bluuebunny/crossref_metadata_2025_split huggingface dataset:
The sex related association between TDP‐43 and cognitive function: a population‐based autopsy study
Authors: Silva Caroline Matos , Justo Alberto Fernando Oliveira , Leite Renata Elaine Paraizo , Paes Vitor Ribeiro , Grinberg Lea T. , Pasquallucci Carlos Augusto , Jacob‐Filho Wilson , Nitrini Ricardo , Suemoto Claudia Kimie 
Published: January 2025

AbstractBackgroundTransactive DNA‐binding protein 43 (TDP‐43) proteinopathy is associated with neurodegeneration, including LATE and linked to cognitive deterioration. While some research suggests a higher prevalence of TDP‐43 in women, no differences have been identified among racial groups. Nonetheless, the influence of gender on cognition within the context of TDP‐43 remains uncertain. Our objective was to investigate gender and racial distinctions in the relationship between TDP‐43 presence and cognitive function.MethodCross‐sectional study in a population‐based sample of 1,164 Brazilians from the Biobank for Aging Studies of the University of Sao Paulo Medical School. We used linear regression to evaluate the association of progressive LATE stages with cognitive abilities evaluated by Clinical Dementia Rating Sum of Boxes (CDR‐SOB). Models were adjusted for sociodemographic (age at death, sex, education, and race), clinical variables (hypertension, diabetes, heart disease, stroke, alcohol consumption, smoking, and body mass index) and neuropathological lesions (Braak staging, CERAD, Lewy body diseases pathology, lacunar infarcts, hyaline arteriolosclerosis and cerebral angiopathy amyloid). Additionally, we investigated the interaction of TDP‐43 pathology with race (white and black) and sex on CDR‐SOB.ResultSociodemographic and clinical variables were different between the participants with and without LATE (Table 1). Adjusted analysis, accounting for sociodemographic and clinical factors, revealed a significant association between the presence of LATE and impaired cognitive abilities (β = 5.13, 95% CI = 3.63;6.33, p<0.001). We did not find an interaction between race and LATE (p = 0.73). However, we found a significant interaction between TDP‐43 and sex (p = 0.001) (Figure 1). Upon conducting a stratified analysis, LATE had a more pronounced impact on cognitive abilities in women than in men (Men: β = 2.56, 95% CI = 1.26;3.86, p<0.001; Women: β = 4.94, 95% CI = 3.52;6.36, p for interaction <0.001).ConclusionThe presence of LATE is associated with poor cognition, particularly in women.
Cerebral vascular mitochondrial function is dependent on APOE genotype and estrogen status
Authors: Kehmeier Mackenzie N , Famiano Alexandra , Leonhardt Thomas A , Ferguson Sky J , Alkayed Nabil J , Walker Ashley E 
Published: January 2025

AbstractBackgroundPostmenopausal females who carry an APOE4 allele are at higher risk of late‐onset Alzheimer’s Disease (LOAD) compared to age‐matched APOE4 males. Estrogen deficiency predisposes females to an increased risk of vascular, cognitive and metabolic impairments. Estrogen and APOE genotype are known to impact metabolic and mitochondrial function in the brain, but their effects on cerebral vessels are unknown. Thus, the purpose of this study was to determine the interaction between APOE genotype and estrogen deficiency in relation to cerebrovascular mitochondrial function.MethodYoung female homozygous APOE3 and APOE4 mice (n = 6‐8 per group; 6 months old) fed a high‐fat diet were ovariectomized (“ovx”), ovariectomized and supplemented with 17β‐estradiol (0.36 mg, 60‐day release, “estradiol”), or left intact (“sham”). At 2 months after ovariectomy, a glucose tolerance test (GTT) was performed, then cerebral arteries and arterioles were dissected, incubated in saponin, then assessed for mitochondrial respiration in response to substrates probing carbohydrate metabolism (Oroboros). Data are presented as mean±SEM.ResultThere was an interaction between APOE genotype and ovx/estradiol status in relation to cerebrovascular complex I (CI)‐ (p = 0.04) and complex II (CII)‐coupled respiration (p = 0.04). Additionally, there was a significant effect of genotype, such that vessels from APOE3 mice had greater CI‐coupled respiration than vessels from APOE4 mice (p = 0.02). When examining differences between APOE3 groups, APOE3‐estradiol mice had a 53% greater CI‐coupled respiration than APOE3‐sham mice (15.4±3.4 vs. 7.2±1.2 pmol/(s*mg), p = 0.03) and a 60% greater CI‐coupled respiration than APOE3‐ovx mice (6.2±1.6 pmol/(s*mg), p = 0.007). The APOE3‐estradiol group also had greater CI+CII‐coupled respiration compared to both APOE3‐sham (50.8±7.1 vs. 27.3±1.7 pmol/(s*mg), p = 0.006) and ovx groups (28.0±5.7 pmol/(s*mg), p = 0.009). Interestingly, CI and CI+CII coupled respiration did not differ between sham, ovx, and estradiol in APOE4 mice (p>0.05). Maximal uncoupled respiration was greater in the APOE3 mice than APOE4 mice (p = 0.01). Whole‐body glucose tolerance did not differ between groups (all p>0.05).ConclusionOverall, these results indicate that APOE genotype modulates the impact of estrogen on the cerebrovasculature. We found that 17β‐estradiol enhances cerebrovascular mitochondrial function in APOE3 mice but not APOE4 mice. The results suggest that estradiol supplementation may have more therapeutic benefit for APOE4 non‐carriers.
