bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Preliminary Validation of the Details of Function of Everyday Life Scale for the Detection of Early‐Stage Alzheimer’s Disease
Authors: Calia Clara , O'Donald Freddie , Parra‐Rodriguez Mario A 
Published: January 2025

AbstractBackgroundAssessments for early‐stage Alzheimer’s disease (AD) aim to identify neuropsychological and functional impairments, which rarely correlate with early disease stages. We need to enhance our understanding of the cognitive aspects contributing to functional decline to improve sensitivity in functional assessment. The ability to bind information in memory declines in preclinical AD stages. However, it is unclear whether such cognitive deficits underlie functional impairment in prodromal AD stages. To explore this, the Details of Function of Everyday Life (DoFEL) has been developed, aiming to link the cognitive constructs of memory‐binding to specific impairments in activities of daily living.MethodThe DoFEL underwent revision and latent structure exploration through Exploratory Factor Analysis in a non‐clinical sample (N = 559). This revised DoFEL was subjected to content validity review by eight dementia professionals, and factor structure was reassessed with Confirmatory Factor Analysis in a different sample (N = 135). Forty‐nine participants with MCI and thirty‐three healthy controls completed the DoFEL, Addenbrookes Cognitive Examination‐Revised (ACE‐R), and a Visual Short‐Term Memory Binding Task (VSTMBT). The correlation of revised DoFEL scores was examined in relation to ACE‐R and VSTMBT. Binomial regression was used to establish whether the revised DoFEL could differentiate healthy controls from MCI.Result(1) Conjunctive and relational binding appeared to be represented as dimensions within DoFEL subscales. However, the factor structure was not replicated across all subscales, suggesting further scale revision would be of benefit. (2) Dementia professionals considered the revised DoFEL useful for detecting functional impairment in early‐stage AD. However, the relevance of some items to binding was questionable due to their broad nature. (3) Performance on the revised DoFEL (higher score indicating impairment) strongly correlated with performance on the ACE‐R, r(82) = ‐0.663, p < .001, and moderately correlated with performance on the VSTMBT, r(82) = ‐0.518, p = 0.003. (4) The revised DoFEL differentiated those on a healthy ageing trajectory from individuals diagnosed with MCI, demonstrating comparability with the ACE‐R.ConclusionThese findings offer initial evidence for the validity of the DoFEL. It indicates that the connection between binding and performance in functional activities could offer a valuable avenue for improving functional assessment during early‐stage AD.
Tangle distribution is differentially influenced by age at onset, APOE ε4, and MAPT H1 along the corticolimbic axis
Authors: Boon Baayla D. C. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is heterogeneous in both its clinical and neuropathologic course. Age at onset and distribution of corticolimbic tangles can vary widely among individuals. Genetic risk factors APOE ε4 and MAPT H1 increase AD risk. However, the association with the spatial distribution of pathology remains a key gap in knowledge. We investigated the effects of age at onset, APOE ε4, MAPT H1, and family history of cognitive symptoms on corticolimbic tangle density variability to better distinguish how each factor contributes.MethodThe FLorida Autopsied Multi‐Ethnic (FLAME) cohort was queried for neuropathologically confirmed AD cases (n = 1233). Tangle density (count per 0.125mm2) was quantified using thioflavin‐S staining in nucleus basalis of Meynert (nbM), hippocampal CA1 and subiculum, association cortices, and primary cortices. Cortical thickness was measured using digital pathology on hematoxylin‐eosin‐stained sections. We employed univariate and multivariate negative binomial regression models to evaluate the association of each factor on tangle density across the corticolimbic axis. Multivariate analysis was adjusted for significant variables from univariate analyses.ResultDonors with young‐onset (<65) AD (YOAD; n = 314) had more tangles than those with late‐onset AD (LOAD; n = 919) across most corticolimbic regions (Fig. 1). Except for CA1, younger age at onset was associated with a higher expected tangle density with an increase ranging from 8% in subiculum up to 99% in motor cortex (Table 1). Male sex was associated with lower expected tangle density throughout all corticolimbic regions. Being male associated the strongest in visual cortex with a 41% tangle density decrease. The APOE ε4 allele associated with an increase of tangle density in the nbM, CA1, subiculum, and visual cortex, whereas the MAPT H1 haplotype associated with a decrease in association and motor cortices. A positive family history for cognitive problems was associated with a 16% decrease of tangle density in visual cortex. Tangle density correlated closely with (sub)cortical thickness in the CA1+subiculum, superior temporal, inferior parietal, and middle frontal cortex (Spearman Rho = ‐0.39 ‐ ‐0.58, p<0.001).ConclusionThese data contribute to the concept that brain regions may experience aging and genetics differentially, underlining the need to distinguish these aspects when investigating AD disease mechanisms.
Clinical criteria for a limbic‐predominant amnestic neurodegenerative syndrome highly associated with TDP‐43 and slow clinical progression
Authors: Corriveau‐Lecavalier Nick , Botha Hugo , Graff‐Radford Jonathan , Switzer Aaron , Przybelski Scott A. , Wiste Heather J. , Murray Melissa E. , Reichard Ross R. , Dickson Dennis W. , Nguyen Aivi T. , Ramanan Vijay K. , McCarter Stuart J. , Boeve Brad , Machulda Mary M. , Fields Julie A. , Stricker Nikki H. , Nelson Peter T , Grothe Michel J. , Knopman David S. , Lowe Val J. , Petersen Ronald C. , Jack Clifford R. , Jones David T. 
Published: January 2025

