bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glycemic variability and dementia risk in a diverse cohort of older adults with type 2 diabetes
Authors: Moran Chris , Whitmer Rachel A. , Dove Zoe , Lacy Mary E , Soh Yenee , Tsai Ai‐Lin , Quesenberry Charles P. , Karter Andrew , Adams Alyce S , Gilsanz Paola 
Published: December 2023

AbstractBackgroundType 2 diabetes is associated with a two‐fold increase in dementia risk. Although glycemic variability is becoming increasingly recognised as contributing to end‐organ damage, less is known about its contribution to dementia risk. We aimed to study the association between HbA1c variability and dementia risk in a large, diverse sample of people in Northern California.MethodOver 209,000 members of a fully integrated health care delivery system with type 2 diabetes aged ≥ 50 years were followed from 1996 to 2018 to obtain repeated measures of HbA1c, dementia diagnoses, and comorbidities. Variability was measured using standard deviation (SD), coefficient of variation, and average real variability. Cox proportional hazards models estimated the association between HbA1c variability in the first 3 years of cohort entry and incident dementia at least 2 years after the end of the exposure period adjusting for age (as timescale) and baseline health conditions.ResultThere were a total of 209,703 people in the cohort (mean baseline age 61.0 years (SD = 9.2), 47.5% women) (Table1). Approximately 49.6% of the sample were non‐Latino White. The mean number of HbA1c values available for each participant was 5.8 (SD = 2.3). The mean HbA1c for each participant in the first 3 years was 7.4% (SD = 1.33). Greater HbA1c variability was associated with greater hazard of dementia when measured using SD (aHR = 1.12 [95%CI: 1.10, 1.14]), coefficient of variation (aHR = 2.17 [95%CI: 1.85, 2.55]) (Figure1), or average real variability (aHR = 1.06 [95%CI: 1.06, 1.07]). When stratified by mean HbA1c, we found that ‐ relative to the lowest quintile of variation ‐ increasing variability of SD of HbA1c was associated with greater hazard of dementia in HbA1c categories of <6% (p = 0.0004) and 6 ‐8% (p<0.0001) but not in those with a mean HbA1c ≥8% (p = 0.42).ConclusionGreater HbA1c variability is associated with greater dementia hazard in those with good glycemic control. The absence of association in less well controlled (HbA1c ≥8%) patients may stem from greater variability including lower risk periods of optimal glycemic control. These results support current clinical recommendations to minimize glycemic variability and extend known benefits to include lowering of dementia risk.
Air pollution exposure is associated with widespread cortical thinning in cognitively unimpaired older women
Authors: Wang Xinhui , Salminen Lauren , Petkus Andrew J , Millstein Joshua , Beavers Daniel P. , Espeland Mark A. , Braskie Meredith N , Liu Joshua D , Thompson Paul M , Gatz Margaret , Resnick Susan M. , Kaufman Joel D. , Rapp Stephen R. , Fennema‐Notestine Christine , Hagler Donald J. , Elman Jeremy A. , Kremen William S. , Franz Carol E , Chen Jiu‐Chiuan 
Published: December 2023

AbstractBackgroundLate‐life ambient air pollution exposures are associated with increased Alzheimer’s disease (AD) risk1. Cortical thinning in temporal areas vulnerable to AD is associated with memory decline, neuropathological changes, and increased AD risk. However, most neuroimaging studies on air pollution neurotoxicity analyzed volumetric indices that are not sensitive to early cortical changes, and focused on discrete regions of interest (ROI) selected a priori rather than taking an ROI approach across the whole brain. Therefore, the mechanisms linking exposures to early neuropathological processes in older age are poorly understood.MethodWe examined data from 1068 cognitively unimpaired women from the Women’s Health Initiative Memory Study who underwent neuroimaging in 2005‐6 (Meanage = 77.8±3.7). Long‐term residential exposures to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) were quantified as the 3‐year average of monthly estimates prior to MRI using spatiotemporal models with regionalized universal kriging. Brain scans were processed using FreeSurfer‐v.5.3.0 to estimate cortical thickness in 34 bilateral regions parcellated with the Desikan‐Killiany