bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alzheimer’s Disease and Lewy Body Co‐Pathology Presenting with Corticobasal Syndrome
Authors: Nouh Claire Delpirou , Vallejo Kristen , Tan Simon , Zeineh Michael , Sha Sharon J , Nirschl Jeffrey 
Published: January 2025

AbstractBackgroundCorticobasal syndrome (CBS) corresponds to a clinical phenotype with heterogeneous neuropathology, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Alzheimer’s disease (AD), and synucleinopathies such as Lewy Body Disease (LBD), in rare cases. Previous reports of CBS‐LBD describe patients with diffuse LBD, a younger age of onset and occasionally lacking core features like REM sleep Behavior Disorder (RBD).MethodWe present a young patient with CBS who had a rapid progression and was found to have a high burden of limbic LBD and high AD co‐pathology at autopsy.ResultA 58‐year‐old right‐handed woman consulted for progressively worsening apraxia, writing, and visuospatial difficulties over the year prior to presentation. She had minimal short‐term memory loss initially, did not have RBD nor visual hallucinations and remained independent in activities of daily living. She scored 20/30 on the Montreal Cognitive Assessment, with difficulties in visuospatial and executive tasks. The neurological exam showed predominant apraxia, asymmetric parkinsonism and sensory neglect, all left‐sided. The brain MRI confirmed striking asymmetric atrophy affecting the right parieto‐temporal lobes. Cerebrospinal fluid (CSF) demonstrated decreased Abeta 42/tau index and elevated total and phosphorylated tau. Her condition progressed quickly over the next year, and she passed away four years after diagnosis. Brain autopsy showed asymmetric moderate‐severe cortical atrophy with abundant phospho‐synuclein positive Lewy bodies extending to the temporal but not frontal/parietal cortices, consistent with limbic (transitional) LBD and high Alzheimer’s disease co‐pathology (A3, B3, C3). There was severe Lewy body pathology in the hippocampal CA2 subfield, prominent phospho‐tau in the substantia nigra, severe neuron loss in the locus coeruleus, and severe gliosis in the motor cortex.ConclusionAD and LBD commonly occur together, but the frequency of AD and LBD as a cause of CBS is unknown. Here, we add to the literature of co‐pathology in CBS and consider that early age and rapid progression could suggest dual pathology and potential synergistic effects. CSF testing limited to AD biomarkers will miss this dual pathology. Thus, CSF α‐synuclein seeding amplification may help identify patients with dual AD‐LBD pathology and assist prognostication.
Contrasting Manual and Automatic Approaches for Extracting Linguistic Features in Predicting Alzheimer’s Disease through Chinese Speech
Authors: Wang Yi‐Hsuan , Fang Cheng Chia‐ , Chou Chia‐Ju , Liu Yi‐Chien , Lee Chia‐Ying , Chang Ya‐Ning 
Published: January 2025

AbstractBackgroundContinuous speech analysis is considered as an efficient and convenient approach for early detection of Alzheimer’s Disease (AD). However, the traditional approach generally requires human transcribers to transcribe audio data accurately. This study applied automatic speech recognition (ASR) in conjunction with natural language processing (NLP) techniques to automatically extract linguistic features from Chinese speech data. Machine learning (ML) models were then used to predict early AD. The obtained results were compared with those derived from manual processes.MethodContinuous speech samples were obtained from 81 native Chinese speakers in Taiwan performing a picture description task. The participants included 34 normal controls (61‐89 yrs) and 47 patients diagnosed with amnestic mild cognitive impairment (aMCI) and early AD (59‐89 yrs). Fifteen linguistic features (Table 1) were measured via both manual and automatic processes. In the automatic extraction process, an ASR model transcribed the speech automatically, followed by the application of NLP techniques for automatic extraction of linguistic features. To classify AD, six ML models were trained with the two sets of features, and their performance was compared. The training‐to‐testing data ratio was 7:3, and cross‐validation was employed to mitigate overfitting.ResultThe Random Forest classifier achieved the best prediction accuracy and F1 score in both the datasets processed manually (acc = 0.92, F1 score = 0.908) and automatically (acc = 0.88, F1 score = 0.857) (see Table 2). Figure 1 illustrates the top five linguistic features for both the manually‐processed (Figure 1A) and auto‐processed (Figure 1B) datasets. The results showed an overlap in three out of five key features were overlapped including mean length of utterance (MLU), long pause ratio and pronoun ratio.ConclusionOur automatic approach for extracting linguistic features achieved comparable accuracy (88%) with those extracted through human judgment in Random Forest classifiers (92%). Importantly, MLU emerged as the predominant feature in both manually‐ and automatically‐processed datasets. This outcome suggests a noteworthy decline in syntactic complexity during the early stages of AD in Chinese‐speaking patients.
