bluuebunny/crossref_metadata_2025_split huggingface dataset:
LANGaware: Robust Multimodal Machine Learning Methods for the Early Detection of Neurodegenerative and Psychiatric Diseases
Authors: Rentoumi Vassiliki , Vassiliou Evangelos , Pittaras Nikiforos , Demiraj Admir , Alexandridou Martha , Danezi Maria , Hatzopoulou Maria , Kamtsadeli Vassiliki , Papatriantafyllou John D , Paliouras George 
Published: December 2022

AbstractBackgroundMultiple neurodegenerative and psychiatric diseases can affect speech, manifesting as subtle changes in spoken language. We perform a rigorous evaluation of a Machine Learning (ML) pipeline on a large‐scale multiaxial experimental setting, to investigate its capacity for detecting early signs of cognitive decline as manifested in speech. Using a diverse dataset of speech samples spanning different languages, patient cohorts and cognitive status diagnoses, we propose that the developed pipeline showcases robust performance, facilitating efficient decision support for early cognitive decline detection.MethodWe build upon previous research efforts on data‐driven cognitive decline prediction. Random forest models are constructed from a dataset of more than 3000 audio recordings and ASR‐generated transcripts, constituting cognitive assessment test tasks (e.g. picture description, everyday activity recounting, etc.). A multimodal NLP and audio analysis procedure derives sophisticated predictive biomarkers, using three methods for feature selection, feature decorrelation preprocessing and rigorous, grid search‐based hyperparameter optimization. We introduce novel experimental axes of investigation, including the spoken language (English and Greek), single and multi‐task verbal task settings, and different neurodegenerative diseases for the pathological cohorts (Alzheimer’s Disease or Dementia, along with age and education‐matched healthy cohorts). Four different NLP analysis tools for tokenization, syntax and dependency extraction are considered, using both ML and Deep Learning (DL) techniques. Model stability and generalization is supported via 5‐fold cross‐validation and the use of a separate test set.ResultResults are validated against medical expert diagnosis. Αverage performance across all investigative axes reaches high scores for accuracy (0.73), sensitivity (0.72), specificity (0.74), precision (0.77), F1 (0.74), and AUC (0.78). Additional findings suggest that single‐task models outperform multitask ones (e.g. reaching AUC scores of 0.85). Moreover, cognitive decline detection is more efficient for pathological cohorts of Alzheimer's, versus patients with Dementias.ConclusionThe broad empirical evaluation verifies the effectiveness of the deployed ML system, adding evidence in favor of multimodal AI solutions for predicting early cognitive decline and showcasing their robustness in diverse evaluation settings. Future work includes leveraging DL methods for classification and evaluation on differential diagnosis discrimination tasks.
Amyloid independent pathways have an impact on longitudinal tau deposition
Authors: Vemuri Prashanthi , Lesnick Timothy G. , Przybelski Scott A. , Graff‐Radford Jonathan , Ramanan Vijay K , Lowe Val J. , Machulda Mary M. , Mielke Michelle M. , Petersen Ronald C. , Knopman David S. , Jack Clifford R. 
