bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vitamin D and donepezil intervention in ovariectomized rats: modulating neuroinflammation in the aging brain
Authors: Danielski Lucineia , Medeiros Eduarda Behenck , Fenilli Gabriela Piovesan , Zabot Gabriel Casagrande , Vargas Adrielly , Boaventura Amanda L , Lumertz Mariana Cardoso , Bobinski Franciane , Giridharan Vijayasree V , Barichello Tatiana , Budni Josiane 
Published: January 2025

AbstractBackgroundAging is a natural, irreversible process that can be successful or pathological, resulting in chronic degenerative diseases such as Alzheimer’s disease. Low levels of estrogen characterize menopause. Research reveals that the lack of these hormones may be related to dementia and that vitamin D (vit D), when supplemented, has a neuroprotective and neuromodulator effect.Method60‐ or 120‐day‐old Wistar rats were subjected to ovariectomy (OVX) for either 1 or 8 months, treatment with oral administration of Vit D (42 or 420 IU/kg) and/or DONE (1 mg/kg) spanned 21 days. On the 22nd day of the protocol, 24 hours post the final administration, the prefrontal cortex and hippocampus were dissected for cytokine analysis, including interleukin 10 (IL‐10), IL‐1 β, and tumor necrosis factor α (TNF‐ α), conducted through enzyme immunoassay.ResultIn 60‐day‐old rats undergoing one month of ovariectomy (OVX), elevated IL‐1β and TNF‐α levels were observed in the brain. The optimal dose for mitigating these effects was found to be vitamin D (Vit D) at 420 IU/kg, either alone or in combination with DONE. This dosage successfully reversed the increased IL‐1β levels in the frontal cortex and normalized the elevated TNF‐α levels in the hippocampus. Similarly, in rats subjected to OVX for eight months, the most effective dose for reversing increased IL‐1β levels in the frontal cortex and hippocampus was Vit D at 420 IU/kg. However, in this protocol, TNF‐α levels remained unchanged, emphasizing the selective impact of this particular dosage. Additionally, the optimal dose for modulating IL‐10 levels in the frontal cortex, particularly in the context of increased IL‐10 following OVX, was Vit D at 420 IU/kg.ConclusionThe administration of vitamin D either alone or in combination with DONE (a specific treatment) demonstrated favorable outcomes in the rats, effectively mitigating the inflammatory response.
Microglial extracellular vesicles’ proteome sheds light on the mechanisms underlying Alzheimer’s disease progression
Authors: Gabrielli Martina , Tonoli Elisa , Battocchio Elisabetta , Coveney Clare , Boocock David , Arancio Ottavio , Verderio Elisabetta A M , Verderio Claudia 
Published: January 2025

AbstractBackgroundWe recently demonstrated that large extracellular vesicles (EVs) released by Aβ‐loaded microglia and carrying Aβ (Aβ‐EVs) propagate synaptic dysfunction in the mouse brain by moving at the axon surface (Gabrielli et al., Brain, 2022; Falcicchia et al., Brain Commun, 2023). Compared to ctrl‐EVs, not carrying Aβ, a higher number of Aβ‐EVs move along axons and travel longer distances through a yet undefined mechanism. Our previous work indicates that large EVs motion can be passively driven by neurons, via EV interaction with a neuronal receptor linked to the cytoskeleton, or may happen autonomously when EVs contain actin filaments and ATP in their lumen. To get insights into the mechanisms underlying higher extracellular Aβ‐EVs motion, we here analysed microglial EVs proteome.MethodAβ‐EVs were obtained from primary microglia exposed to Aβ42. High‐resolution accurate‐mass spectrometry SWATH™‐MS followed by DIA‐NN quantitative analysis was employed to identify differentially expressed proteins in Aβ‐ vs. ctrl‐EVs, which may justify Aβ‐EVs empowered motility and describe the molecular mechanisms underlying EVs extracellular motion. Western blot and optical manipulation coupled to time‐lapse imaging were also employed to explore the involvement of additional candidate molecules, such as transglutaminase 2 (TG2).ResultA total of 148 proteins were upregulated in Aβ‐ compared to ctrl‐EVs, while 169 were downregulated. Panther GO analysis showed that terms enriched in large Aβ‐EVs include cytoskeletal protein binding (GO:0008092) and ATP hydrolysis activity (GO:0016887), suggesting that a higher fraction of Aβ‐EVs may undergo independent motion. STRING analysis revealed a high protein‐protein interaction (PPI) among Aβ‐EVs enriched molecules, some of which are differentially expressed also in EVs from AD/MCI patients or AD mouse models, validating the relevance of our findings.ConclusionOur data suggest that Aβ‐EVs higher motility and capability to propagate synaptic dysfunction may be due to their augmented capacity to undergo active motion, and identify novel proteins potentially involved in EVs motion. Further analysis will be necessary to validate these findings in AD.Fundings: 2018‐AARF‐588984, Horizon2020#874721PREMSTEM.
Predicting Objective Cognitive Impairment on MMSE with CDFAQ
Authors: Tavares Caio Peixoto , Maia Isabelle de Aguiar , Moro Giovanna Correia Pereira , de Souza Aline Siqueira , Ferreira Jéssica Diniz , Burgos Ivonne Carolina Bolaños , Engelmann Gabriela Tomé Oliveira , Diniz Maissa Ferreira , Romano‐Silva Marco Aurélio , de Paula Jonas Jardim , Bicalho Maria Aparecida Camargos , de Mattos Viana Bernardo 
Published: January 2025

