bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using a novel cognitive screening test to identify dementia risk amongst community‐dwelling cognitively unimpaired older adults from underserved populations.
Authors: Parra‐Rodriguez Mario A , Gonzalez‐Hernandez Alfredis , Bonilla‐Santos Jasmin , Cala Dorian , Gomez Duvan , Forero Eduardo A 
Published: January 2025

AbstractBackgroundRecent studies suggest that among cognitively unimpaired older adults, there are individuals who might present with subtle cognitive impairments suggesting the risk of Alzheimer’s disease (AD; Bos et al., 2018). The Visual Short‐Term Memory Binding Test (VSTMBT) identifies older adults who are accumulating AD pathology even though they are otherwise cognitively unimpaired (Parra et al., 2024). We investigated whether community dwellers from different socioeconomic groups above their 60s and displaying subtle VSTMB impairments also present neuropsychological profiles compatible with dementia risk.MethodsA sample of 235 community‐dwelling older adults were assessed with an extensive neuropsychological battery (Bonilla‐Santos et al., 2023) and a sensitive scale of functional abilities (T‐ADLQ; (Muñoz‐Neira et al., 2012). We divided the sample following recent recommendations drawn from the VSTMBT (Parra et al., 2024). We found that out of the total sample, 43 participants were classified as normal binders (performance on two VSTMBT above cut‐off), 99 were classified as suspicious binders (performance on at least one VSTMBT below cut‐off), and 93 were classified as weak binders (performance on both VSTMBT below cut‐off).ResultsGroup comparisons revealed that relative to normal and suspicious binders, weak binders have poorer performance on cognitive screening tools (MMSE, F(2,230) = 4.01, p = 0.019; ACE‐R F(2,230) = 3.4, p = 0.035) and functional scales (T‐ADLQ, F(2,230) = 4.53, p = 0.012). Such effects were unaccounted for by years of education, gender, socioeconomic status, comorbidities, or toxic habits. Age was a significant predictor with weak binders being older (F(2,234) = 6.31, p = 0.002). Assessment of subjective cognitive experiences (SCD) revealed no group effects (F(2,202) = 0.57, p = 0.566). Standard neuropsychological tests from the CERAD revealed marginal group effects for variables previously acknowledged as markers of AD.ConclusionsThe VSTMB test identified AD risk profiles in community‐dwelling older adults from an underserved population. The fact that such a test proved insensitive to gender, education, socioeconomic status, comorbidities and toxic habits, suggests that this assessment tool can be reliably used to identify, in community settings, older adults who are at risk of dementia even if they have not yet complained about their cognitive abilities or sought medical help.
Remote Naturalistic Speech Analysis as a Tool to Classify Behavioral Variant Frontotemporal Dementia
Authors: Vonk Jet M. J. , Morin Brittany T. , Dhanam Sreya , Clark Annie L. , Young J. Clayton , Taylor Jack C. , Rosado‐Rolon David , Heuer Hilary W. , Forsberg Leah K. , Boeve Brad F. , Rosen Howard J. , Tempini Maria Luisa Gorno , Boxer Adam L. , Staffaroni Adam M. 
Published: January 2025

AbstractBackgroundFrontotemporal dementia (FTD) is a diverse spectrum of neurodegenerative disorders impacting the frontal and temporal lobes, primarily manifesting as behavioral and/or language issues. Accurate diagnosis is crucial for effective management, potential treatment, and care planning. While speech analysis has shown promise in detecting cognitive markers of Alzheimer’s disease (AD), its exploration in FTD is limited. This study examined if linguistic features from remote, app‐based speech collection can differentiate healthy controls (HC) from individuals with behavioral variant FTD (bvFTD), the most common FTD variant.MethodParticipants included 15 bvFTD (mean age = 64.3, SD = 9.1 years) and 19 HC (mean = 55.8, SD = 14.2) from the ALLFTD Consortium. Participants were prompted to talk freely about a happy memory; audio recordings were collected with the ALLFTD Mobile App, transcribed using OpenAI’s large Whisper model, and manually quality‐checked. We extracted 98 linguistic features using our in‐house pipeline (Fig 1). Features were selected for classification analysis if they differed between groups based on a MANCOVA adjusted for age, sex/gender, and education, with feature reduction in case of collinearity. We then determined if these features could classify groups using multi‐variable logistic regression models, and subsequently calculated its ROC‐AUC score to measure sensitivity/specificity.ResultBased on the MANCOVA, three features were selected for classification analysis: average seconds of non‐speech (i.e., silence), ratio of number of complex nominal clauses to total clauses, and number of restarts (i.e., disfluency). The logistic model showed that this set could distinguish between groups (Omnibus p = .001; Nagelkerke R2 = .499), and their saved prediction probabilities indicated a ROC‐AUC score of 84.8% accuracy (Fig 2).ConclusionLeveraging a flexible speech capture app with remote accessibility and state‐of‐the‐art automated speech analysis, we identified linguistic features that can distinguish HC from bvFTD. This approach presents a promising screening tool for detecting bvFTD, offering quick, easily administered assessments with the potential for scalable implementation outside of clinical settings. Next steps are to investigate linguistic changes in presymptomatic mutation carriers and compare speech profiles between FTD and AD. These results hold meaningful implications for addressing current challenges in FTD therapeutics, potentially offering sensitive outcome measures for clinical trials and future tools for personalized cognitive assessment and long‐term monitoring.