Published: December 2022

AbstractBackgroundAmyloidosis‐driven tau deposition has been a significant focus of imaging research in Alzheimer’s disease (AD). However, the 3R/4R tau seen in AD can be observed in the transentorhinal/entorhinal regions (Braak I/II) in the absence of amyloidosis. The underlying drivers of this phenomenon are not well understood. Our goal was to examine amyloid‐independent pathways of longitudinal Tau‐PET SUVR progression in the entorhinal cortex (ERC) using a broad range of risk and protective factors.MethodWe identified 449 participants from the population‐based sample of Mayo Clinic Study of Aging >50 years old with baseline amyloid PET and at least two serial tau PET scans (mean number of scans=2.3; mean follow‐up time=3.2 years). Using an amyloid SUVR cut‐point of 1.48, we categorized participants into A+ (n=167; mean age=77.5 years; 56% male; baseline ERC tau=1.20; 83% cognitively unimpaired) and A‐ (n=282; mean age=67.5; 56% male; baseline ERC tau=1.07; 92% cognitively unimpaired). We used an ERC tau SUVR cut‐point of 1.21 to determine T+. We fit mixed effects and growth curve models with age, sex, baseline amyloid, risk factors (midlife activities, sleep, stress, education/occupation, cardiovascular metabolic conditions) as predictors and longitudinal ERC tau as the outcome. We fit separate models in A‐, A+, and all participants.ResultsFor models of all participants and A+ participants, the only predictors of higher rates of ERC tau deposition were increasing age and amyloid SUVR (p<0.05). In the A‐ models (figure below), amyloid SUVR and age were predictors of baseline, but not longitudinal ERC tau. However, a greater number of cardiovascular metabolic conditions predicted a higher rate of ERC tau accumulation (0.007 (0.002), p<0.05). Only 13% of the 23 A‐T+ participants were APOE4 carriers (compared to 31% in the overall sample), suggesting the role of non‐APOE4 pathways to tau deposition.ConclusionOur results support previous evidence that significant amyloidosis is causal to higher rates of tau deposition. However, in those without significant amyloidosis, cardiovascular metabolic conditions predicted higher rates of ERC tau accumulation. Further work is warranted to investigate the mechanisms through which genetics, comorbidities, and lifestyle may play a role in early tau deposition.
Association of mitochondrial haplogroups and cognitive impairment in the Amish
Authors: Dorfsman Daniel A. , Prough Michael B. , Caywood Laura J. , Clouse Jason E. , Herington Sharlene D. , Slifer Susan H. , Adams Larry D. , Laux Renee A. , Song Yeunjoo E. , Lynn Audrey , Fuzzell M. Denise , Fuzzell Sarada L. , Hochstetler Sherri D. , Miskimen Kristy L. , Main Leighanne R. , Osterman Michael D. , Ogrocki Paula K. , Lerner Alan J. , Vance Jeffery M. , Cuccaro Michael L. , Haines Jonathan L. , Pericak‐Vance Margaret A. , Scott William K. 
Published: December 2022

AbstractBackgroundMitochondrial dysfunction is an important feature of Alzheimer’s Disease (AD) pathogenesis. Reduced glucose utilization and increased oxidative stress are intermediates through which impaired mitochondria may promote AD‐associated brain changes. Association between groups of variants (“haplogroups”) in the mitochondrial genome and AD have been reported for haplogroups U, J, and K. To test these effects in the Amish, we looked for evidence of association between AD‐associated haplogroups and cognitive impairment in a sample of aged Amish individuals.MethodCognitive status in adult Amish participants (n=670) with whole‐genome sequence (WGS) data was determined based on modified mini‐mental status exam results (3MS). An outcome of cognitively impaired (CI) was assigned to individuals with an education‐adjusted 3MS < 87 at any age. A status of cognitively unimpaired (CU) was assigned to those aged ≥ 75 scoring ≥ 87 on the 3MS. Mitochondrial variants detected by WGS were used to derive broad haplogroups for each sample using Haplogrep2. Mixed model association testing was performed in GENESIS with CI as the outcome, and haplogroup (U, J, or K), APOE ε4 carrier status (ε4 vs no ε4), sex, and age as predictors. Based on reports of sex‐specific haplogroup U effects on AD, a sex‐stratified analysis was conducted. A random‐effect kinship matrix was used to account for relationships.ResultAssociation between mitochondrial haplogroups U, J, or K and CI was not observed at a 5% significance level. The sex‐stratified analysis showed the strongest association of CI with haplogroup U (OR 1.8, 95% CI 0.92‐3.5) among women. Among men, the estimated effect was 0.77 (95% CI 0.37‐1.62). The overall direction of association was opposite in men and women, though neither was statistically significant at 5%.ConclusionAlthough significant evidence of a haplogroup effect on cognitive status was not observed, the moderate sex‐dependent effect of haplogroup U on impairment warrants further examination in an expanded dataset.Previously, haplogroup U was proposed as an AD risk factor among men, whereas it appears as a risk factor for CI in women in the present study.