AbstractBackgroundThe Cognitive Domains and Functional Assessment Questionnaire (CDFAQ) assess cognitive and functional decline for Neurocognitive Disorders based on the DSM‐5 criteria (1). It’s accuracy to the Informant Questionnaire on Cognitive Decline in the Elderly ‐ Long Version (IQCODE‐LV) has been assessed (2), and was translated and validated into English (3). The informant version (CDFAQ‐IV) assess: Complex Attention (CA), Executive Functions (EF), Learning and Memory (LM), Language (L), Perceptual‐Motor (PM) and Social Cognition.MethodsTo predict objective cognitive impairment on Mini‐Mental State Examination (MMSE) with CDFAQ‐IV. Both instruments were applied in 196 older adults and their informants. The cut‐off points on MMSE were 19/20 for illiterates and 23/24 for those with one year or more of formal education (4). A multiple logistic regression was made to assess the CDFAQ likelihood to predict a performance below the cut‐off points on MMSE controlled by years of age and of education. This study was approved by the ethics committee of UFMG.ResultsThe median age of the older adults was 73 years (IQR = 13.25), median years of education of 4 years (IQR = 5), median CDFAQ‐IV score of 64 (IQR = 9), and median MMSE score of 23 (IQR = 9). One hundred and six participants (54.08%) had impaired results on MMSE. When controlled by age and education, the Odds Ratio (OR) of one point increase in CDFAQ had an OR of 1.039 (p = 0.029) to predict an objective cognitive impairment on MMSE. A one‐year increase in formal education, had a decreased OR of 0.862 (p < 0.001). Age was not associated to the prediction of an objective cognitive impairment on MMSE, when controlled by education and CDFAQ performance (p = 0.106).ConclusionsYears of education and CDFAQ scores were related to the prediction of objective cognitive impairment measured by MMSE. These are still preliminary studies, but these results point to the need of considering the importance of years of education for future norms of the CDFAQ.
Androgen receptor upregulation regulates tau pathology in a female tauopathy mouse model
Authors: Munoz‐Mayorga Daniel , Lyu Xinchen , Tao Yuren , Kauffman Alexander S. , Rissman Robert A. , Chen Xu 
Published: January 2025

AbstractBackgroundAccording to data from the Alzheimer’s Association, more than two‐thirds of patients living with Alzheimer’s disease (AD) in the United States are women. The interplay between aging and hormone depletion during menopause has been proposed as a leading cause, but the molecular underpinnings of this vulnerability are not fully understood. On the one hand, approaches that seek to supplement estrogens to rescue pre‐menopausal hormonal levels have had contradictory outcomes in clinical trials. On the other hand, androgen effects in women in a neurodegeneration context are dramatically understudied. Furthermore, the number of XX chromosome individuals using androgens for sex‐reassignment purposes has steadily increased. Whether androgens can regulate tau pathology and how is poorly understood, especially in the context of female physiology.MethodWe performed a dihydrotestosterone (DHT) supplementation paradigm in 5‐6 month old P301S female mice and harvested brain tissue at 9 months of age. Pathological and biochemical tau markers, as well as androgen receptor content were evaluated in the hippocampus and cortex.ResultHere, we report an exacerbation of tau pathology in tauP301S female mice treated with DHT, an androgen receptor (AR)‐specific ligand, in the hippocampus, as evaluated by AT8 and MC‐1 immunostaining. Furthermore, we report upregulation of AR almost exclusively in neurons upon DHT treatment, potentially mediating our observations.ConclusionOur results implicate AR activation in females as a potential risk factor for tau pathology. Overall, the AD field will benefit from a more thorough understanding of neurodegeneration in women and transmasculine individuals, facilitating the identification of different risk and protection factor, paving the way to the development of novel and targeted therapies, and better addressing the health issues of our diverse society.
Cognitive profile of post‐COVID19 syndrome patients after cognitive rehabilitation on a six‐month follow‐up study in a public Brazilian center
Authors: Spera Raphael Ribeiro , de Luca e Tuma Raphael , Rodrigues Júlia Chartouni , Peixoto Satiko Andrezza Takano , Neto Adalberto Studart , Miotto Eliane C , Coutinho Artur Martins , Brucki Sonia Maria Dozzi 
Published: January 2025