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a neuropathologically‐defined disease, and it is frequently comorbid with Alzheimer’s disease neuropathological change (ADNC). However, the neurological syndrome associated with LATE neuropathological change (LATE‐NC) is not defined. We propose a set of clinical criteria for a limbic‐predominant amnestic neurodegenerative syndrome (LANS) that is highly associated with LATE‐NC. These criteria assess degree of certainty (highest, high, moderate, low) based on features that are measurable in vivo, including older age at evaluation, a mild clinical syndrome, impaired semantic knowledge, disproportionate hippocampal atrophy, limbic hypometabolism, absence of neocortical degeneration patterns and low likelihood of neocortical tau. We operationalized these criteria using two large datasets with clinical and pathologic outcomes.MethodWe screened autopsied patients from Mayo Clinic and ADNI cohorts and applied the LANS criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; ADNI, n = 53). We compared frequencies of neuropathological diagnoses across LANS likelihoods, compared longitudinal CDR‐SB trajectories across LANS likelihoods, and stratified ADNC/LATE‐NC patients according to their LANS likelihood and compared their longitudinal CDR‐SB trajectories to those with ADNC or LATE‐NC.ResultADNC, ADNC/LATE‐NC and LATE‐NC accounted for 35%, 37% and 4% of cases in the Mayo cohort, respectively, and 30%, 22%, and 9% of cases in the ADNI cohort, respectively (Fig. 1). ADNC cases had the lowest LANS likelihoods, LATE‐NC patients had the highest likelihoods, and ADNC/LATE‐NC patients had intermediate likelihoods. Patients with high LANS likelihoods had a milder and slower clinical course and more severe temporo‐limbic degeneration compared to those with low likelihoods (Fig. 2). ADNC/LATE‐NC patients with higher likelihoods had more temporo‐limbic degeneration and a slower rate of cognitive decline, and those with lower likelihoods had more lateral temporo‐parietal degeneration and a faster rate of cognitive decline (Fig. 3).ConclusionThe implementation of LANS criteria has implications for disambiguating the different driving etiologies of progressive amnestic presentations in older age to guide prognosis, treatment, and clinical trial design and enrollment. The development of in vivo biomarkers specific to TDP‐43 pathology are needed to further refine molecular associations between LANS and LATE‐NC and precise antemortem diagnoses of LATE.
The association of body mass index with the mesolimbic system and cognition in Alzheimer’s disease
Authors: Li Qin , Li Xiaofeng 
Published: January 2025