atlas. Exposure effects on AD‐vulnerable regions were assessed by calculating an AD signature (higher value representing thicker cortices) of surface‐area‐weighted thickness in the bilateral entorhinal, fusiform, inferior temporal, and middle temporal cortices2. We used linear mixed models to estimate exposure effects on standardized regional cortical thickness and the AD signature, adjusting for sociodemographic, lifestyle, and clinical characteristics, and a random effect for scanner manufacturer.ResultAfter adjusting for covariates and multiple comparisons using the False discovery rate (FDR) method, higher exposures to PM2.5 and NO2 were associated with thinner cortices in at least 31 brain regions (FDR‐adjusted p’s<0.05). There were also significant adverse effects of PM2.5 (β = ‐0.055, 95%CI = [‐0.07,‐0.04] per 1µg/m3) and NO2 (β = ‐0.022, 95%CI = [‐0.03,‐0.01] per 1ppb) on the AD signature, equivalent to 1.1 and 0.5 years of aging, respectively. Across all analyses the strongest effects were observed in the frontal lobe, especially the motor cortex.ConclusionIn cognitively unimpaired older women, higher exposures to PM2.5 and NO2 were associated with widespread cortical thinning, including regions sensitive to AD. However, the strongest associations in the frontal lobe suggest a greater impact of air pollution neurotoxicity on brain aging rather than AD risk.
Parietal‐temporal structural network reorganization is associated with pathological load and axonal damage in Alzheimer’s disease: a post‐mortem MRI and pathology study.
Authors: Jonkman Laura E. , Reijner Niels , Frigerio Irene , Bouwman Maud M.A. , Lin Chen‐Pei , Rozemuller Annemieke J.M. , Bouwman Femke H. , Douw Linda , Berg Wilma D.J. 
Published: December 2023

AbstractBackgroundThe characteristic spatial pattern of Aβ and p‐tau distribution suggests that pathology spreads from brain regions exhibiting pathology to interconnected regions through large‐scale axonal networks. Advances in MRI and graph theory have made it possible to study brain network organization. The current study aims to assess whether local proteinopathy and/or axonal degeneration contributes to regionally altered network measures of integration and segregation in clinically‐defined and pathologically‐confirmed Alzheimer’s disease (AD) and control brain donors.MethodPostmortem In‐situ 3T‐MRI (3DT1 and DTI) data were collected for 25 AD (6F/19M, 66y±11y) and 14 control (7F/7M, 72y±8y) brain donors. Following probabilistic tractography and structural network reconstruction, graph theoretical measures of integration (eigenvector centrality) and segregation (clustering coefficient) were calculated. After autopsy, the middle frontal gyrus (MFG), middle temporal gyrus (MTG), precuneus and middle hippocampus were immunostained for amyloid‐beta (Aβ), phosphorylated tau (p‐tau) and neurofilament light (NfL), and quantitative area% load was determined. Clinical Dementia Rating (CDR) scores were obtained from clinical records. Group differences were assessed with linear models and regional associations with Spearman and Pearson correlations, corrected for age, gender, and postmortem delay.ResultIn AD, no differences were observed in Aβ, p‐tau and NfL load among the selected neocortical regions, the hippocampus had lower Aβ and NfL load. Compared to controls, the AD group showed lower integration (p = 0.078) of the MTG, associated with higher CDR scores (r = ‐0.50;p = 0.035), more p‐tau pathology (r = ‐0.61;p = 0.002) and axonal damage (r = ‐0.64;p = 0.001). Furthermore, higher segregation (p = 0.006) of the MTG was observed and associated with higher p‐tau burden (r = 0.51;p = 0.015). In contrast, the precuneus showed higher integration (p = 0.038) and lower segregation (p = 0.023) in AD compared to controls, associated with less axonal damage (r = ‐0.44;p = 0.036) and less p‐tau pathology (r = 0.46;r = 0.033) respectively. No effects were found for the MFG and hippocampus.ConclusionIn AD decedents, a reorganization of the structural network is observed, predominantly in the parietal‐temporal region; while the temporal region is more disconnected, the parietal region is more strongly connected. Our work furthermore shows that this network (dis)integration is driven by p‐tau pathology and axonal damage, and associates with cognitive outcome.
