studies where cognitive examinations were performed within one year before death (Nelson et al., J Neuropathol Exp Neurol, 2012).At pFDR<0.05, we identified 492 differentially expressed genes (DEGs) in the insula and 333 DEGs in the BA32. We have further built a model regressing individual RDoC levels against their DEGs in the two brain regions. In each domain, we observed a cluster of genes that is up‐ or downregulated in relation to their RDoC score (higher/lower domain burden). In addition, we saw that the majority of DEGs are RDoC‐specific. 223 DEGs were uniquely related to one domain (170 DEGs in the insula and 53 DEGs in BA32), while a total of 211 DEGs were associated with at least two domains (151 DEGs in the insula and 60 DEGs in BA32).ConclusionNLP‐based analysis of RDoC can be applied to post‐mortem case collections to phenotype brain donors and show promising associations with neuropathology or RNAseq data that can be used to discover novel molecular pathways related to psychiatric symptoms.
Scoring Accuracy of the Self‐Administered Gerocognitive Examination by Primary Care Providers
Authors: Scharre Douglas W. , Vrettos Nicole E , Nagaraja Haikady N 
Published: December 2023

AbstractBackgroundPrimary Care Providers (PCPs) are critical for case finding of Mild Cognitive Impairment to provide management, referrals, and treatments. Conducting cognitive assessments are time consuming and difficult to incorporate into time‐limited visits. The Self‐Administered Gerocognitive Examination (SAGE) is a reliable and valid, pen and paper, cognitive assessment tool easily incorporated into a PCP visit without time required for staff to administer. Accurate scoring by PCP or staff is critical to interpreting the degree of impairments and any changes over time.MethodsPatients over 64 years‐old without a diagnosed cognitive disorder, presented for a non‐acute care visit with their PCP and were given a SAGE test during their appointment. The SAGE was administered as part of the provider’s standardized method for screening for cognitive impairment. Detailed scoring instructions were provided to the PCP office before subject enrollment. Differences in SAGE scoring between the PCP office and the Ohio State University Memory Disorders Research Center (MDRC) were evaluated. Paired t test and 95% confidence interval were used to compare the mean SAGE scores.ResultsOf the 110 potential recruits, 93 SAGE tests were graded by the PCP office and by MDRC. Scoring discrepancies, the MDRC scored SAGE minus PCP office scored SAGE, ranged from ‐7 points to +3 points with a total of 80% of the SAGE tests resulting in a scoring error by the PCP office; 74% of the total score discrepancies were within ± 2 points. The mean difference was ‐1.49 with a 95% CI (‐1.82, ‐1.17) and p<0.0001 with PCPs scores tending about 1.5 points higher. The largest discrepancies between the scores occurred with the problem‐solving question (40%) and the 3‐D figure question (29%).ConclusionsThe PCP office provided an incorrect score (typically higher) 80% of the time which downplays cognitive deficits. When scoring mistakes are made, accuracy is diminished, impacting the interpretation of the test results and perceived changes over time. PCP offices need to emphasize accurate scoring or consider utilizing the digital format of SAGE, called eSAGE or BrainTest® (available at https://braintest.com). It can send HIPPA compliant automatically scored results to the PCP office.
Changes in cognitive impairment after multidimentional rehabilitation in Neuro COVID severe respiratory failure patients
Authors: Carabelli Valeria P , Previgliano Martin J , Foster Carolina , Previgliano Ignacio J 
Published: December 2023

AbstractBackgroundA Post Intensive Care Syndrome Unit (PICSU) was developed during COVID 19 pandemic. The aim of this study was to evaluate Cognitive Impairment (CI) evolution after PICSU treatment in Neuro COVID patients.MethodsProspective observational study. Population: Neuro COVID patients treated in a PICSU. CI was achieved by means of the Spanish version of the MoCA at ICU discharge and one month after, muscle function was evaluated by means of Medical Research Council test for Intensive Care Acquired Weakness (ICUAW). Statistical analysis was performed by ANOVA and Chi squared test. Age, sex, comorbidities, mechanical ventilation days and length of stay at the PICSU wre also measured.Patients were submitted to an intensive rehabilitation program that included physical, swallowing, speech therapy, occupational therapy ones, as well as nutritional and psychological support.Results27 patients were admitted to PICSU, 5 were female, average age was 57 yo. 30% of them presented normal cognition. Regarding CI patients mean initial MoCA value was 18 and improved to 23 (p < 0.05), MRC values were 42 y 52 respectively (p < 0.05). According MoCA values using a cutoff point of 26 to determinate normal cognition, 16 to 25 for MCI and 15 for Mild Dementia, 26% had MCI and 74% at ICU discharge that evolved to normal (26%), MCI (58%) and MD (16%) (p < 0.05). There was a close relationship between MoCA and MCR enhancement, CI and ICUAW improved simultaneously (p < 0.05).ConclusionPICSU rehabilitation program was useful for cognition and motor function improvement. The close relationship between cognition and motor function could be explained by the myokines and neurotrophic factors release toward muscle activity. This could be an opportunity for future research.
Identifying preclinical Alzheimer’s disease in the community with brief automated hand movement analysis: validation against plasma ptau181 and asymptomatic episodic memory decline
Authors: Alty Jane E , Bai Quan , Wang Xinyi , Li Renjie , Lawler Katherine , George Rebecca J St , Bindoff Aidan D , Roccati Eddy , Bartlett Larissa , Huang Guan , Rudd Kaylee , Collins Jessica M , Garg Saurabh , Hinder Mark , King Anna E , Vickers James C 
Published: December 2023