AbstractBackgroundPost‐COVID19 syndrome is characterized by signs and symptoms that occur within 3 months of the onset of COVID19 acute phase and last at least 2 months. In the past 3 years, cognitive impairment has frequently been associated with COVID19 with descriptions of attentional, executive, memory, and language disorders. Many studies have assessed these cognitive disturbances using online and telephone tests, often in isolated interviews on a cross‐sectional design in high‐income countries. Few studies evaluated the role of cognitive rehabilitation in this situation.MethodObjective: To characterize the cognitive profile and psychological batteries of this population pre‐and post‐cognitive rehabilitation after 6 months. We selected patients younger than 65 years of age with COVID19 and cognitive symptoms for more than 3 and less than 6 months and no records of previous neurodegenerative or severe psychiatric diseases. They were evaluated 3 times (0, 3, and 6 months) with cognitive battery tests and questionnaires and later by a neuropsychologist for evaluation and cognitive training.Result46 patients were recruited; 41 matched the inclusion criteria and were referred to cognitive rehabilitation. 33 finished the third medical assessment. General and demographic data are shown in Table 1. Cognitive assessment in the first evaluation is demonstrated in Table 2. Only 32% of the sample had an unremarkable evaluation, and 68% were classified as having Cognitive impairment no dementia (CIND). Table 3 demonstrates patients that completed the follow‐up and the changes in cognitive tests at 6 months after rehabilitation, showing a statistically significant (p<0,05) improvement on some specific tests and questionnaires: Forward digit span, delayed memory on brief cognitive screening battery, lexical fluency (F‐A‐S), Boston naming test‐15, cognitive function instrument, geriatric anxiety inventory, and geriatric depression scale.ConclusionPost‐COVID‐19 syndrome and cognitive impairment are relatively common also in mild infection and healthy adult patients. After cognitive rehabilitation, we depicted significant results in attention, episodic memory, verbal fluency, and psychiatric symptoms.
Multi‐omics QTL provide insights into cell specific effects on molecular functions and intermediate traits in Alzheimer’s disease and its iPSC‐derived model systems
Authors: De Jager Philip L. , Wang Gao 
Published: January 2025

AbstractBackgroundWe examined AD‐associated loci to demonstrate how the new FunGen‐xQTL resource reveals new insights into the sequence of events leading from health to the amyloid and tau proteinopathies that define AD, as well as subsequent cognitive decline.MethodWe utilized FunGen‐xQTL resources (including cell subtype‐specific eQTL results) to deconstruct the genetic regulation and cellular specificity of AD loci. Using transcriptomic and proteomic data systematically derived from iPSC‐derived neurons and astrocytes in up to 48 iPSC lines we highlight and further dissect those genetic effects that replicate in the proper induced iPSC‐derived neuron (iN) or astrocyte (iAstro) model system.ResultWe will discuss illustrative results from our analyses, such as an interaction of CD33 and TREM2: the CD33 risk allele influences the abundance of the CD33 protein isoform and also affects the abundance of TREM2 protein in trans on the same cell surface. Further, in the APOE locus, the e2, e3, e4 haplotypes influence AD risk but not gene expression. We discovered a novel microglial‐specific eQTL for APOE driven by a variant that is not in linkage disequilibrium with APOEe4. Unlike APOEe4, this variant is not associated with AD susceptibility, but it is associated with cerebral amyloid angiopathy (CAA). Thus, APOE expressed by microglia is implicated in the emergence of CAA. Finally, we find that many neuron‐ and astrocyte‐specific QTLs discovered in single nucleus‐derived brain data, replicate in iN and iAstro. However, some eQTLs ‐ such as one affecting MAPT ‐ were significant in both datasets but had an opposite effect size in the iAstro/iN vs. the brain.ConclusionOur findings highlight how the FunGen xQTL integrated resource facilitates the discovery and elaboration of the causal chain linking a genetic variant to a series of molecular phenotypes and ultimately a clinical syndrome. We will gradually expand this foundation to map how AD loci interact with one another to perturb the molecular state of the brain and eventually lead to cognitive decline.
Novel mechanisms of cytosolic phospholipase A2 beta in neurodegeneration and cognitive impairments of Alzheimer’s disease
Authors: Ma Qiulan , Ebright Brandon , Li Jing , Dikeman Dante , Sanchez Ashley , Galvan Jasmin , Badie Daniel , Li Boyang , Wang Shaowei , Kerman Bilal Ersen , Hawes Debra , Hurth Kyle , Bennett David A. , Arvanitakis Zoe , Louie Stan G , Yassine Hussein N 
Published: January 2025