Differences in the pattern of influencing factors on instrumental activities of daily living in persons at different stages of mildly impaired cognition
Authors: Bruderer‐Hofstetter Marina , Gorus Ellen , Cornelis Elise , Vriendt Patricia De 
Published: December 2023

AbstractBackgroundInstrumental Activities of Daily Living (IADL) are crucial for a person’s autonomy. A better understanding of potentially influencing factors at different levels of cognitive impairment is relevant for diagnostic and therapeutic purposes. Therefore, we aimed to explore whether the pattern of influencing factors varies between persons with mild cognitive impairment (MCI) and mild dementia.MethodWe exploratively extended the secondary analysis of a cohort, including persons with amnestic (a‐)MCI and mild Alzheimer’s dementia (MD). We fitted linear regression models to the data within the two subgroups, with IADL as the response variable measured using the Brussels Integrated Activities of Daily Living Inventory (BIA) [1]. Selection of the predictors followed a multi‐step approach, including criterion‐based model selection and model fit. We used multivariate imputation by chained equations to estimate the coefficients of the final models and standardized coefficient estimates to relate and compare the effects of the predictors.ResultPersons with a‐MCI (n = 64, mean age 81.7 years, 69% females) and with MD (n = 41, mean age 82.3 years, 73% females) differed in their mean BIA scores (p<0.001). In persons with MCI, the final model (R2 = 0.46) included memory, attention, executive function, mobility, balance, vision, hearing, education, and living situation. Mobility was the only significant predictor and the predictor with the most considerable effect, followed by memory and attention. The final model (R2 = 0.21) in persons with MD included the same predictors; however, executive function and attention were derived from other assessments. The predictors with the most considerable effect were the living situation, mobility, and executive function, yet none was significant.ConclusionThe pattern of potentially influencing factors on IADL functioning differs between persons with aMCI and MD. Our results suggest that physical function plays an essential role in IADL functioning in persons with aMCI, whereas in MD, no significant predictor was detected. Furthermore, our results indicate that IADL functioning may be used to differentiate between diagnostic groups.[1] De Vriendt P, Cornelis E, Cools W, Gorus E. The Usefulness of Evaluating Performance of Activities in Daily Living in the Diagnosis of Mild Cognitive Disorders. International Journal of Environmental Research and Public Health. 2021;18(21):11623.
Computational progression subtypes of hypometabolism due to Alzheimer’s disease: towards linking antemortem and postmortem diagnoses
Authors: Oxtoby Neil P , Shand Cameron , Bourgeat Pierrick 
Published: December 2023

AbstractBackgroundPostmortem diagnosis of Alzheimer’s and related pathologies remains the gold standard. Advanced neuroimaging techniques enable assessment of some pathologies in living subjects, but antemortem signatures are often defined post hoc in postmortem‐defined groups. Here we flip this and estimate data‐driven antemortem signatures of pathology using Subtype and Stage Inference (SuStaIn), then predict postmortem classification. SuStaIn is a machine learning algorithm that jointly estimates subtype clusters of data‐driven disease progression signatures to uniquely unravel spatiotemporal heterogeneity using cross‐sectional neuroimaging data. We evaluate SuStaIn on FDG‐PET scans to produce the first AD subtypes of hypometabolism and explore links with LATE‐NC.MethodADNI data was downloaded 06/2022. Model inputs were baseline FDG‐PET SUVR (Desikan‐Killiany parcellation) extracted using FreeSurfer from the N = 1181 (286/791/104 AD/MCI/Ab+CN) available ADNI participants having both T1w MRI and FDG‐PET at baseline. Biomarkers were converted into w‐scores relative to 203 controls (Ab–CN), adjusted for control trends in age and sex using robust linear regression. Postmortem diagnoses (N = 43) of AD/LATE‐NC/mixed were predicted.