The Association Between Mild Behavioral Impairment‐Apathy Symptoms and Cognitive Symptoms
Authors: Vellone Daniella Alicia , Guan Dylan X. , Ismail Zahinoor 
Published: January 2025

AbstractBackgroundApathy may appear as a less acute late‐life syndrome; however, it is associated with accelerated progression to dementia and contributes to adverse outcomes for patients and caregivers. These findings are not surprising since apathy can cause individuals to forego activities that improve cardiovascular and cognitive health (e.g., exercise), while inadvertently engaging in behaviors associated with greater dementia risk (e.g., social isolation). The objective of this research was to investigate the association between apathy symptoms (in the context of mild behavioral impairment [MBI)]) and cognitive symptoms. We hypothesized that greater MBI‐apathy severity would be significantly associated with greater severity of cognitive symptoms.MethodAll participants enrolled in the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging (CAN‐PROTECT) aged ≥50 years who had complete MBI‐Checklist (MBI‐C) and Everyday Cognition (ECog‐II) scores were included (n = 1339). Apathy domain scores for interest, initiative, and emotional reactivity were also generated using the six MBI‐C apathy items, and total apathy severity was the sum of all three domain scores. Likewise, ECog‐II domain scores for memory, language, visual‐spatial, and executive function were calculated as the sum of domain items, and total ECog‐II severity was the sum of all domains. Negative binomial regressions (zero‐inflated, if appropriate) assessed associations between total apathy severity and ECog‐II total scores. Domain‐specific analyses were also conducted. Covariates included age, sex, years of education, and non‐apathy MBI (affective dysregulation, impulse dyscontrol, social inappropriateness, psychosis) score.ResultAcross all participants (mean age = 64.5±7.4; 79.5% female), higher MBI‐apathy scores were associated with more severe cognitive symptoms (standardized β [95%CI], 7.2% [4.3‐10.2%]; p<0.001). Higher interest (16.5% [9.4‐24.1%]; p<0.01) and initiative (18.4% [11.9‐25.4%]; p<0.001) apathy domain scores were associated with more severe cognitive symptoms. Total apathy score was also associated with ECog‐II memory (4.9% [2.4‐7.4%]; p<0.001), language (5.6% [2.5‐8.6%]; p<0.001), visual‐spatial (8.3% [3.3‐13.2%]; p<0.01), and executive (10.7% [6.7‐14.7%]; p<0.001) domain scores.ConclusionThese findings provide valuable insight into the complex interplay between apathy and cognitive function, with potential implications for the development of targeted interventions for those affected by apathy‐related cognitive deficits.