The role of Abca7 in late‐onset Alzheimer’s disease animal models
Authors: Oblak Adrian L , Kotredes Kevin P , Ingraham Cynthia , Territo Paul R , Rizzo Stacey J Sukoff , Carter Gregory W , Sasner Michael , Howell Gareth R , Lamb Bruce T ,   MODEL‐AD
Published: December 2022

AbstractBackgroundAlzheimer's disease (AD) and other neurodegenerative diseases are typified by a robust microglial‐mediated immune response. Genetic studies have demonstrated that variants in microglial genes are linked to risk for AD. Genome‐wide association studies (GWAS) originally identified ATP‐binding cassette, sub‐family A, member 7 (ABCA7), as a novel risk gene of Alzheimer's disease (AD). Since then, accumulating evidence from in vitro, in vivo, and human‐based studies has extended this association, promoting ABCA7 as one of the most important risk genes of late‐onset AD (LOAD), harboring both common and rare risk variants with relatively large effect on AD risk. Besides associations with disease status, genetic and epigenetic ABCA7 markers show significant correlations with AD endophenotypes; in particular amyloid deposition and brain morphology. In conclusion, human‐based ‐omics studies provide converging evidence of (partial) ABCA7 loss as an AD pathomechanism.MethodTo investigate the impact of Abca7 gene expression on microglia biology and disease pathology, we have generated Abca7A1527G mice on an APOE4.Trem2R47H (LOAD1) and APOE4.Trem2R47H.hAß (LOAD2) background. Cohorts of mice were established at JAX and IU and aged to either 4 and 12 months (LOAD1) or 4‐, 12‐, 18‐, and 24‐month. In vivo behavior and wellness assays included continuous activity monitoring, frailty assessment, open field, grip strength, spontaneous alternation, rotarod, delayed spatial novelty, episodic memory, and general health were completed as well as MRI and PET studies. Post‐mortem studies included blood chemistry, immunohistochemistry, and molecular studies. Studies of transcriptomics and proteomics were also completed on brain tissue.ResultCorrelation of transcriptional profiling with human AMP‐AD modules determined individual and synergistic effects with genetic risk factors. At 12 months of age, LOAD1.Abca7A1527G mice show similar correlations to LOAD in Consensus Cluster B (immune system), Consensus Cluster D (cell cycle), and Consensus Cluster E (organelle biogenesis). Neuropathology analysis in brain tissue is in progress, as are cytokine panels in brain homogenates and plasma of LOAD2. Abca7A1527G mice.ConclusionOur findings provide evidence that Abca7 plays an important role in LOAD and the addition of Abca7A1527G to a sensitized LOAD model (LOAD1 and LOAD2) more closely align phenotypes in the mouse to outcomes observed in human AD.
Fingolimod (FTY720) offers neuroprotection against AlCl3 induced Experimental Dementia in Rats
Authors: Kumari Shilpa , Agrawal Mohit , Deshmukh Rahul Renukadas 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is an age related progressive neurodegenerative disorder mainly characterized by cognitive decline, synaptic loss, and other mental functions. Extracellular amyloid beta (Aβ) deposits and intracellular accumulation of neurofibrillary tangles of tau protein are the two major hallmarks of AD. Multiple etiological factors have been linked with AD pathophysiology, oxidative stress, neuroinflammation, neurotransmitter deficit and foremost are the dysregulation of lipid metabolism, consistently involve in AD pathology and cognitive deficit.MethodIn the present study, we have explored the neuroprotective potential of Fingolimod (FTY720), against Aluminium Chloride (AlCl3) induced experimental dementia in the rats. AlCl3 at the dose of 175mg/kg, p.o was given daily from 1st to 35th day. Spatial and non‐spatial memory was evaluated by using Morris Water Maze (MWM) and Object Recognition Test (ORT). We further performed biochemical tests to check the levels of different oxidative stress markers.ResultAdministered AlCl3 in rats produced cognitive deficit and caused significant elevation in markers of oxidative stress and showed degenerative changes in hippocampus and cortical brain region. On the contrary, fingolimod treatment attenuate AlCl3 induced cognitive decline, reduced oxidative burden and showed potential of restoring neuronal architecture and prevent neuronal loss in hippocampus and cortical brain region of the rats. The present study suggests that Fingolimod (FTY720) show beneficial effects in treating dementia.ConclusionOur data demonstrated that Fingolimod could prove to be a beneficial therapeutic target in the protection of neurotoxicity induced by Aluminium chloride and help in improving memory and other cognitive functions.