AbstractBackgroundThe mesolimbic system plays a crucial role in weight regulation and cognition. Previous studies suggest that the pathology of Alzheimer’s disease (AD) can lead to the atrophy of the mesolimbic system and body mass index (BMI) decline. It remains unknown whether BMI is associated with the the mesolimbic system in AD.MethodThe data used in this study was obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. All participants underwent at least one Aβ PET imaging. PET imaging was carried out concurrently with brain MRI data and comprehensive neuropsychological assessments. Follow‐up data were collected at 2, 4, and 6 years. Hippocampus, amygdala, accumbens, caudate, and putamen were selected as regions of interest (ROIs) in the mesolimbic system. Linear regression was conducted to assess the relationship between BMI and cognition, and the volume of the ROIs. Linear mixed‐effects models were employed for longitudinal data analysis.ResultA total of 1182 participants were included in this study, including 608 cases of Aβ positive and 574 cases of Aβ negative. (1) Compared with the Aβ negative group, the Aβ positive group exhibited a decreased volume of hippocampus, amygdala, accumbens, and putamen and lower BMI (P < 0.01); (2) BMI was associated with baseline hippocampal volume (β = 0.12, P < 0.001), amygdala volume (β = 0.12, P < 0.001), accumbens volume (β = 0.07, P = 0.046), caudate volume (β = 0.09, P = 0.021), and putamen volume (β = 0.09, P = 0.023) in Aβ positive group, whereas, in the Aβ negative group, BMI was not associated with the volume of ROIs; (3) BMI was associated with baseline Mini‐Mental State Examination (MMSE) z‐score (β = 0.09, P = 0.002) and memory composite score (β = 0.07, P = 0.015), whereas, in the Aβ negative group, BMI was not associated with cognition; (4) longitudinal data analyses involving Aβ positive participants indicated that BMI was associated with the volume of hippocampus, amygdala, accumbens, putamen, MMSE z‐score, and memory score.ConclusionA lower BMI was associated with smaller volume of mesolimbic system and poorer cognition in AD patients.
Prostaglandin D2 synthase is differentially methylated specifically in Huntington’s Disease
Authors: Wheildon Greg , Weymouth Luke , Smith Adam , Smith Rebecca G. , Troakes Claire , Al‐Sarraj Safa , Lunnon Katie 
Published: January 2025

AbstractBackgroundHuntington’s disease (HD) is an autosomal dominant condition causing severe neurodegeneration in the striatum and the entorhinal cortex (EC). An epigenome wide association study of DNA methylation in HD by our group, identified potential hypomethylation at the PTGDS gene in the striatum. We aimed to validate this result through pyrosequencing, examining the locus in fine detail, and to assess the signal specificity by profiling multiple neurodegenerative diseases.Method379 EC and striatal DNA samples from 85 control, 73 Alzheimer’s disease (AD), 90 dementia with Lewy bodies (DLB), 20 HD, 34 Parkinson’s disease (PD) and 24 vascular dementia (VaD) subjects were matched for sex and age. DNA was bisulfite converted, before PTGDS target region amplification and subsequent pyrosequencing. Samples were analysed using linear models comparing the control group to each disease, controlling for sex, age, and batch effects. Average methylation levels across the amplicon were also compared. Additional analysis stratifying DLB and VaD cases by co‐existing AD pathology was also performed.ResultWe confirmed our previous findings of DNA hypomethylation at PTGDS in the striatum in HD. Furthermore, we found significant hypomethylation in the targeted region, both at the level of individual CpG sites, and across the amplicon in the EC. We also observed nominally significant changes in PD and DLB with co‐existing AD pathology across the amplicon, but these did not pass multiple correction.ConclusionThis study validates our previous findings of PTGDS hypomethylation in HD in the striatum and presents novel associations at the EC. Together, these findings suggest further investigation of PTGDS, given others report differential expression in HD oligodendrocytes. Future studies should address the cell‐specific profile of PTGDS methylation and its transcriptional regulation in HD through fluorescent activated cell sorting.
Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer’s disease
Authors: Huang Shu‐Yi 
Published: January 2025

AbstractBackgroundAlthough glymphatic function is involved in Alzheimer’s disease (AD), its potential for tracking the pathological and clinical progression of AD and its sequential association with core AD biomarkers is poorly understood.MethodWhole‐brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI‐ALPS) in participants with AD (n = 47), mild cognitive impairment (n = 137), and normal controls (n = 235) from the Alzheimer’s Disease Neuroimaging Initiative.ResultDecreased ALPS‐index was observed in AD dementia, prodromal AD, and preclinical AD patients. Lower ALPS‐index was significantly associated with faster changes in amyloid PET burden (AV45 PET) and AD‐signature ROI volume, higher risk of amyloid‐positive transition and clinical progression, and faster rates of amyloid‐ and neurodegeneration‐related cognitive decline. Furthermore, the associations of ALPS‐index with cognitive decline were fully mediated by amyloid PET and brain atrophy.ConclusionGlymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD.
The Dark Side of STING Signaling In Niemann‐Pick Disease Type C And Other Neurodegenerative Diseases
Authors: Chu Ting‐Ting 
Published: January 2025