AbstractBackgroundSynaptic loss predicts cognitive decline in Alzheimer’s disease (AD). However, the critical disease modifying molecular mechanisms of synaptic failure remain elusive. Animal studies implicate the increased activation of cytosolic phospholipase (cPLA2) activation in synaptic loss and neuroinflammation. cPLA2 activation in human brain synapses have not yet been demonstrated. cPLA2 preferentially catalyzes the conversion of arachidonic acid (AA) to generate eicosanoids: lipid mediators of inflammation. Synaptosomes represent an excellent ex vivo model to study synaptic function in humans. Both PSD‐95 and CamKII are synaptic markers that play essential role in learning and memory. In this study, we sought to determine whether cPLA2β is associated with synaptic markers, AD pathology and cognition in synaptosomes derived from human brain tissues.MethodcPLA2β expression was analyzed in synaptosomes isolated from midfrontal cortex of postmortem brains in participants with no cognitive impairment (NCI, n = 20), mild cognitive impairment (MCI, n = 14) and AD (n = 19) from the clinically and pathologically well‐characterized Religious Orders Study (ROS). Experimental methods included Western blotting, immunofluorescence staining, and liquid chromatography‐tandem mass spectrometry to measure AA and its metabolites.ResultcPLA2β was increased in synaptosomes/synapses of both MCI (*p < 0.05) and AD (***p < 0.001) compared to NCI. cPLA2β was inversely corelated with global cognitive function (r = ‐0.3667, **p < 0.01), and positively correlated with neurofibrillary tangles (r = 0.2877, *p < 0.05). Interestingly, cPLA2β was highly positively correlated with postsynaptic proteins of PSD‐95 (r = 0.7901, ****p < 0.0001) and calcium/calmodulin dependent protein kinase II (CaMKII, r = 0.2825, *p<0.05). Immunofluorescence staining revealed the colocalization of cPLA2β with phospho‐tau (AT8), synaptic PSD‐95 and CaMKII in both AD and NCI brains. cPLA2β stained degenerative excitatory neurons. On a functional level, cPLA2b was positively correlated with AA (r = 0.5203, *p = 0.01) and its inflammatory metabolites of PGD2 (r = 0.496, *p<0.05) and PGE2 (r = 0.4623, *p<0.05).ConclusionThis is the first report revealing increased expression of cPLA2β in synaptosomes from brains with MCI and AD compared with controls. cPLA2β is associated with tau pathology, AA and its metabolites, synaptic and cognitive performance. Whether reducing cPLA2b reverses AD pathology merits further investigation.
Attention mechanism‐based prediction of early tau accumulation using MRI
Authors: Kim Jin‐Yang , Song Yeong‐Hun , Lee Wha Jin , Seong Joon‐Kyung ,   ADNI
Published: January 2025