Modeling: Hypometabolism subtypes were estimated using SuStaIn. A bespoke “disease signal” approach selected informative biomarkers for w‐score events of interest: 1 (mild), 1.5 (moderate), 3 (severe). Average out‐of‐sample log likelihood (10‐fold cross‐validation) selected the final model (#subtypes, max 5).
Statistical Analysis: Subtype group comparisons of cross‐sectional outcomes and postmortem pathology were performed using common statistical tests.ResultFigure 1 shows the four subtypes of hypometabolism resulting from our analysis: Typical (limbic+temporal, N = 283: 21/190/72 CN/MCI/AD), Limbic Sparing (N = 261: 19/157/85), Aggressive Typical (early high w‐scores; N = 90: 2/40/48), and Lateral Cortical (N = 62: 1/33/28), with N = 485 (41%) not subtyped. Cognition was worse in the Aggressive Typical/Lateral Cortical subtypes than the Typical/Limbic Sparing (MMSE 25 vs 27; ADAS‐Cog13 19 vs 27) Kruskal‐Wallis test p<10‐3. Figure 2 shows subtyping and staging results (59% subtypeable: N = 696), with AD cases distributed evenly within each subtype and MCI at earlier stages, as expected. Figure 3 is a confusion matrix showing that our model imperfectly predicted postmortem LATE‐NC diagnosis.ConclusionData‐driven antemortem spatiotemporal subtypes of hypometabolism in Alzheimer’s disease were imperfectly predictive of postmortem LATE‐NC/AD classification in a small sample. Validation on larger histopathology samples is necessary to make general conclusions.
Associations of plasma pT205/T205 with Alzheimer’s disease pathology and cognitive function: a comparison with pT217/T217 and pT181/T181
Authors: Janelidze Shorena , Barthélemy Nicolas R. , Stomrud Erik , Bateman Randall J. , Hansson Oskar 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) related amyloid (Aβ) and tau pathologies both lead to changes in the cerebrospinal fluid (CSF) levels of phosphorylated tau (p‐tau). However, the extent of these changes appears to vary across different p‐tau variants. Recent evidence has indicated that CSF measures of tau phosphorylation occupancy at T205, pT205/T205, correlated strongly with tau deposition detected by PET and cognitive impairment but were less associated with brain levels of Aβ on PET. Here, we investigated associations of plasma pT205/T205 with tau‐PET and Aβ‐PET as well as cognitive performance in comparisons with two other established plasma p‐tau biomarkers, pT217/T217, and pT181/T181.MethodThis cross‐sectional study included cognitively unimpaired individuals (N = 231) and patients with mild cognitive impairment (N = 106), AD dementia (N = 66) and non‐AD neurodegenerative diseases (N = 18) from the Swedish BioFINDER‐2 study. pT205/T205, pT217/T217, and pT181/T181 were measured in plasma (all participants) and CSF (N = 118) using immunoprecipitation‐coupled mass spectrometry. Tau‐PET, Aβ‐PET and cognitive testing were available in 410, 320 and 406 participants, respectively. Aβ status (A) was defined using either CSF Aβ42/Aβ40 or Aβ‐PET.ResultWe found strong correlations between CSF and plasma levels for all 3 biomarkers (pT205/T205, Pearson r = 0.76; pT217/T217, r = 0.85; pT181/T181, r = 0.67; p<0.001, N = 118) (Figure 1). In A+ individuals (N = 195), associations with tau‐PET (Figure 2) were similar for plasma pT205/T205 (partial Spearman ρ = 0.57, p<0.001) and pT181/T181 (ρ = 0.51, p<0.001) and higher for pT217/T217 (ρ = 0.78, p<0.001). Associations with Aβ‐PET (N = 113) were moderate for plasma pT205/T205 (ρ = 0.38, p<0.001) and pT181/T181 (ρ = 0.36, p<0.001) and stronger for plasma pT217/T217 (ρ = 0.69, p<0.001) (Figure 2). We found similar associations of cognitive performance (based on MMSE, N = 185) with plasma pT205/T205 and pT217/T217 (standardized coefficient β, ‐0.42 and ‐0.46, respectively; p<0.001) whereas associations with pT181/T181 were weaker (β = ‐0.30, p<0.001) (Figure 3). In multivariable models, pT205/T205 (β = ‐0.22, p = 0.015) and pT217/T217 (β = ‐0.39, p<0.001) but not pT181/T181 were independently associated with MMSE. Associations of plasma biomarkers with Aβ‐PET and MMSE were similar in the whole samples but somewhat lower for tau‐PET (Figures 2‐3). A larger dataset will be presented at AAIC.ConclusionPlasma pT205/T205 is a promising novel biomarker that might prove particularly useful when combined with pT217/T217 for monitoring cognitive decline in AD.