Pathogenic Mechanism of PRNP 2‐Octapeptide Deletion Mutation in Creutzfeldt‐Jakob Disease
Authors: Wu Yiming , Nan Haitian , Zhang Yan 
Published: January 2025

AbstractBackgroundPrion diseases are a group of neurodegenerative diseases associated with prion protein. The disease can be caused by mutations in the PRNP gene, the gene that encodes prion protein. An octapeptide repeat on the N‐terminus of prion protein plays an important role in normal intercellular function of prion protein. At present, numerous prion disease patients with PRNP 2‐octapeptide deletion mutation case have been reported, but it is still unclear whether and how the mutation causes the disease. In this study, we aim to preliminarily identify the pathogenicity of PRNP 2‐octapeptide deletion mutation.MethodThe gDNA sample was obtained from a patient with familial creutzfeldt‐Jakob disease. The gDNA was identified to contain heterozygous PRNP 2‐octapeptide mutation deletion. We separated and amplified the gene and constructed N1 plasmid models with overexpression of the gene. Finally, we transfected HEK‐293T cell with the plasmid and used Western Blot to quantify the difference of apoptosis level of the mutated gene group and the control group.ResultDue to limited sample size, the result shows no significant statistical difference between the experimental group and the control group, but still reflected potential trend of increased apoptosis (p<0.1).ConclusionFurther study of this mutant gene is necessary to determine its pathogenicity.
Everyday functioning beyond cognition: Using Structural Equation Modelling to explore relationships between cognitive domains and everyday functioning in Alzheimer’s disease
Authors: van der Landen Sophie M. , Postema Merel C. , Tewolde Mukrabe E. , Barkhof Frederik , van Harten Argonde C. , Teunissen Charlotte , van de Giessen Elsmarieke , Ponds Rudolf W. H. , van der Flier Wiesje M. , Rhodius‐Meester Hanneke F.M. , Sikkes Sietske A. M. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) causes increasing cognitive and functional impairments, and both are therefore important outcome measures for intervention studies. Cognition and everyday functioning are often used interchangeably, yet the extent of their relationship is still unclear. We therefore aim to assess the relationship between different cognitive domains and everyday functioning across the AD spectrum.MethodsIn this cross‐sectional study, we included 613 participants (Mean age ± Standard Deviation = 64 ± 8 years, n = 298(52%) female) from the memory‐clinic based Amsterdam Dementia Cohort, who were amyloid‐β positive based on cerebrospinal fluid. Cognitive functions were assessed using a standardized neuropsychological test battery assessing three domains: memory (Rey Auditory Verbal Learning Test (RAVLT) and Visual Association Test (VAT)), executive functioning (Trail Making Test‐B, Digit Span forward and backward, and letter fluency DAT) and language (animal fluency and naming condition of the VAT). Everyday functioning was assessed by the proxy‐based Amsterdam Instrumental Activities of Daily Living Questionnaire (A‐IADL‐Q). Structural equation modelling (SEM) analysis was performed to examine the relationship between each of the cognitive domains (i.e., composite Z‐scores) as independent variables and everyday functioning as dependent variable, adjusted for age, sex and education. The relations between latent variables (cognitive domains) were calculated while accounting for measurement error in observed variables (cognitive tests).ResultsOf the 613 participants, the majority had a dementia diagnosis (n = 443, 72%), followed by mild cognitive impairment (n = 100, 16%) and subjective cognitive decline (n = 70, 11%). The SEM showed good model fit (CFI = 0.822), and confirmed that the latent cognitive domains (identified as memory, executive functioning and language) were substantially explained by their respective observed indicators with standardized estimates ranging from 0.44 to 0.91. Taking into account interdependencies and unexplained variance, the standardized estimate of memory was significantly related to the A‐IADL‐Q, demonstrating that approximately 28% of variance was explained by memory functioning.ConclusionMemory performance was found to be uniquely related to difficulties in everyday functioning, although to a limited extent. Our findings suggest that factors beyond cognition substantially contribute to everyday functioning, highlighting that both have independent value as outcome measures.
Language switching and executive control in bilinguals with Mild Cognitive Impairment
Authors: Calabria Marco , Suades Anna , Juncadella Montserrat , Ortiz‐Gil Jordi , Ugas Lidia , Sala Isabel , Lleo Alberto 
Published: January 2025

AbstractBackgroundBilingual Language Control (BLC) is a dynamic processing system that enables speakers to mitigate cross‐language interference while conversing and transitioning between languages. Research indicates that neurodegenerative diseases may compromise the effectiveness of language‐switching abilities in bilingual individuals, particularly those impacting the frontostriatal pathways. However, it remains unclear whether neurodegeneration affecting other neural pathways, such as Mild Cognitive Impairment (MCI), might influence the efficiency of BLC.MethodThe study involved 40 patients diagnosed with MCI and 30 older adults. All participants were proficient bilinguals in Catalan and Spanish and early proficiency in both languages. Each participant engaged in a set of five tasks, including one task focused on language control (language switching) and four non‐linguistic control tasks: task switching, n‐back, Spatial Stroop, and flanker task.ResultMCI patients exhibited higher switch costs (switch minus repeat trials) compared to healthy controls, while demonstrating similar mixing costs (repeat minus single trials). Within the non‐linguistic control domain, MCI patients showed significant performance deficits only in the n‐back task when compared to controls. The regression analysis model, which incorporated the performance of non‐linguistic tasks as predictors for language switching performance, did not yield statistical significance.ConclusionNotably, language control abilities may be compromised in bilingual patients even in the absence of neurodegeneration in brain regions traditionally linked to language selection and inhibition, such as the basal ganglia. Crucially, cognitive decline appears to have a more pronounced impact on language‐switching abilities than on the monitoring of the two languages. However, the existence of language control deficits does not correlate with executive control deficits, suggesting that these two control domains are not entirely overlapping.