AbstractBackgroundAssessing tau accumulation in early affected areas like the lateral entorhinal cortex (EC) and inferior temporal gyrus (ITG) enables early prediction of disease progression and cognitive decline. However, positron emission tomography (PET) imaging poses radiation exposure and cost concerns. This research aims to develop a deep learning model predicting tau positivity in these regions using MRI.MethodIn this study, we used the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, of which dataset was partitioned into train, validation, and test sets (8:1:1 ratio), encompassing a total of 1010 scans, all of whom underwent T1‐weighted magnetic resonance imaging (MRI) and [18F] flortaucipir‐PET imaging. For the T1‐weighted MRI images, FreeSurfer v7.2 was employed to perform pre‐processing and extract cortical thickness measurements. Simultaneously, [18F] flortaucipir‐PET imaging was processed to compute voxel‐wise regions of interest (ROIs) for 66 specific brain regions. Regional tau positivity was established using a cutoff at a z‐score of 1.25, with a focus on cognitive normal (CN) subjects within the train set. To predict early tau accumulation regions, we developed an attention mechanism‐based encoder‐decoder model by adopting a Transformer model into our problem setting, performing sequential predictions for each of the 66 regions. Notably, the model’s predictive performance in initial regions significantly influences subsequent predictions. Consequently, we implemented a prioritization strategy, emphasizing predictions from areas where the model demonstrated high accuracy. This approach was designed to enhance the overall predictive accuracy of the model.ResultPredicting five early tau accumulation regions per hemisphere, our model achieved an average AUC of 0.84 and accuracy of 84% for the test dataset (112 participants). Notably, in critical early disease progression regions (fusiform gyrus and ITG), AUC values of 0.84, 0.85, and accuracies of 84.4%, 84% were observed. Furthermore, the proposed prioritization strategy improved performance compared to predictions using vanilla attention‐based model.ConclusionWe developed an attention mechanism‐based architecture with an encoder‐decoder structure. By predicting outcomes not only based on cortical thickness values but also their cross‐attention‐based contexture information, we could achieve highly accurate tau prediction in early and challenging regions
Everyday functioning in young onset dementia: differences in diagnostic groups independent of disease stage
Authors: Weltings Emma , Postema Merel C. , Tewolde Mukrabe E. , Duits Flora H. , Lemstra Afina Willemina , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Sikkes Sietske A.M 
Published: January 2025

AbstractBackgroundYoung onset dementia (YOD) is characterized by an atypical clinical manifestation, and it is unclear to what extent impairments in everyday functioning are part of this manifestation. This study aims to describe the prevalence and differences of difficulties in instrumental activities of daily living (IADL) in YOD.MethodsIn this cross‐sectional study, 394 subjects with sporadic YOD (onset<65 years,mean(M)age 58.4±standard deviation(SD)4.4 years;49.2% female) were included from the Amsterdam Dementia Cohort (ADC). Diagnoses were established in multidisciplinary consensus meetings according to disease‐specific diagnostic criteria. Everyday functioning was assessed using the proxy‐based Amsterdam IADL Questionnaire (A‐IADL‐Q). Linear regression analyses were performed to assess differences between YOD subtypes in IADL with group (YOD subtypes with AD as reference group) and IADL as outcome, adjusted for age, sex, education and disease severity (Mini Mental State Examination). A bifactor analysis was performed to identify item clusters and explore differences between groups (using linear regression).ResultsThe majority of sporadic YOD were diagnosed with Alzheimer’s Disease (AD,n = 291(74%)), followed by Dementia with Lewy Bodies (DLB,n = 25(6%)), behavioral variant Frontotemporal Dementia (bvFTD,n = 49(12%)), Primary Progressive Aphasia (PPA,n = 20(5%)) and semantic variant Primary Progressive Aphasia (svPPA,n = 9(2%)). Most IADL difficulties were observed in DLB ((M) A‐IADL‐Q 41.8±(SD)7.78, reflecting moderate problems), and the fewest in PPA ((M)59.9±(SD)6.62, reflecting no problems)(Figure 1). When compared to AD (reference group), multiple linear regression analysis confirmed lower IADL scores for DLB (β = ‐6.37, SE = 1.63,p≤0.001), and higher for PPA (β = 10.29, SE = 1.76, p≤0.001), and svPPA (β = 6.83, SE = 2.61,p = 0.009), after adjustment for all covariates and confirmed in post‐hoc testing (Table 1). The bifactor analysis showed good reliability of the A‐IADL‐Q (Omega (ω_total) = 0.833), suggesting the presence of an underlying unimodal construct. Additional item clusters (Table 1) showed differences across groups, e.g. bvFTD showed more impairments in household activities compared to AD (β[95%CI] = ‐3.12 [‐5.64 – ‐0.61]). Further activity‐level differences can be found in Figure 2.ConclusionsOur results suggest that YOD‐subtypes differ in everyday functioning difficulties, independent of disease stage. These findings contribute to the understanding of everyday functioning difficulties in YOD, ultimately contributing to earlier recognition of the disease and personalized care.