Chimeric hippocampal organotypic slices enable the in vitro investigation of human iPSC‐derived microglia in a three‐dimensional environment with preserved neural network activity
Authors: Devoght Jens , Nonneman Annelies , Swijsen Sofie , Wuyts Dirk , Van den Daele Johanna , Maurin Hervé , De Vos Winnok H , Ebneth Andreas , Yu Shih Pei‐ , Almenar Juan Diego Pita 
Published: January 2025

AbstractBackgroundMicroglial cells have emerged as key players in the pathogenesis of Alzheimer’s disease (AD). They act as a first line defense and fulfil a crucial role during brain development and circuit homeostasis. Microglia are involved in the removal of debris, control neural activity, regulate synaptic plasticity, and synapse pruning. Normal microglial functioning can be impaired by aging, stress, and genetic predisposition, provoking a pathophysiological turnover towards excessive neuroinflammation, neurodegeneration and synaptic loss, all hallmarks of AD. Despite similarities between human and mouse microglia, major discrepancies exist across species regarding gene expression and functionality. Even more, a variety of human microglial risk genes lack the proper murine orthologues, urging for the use of human cell‐based assays. Although in vitro (human) cell culture systems provide useful insights of microglial functionality, they lack a functional three‐dimensional brain environment.To investigate human microglia in a functional brain network, we developed an easy‐to‐manipulate chimeric platform of murine hippocampal organotypic slice cultures (OSCs) with integrated human iPSC‐derived microglia.MethodOSCs depleted from endogenous mouse microglia were engrafted with human iPSC‐derived microglia to develop a chimeric OSC model which was validated using electrophysiology, immunostaining, RT‐qPCR and MSD.ResultThe intact neural network activity of OSCs and effects of microglial depletion and activation were verified using a high‐density multielectrode array. Further evaluation of endogenous microglial effects on synaptic signaling within OSCs was measured using whole‐cell patch‐clamp. A co‐immunostaining with STEM121 (human) and IBA1 (microglia) validated the engraftment and presence of mature human iPSC‐microglia. Morphological analysis of the engrafted human iPSC‐microglia revealed a larger cell body, a higher number of ramifications per microglia and an increase in length of these ramifications, when compared to monocultures. Besides validation of the expression of microglial markers and morphological assessment, proper functioning of these human iPSC‐microglia engrafted cells was confirmed. The engrafted human iPSC‐microglia revealed damage‐induced migratory responses and release of human‐specific proinflammatory cytokines upon LPS stimulation.ConclusionThe developed chimeric OSCs model with engrafted human iPSC‐microglia provides an ex vivo platform to investigate human iPSC‐derived microglia within a physiologically relevant and functional brain network.
Association between self‐reported SCD‐plus criteria and Alzheimer’s disease biomarkers in cognitively unimpaired older adults: meta‐analyses
Authors: Kuhn Elizabeth , Klinger Hannah M , Amariglio Rebecca E , Jessen Frank , Wagner Michael , Chételat Gael , Rentz Dorene M , Sperling Reisa A , Ebenau Jarith L. , Butterbrod Elke , van der Flier Wiesje M. , Sikkes Sietske A.M , Rami Lorena , Sánchez‐Benavides Gonzalo , Gifford Katherine A. , Van Hulle Carol A. , Buckley Rachel F ,   the Alzheimer’s Disease Neuroimaging Initiativethe Australian Imaging Biomarkers and Lifestyle flagship study of ageingthe A4 study team, the DELCODE study groupthe Harvard Aging Brain Study
Published: January 2025

AbstractBackgroundIn cognitively unimpaired (CU) older adults, the presence of a subjective cognitive decline (SCD) combined with evidence of abnormal b‐amyloid (Ab) is proposed as stage 2 of Alzheimer’s disease (AD) by the NIA‐AA framework (Jack et al., 2018). However, the associations found between SCD and preclinical AD are inconsistent across studies, highlighting the importance of better understanding which specific SCD features are associated with either Ab or tau burden.MethodsThe present study includes cross‐sectional data from 9 independent cohorts with a total of 7217 CU older adults (57% female), aged 69.34 (1.20) years, recruited from general and memory‐clinic populations. Ab and tau