bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a composite score to predict Lewy body pathology burden
Authors: Choudhury Parichita , Chen Kewei , Zhang Nan , Tremblay Cécilia , Ho Andrew , Belden Christine , Adler Charles , Shill Holly , Mehta Shyamal , Driver‐Dunckley Erika , Shprecher David , Serrano Geidy E , Beach Thomas G. , Reiman Eric M. , Atri Alireza 
Published: January 2025

AbstractBackgroundLewy body (LB) diseases can present with overlapping prodromal, cognitive, motor, autonomic or neuropsychiatric symptoms. Intuitively, greater symptom severity should correlate with greater pathological burden, but this has not been consistently shown. LB pathology does not translate to clinical expression in Incidental LB disease. While several composite scores/toolkits utilize overlapping schemes for diagnosis, a composite data‐derived score to predict LB pathologic burden is lacking. We aimed to utilize an autopsy‐confirmed cohort, and validated, brief, and standardized clinical, functional, pathologic assessments, and machine learning (ML)/quantitative modeling techniques to identify clusters and importance rankings among assessments/measures to predict LB pathologic severity and density.MethodA total of 234 subjects with neuropathological finding of LB at autopsy in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) who were classified as Cognitively Unimpaired or Mild Cognitive Impairment after their first study clinical evaluation were included. Of these, 145 subjects had complete scores for 32 of 46 measures (clinical, cognitive, behavioral and functional) that were utilized as predictors of LB pathology. Olfactory function was assessed using the University of Pennsylvania Smell Identification Test (UPSIT). LB severity was assessed by the Unified Staging System for Lewy Body Disorders (USSLB). Several ML algorithms and quantitative prediction models were explored and compared: artificial neural network (ANN), partial least square regression (PLSR), support vector regression (SVR), relevance vector regression (RVR) and ensemble forest regression (EFR) with leave‐one‐out (LOO) scheme. Game‐theory based Shapley methods assessed the impact, including rankings, consistency and magnitude, of model predictors.ResultRVR predicted aggregate LB density with large effect size (R2 = 0.691, p<0.00001). ANN predicted USSLB severity stage with large effect size (R2 = 0.74, p<2.5e‐43). All other ML algorithms/models provided substantial prediction. Across all models, UPSIT was the most influential predictor (>65%), followed by Controlled Oral Word Association Test (COWAT) and age.ConclusionThese preliminary and exploratory results support the utilization of ML techniques/models to assess LB pathologic burden with key measures collected in relatively small samples. UPSIT was consistently ranked highest impactful among clinical and functional measures/predictors. Integrated together in ML/data‐derived composites, UPSIT, COWAT and other clinical characteristics may be of antemortem utility to predict USSLB stages.
Optimizing the Assessment of Self‐Perceived Cognitive Functioning for Predicting Mild Cognitive Impairment: Integrating Traditional Methods with Daily Digital Diary Assessments: Results from the Einstein Aging Study (EAS)
Authors: Garza Angel Garcia De La , Mogle Jacqueline A. , Wang Cuiling , Katz Mindy J. , Derby Carol A. , Cameron Jack , Lipton Richard B. , Rabin Laura , Sliwinski Martin J. 
Published: January 2025