Bilingualism and education may have distinct reserve/resilience trajectories: Evidence from white matter changes
Authors: Thanissery Nithin , Kenchaiah Raghavendra , Mekala Shailaja , Jala Sireesha , Khokhar Sunil Kumar , Rajan Amulya , Kashyap Vani , Surampudi Bapiraju , Kaul Subhash , Alladi Suvarna 
Published: January 2025

AbstractBackgroundBilingualism and education have been known to enhance reserve/resilience through white matter (WM) microstructural changes. Reserve/resilience is the ability of the brain to cope with neurocognitive adversities. Two key hypotheses have been proposed under this framework. Firstly, brain reserve, which refers to the structural integrity of the brain to preserve cognitive functioning. Secondly, cognitive reserve, which suggests that cognitive functioning can be maintained despite reduced structural brain integrity. Notably, the concepts of brain reserve and cognitive reserve exist along a continuum of brain health. Given the criticism surrounding bilingual literature due to the potential influence of education, the present study aims to delineate the effects of bilingualism and education (proxy measures of reserve/resilience) on WM integrity.Method40 cognitively normal older adults (20 bilinguals and 20 monolinguals) were recruited. Cognitive evaluation was carried out using a set of assessments/tests (see Table 1). Diffusion tensor imaging was done using a 3‐Tesla scanner. Tract‐based spatial statistics was performed. Fractional anisotropy (FA), axial diffusivity, radial diffusivity, and mean diffusivity were assessed.ResultBilinguals did not differ from monolinguals in age, sex, and socioeconomic status (Table 1). Bilinguals were more educated than monolinguals. Bilingual older adults had lesser WM integrity (i.e., lesser FA values) compared to monolinguals in the regions that adapt to bilingual experience as well as those that are affected by aging (figure 1). Despite having lesser FA, bilinguals had similar cognitive functioning compared to monolinguals (Table 1). Contrastingly, higher education was associated to higher FA values in several commissural and association WM fibres (figure 1). Education also showed a positive relationship with cognitive scores (figure 2).ConclusionThe study demonstrate that bilingualism is associated with better cognitive reserve (preserved cognition despite reduced structural integrity), while education is associated with better brain reserve (better structural integrity and cognition). Advances in reserve/resilience theory propose that the neuroprotective effect, which is responsible for better structure (brain reserve) will be followed by a compensatory effect (cognitive reserve) as the structural integrity decline over time. Our study suggests that bilingualism and education may have two distinct reserve/resilience trajectories in the face of age‐related changes.