AbstractBackgroundThe classic mode of STING activation is through binding the cyclic dinucleotide 2′3′‐cyclic GMP–AMP (cGAMP), produced by the DNA sensor cyclic GMP–AMP synthase (cGAS), which is important for the innate immune response to microbial infection and autoimmune disease. Modes of STING activation that are independent of cGAS are much less well understood. We wanted to explore the interactome of STING on the organelles during its trafficking route and to understand the regulatory network of STING signaling.MethodTo achieve this, we conducted an unbiased spatiotemporally resolved proximity labeling screen, followed by quantitative proteomics. This led us to discover a novel regulator of STING, NPC1, which is a lysosomal membrane protein that plays a role in cholesterol efflux. Mutations in NPC1 can cause Niemann Pick disease Type C, a neurodegenerative disease. Genetic deletion of Sting1 (the gene that encodes STING) or Irf3, but not that of Cgas, significantly reduced the activation of microglia and relieved the loss of Purkinje neurons in the cerebellum of Npc1−/− mice, leading to improved motor function.ResultWe found that NPC1 interacts with STING and recruits it to the lysosome for degradation in both human and mouse cells. Our findings also revealed that knockout of Npc1 ‘primes’STING signaling by physically linking or ‘tethering’ STING to SREBP2 trafficking. Loss of NPC1 protein also ‘boosts’ STING signaling by blocking lysosomal degradation. Both priming and boosting of STING signaling are required for severe neurological disease in the Npc1−/− mouseConclusionBoth priming and boosting of STING signaling are required for severe neurological disease in the Npc1−/− mouse. This study provides a comprehensive understanding of the STING interactomes and its regulatory network, shedding light on potential therapeutic targets for neurological diseases.
Computational Docking Analysis of APOE‐TREM2 Crosstalk with Therapeutic implications in Alzheimer’s disease (AD)
Authors: Basha SK Chand , Mekala Janaki Ramaiah 
Published: January 2025

AbstractBackgroundApolipoprotein E (APOE) and Triggering receptor expressed on myeloid cells 2 (TREM2) are the foremost genetic risk factors for late onset Alzheimer’s disease (LOAD). Recent findings suggests that crosstalk of APOE‐TREM2 has immunomodulatory effect on microglial phagocytosis, which have pathological implications in Alzheimer’s disease (AD). APOE has three isoforms: APOE (ε) 2, 3 and 4, with highest AD risk is attributed to APOE 4. R47H, a mutational variant of TREM2 increases the AD risk. The current work is done as a corroborating study, which is an extension of our work on computational investigation of TREM2 – Aβ ligands interaction.MethodThe coordinates of the APOE ligands‐isoforms: 2 and 4 were imported from the PDB database. I‐TASSER server was used for the structural prediction of TREM2 and R47H TREM2 proteins. HawkDock Server was utilised for the docking of TREM2‐APOE and R47H TREM2‐ APOE.ResultThe top model of TREM2 – APOE 2 docking exhibited a score of ‐ 5290.01 (Fig. 1). GBSA analysis reveals the binding free energy of the complex: ‐ 20.09 (kcal/mol). The top ranked docking model of TREM2 – APOE 4 exhibited a docking score of ‐ 5693.83 (Fig. 2) and binding free energy of the complex: ‐ 39.76 (kcal/mol). The top model of R47H TREM2 – APOE 2 docking exhibited a score of ‐ 4101.03. GBSA analysis reveals the binding free energy of the complex: ‐ 1.02 (kcal/mol). The top ranked docking model of R47H TREM2 – APOE 4 exhibited a docking score of ‐ 4969.52 and binding free energy of the complex: ‐ 10.03 (kcal/mol).ConclusionComputational docking analysis suggests that, TREM2 exhibited highest docking scores than R47H TREM2 which signify the latter’s role in increasing AD risk. Interestingly, both TREM2 and R47H TREM2 exhibited highest docking scores against APOE 4 in comparison with APOE 2. Our computational docking analysis has therapeutic implications in AD which requires further experimental verification.
ZNF653 transcription factor activity is associated with FDG‐PET changes in AD brain‐vulnerable regions
Authors: De Bastiani Marco , Povala Guilherme , Bellaver Bruna , Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , Rosa‐Neto Pedro , Zatt Bruno , Pascoal Tharick A. , Zimmer Eduardo R. 
Published: January 2025