Effect of administration of vitamin D3 alone or combined with donepezil on the memory of adult and aged ovariectomized rat
Authors: Danielski Lucineia , Medeiros Eduarda Behenck , Zabot Gabriel Casagrande , Vargas Adrielly , Fenilli Gabriela Piovesan , De Jesus Laura Ceolin , Silveira Gustavo De Bem , Giridharan Vijayasree V , Barichello Tatiana , Budni Josiane 
Published: January 2025

AbstractBackgroundThe increasing prevalence of neurodegenerative diseases, particularly among women post‐menopause, is linked to the decline in 17 β estradiol (E2). Vitamin D deficiency, common in older individuals, exacerbates this risk due to its anti‐inflammatory and neuroprotective properties. Hypovitaminosis D is associated with age‐related conditions, including cognitive decline. Donepezil, an acetylcholinesterase inhibitor used for Alzheimer’s dementia, targets cholinergic dysfunction in normal aging and prodromal states of this disease, suggesting a potential intervention for early disease modification.MethodAdult female Wistar rats aged 60 or 120 days were used, submitted to ovariectomy (OVX) for 1, 4, or 8 months, supplemented with vit D, at doses of 42 and 420 IU/kg, or water or combined with DONE (1 mg/kg) orally by gavage for 21 days. The open field test (OFT) and Y‐maze test were performed.ResultOvariectomized rats at 60 and 120 days of age exhibit deficits in short‐term spatial reference memory, as evidenced by performance in the Y‐maze task. In the OFT, 60‐day‐old rats subjected to OVX for four months displayed impairment, a trend also observed in rats of the same age undergoing OVX for eight months, both in the control and OVX groups. Notably, 120‐day‐old rats subjected to OVX for 4 and 8 months failed to learn, along with their respective control groups. However, the majority of interventions successfully reversed these memory impairments, with particular efficacy observed in treatments involving vitamin D at 42 IU/kg and the combination of vitamin D with DONE.ConclusionMemory impairment occurs as a result of ovariectomy (OVX). This effect persists with aging, and vit D, either alone or in combination with DONE, emerges as a significant alternative for reversing or mitigating this cognitive decline.
Exploring selective neuronal vulnerability in Alzheimer’s disease – key pathways are downregulated in vulnerable subpopulations of RORB and CDH9 excitatory neurons of the entorhinal cortex at Braak 0
Authors: Soloviev Alexander V. , Pereira Felipe Luiz , Leite Renata Elaine Paraizo , Suemoto Claudia Kimie , Leng Kun , Kampmann Martin , Grinberg Lea T. 