AbstractBackgroundEcological momentary assessments (EMA) are increasingly used to monitor self‐perceived memory and cognitive difficulties. We investigate how traditional self‐reported, recall based assessments of cognitive difficulties correlate with EMA measures. We identify factors explaining shared variance between measures from the 40‐item version of the Cognitive Change Index (CCI) and from EMA daily diaries, and factors explaining unique variance in each assessment. We compare EMA and CCI individually, as well as factors derived from both assessments, in predicting incident mild cognitive impairment (MCI).MethodsIn neuropsychologically unimpaired Einstein Aging Study participants, we collected daily digital diary data on 18 cognitive lapses and their perceived disruption of everyday function over 14 days. Additionally, we assessed the conventional recall‐based indicators using the paper‐and‐pencil CCI, referencing both current ability and change over five years. Bayesian Canonical Correlation Analysis (BCCA) was employed to identify factors explaining the relationship between EMA and CCI, and factors explaining the unique variance in each. Separate Cox regressions were employed to assess whether baseline standardized CCI total scores, total number of cognitive lapses reported on EMA, and factors derived from the BCCA, were associated with the incidence of MCI after adjusting for age, gender, race/ethnicity, and depression status.ResultsAnalyses included 205 community‐dwelling participants (mean age = 77.11, SD = 4.78, 66.82% female, 53.17% white) without MCI at baseline. We identified one shared factor between CCI‐40 and EMA that explains 69% of CCI‐40 variability and 12% of EMA variability (canonical correlation = 0.58). We also found two factors unique to EMA explaining 32% and 27% of the variance. The shared CCI‐EMA factor (HR = 1.56, 95% CI = 1.11‐2.19, p = 0.0017), and total CCI‐40 scores (HR = 1.60, 95% CI = 1.14‐2.25, p = 0.011), significantly predicts MCI incidence at any follow‐up. Neither of total number of cognitive lapses reported on EMA nor BCCA factors unique to EMA significantly predict incidence MCI.ConclusionsResults suggest that traditional assessments and EMA measurements of memory and cognitive difficulties provide both shared and unique information. This information could be harnessed using advanced data analysis techniques to improve the prediction of incident MCI.
Exploring relationships among neuropsychiatric symptoms, subjective cognitive complaints, cognitive performance, and incident dementia: Findings from the Sydney Memory and Ageing Study
Authors: Numbers Katya T. , Chander Russell J , Chen Jason , Brodaty Henry 
Published: January 2025

AbstractBackgroundSubjective cognitive complaints (SCCs) and neuropsychiatric symptoms (NPS) are emerging as potential early indicators of neurodegenerative diseases like Alzheimer’s disease (AD). SCCs refers to a self‐perceived decline in cognitive abilities without objective impairment, while NPS describe neuropsychiatric symptoms that emerge in later life that may precede or co‐occur with cognitive decline. This study explores the association between SCCs, NPS, global cognition, and incident dementia using data from the Sydney Memory and Ageing Study (MAS).MethodParticipants were 754 older adults from MAS (M age = 78.76, SD = 4.71) with a diagnosis of normal cognition at baseline. SCC was determined based on participants reporting having noticed changes in their memory. NPS was defined as having scored >1 on the Neuropsychiatric Inventory (NPI) total score. Participants were categorised into four groups based on the presence of SCC and/or NPS. Outcome variables were global cognition (composite z‐score derived from tests of attention/processing speed, language, executive functions, visuospatial abilities, and memory) and clinical consensus diagnosis of dementia according to DSM‐IV criteria.ResultOf the total participants, 217 (28.8%) had neither SCC nor NPS (SCC‐ NPS‐), 350 (46.4%) had SCC only (SCC+ NPS‐), 52 (6.9%) had NPS only (SCC‐ NPS+), and 236 had both SCC and NPS (NPS+SCC+). At baseline, SCC‐ NPS+ had significantly poorer global cognition than SCC‐ NPS‐ or SCC+ NPS‐. At wave 4 (6‐year follow‐up), SCC‐ NPS+ showed a steeper decline in global cognition compared to other groups. A greater proportion of SCC+ NPS+ at Wave 6 (10‐year follow‐up) had developed dementia compared to SCC‐ NPS‐. Multivariable logistic regression with age at baseline as the only covariate surviving stepwise elimination showed SCC‐ NPS+ (OR 3.70; SE 2.15; p = 0.025) and SCC+ NPS+ (OR 3.18; SE 1.25; p = 0.003) had increased odds over SCC‐ NPS‐ in developing dementia by Wave 6.ConclusionNPS is associated with poorer global cognition and, with or without SCC, is a significant long‐term risk factor for dementia. The findings highlight the potential importance of considering NPS alongside cognitive features, and suggest that assessing both neurobehavioral and neurocognitive dimensions could offer a more comprehensive risk assessment in cognitively normal individuals.
Progressive Dysexecutive Syndrome (PDS) due to Alzheimer’s Disease: Genetic and Neuroinflammatory Correlates in a Rapidly Progressive Case
Authors: Ritter Aaron , Brouwers Kaley , Kinney Jefferson W 
Published: January 2025