AbstractBackgroundDementia prevention and drug development is hindered by the lack of low‐cost population‐level tests to help identify preclinical Alzheimer’s disease (AD) in the community. Recent evidence suggests that precise analysis of hand movements may detect motor changes indicative of preclinical AD. The objective was to evaluate how TAS Test, a new online automated hand movement test, predicts preclinical AD biomarkers (plasma ptau181 and subtle episodic memory decline) in a cognitively asymptomatic cohort of older adults.MethodParticipants completed TAS Test online at home using their own computer without researcher assistance: a series of 10‐30 second index finger‐key and index finger‐thumb tapping tests recorded with a keyboard and/or webcam. Movement features including frequency, rhythm, pauses and accuracy were extracted. Participants also completed online tests of episodic memory, CANTAB Paired Associate Learning (CANTAB). A subset provided blood samples for ptau181 analysis. Accuracy of linear regression models comprising hand motor features to predict PAL scores and ptau181 levels, adjusted for confounding, was compared to null models (with only confounders: age, gender, education level, anxiety and depression) using R2
adj and AIC. ΔAIC > 2 denotes statistical difference.Result1,228 adults (mean (SD) age, 65.8 (7.4) years; 73.0% female) completed TAS Test and CANTAB; 459 underwent ptau181 analysis. All keyboard tests improved prediction of asymptomatic episodic memory decline; the 3 step‐ (ΔAIC = 11.2; R2
adj = 8.1%) and alternate‐ key (ΔAIC = 3.3; R2
adj = 7.5%) tests ranked highest and were the only keyboard tests to improve prediction of ptau181 (3 step ΔAIC = 7.0; R2
adj = 17.8%; alternate key ΔAIC = 3.4; R2
adj = 17.4%). All finger‐thumb motor measures improved predictions of CANTAB scores and ptau181 levels; the highest performing tests were dominant hand tapping (CANTAB ΔAIC = 2.9; R2
adj = 8.2%; ptau181 ΔAIC = 2.4; R2
adj = 12.9%) and both hands dual‐task tapping (CANTAB ΔAIC = 3.0; R2
adj = 6.8%; ptau181 ΔAIC = 8.7; R2
adj = 11.9%).ConclusionTAS Test provides an accessible brief home‐based test for identifying preclinical AD risk. This novel approach holds potential as a pre‐screening/enrichment tool for identifying at risk cohorts for further investigation.
Identifying genes associated with Alzheimer’s disease using gene‐based polygenic risk score
Authors: Lai Dongbing , Zhang Michael , Li Rudong , Zhang Chi , Zhang Pengyue , Liu Yunlong , Gao Sujuan , Foroud Tatiana M. 
Published: December 2023