Published: January 2025

AbstractBackgroundUnderstanding the molecular mechanisms underlying selective neuronal vulnerability is crucial for developing effective treatments for Alzheimer’s disease (AD). Our group has shown that RORB/CDH9‐positive excitatory neurons in the entorhinal cortex (EC) display selective vulnerability as early as Braak stage (BB) 2. However, not all RORB/CDH9‐positive neurons are vulnerable. By further leveraging single‐nucleus RNA sequencing (snRNA‐seq) data, we aimed to identify molecular signatures of selective neuronal vulnerability. This involved comparing resilient‐like subpopulations (BB0 cells with RNA expressions similar to BB6) and vulnerable‐like subpopulations (BB0 cells with different RNA expressions than BB6) within each RORB and CDH9 subpopulation.MethodBioinformatic analyses were conducted using the Seurat R library on a published snRNA‐seq dataset of isolated nuclei extracted from the EC of postmortem brain tissue from healthy controls and AD patients (BB0 [n = 3], BB2 [n = 4], and BB6 [n = 3]) (Fig. 1). The Wilcox statistical test (p‐adjusted <0.05) was applied throughout the FindMarkers function to identify differentially expressed genes (DEGs) on vulnerable‐ and resilient‐like cells.ResultFrom the original dataset, with EC excitatory neurons (11488 nuclei), we found one RORB‐ and two CDH9‐positive (CDH9.2 and CDH9.9) vulnerable‐like neuronal subpopulations (Fig. 1). In RORB neurons, downregulated genes are involved in insulin signaling, autophagy, and ErbB signaling pathways (Fig. 2A). In CDH9.2 neurons downregulated genes are involved in membrane trafficking, axon guidance, proteasome‐mediated ubiquitin‐dependent protein catabolic process, and protein polyubiquitination (Fig. 2B). Additionally, in CDH9.9 neurons downregulated genes are involved in membrane trafficking, Ras protein signal transduction, GTPase activator activity, and ubiquitin‐like protein ligase binding (Fig. 2C). These three susceptible subpopulations share eight downregulated genes, some of which are highly involved in the Heme Biosynthetic Process. Heme is a common element linking various metabolic disruptions in AD, including oxygenase, mitochondrial dysfunction, and inhibition of muscarinic acetylcholine receptor binding.ConclusionOur analyses suggest that changes in metabolic, ubiquitin‐proteasome, and cell growth/survival pathways occur in vulnerable‐like cells of the EC in BB0. Therefore, these pathways may be potential therapeutic targets in the earliest stages of AD. By looking into younger cohorts, we will further investigate if the molecular differences between these neuronal subpopulations are canonical (indicating a pathological predisposition) or an early pathological response.
Contribution of neuropathological changes to cognitive decline in late life; The 90+ Study
Authors: Yu Jiaxin , Woodworth Davis C. , Bukhari Syed A. , Ezzati Ali , Montine Thomas J. , Kawas Claudia H. , Corrada María M. M. , Qian Tianchen , Sajjadi S. Ahmad 
Published: January 2025

AbstractBackgroundCognitive impairment and dementia in late life are often due to co‐occurrence of multiple neuropathologic changes (NC) leading to multiple etiology dementia (MED). Our aim was to assess the contribution of these NCs by first studying the shape of cognitive trajectories in the absence of pathology and then to capture the association between longitudinal change in cognition and multiple common age‐related NCs in an oldest‐old cohort.Method415 participants from The 90+ Study with longitudinal evaluations and autopsy data were included. The following criteria were used for NC presence: moderate or severe likelihood of Alzheimer’s disease NC (ADNC) according to NIA‐AA criteria; hippocampal or cortical limbic‐predominant age‐related TDP‐43 encephalopathy (LATE‐NC); presence of hippocampal sclerosis; limbic/neocortical Lewy bodies disease (LBD); moderate/severe scoring for cerebral amyloid angiopathy (CAA), atherosclerosis, and arteriolosclerosis, and ≥2 microvascular lesions (MVLs). We considered longitudinal scores of the clinical dementia rating sum of boxes (CDR‐SB), global cognition measured by mini mental state examination (MMSE), and composite scores for 6 cognitive domains (Figure 1). We quantified the time‐varying relationship between each of clinical and cognitive measures, as outcome, and the neuropathologic changes, as independent variables, using varying‐coefficient mixed effects models that can identify nonlinear relationships and account for within‐subject repeated measures. The models were adjusted for age at death, sex, and education.ResultTable 1 summarizes the demographic and neuropathologic characteristics of the participants. Mean age at death was 97.2, 68% were female, and 50% were college graduate. Most NCs were significantly more frequent in the dementia group. Figure 1 shows the trajectories of CDR‐SB and various cognitive domains in a hypothetical individual with no NCs. Attention and executive function showed early decline while CDR and cognitive domains showed an NC independent decline around five years before death. Figure 2 demonstrates the significant associations of NCs with decline in CDR‐SB and cognitive domains. LATE‐NC was the strongest predictor of CDR and cognitive outcomes closely followed by ADNC, HS, LBD, and MVL.ConclusionOur results demonstrate the contribution of various NCs to trajectories of cognitive outcomes in the oldest old and highlight the importance of non‐Alzheimer’s NCs in this age group.