AbstractBackgroundMany patients present to our clinic with primarily executive rather than amnestic impairments. Recently, Townley and colleagues proposed criteria for a progressive dysexecutive syndrome (PDS). To date, PDS has been reported to be more common in younger individuals (55‐65 years old) and is associated with Alzheimer’s biomarkers (AD). Less is known about the genetic and neuroinflammatory profile of patients with PDS.MethodWe report the clinical, biomarker, genetic, and autopsy data of a participant from the Center for Translational and Neuroscience (CNTN) meeting criteria for PDS.ResultA 57‐year‐old left‐handed male presented with primary executive difficulties (bill paying, financial difficulties). Apathy was the only behavioral symptom reported. His initial neuropsychological testing showed impairments across a broad range of executive measures which worsened significantly over three years. Biomarker testing was consistent with Alzheimer’s disease (A+T+N+) with a significant elevation in plasma p‐tau 181 and neuroimaging showing peak involvement of the parietal lobes. Several plasma markers of neuroinflammation were elevated (GFAP, NFL) while others were depressed (IL‐6, IL‐10, TNF‐alpha). He was negative for autosomal dominant mutations (PS1, PS2, APP) but carried two apolipoprotein E4 genes (APOE 4/4) with an elevated polygenic risk score. Exome sequencing revealed polymorphisms within several known risk genes: CR1, PICALM, ABCA7. After experiencing a rapid cognitive decline, the participant died only five years after the onset of symptoms. Due to sparse neurofibillary tanges in the mesial temporal cortex he was characterized as having “hippocampal sparring” Alzheimer’s disease.ConclusionProgressive dysexecutive syndrome is a newly described variant of AD that affects younger individuals, causes impairments in executive functioning, and primarily impacts the fronto‐parietal networks. Findings from our case report suggest a possible neuroinflammatory susceptibility and multi‐factorial genetic basis.
Understanding the Interplay between Insulin Resistance and Cognitive Function: A Longitudinal study conducted in the Urban Cohort, Southern India
Authors: Menon Anjana J , S Monisha , Issac Thomas Gregor 
Published: January 2025

AbstractBackgroundRecent epidemiological studies have shown that diabetes can have negative effects on cognitive function, and insulin resistance (IR) acts as a key factor in this association. IR can impede glucose uptake in brain, leading to energy deficits and toxic protein accumulation which may cause cognitive decline. Type 3 diabetes mellitus (T3DM), or AD type of diabetes is caused due to impaired insulin signalling restricted to brain regions, resulting in memory decline. This study therefore aims to explore the link between IR and cognitive dysfunction, which will help in understanding the role of IR as a potential risk factor of cognitive impairment.MethodThis study utilized 1007 participants aged 45 years and above, recruited by CBR‐Tata Longitudinal Study of Ageing (TLSA), which is a community‐based urban longitudinal study cohort. 569 participants were with IR, and 438 participants were healthy. Addenbrooke’s Cognitive Examination (ACE III) was utilised to assess cognitive performance of the participants and IR was measured using Homeostatic Model Assessment‐insulin resistance (HOMA‐IR). Mann Whitney U test was performed to compare between ACE scores and IR status. Further, Generalized Linear Model (GLM) analysis was performed between cognitive variables and IR status after adjusting for covariates.ResultMann Whitney U test showed a statistically significant association between IR status and ACE scores in ACE total, ACE attention and ACE visuospatial. GLM analysis revealed a significant negative correlation between IR status and performance in attention (B = ‐0.271, 95% CI (‐0.468, ‐0.073), p<0.05), as well as in visuospatial tasks (B = ‐0.258, 95% CI (‐0.494, ‐0.022), p<0.05). After adjusting for confounders such as age, education, and inflammatory marker like CRP, results showed that ACE attention scores (B = ‐0.396, 95% CI (‐0.396, ‐0.008), p<0.05) were significantly lower in participants with IR.ConclusionAccording to the findings of our study, insulin resistance was associated with poor cognitive outcome in the attention domain. This finding could be attributed to the increased sensitivity of prefrontal cortex to altered insulin levels. Thus, considering the association between IR and cognition, it is important to devise strategies that can help in detecting and treating IR at an early stage to prevent cognitive impairment.
Efficacy of brexpiprazole on frequently occurring agitation behaviors in patients with dementia due to Alzheimer’s disease: post hoc pooled analysis of two randomized controlled trials
Authors: Brubaker Malaak , Wang David , Chumki Sanjeda R , Such Pedro , Zhang Zhen , Palma Anton M 
Published: January 2025