biomarkers were measured by positron emission tomography (PET) or cerebrospinal fluid (CSF). Using established cut‐offs, 28% of participants were Aβ+, and 12% were Aβ+T+ (approximately one‐third of the sample had available tau data). We examined four SCD‐plus criteria as well as the mean number of SCD criteria met (i.e., mean SCD‐severity) in relation to both biomarker status and levels in logistic/linear regressions adjusted for age and sex for each cohort. Summary statistics were extracted for meta‐analyses.ResultsThe overall frequency of stage 2 AD varied from 7‐16% [4‐26%] according to each SCD‐plus criterion endorsement. Only 1‐5% [0‐8%] of participants meeting the SCD‐plus criteria also had both high Aβ and tau burden (Fig.1). The presence of self‐reported memory decline (SMD), an associated concern/worry, and a higher mean SCD‐severity were each associated with high Ab (status and continuous). Only the latter was associated with high tau status (Fig.2). Onset of SCD within the last 5 years, and feeling of worse performance than same‐age peers, were not associated with AD biomarkers at a Bonferroni‐corrected threshold.ConclusionsOur results suggest that widespread endorsement of multiple SCD features is more powerful than a single criterion alone in identifying both Aβ and tau in CU older adults. We found that the isolated SCD criterion was particularly sensitive to elevated Aβ, even after adjustment for tau, supporting the power of SCD as a very early behavioral marker of preclinical AD.
Remote cognitive testing in Insight46: relationship to standard cognitive assessments and biomarkers of neurodegeneration
Authors: Giovane Martina Del , Leoni Marguerite , Giunchiglia Valentina , Cai Ziyuan , Street Rebecca E , Lu Kirsty , Wong Andrew , Popham Maria ,   Insight 46 study Team, Murray‐Smith Heidi , Richards Marcus , Crutch Sebastian J , Hampshire Adam , Schott Jonathan M 
Published: January 2025

AbstractBackgroundDementia‐related biomarkers can detect pathology years before clinical diagnostic criteria are met. Understanding the relationship between biomarkers and early cognitive changes is crucial as disease‐modifying therapies may have maximum benefits when delivered early. We aimed to demonstrate the utility of remote computerised cognitive tests in a large cohort of cognitively normal older individuals, comparing these to standard in‐person assessments and investigating their associations with biomarkers.MethodsUsing the Cognitron platform, we remotely deployed 11 computerised tests (Figure 1) in 255 members of the Insight46 study. Participants had previously completed biomarker and in‐person standard cognitive assessments at age 71‐73 (1). We generated brain, hippocampal, and white matter hyperintensity volumes, rates of brain and hippocampal volume change between age 71‐73, amyloid load (SUVR) and positivity as previously described (1). General linear models (GLMs) assessed the relationship between the Cognitron tests and biomarkers. Principal component analysis was used for dimensionality reduction, and bivariate correlations compared the standard tests total composite score with the Cognitron accuracy and response time (RT) composite scores. Canonical Correlation Analysis (CCA) further quantified these associations.ResultsOf 255 participants (132 males, 234 right‐handed, age at assessment 77), 66 were amyloid positive. Amyloid positivity was significantly predicted by RT for the Objects memory test (delayed recognition) (OR = 1.58 (95% CI 0.09,0.85)). We found an association between the Cognitron Objects memory tests and biomarkers (Table 1). Immediate recognition was significantly associated with hippocampal volume change (F(2,204) = 4.34; CI: ‐7.78, ‐7.74), while the amount of amyloid positivity was significantly predicted by delayed recognition (F(2,225) = 4.48; CI: ‐0.06, ‐0.04) and retention (F(2,204) = 3.47; CI: 0.01, 0.1). Both Cognitron accuracy and RT composites significantly correlated with the standard composite (r = 0.56, p<0.001; r = ‐0.32, p<0.001) (Figure 2). CCA indicated shared variance with significant canonical variables between the standard tests and the Cognitron accuracy (M1:r = 0.73, p<0.001; M2:r = 0.54, p<0.001; M3:r = 0.49, p = 0.01) and RT (M1:r = 0.54, p<0.001) scores.ConclusionsRemote computerised cognitive testing correlates with standard supervised assessments and holds potential for studying early cognitive changes associated with neurodegenerative biomarkers at scale and longitudinally.Reference1. Lane et al. (2017) ‐ BMC Neurol, 17(75). https://doi.org/10.1186/s12883‐017‐0846‐x