AbstractBackgroundRecent large‐scale genome‐wide association studies (GWAS) have identified >100 Alzheimer’s disease (AD) associated genes but together they only explain a small portion of AD heritability1‐11. Dramatically increasing the sample size can detect genes with small effects but it is not feasible in the near future. If polygenic risk score (PRS) calculated using SNPs located within genes (gene‐based PRS) has higher predictability, then these genes are likely AD‐associated. Additionally, many drugs target AD‐associated genes and they should be prioritized for future investigations.MethodWe used SNPs having the same directions of effects (concordant SNPs) in different large‐scale European ancestry AD GWAS cohorts (Kunkle et al, 20194,9, the UK Biobank8,9, FinnGen consortium1,12) to calculate gene‐based PRS. Retaining concordant SNPs excludes cohort‐specific findings and reduces false positives, thereby improving PRS predictability. We used megaPRS13 to measure the PRS predictability, which can use GWAS summary statistics as the target dataset13. Leave‐one‐cohort‐out (LOCO) strategy was used and for each LOCO, two GWAS cohorts were used as the discovery dataset and the third cohort was used as the target dataset. Genes identified by all three LOCOs were considered as AD‐associated. Given the large effect of APOE on AD prediction, LOCO was also performed excluding APOE. We then searched the Drug Gene Interaction Database14 for drugs targeting AD‐associated genes. To prioritize identified drugs, we use lmQCM15 and the STRING database16 to identify AD‐associated genes in the same co‐expression module or in the same protein‐protein interaction (PPI) network, respectively, as drugs targeting them may also have effects on other genes via co‐regulation and/or interaction and thus may have large efficacies.ResultUsing this strategy, we identified 389 genes, nearly half of which were not previously reported as AD‐associated. These genes explained large portions of heritability (47%‐97%). Sixty‐four genes were in the same co‐expression modules and/or PPI networks and 688 drugs targeting them were prioritized for further evaluation.ConclusionGene‐based PRS is a cost‐effective way to identify AD‐associated genes using currently available data. Co‐expression modules and PPI networks can potentially identify drugs having large efficacy which can be further investigated for their potentials to treat AD.
Developing an anatomically valid segmentation protocol for early tau regions: the anterior medial temporal lobe cortices
Authors: Sadeghpour Niyousha , Ittyerah Ranjit , Denning Amanda E , Trotman Winifred , Lim Sydney A , Chung Eunice , Sadaghiani Shokufeh , Prabhakaran Karthik , Bedard Madigan L , Ohm Daniel T , Schuck Theresa , Artacho‐Perula Emilio , Martin Maria Mercedes Iniguez de Onzono , Munoz Monica , Romero Francisco Javier Molina , Gonzalez Jose Carlos Delgado , del Mar Arroyo Jimenez Maria , del Pilar Marcos Rabal Maria , Sanchez Sandra Cebada , de la Rosa Prieto Carlos , Parada Marta Corcoles , Insausti Ricardo , Wuestefeld Anika , McMillan Corey T , Grossman Murray , Lee Eddie B , Detre John A. , Trojanowski John Q , Tisdall Dylan M , Irwin David J. , Wolk David A. , Yushkevich Paul A. , Wisse Laura EM 
Published: December 2023

AbstractBackgroundThe anterior portion of the medial temporal lobe (MTL) is one of the earliest regions showing tau deposition in Alzheimer’s disease (AD) and hence a key focus area for AD imaging biomarkers. However, the anatomical variability of the anterior MTL presents a challenge for segmentation protocols. Leveraging a novel postmortem dataset with histology and MRI, we aimed to develop a histologically‐informed segmentation protocol for the anterior entorhinal cortex (ERC), Brodmann Area (BA) 35 (approximates transentorhinal cortex), and BA36 for in vivo 3 tesla (T) MRI.MethodDigitized 50‐µm thick MTL Nissl‐stained coronal histology sections from 20 cases (Table 1) were annotated by expert neuroanatomists. Cases with and without neurodegenerative diseases were included to ensure broad generalizability of the protocol. The histology sections were registered to same‐subject 0.2×0.2×0.2‐mm3 9.4 T postmortem MRI and were analyzed together to determine the location of the histological borders of the MTL cortices in relation to anatomical landmarks observable on MRI.ResultThe distance between the anterior histological border of ERC, BA35 and BA36 was assessed in relation to different anatomical landmarks observable on MRI. The distance relative to the hippocampus was chosen, as there was relatively low between‐subject variability in distance (low SD in Table 2) and this region is easily identifiable on MRI. The ERC starts 4.75 mm (median) anterior to the hippocampus, BA35 9.25 mm and BA36 10.25 mm. There was no significant difference in distances between patients with and without neurodegenerative disease. Next, we analyzed the location of the ERC on histology sections. We determined that regardless of the depth of the collateral sulcus (CS) (contrary to more posterior regions), the inferior border of the ERC is on average at the edge of the CS and the superior border at the superior edge of the parahippocampal gyrus (Figure 1a), but at the halfway point for the first section with ERC. These segmentation rules for ERC can be applied to T1‐MRI (Figure 1b).ConclusionSegmentation rules for anterior BA35 and BA36 are under development. This histologically‐informed segmentation protocol is expected to improve the efficacy of imaging biomarkers for tau deposition in AD.