AbstractBackgroundPatients with dementia due to Alzheimer’s disease may experience multiple different agitation symptoms – including excessive motor activity, verbal aggression, and physical aggression – at varying frequencies. The efficacy of brexpiprazole 2 or 3 mg/day on 29 individual agitation behaviors (Cohen‐Mansfield Agitation Inventory [CMAI] items) was previously evaluated. Building upon that work, this post hoc analysis aimed to determine the efficacy of brexpiprazole on the same individual agitation behaviors, but specifically focusing on those patients who were frequently experiencing the behaviors at baseline.MethodData were included from two 12‐week, randomized, double‐blind, placebo‐controlled, parallel‐arm trials of fixed‐dose brexpiprazole in patients with agitation associated with dementia due to Alzheimer’s disease (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Efficacy was assessed using the CMAI, which measures the frequency of occurrence of 29 agitation behaviors (each scored 1 [never] to 7 [a few times an hour]). In this analysis, least squares mean change from baseline to Week 12 in each CMAI item score was determined in subsamples of patients for whom the corresponding behavior occurred at least once per week (item score ≥3) at baseline. Data for brexpiprazole 2 or 3 mg/day (FDA‐approved dose) and for placebo were pooled.ResultData were analyzed for 610 patients (brexpiprazole, n = 363; placebo, n = 247). At baseline, the mean (standard deviation) number of different agitation behaviors occurring at least weekly was 12.8 (4.3) per patient. The agitation behaviors most commonly occurring at least weekly were general restlessness (n = 572), pacing/aimless wandering (n = 513), and cursing or verbal aggression (n = 496). For some behaviors (e.g., intentional falling, n = 27), conclusions were limited by small subsample sizes. Across the CMAI items, least squares mean score changes from baseline to Week 12 ranged from ‐1.80 to ‐0.04 for brexpiprazole, and ‐1.34 to +0.84 for placebo, with a greater numerical reduction for brexpiprazole versus placebo on 24/29 items (Figure).ConclusionPatients with agitation associated with dementia due to Alzheimer’s disease exhibited many different frequently occurring agitation behaviors. Fixed‐dose brexpiprazole 2 or 3 mg/day was associated with a numerically greater reduction in the frequency of most of these frequently occurring agitation behaviors versus placebo.
Mild Behavioral Impairment association with the Visual Cognitive Assessment Test (VCAT) in a Southeast Asian Population with Vascular Mild Cognitive Impairment ‐ Biomarkers and Cognition Study, Singapore BIOCIS
Authors: Leow Yi Jin , Tanoto Pricilia , Vipin Ashwati , Azam Mohammed Adnan , Sandhu Gurveen Kaur , Lee Faith Phemie Hui En , Ghildiyal Smriti , Liew Shan Yao , Tan Isabelle Yu Zhen , Kandiah Nagaendran 
Published: January 2025

AbstractBackgroundThe Visual Cognitive Assessment Test (VCAT) is a visual based, language neutral cognitive assessment validated across cultures and ethnicities, that allows for early diagnosis of cognitive impairment. The VCAT assess domains of cognition – Memory, Visuospatial function, attention, language and Executive function. The Mild Behavioural Impairment Checklist (MBI‐C) was developed to assess five domains of NPS – Decreased motivation, emotional dysregulation, impulse control, social inappropriateness and abnormal beliefs/perceptions Current research indicates an association between MBI symptom severity and poorer cognitive performance in the domains of memory. We examined the association between mild behavioural impairment and domains of cognition as assessed by the VCAT in a multi‐ethnic Southeast Asian population.Method204 participants with vascular mild cognitive impairment (VMCI) were recruited from the community living in Singapore. VMIC was defined by Fazekas White Matter Hyperintensity(WMH) visual ratings of 4 and above. The mean age = 66.82 years, mean education = 13.54years with 39.8% males. Participants underwent neuropsychological assessments including the VCAT administered by trained raters and self‐reported questionnaires including the Mild Behavioural Impairment‐Checklist (MBI‐C).ResultThe VCAT‐Attention domain had a significant negative correlation with MBIC‐social subdomain (r = ‐0.276, p<0.05). With every 1 point increase in VCAT‐Attention. MBIC‐social subdomain decreased by 9% (estimate ‐0.357; 95% CI[0.516, 0.239]; p = 0.022).ConclusionCurrent research indicated that social isolation is one of the biggest risk factors for cognitive impairment, and our results reveal that social issues are associated with behavioural impairment as well. Attentional difficulties could lead to issues in inhibitory control, resulting in social inappropriateness. The V‐CAT’s ability to associate specific subdomains with MBI‐C subdomains suggest both tools could be a valuable tool for early detection and intervention in cognitive disorders.
A Data‐Driven Examination of Apathy and Depression in Cognitively Normal Older Adults
Authors: Da Silva Miguel Vasconcelos , Aarsland Dag , Ballard Clive G , Corbett Anne , Ismail Zahinoor , Creese Byron 
Published: January 2025