AbstractBackgroundPositron emission tomography (PET) imaging greatly impacted Alzheimer’s disease (AD) research and diagnosis. which makes predicting PET brain imaging alterations using blood data is of high interest. Additionally, integrating PET and omics data can provide new insights into AD pathophysiology. Here, we implemented a module‐based framework combining blood transcriptomics with PET to search transcription factors (TFs) activities associated with brain metabolic changes in AD. We hypothesized that integrating omics and PET data will help advance our understanding of AD neurobiology and may reveal relevant new peripheral biomarkers.Methods[18F]Fluorodeoxyglucose ([18F]FDG)‐PET imaging and transcriptomics data were acquired from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Blood microarray gene expression from ADNI, GSE63063 and GSE97760 (https://www.ncbi.nlm.nih.gov/geo/) datasets were submitted to differential expression (DE) analysis. Regulatory units (regulons) of TFs and their predicted target genes were reconstructed using the ARACNe method. Altered regulons in AD submitted gene set variation analysis to infer their TF activity prior to neuroimaging integration with [18F]FDG‐PET images using voxel‐wise eneralized linear regression (GLR) models adjusted for age, gender, years of education, and APOEε4 (RMINC package).ResultsSixty‐one regulatory units were significantly enriched with altered genes in at least ⅔ of the datasets explored, and 12 were altered in all three (Figure A‐B). The voxel‐wise correlation between [18F]FDG‐PET and regulons resulted in t‐statistical maps, where uncorrected t‐value > 2.0 was used as the threshol. We observed that ZNF653 has a positive correlation with [18F]FDG‐PET in the precuneus (24.24% left, 39.51% right), medial frontal gyrus (17.26% left), medial frontal‐orbital gyrus (12.50% left) and precentral gyrus (9.08% left, 8.28% right). Interestingly, the ZNF653 regulatory unit is composed majoritarily by genes related to energetic metabolism and protein kinase activity (Figure 1C‐D).ConclusionWe identified the activity of the ZNF653 regulatory unit associated with [18 F]FDG‐PET metabolism in the brain of AD individuals. Furthermore, ZNF653 activity could be modulating metabolic and protein kinase activity‐related genes, highlighting a potential role of this TF in AD.
Assessing Short‐term Memory with Different Memory Modalities in Mild Cognitive Impairment
Authors: Smith Elaina , Cortez Christopher , Wiechmann April R , Davis Sandra , Dyson Hannah , Kucharski Krystyn , Ross Sarah M , Kline Geoffrey P , Mallet Robert T , Shi Xiangrong 
Published: January 2025

AbstractBackgroundMild cognitive function (MCI) is associated with a declined short‐term memory (STM). This study compared STM between adults with MCI and normal cognition assessed by verbal memory vs visuospatial memory.MethodsSixteen subjects with MCI and 11 subjects with normal cognition gave their written consent to participate in the study which was approved by the North Texas Regional IRB. Subjects having a self‐ or family member‐reported memory complaint, whose clinical dementia rating was ≤0.5, and/or whose testing scores in two or more cognitive domains were below the age‐/education‐adjusted group averages, were determined to have MCI. Digit‐Span‐Test (DST) and California‐Verbal‐Learning‐Test (CVLT‐II) were assessed for digit‐verbal memory and word‐verbal memory, respectively. Brief‐Visuospatial‐Memory‐Test–Revised (BVMT‐R) was performed for visuospatial memory. Values from the MCI and normal groups were compared using t‐tests. Two‐factor ANOVA was applied to test the significance of the group factor (i.e., MCI vs normal) and the trial factor (i.e., trials 1‐4 in CVLT‐II and trials 1‐3 in BVMT‐R).ResultsNeither group age nor education attainment was different in MCI vs normal (71.3±1.6 vs 67.9±1.7 years old). Although MMSE scores were not different between the groups, Trail‐Making‐Test performance was significantly poorer in the MCI. DST‐Sequencing scores were lower (P = 0.011) in the MCI (4.8±0.4) vs normal (6.4±0.3) subjects. However, neither DST‐Forward nor DST‐Backward scores differed between the groups. CVLT‐II immediate free‐recall and BVMT‐R recall scores were consistently superior in the normal vs MCI subjects (group factor P<0.001) and improved significantly with trial repetitions (trial factor P<0.001) in both groups. The rates of performance improvement with repeated CVLT‐II and BVMT‐R trials were similar in the groups, indicating similar learning effects. Both 30‐s short‐delayed and 10‐min long‐delayed free‐recall scores in CVLT‐II and 30‐min delayed recall scores in BVMT‐R were significantly lower in the MCI vs normal subjects (CVLT‐II short‐delayed: 6.9±0.3 vs 8.4±0.2 [P<0.001]; long‐delayed: 5.9±0.4 vs 8.2±0.3 [P<0.001], and BVMT‐R delayed recall: 5.1±0.9 vs 7.9±0.5, [P = 0.021]).ConclusionsBoth the verbal memory and visuospatial memory are significantly diminished, but learning ability may be preserved in MCI. CVLT‐II seems to be more specific and/or sensitive for detecting MCI‐related difference in STM.