Association of Sleeping Pills on Anxiety Symptoms in Dementia and Borderline Groups: Insights from the 2022 National Health and Aging Trends Study
Authors: Yoo Sanghee , Hong Ickpyo 
Published: January 2025

AbstractBackgroundOld adults' sleep patterns change during the aging process1. Among old adults, 40% of individuals experience insufficient sleep and complain of sleeping disorder, including a decline in the quality of sleep2. Patients with dementia also experience sleep disorders, and the most common intervention for this is pharmacotherapy3,4. This study aims to investigate the relationship between anxiety and sleeping pills in patients with dementia and borderline groups.MethodIn this study, the 2022National Health and Aging Trends Study was used to examine the association between anxiety symptoms and sleeping pill use in patients with dementia and borderline groups. The analysis was conducted using a multiple regression model by accounting for demographics.ResultThis study analyzed a sample of 1,189 and there were 351 (29.52%) patients with dementia and borderline groups who reported taking sleeping pills. As a result of multiple regression analysis, the group that took drugs for sleep showed a significantly higher risk of anxiety symptoms than the group that did not take drugs (odds ratio [OR] 2.999; 95% confidence interval [CI] 2.235, 4.023). Compared to men, the risk of showing anxiety symptoms was significantly higher in women (OR 1.666; 95% CI 1.224, 2.267). Compared to whites, blacks had a significantly lower risk of anxiety (OR 0.770; 95%CI 0.535, 1.108).ConclusionThis study showed a strong association between sleep medication use and anxiety symptoms in American patients with dementia and a borderline group. This suggests the need for treatment that addresses the mental health of dementia and borderline groups who experience sleep disorders.
Exploring an Audio‐based Approach for Early Detection of Alzheimer’s Disease using Chinese Speech Data
Authors: Lee Hung‐Wei , Fang Cheng Chia‐ , Wang Yi‐Hsuan , Chang Ya‐Ning 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) has been associated with speech and language impairment. Recent progress in the field has led to the development of automated AD detection using audio‐based methods, because it has a great potential for cross‐linguistic detection. In this investigation, we utilised a pretrained deep learning model to automatically detect AD, leveraging acoustic data derived from Chinese speech.MethodSpeech samples from a picture description task were obtained from 81 native Chinese speakers in Taiwan. This group included 34 normal controls (NC) (14 females; age range: 61‐89 years; average age: 73.9 years; SD: 6.7) and 47 patients diagnosed with early AD (24 females; age range: 59‐89 years; average age: 76.8 years; SD: 7.6). The audio data were first segmented into 6‐second clips, resulting in a total of 1117 clips for the NC group and 1770 for the AD group. Due to the data imbalance, we equalized the groups by randomly selecting 1117 clips from the AD group. The dataset was then divided into a training‐to‐testing ratio of 8 to 2. The training clips were initially processed using a pre‐trained Wav2vec2 model to generate internal acoustic representations. Subsequently, these acoustic representations, now serving as feature data, were input into a two‐layer fully connected neural network for additional training and classification.ResultThe model achieved a training accuracy of 83%. Notable metrics for test performance were observed as follows: Accuracy ‐ 81.25%, Precision ‐ 80.92%, Recall ‐ 81.79%, and F1 Score ‐ 81.35%. These findings suggest a promising capability of wav2vec2 in Alzheimer’s Disease detection, demonstrating a commendable balance between precision and recall.ConclusionThe pre‐trained Wav2vec2 model emerges as a promising tool for AD detection through Chinese speech data. This research sets the foundation for additional investigation into the model’s potential for cross‐linguistic detection using speech data. Additionally, future work can also be conducted to investigate what acoustic features are used and their significances in classification process.