Association Between Incident Neuropsychiatric Symptoms and Cognitive Decline in Cognitively Unimpaired Older Adults
Authors: Kim Therese H , Head Elizabeth , Stark Craig EL , Sordo Lorena , Sultzer David L 
Published: January 2025

AbstractBackgroundNeuropsychiatric symptoms (NPS) are highly prevalent in older adults. While the association between NPS and cognitive decline in older adults is widely acknowledged, there remains a lack of specificity regarding emerging NPS and cognitive outcomes in cognitively unimpaired older individuals. Our study assessed the incidence of NPS development, its link to cognitive decline, and other factors associated with development of MCI among cognitively unimpaired older adults without NPS at baseline.MethodUtilizing data from the UCI ADRC cohort, we included cognitively unimpaired participants without neuropsychiatric symptoms at baseline, followed longitudinally for at least 5 years. Comprehensive clinical assessments and expert diagnostic classifications occurred annually. NPS were evaluated using the Neuropsychiatric Inventory (NPI), the Mild Behavioral Impairment Checklist (MBI‐C), and the Geriatric Depression Scale (GDS). Demographic characteristics, cognitive test scores, ApoE genotype, CSF pTau181 level, and progression to MCI were compared between NPS developers and non‐developers. Logistic regression analysis, with progression to MCI as a dependent variable, was employed to explore factors influencing the likelihood of cognitive decline.ResultParticipants were followed for an average of 8.4 years. The rate of NPS development was 32.4%, and 13.1% of participants progressed to MCI. There was no significant difference in demographic characteristics, baseline cognitive test scores, or biological markers between NPS developers and non‐developers. NPS developers exhibited a significantly higher rate of progression to MCI compared to non‐developers (24.6% vs. 7.6%, p = 0.002). In logistic regression analysis to predict progression to MCI, NPS development emerged as the most significant factor (OR = 5.209, p<0.001), followed by high CSF pTau181 level (OR = 1.122, p = 0.012), ApoE4 carrier status (OR = 2.928, p = 0.027), and low 5‐minute recognition score on the CERAD Word List Test (OR = 0.405, p = 0.029).ConclusionThese findings underscore the importance of assessing cognitive change in cognitively unimpaired older adults with recent‐onset NPS. Additionally, they indicate the potential benefits of combining NPS assessments with biological markers and cognitive test scores to predict those at risk of cognitive decline. These results further support the role of NPS in the pathophysiology of cognitive decline.
Correlation between changes in apathy and cognition in Alzheimer’s disease associated apathy: analysis of the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2)
Authors: Sankhe Krushnaa , Tumati Shankar , Perin Jamie , Rivet Luc , Vieira Danielle , Rosenberg Paul B. , Herrmann Nathan , Shade David , Lerner Alan J. , Padala Prasad R , Brawman‐Mintzer Olga , van Dyck Christopher H. , Porsteinsson Anton P. , Craft Suzanne , Levey Allan I. , Mintzer Jacobo , Lanctôt Krista L. 