Involvement of the choroid plexus in Alzheimer’s disease pathophysiology: A mouse and human proteomic study
Authors: Delvenne Aurore , Vandendriessche Charysse , Gobom Johan , Burgelman Marlies , Dujardin Pieter , De Nolf Clint , Tijms Betty M. , Schindler Suzanne E. , Verhey Frans R.J. , Ramakers Inez H.G.B. , Zetterberg Henrik , Visser Pieter Jelle , Vandenbroucke Roosmarijn E , Vos Stephanie J. B. ,   EMIF‐AD MBD study group
Published: January 2025

AbstractBackgroundStructural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer’s disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relationship between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans.MethodWe used an App knock‐in mouse model, AppNL‐G‐F, with amyloid pathology to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF, using liquid chromatography mass spectrometry. Mouse proteomes were investigated at 7 weeks old (n = 5) and at 40 weeks old (n = 5). Results were compared to human AD CSF proteomic data (n = 496; from EMIF‐AD MBD, Knight ADRC, and Maastricht BB‐ACL studies) to identify key proteins and pathways associated with ChP changes in AD.ResultCompared to wild‐type (WT) mice, AppNL‐G‐F mice aged 7 or 40 weeks old had significant differences in some protein levels in ChP tissue (Figure 1 and 2). At both ages, ChP tissue proteomic changes were related to pathways associated with epithelial cells, mitochondrion, protein modification, extracellular matrix (ECM) and lipids. Pathways related to lysosomal function, endocytosis, protein formation, actin, and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. Mouse CSF proteomics showed changes in similar pathways as seen in ChP tissue proteomics (Figure 3). Proteomic analyses were also performed in non‐demented human participants with abnormal amyloid but normal tau levels. Among proteins that were up‐regulated in CSF of those participants compared to controls, a significant number were predominantly expressed in the ChP (38 to 56% of the up‐regulated proteins). The dysregulated proteins with a predominant expression in the ChP in those individuals were related to similar pathways as seen in AppNL‐G‐F mice ChP tissue and CSF proteomics (Figure 3).ConclusionChP changes are associated with amyloid pathology. Key pathways involved in ChP dysfunction in AD are associated with the ECM, lysosomal function, lipids, protein processing, complement, vascular system and mitochondrion. The ChP could become a novel promising target for AD treatment.
Neuroinflammatory Stress Exerts Distinct Proteomic Effects on Soma, Synapses and Mitochondria in Excitatory Neurons
Authors: Espinosa‐Garcia Claudia , Srivastava Upasna , Kumar Prateek , Tobin Brendan R , Xiao Hailian , Cheng Lihong , Bagchi Pritha , Duong Duc M , Seyfried Nicholas T , Faundez Victor , Wood Levi B , Rangaraju Srikant 
Published: January 2025

AbstractBackgroundNeuroinflammation plays a critical role in Alzheimer’s disease pathogenesis. Neurons are anatomically divided in subcellular compartments (axons, soma, and synapses), which may be distinctly impacted by neuroinflammation. This study aims to examine cellular compartment‐specific proteomic signatures in excitatory neurons following a systemic neuroinflammatory stress.MethodWe used our innovative CIBOP (cell type‐specific in vivo biotinylation of proteins) approach to selectively label Camk2a excitatory neuron proteomes in vivo. Neuron‐CIBOP transgenic mice and their littermate controls were treated with lipopolysaccharide (LPS, [500 µg/kg, i.p.]) during 4 consecutive days, which induces robust microglial activation and sickness behavior. After euthanasia, brains were quickly removed, and crude synaptosomal fractions (P2 fractions) were prepared by differential centrifugation. Neuron‐specific biotinylated proteins were then enriched and analyzed by label‐free quantitative mass spectrometry (MS) to identify differentially‐enriched proteins (DEPs) and biological pathways (by gene set variation analysis/GSVA). Neuron‐derived biotinylated key cellular signaling pathways (MAPK and Akt/mTOR) were directly measured by Luminex in homogenates and P2 fractions (Fig. 1A).ResultElectron micrographs validated the subcellular composition of the P2 fractions showing synaptosomes containing synaptic vesicles and mitochondria (Fig. 1B). MS studies confirmed that neuronal homogenates were enriched in microtubule and cytoskeleton‐related proteins, while P2 fractions were enriched in mitochondria and synapse‐related proteins (Fig. 1C). Interestingly, LPS induced unique compartment‐specific proteomic effects, P2 fraction has 52 unique DEPs, while homogenate has 57 DEPs, and only 2 DEPs overlapped (Fig. 1D). Neuronal homogenate proteomes showed upregulation of detoxification and oxidoreductase activity, while a reduced neuron‐synapse, somatodendritic compartment, and cytoskeleton organization. In P2 fraction proteomes, LPS upregulated mitochondrial envelope formation and metabolic activity, including purine containing compound metabolic process, but downregulated nucleoside triphosphate regulator activity. Increased aerobic respiration and mitochondria response overlapped among compartments (Fig. 1E). We also observed LPS‐induced decrease in MAPK signaling specifically in the P2 fraction, not evident at the level of whole neurons, nor at the bulk brain tissue level (Fig. 1F).ConclusionOur neuron and synaptosome‐enriched proteomics approach revealed unique molecular and signaling effects of neuroinflammation that may preferentially impact the synapses of excitatory neurons.