Discrepancy between Apolipoprotein E genotyping and proteotyping as a result of a nonsense mutation
Authors: Vandenbroucke Ina , Yuri Tatsushi , Dobbels Caroline , Minczakiewicz Dagmara , Kamada Jo , Nojima Hisashi , Aoyagi Katsumi , Van Dongen Jasper , Kucukali Fahri , Sleegers Kristel , Degrieck Rosina 
Published: January 2025

AbstractBackgroundApolipoprotein E (APOE) ε4 is a significant genetic risk factor for late‐onset Alzheimer’s Disease and appears to be closely related with brain amyloidosis. Current identification methods for APOE ε4 carriers are mostly based on genotyping which cannot always predict the specific ApoE protein isoform. We present a case study of a sample with a discordant result for genotype compared to the protein isoform (proteotype) and we reflect on possible implications for future applications.MethodProteotyping was performed on plasma using the Lumipulse® G Pan‐ApoE and Lumipulse® G ApoE4 <RUO> immunoassays on the LUMIPULSE G platform (Fujirebio, Japan). Isoelectric focusing electrophoresis (IEF) was performed using the Phenotyping ApoE IEF system (Joko Inc., Japan). Amplicon‐based sequencing of APOE on genomic DNA was performed by targeted long‐read sequencing on the Flongle platform using SQK‐LSK110 chemistry (Oxford Nanopore Technologies).ResultPrevious comparison of genotyping (by real‐time PCR) with proteotyping on 230 paired blood /plasma samples revealed one discordant result (ε2/ε4 genotype versus negative E4 proteotype), achieving a 99.6% concordance rate. The proteotype of this discordant sample was confirmed to be E2 with absence of E4 using IEF. Long‐read gDNA sequencing of the discordant sample revealed a nonsense mutation (c.745G > T; p.E249X) in phase with the APOE ε4 allele. This stop codon could either lead to a truncated protein, with a loss of function or altered function, or lead to degradation of the mRNA via the Nonsense Mediated Decay (NMD) pathway. Since the E4 isoform was not detected by the detecting antibody on the LUMIPULSE G platform, the most likely pathway is the degradation of the RNA by NMD, unless the E4 epitope was altered in the truncated protein.ConclusionApoE4 proteotyping offers advantages over genotyping by determining the effective presence of the protein in plasma, especially in case of mutations affecting the expression or function of the protein. Also, quantifying ApoE protein levels via immunoassays could yield insights into the relation of ApoE protein levels with pathology. Moreover, in case of potential future applications in a laboratory workflow, molecular testing could possibly be avoided, offering advantages in terms of turn‐around‐time and logistics.
TRIDENT cognitive substudy: preliminary results from a Brazilian cohort
Authors: de Souza Ana Cláudia , Borelli Wyllians Vendramini , Miyamoto Kendi Nishino , Alves Ana Claudia , Almudi Mariana , Hess Adriana Binsfeld , Kochhann Renata , Carbonera Leonardo Augusto , Martins Sheila O , Anderson Craig S. 
Published: January 2025

AbstractBackgroundIntracerebral hemorrhage (ICH) is the most severe and disabling stroke, accounting for up to 50% of the cases in low‐to‐middle‐income countries. High rates of cognitive decline and dementia follow acute ICH, due to the common underlying vasculopathy of cerebral small vessel disease (CSVD). The international clinical trial, TRIDENT (Triple therapy prevention of Recurrent Intracerebral Disease EveNts Trial), aims to determine the effectiveness of the fixed low‐dose Triple Pill combination of blood pressure‐lowering agents (telmisartan 20 mg, indapamide 1.25 mg, and amlodipine 2.5 mg) versus placebo on recurrent stroke and additionally on the secondary outcomes of cognitive decline and dementia. The aim of the Brazilian substudy is to assess the Triple Pill effectiveness on memory, cognition, and CSVD progression in ICH patients.MethodThis substudy is part of the TRIDENT international, multicenter, double‐blind, placebo‐controlled, parallel‐group, randomized controlled trial led by The George Institute for Global Health in Australia. A subset of participants recruited from Brazilian local sites are offered the opportunity to undergo additional cognitive assessments through gold‐standard neuropsychological tests at baseline (until up to 6 weeks post‐randomization), and 12 months. MRI evaluation of these patients will be performed to assess CSVD progression through specific parameters at baseline and 12 months.Primary Outcome (MRI) ‐ Changes in T2 FLAIR WMH volume between baseline and 12 months will be assessed.Secondary Outcomes (MRI)1. Whole brain atrophy measured by percentage brain volume change between baseline and 12 months on HIRES‐T1.2. Substructure change (cortical grey matter, white matter, and CSF) between baseline and 12 months.3. Change in the number of CMBs between baseline and 12 months on SWI.ResultThe study recruitment is ongoing.ConclusionThe substudy could potentially evaluate Triple Pill’s effectiveness on cognitive decline, dementia, and CSVC progression.