Early Discharge from home health therapy services for people with Alzheimer’s Disease and Related Dementias
Authors: Knox Sara , Downer Brian , Haas Allen , Ottenbacher Kenneth J 
Published: December 2022

AbstractBackgroundPeople with Alzheimer’s Disease and Related Dementias (ADRD) experience barriers to accessing care that they need, including home health therapy services (physical, occupational, and speech therapy). Clinicians report difficulty engaging patients with ADRD in therapy sessions, especially during the later stages of the disease. There is limited information about how the existing barriers and challenges impact an individual with ADRD’s likelihood of being discharged from therapy services earlier than planned. The purpose of this study was to examine the relationship between early discharge from home health services and (a) dementia severity, (b) caregiver support, and (c) medication management.MethodThis retrospective study derived data from 100% national Medicare Home Health data files from October 1, 2016 through September 30, 2017. A cohort of 111,537 Medicare Fee‐for‐Service beneficiaries with ADRD was identified. A dementia severity categorization scale was used to classify individuals into one of six severity levels. Early discharge rates with associated 95% confidence intervals (CIs) were calculated for each patient characteristic. Multilevel logistic regression was used to estimate the relative risk (RR) of early discharge, by dementia severity level, caregiver support status, and level of medication assistance and adjusted for patient and clinical characteristics.ResultThe overall early discharge rate was 13.3% (13.1, 13.5). Individuals who were in the most severe ADRD stage were the only group that had an increased likelihood of being discharged early (1.163; 1.003‐1.344) amongst people with ADRD. However, individuals who required assistance with medication demonstrated a decreased likelihood of early discharge at all levels (0.828; 0.741‐0.924) There was no significant difference in likelihood for early discharge across caregiver support levels.ConclusionDespite a small increase in the most severe ADRD stage, the number of visits and the risk of early discharge was relatively consistent across severity stages. Further research is needed to assess whether the type and quality of services received varies across dementia stages. Individuals with ADRD who were independent with medication management had an increased likelihood of early discharge. Exploring this relationship in greater detail could inform clinician decisions about frequency and duration of care.
AUC Undermines AD Biomarker Discovery
Authors: Smith Kenneth , Climer Sharlee 
Published: December 2022

AbstractBackgroundEfforts are underway to accelerate precision medicine for late‐onset Alzheimer disease (AD). The realization of this endeavor can only be attained by identifying AD subtypes and developing methods to diagnose and treat each subtype. Liquid biopsies offer great potential for mounting this challenge. Identification of promising biomarkers requires evaluation of its ability to diagnose AD, and the area under the receiver operating characteristic curve (AUC) is commonly used for this purpose. This metric is equally weighted on the true positive rate (TPR) and false positive rate (FPR). When a given biomarker represents a single subtype, we expect the TPR to be relatively low as only a subset of AD cases are associated. Consequently, we hypothesized that screening based on AUC may discard valuable subtype biomarkers.MethodAn in silico experiment was conducted in which an ‘ideal’ biomarker for a subtype was modeled and the corresponding AUC was computed. A pseudo biomarker was designed to perfectly identify 20% of the cases and all other individuals were assigned levels near zero. Biomarker levels were generated to create a normal distribution centered on 0, with a standard deviation of 0.01, to represent 1000 controls and 800 cases, and 200 additional cases were represented by a normal distribution centered on 1, with a standard deviation of 0.2, to represent the subtype cases (Figs. 1 and 2). The experiment was conducted 1000 times.ResultThe mean AUC across the 1000 trials was 0.6001, with a maximum of 0.6292 and minimum of 0.5624. The standard deviation for the AUC values was 0.0109. The AUC plot for one of the trials is shown in Fig. 3.ConclusionThe pseudo biomarker perfectly identified 20% of the cases while having FPR = 0, yet it would likely be discarded due to the low AUC value, indicating that AUC is not a suitable metric for evaluating biomarkers for AD subtypes. Alternative evaluation metrics should be considered while traversing the path towards successful precision medicine for AD.
Targeted bisulfite sequencing analysis of candidate genes associated with Alzheimer’s disease.