Published: January 2025

AbstractBackgroundApathy in Alzheimer’s disease (AD) is associated with cognitive impairment, particularly executive functions such as selective attention, making it unclear whether apathy should be a separate treatment target. Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) is the largest and most recent trial assessing apathy and cognition. This analysis assessed whether changes in apathy correlated to changes in various cognitive domains in ADMET 2.MethodIn this multicentre, randomized, placebo‐controlled trial, 200 participants with mild to moderate AD received 20 mg methylphenidate (MPH) or placebo (PLB) for 6 months. The Neuropsychiatric Inventory apathy (NPI‐A) subscale measured apathy. Cognitive tests included Mini‐Mental State Exam (MMSE), Hopkins Verbal Learning‐immediate (HVLT‐I) and delayed (HVLT‐D), Digit Span forward (DF) and backward (DB), Trail Making (TMT A and B), Action Verbal Fluency (AV), Category Fluency (CF), and Boston Naming Test (BNT). Linear mixed models were conducted with cognitive change scores as the dependent variable and time and change in NPI‐A as the independent variable, overall and in each treatment group. All models were adjusted for baseline cognitive test score and NPI‐apathy, age, sex, diabetes, and treatment group.Result199 ADMET 2 participants (131 (66%) male) were included. For all participants, worsening apathy was associated with worsening MMSE (B (SE) = ‐0.10 (0.03), p = 0.003), CF (B (SE) = ‐0.13 (0.04), p = 0.0009), and HVLT‐I (B (SE) = ‐0.13 (0.05), p = 0.005). In the MPH group (n = 98), worsening apathy was associated only with worsening CF (B (SE) = ‐0.21 (0.06), p = 0.0008). In the PLB group (n = 101), worsening apathy was associated with worsening MMSE (B (SE) = ‐0.13 (0.05), p = 0.006), HVLT‐I (B (SE) = ‐0.30 (0.06), p = 0.000002), and HVLT‐D (B (SE) = ‐0.06 (0.02), p = 0.002). Changes in apathy were not associated with performance on the remaining cognitive tests.ConclusionChanges in apathy are associated with changes in cognition as part of the natural history of AD. However, this association is disrupted by MPH treatment and suggests that improvements in apathy in AD with MPH were not driven by cognitive changes. These results are consistent with the view that apathy as a syndrome is related to, but distinct from cognition.
Gender differences in the association of depressive symptoms with neuroimaging outcomes in the LifeAfter90 Study
Authors: Posis Alexander Ivan B. , Lor Yi , George Kristen M. , Gilsanz Paola , Maillard Pauline , Decarli Charles , Kawas Claudia H. , Corrada María M. M. , Whitmer Rachel A. 
Published: January 2025

AbstractBackgroundDepressive symptoms are associated with reduced brain integrity. However, it is unclear if this association holds among a racially and ethnically diverse population aged ≥90 years and if there are differences by gender.MethodThe LifeAfter90 Study enrolled 212 long‐term members of Kaiser Permanente Northern California who were ≥90 years old, without dementia diagnosis, and received neuroimaging via 3T MRI. Depressive symptoms were measured using the 15‐item Geriatric Depression Scale (GDS). Neurodegeneration outcomes included volumetric measures (residual values accounting for total cranial volume) of total and bilateral hippocampus, regional cortical volume, and lateral and third ventricular volume, as well as amyloid PET, quantified as mean SUVR and amyloid positivity. Vascular injury outcomes included fractional anisotropy, free water, and log‐transformed total white matter hyperintensities. We used multivariable linear or logistic regression models to estimate associations between GDS and MRI outcomes adjusted for age at neuroimaging scan, gender, race/ethnicity, and education. We assessed effect measure modification by testing a gender‐by‐GDS interaction and gender‐stratified models.ResultParticipants had a mean age of 93.1±2.2 years, 58% were women, 22% African American/Black, 27% Asian, 17% Hispanic/Latino, 28% White, and 5% Other/Multiracial. Average GDS score was 2.1±2.0 (women = 2.1±2.1; men = 2.1±1.9), and 16% had scores ≥4 (range = 0‐11), which suggests significant depressive symptoms. While increased GDS scores generally trended with poorer neuroimaging outcomes (e.g., βFrontal Cortex = ‐0.29, 95% CI ‐0.88,0.30; except for occipital cortex volume, third ventricle volume, or vascular injury outcomes), associations were not significant in unadjusted (Figure) or multivariable models (p’s>0.05). There were differences by gender for third ventricle volume (p‐interaction = 0.01), such that increasing GDS scores were associated with lower third ventricle volumes among men only (β = ‐0.06; 95% CI ‐0.11,‐0.01). Increased GDS was associated with higher lateral ventricle volume among women only (β = 1.24; 95% CI 0.01,2.46), however the gender‐by‐GDS interaction was not significant (p‐interaction = 0.13).ConclusionIn this study of diverse adults aged 90+, increased depressive symptoms were associated with lower third ventricle volume among men and higher lateral ventricle volume among women. Results support future longitudinal study to understand change in neuroimaging outcomes that may be impacted by depression and gender among the oldest‐old.