AbstractBackgroundApathy and mood symptoms are increasingly recognised as clinical important aspects of prodromal dementia; both are associated with increased risk of dementia even in cognitively normal people. The clinical overlap between apathy and low mood poses a challenge in distinguishing between the two conditions. It is crucial to differentiate between depression and apathy, along with any underlying syndromes, to facilitate the development of targeted treatments. Using a data‐driven approach, we recently reported the existence of distinct apathy and depression clusters in dementia, confirming observations from the clinic and epidemiology. In this study we sought to establish whether similar patterns of symptoms were present in cognitively normal older adultsMethodWe analysed data from 21,925 community dwelling older adults. Latent class analysis (LCA) was applied to self‐reported and proxy ratings (obtained using the Mild Behavioral Impairment Checklist) of apathy and mood. Polygenic Risk Scores for Alzheimer’s disease (AD) and Major Depression (MDD) were tested for associated with class membership.ResultThe LCA analysis using proxy data showed a 4‐class group which was considered the best model: No symptoms, Depression, Apathy/depression, and an Apathy group. The LCA using self‐reported data reveals the 4‐class group without a as a clear apathy class as the proxy data (see Figures 1 and 2). PRS for AD and MDD were only associated with depression and apathy/depression classes in self‐reported data (not in proxy data).ConclusionThis analysis highlights the apathy phenotype as a unique and separate condition, underscoring the imperative for additional research in this area. This emphasizes the potential for innovative approaches to delve deeper into the exploration and comprehension of apathy. The differences between the self and proxy reported data highlights the possibility of under reporting of apathy by patients.
Olfactory decline profiles and their association with dementia conversion in an older population with 12 years of follow‐up
Authors: Ekström Ingrid , Avelar‐Pereira Bárbara , Ruane Robert , Grande Giulia , Fratiglioni Laura , Larsson Maria , Laukka Erika J 
Published: January 2025

AbstractBackgroundOlfactory impairment represents an early sensory marker of neurodegeneration, but little is known about how interindividual differences in the trajectories of olfactory change relate to dementia conversion. We aimed to characterize olfactory decline profiles during phases of normal cognition to assess their predictive value for dementia conversion.MethodOlfactory trajectory profiles of dementia‐free persons (SNAC‐K; n = 1601; mean age = 70.0 years) were identified using growth mixture models (GMM) of repeated assessments with the Sniffin’ sticks odor identification task over 6 years of follow‐up. Olfactory functioning for old‐old participants (≥78 years) was assessed three times (at 3‐year‐interval), whereas young‐old participants (<78) were assessed twice (6‐year‐interval). Hazard ratio (HR) of dementia occurrence across 6 years after the olfactory trajectories were established was estimated with Cox regression. In total, participants were followed for up to 12 years.ResultGMM analysis identified three distinct olfactory trajectory profiles. As opposed to the “maintained olfaction” profile (n = 952), the “decline” (n = 433) and “accelerated decline” (n = 216) profiles were characterized by lower olfactory ability at baseline, a more rapid decline over follow‐up, and were associated with increased hazard of dementia (HR: 1.82; 95% confidence interval [CI] 1.12‐2.96 for “decline” and HR: 3.55; 95% CI: 2.09‐6.02 for ”accelerated decline”). Sensitivity analyses identified two olfactory trajectory profiles for old‐old (i.e., maintain and decline) and four trajectory profiles for young‐old participants (i.e. maintain, decline, accelerated decline, and pronounced decline). Associations between low‐performing olfactory trajectory profiles and dementia were particularly strong in young‐old participants with “pronounced decline” (n = 66, HR: 9.52; 95% CI:2.54‐35.72).ConclusionWe identified profiles based on olfactory decline trajectories in a sample that was initially cognitively normal. Participants with lower baseline olfaction and more rapid olfactory decline were grouped together, and these profiles were associated with an increased risk of developing dementia, as compared to participants who maintained their olfactory ability. Our results point towards a relatively early onset of dementia‐related olfactory decline. Intact olfactory ability in older age may indicate low risk of dementia conversion. As such longitudinal screening of olfaction may offer prognostic value.