Authors: Wheildon Greg , Smith Adam R. , Soanes Darren , Smith Rebecca G. , Moore Karen , O'Neill Paul , Morgan Kevin , Thomas Alan J , Francis Paul T , Love Seth , Mill Jonathan , Pishva Ehsan , Lunnon Katie 
Published: December 2022

AbstractBackgroundRecent epigenome‐wide association studies (EWAS) have identified a number of loci in specific genes that show robust and reproducible alterations in DNA methylation in Alzheimer’s disease brain samples. The standard method to assess methylation in EWAS is via microarrays, however, these only target a limited number of methylation sites in each gene. Therefore, further analysis of methylation changes across the entire gene are required to determine the exact extent and pattern of methylation changes in disease. In this study we have performed targeted bisulfite sequencing for candidate genes in the Brains for Dementia Research (BDR) tissue sample resource, which is a highly characterized cohort containing tissue with a high degree of standardized pathological, clinical and administrative data available to allow comparative studies.MethodPrefrontal cortex brain samples from 60 individuals were selected from the BDR cohort and grouped by Braak stage (Control 0‐II; mild cognitive impairment III‐IV; AD V‐VI). The DNA was extracted, before 30 genomic regions of interest, identified from previous AD EWAS, were captured using Agilent Sure Select target baits. The DNA was next‐generation bisulfite sequenced, before the sequence reads were aligned and the methylation status of cytosine residues were called using the Bismark Bisulfite Mapper program. Differentially methylated positions (DMPs) were then analyzed across the three groups.ResultThe degree and extent of methylation within the targeted genomic regions were identified and quantified for each group before being analyzed using linear regression models.ConclusionThis study builds on previous work that identified differential methylation in several genomic regions that were associated with Braak stage. By identifying the exact positions that are subjected to differential methylation this work provides further evidence that dysregulation of methylation is associated with pathological changes in AD prefrontal cortex.
Functional role of PLD1 signalosome in Tauopathies
Authors: Natarajan Chandramouli , Phan Phu Cuong , Thomson Bernadette , Krishnan Balaji 
Published: December 2022

AbstractBackgroundPhospholipase D (PLD), a lipolytic enzyme for membrane phospholipids, exists in two isoforms of mammalian phosphatidyl choline (PC) specific PLD, inducible PC‐PLD1 and constitutive PC‐PLD2. Elevated PLD activity is well documented in clinical studies involving Alzheimer’s disease (AD). Our lab was the first to show elevated PLD1 facilitates synaptic dysfunction and underlying memory deficits driven by amyloidogenic insults by Aß/tau. We observed preservation of memory in response to PLD1 specific small molecule inhibitor in transgenic mouse models and documented preservation of dendritic spines as a underlying basis. In this study, we explored a role for PLD1 in Frontotemporal Dementia in an attempt to explore its pathological role in this tauopathy‐driven dementia.MethodWe studied altered expression/activity of key F‐actin signaling elements common to PLD1 signalosome in synaptosomal fractions of human post‐mortem FTD brain regions. Synaptic deficits associated with elevated PLD1 expression in human FTD samples was studied by Fluorescence Analysis of Single Synapse Long Term Potentiation (FASS‐LTP). Using immunofluorescence, we studied the association of PLD1 with tau, presynaptic and post‐synaptic receptors, and neuroinflammation markers.ResultElevated PLD1 expression in synaptosomal fractions of post‐mortem FTD brain tissues was corroborated by synaptic deficits and association of PLD1 with postsynaptic density protein (PSD95). FASS‐LTP assay indicated relatively lower long‐term potentiation in synaptosomal fractions of FTD brains as compared to the control brains implying synaptic deficits in FTD subjects.ConclusionIn the light of these observations, we conclude elevated PLD1 expression is associated with toxicity of tau causing memory deficits in FTD patients. This PLD1‐tau interaction alters PLD signaling partners such as mTOR (mammalian target of rapamycin), cofilin and phosphocofilin. This would implicate the actin‐dependent remodeling of synapse to be a key step in the role of PLD1 signalosome in FTD. Delineating the effects of PLD1 signalosome in tauopathies such as FTD will hugely be beneficial in tau‐targeting therapeutics for a multipronged approach in the treatment of neurodegenerative disorders.