Rheumatoid Arthritis, Antirheumatic Drugs and Risk of Dementia: A Registry‐based Study
Authors: Zhu Nanbo , Eriksdotter Maria , Garcia‐Ptacek Sara , Mitra Sumonto , Ajeganova Sofia , Carrero Juan Jesus , Chang Zheng , Xu Hong 
Published: December 2023

AbstractBackgroundSystemic inflammation is a shared pathogenesis in dementia and rheumatoid arthritis (RA). It has been postulated that patients with RA are at higher risk of dementia, however, prior studies showed conflicting results. In addition, recent research suggested that biological disease‐modifying antirheumatic drugs (DMARDs) could potentially have a protective effect on dementia.MethodUsing data from the Stockholm CREAtinine Measurements (SCREAM) cohort, we identified all individuals with an incident diagnosis of RA (ICD‐10 codes: M05, M06) during 2008‐2019 in the region of Stockholm. For each individual with RA, 10 age‐ and sex‐matched individuals without RA were randomly selected from the general population as reference individuals. The primary outcome was all‐cause dementia, ascertained via linkage with the Swedish Dementia Registry, clinical diagnoses, or initiation of anti‐dementia drugs. Incidence of dementia was compared between RA patients and reference individuals using Cox proportional hazards models. Subsequently, among patients with RA, we examined the association of initiation of any type of DAMRDs, and specifically initiation of biological DAMRDs, with the risk of dementia using inverse probability weighted Cox models. Socio‐demographics, kidney function, comorbidities, and concurrent use of medications were included as potential confounders.ResultA total of 8939 patients with RA (median [IQR] age, 63 [51, 73] years; 6237 [69.8%] women) were identified, with a median follow‐up of 5.2 (IQR: 2.5, 8.9) years. Compared with the reference individuals, patients with RA associated with a higher risk of all‐cause dementia (hazard ratio [HR]: 1.18; 95% CI: 1.01, 1.37). Among RA patients, initiation of biological DMARDs was associated with a reduced risk of dementia (HR: 0.34; 95% CI: 0.13, 0.92). However, initiation of any‐type of DMARDs within 3 months was not associated with the risk of dementia (HR: 0.91; 95% CI: 0.71, 1.18).ConclusionPatients with RA had a higher risk of developing dementia, and treatment with biological DMARDs might be associated with a decreased risk of dementia. These findings suggest more attention to cognitive function in the clinical management of RA and further investigation on biological DMARDs as a potential therapeutic candidate for dementia.
Diagnosis and care challenges in a patient with early onset familial dementia due to Kufs disease
Authors: Jnanasekharan Arathi , Issac Thomas Gregor , Sivakumar Palanimuthu Thangaraju , Arunachal Gautham 
Published: December 2023

AbstractEvaluation of early onset dementia comes with a set of unique challenges. The pathway to a specific diagnosis of a rare genetic disorder like adult onset Kufs disease presents additional challenges. Kufs disease is an adult‐onset Neuronal Ceroid Lipofuscinoses which is an inherited lysosomal storage disorder which presents with dementia, myoclonus, epilepsy, extrapyramidal & cerebellar involvements and has an incidence of 1 in 1,000,000 worldwide. We present the case of a 38‐year‐old gentleman who had presented with a six‐year history of progressive cognitive and behavioural symptoms of apathy, attention deficits, recent memory impairment, mutism, dysphagia, social incontinence all leading to significant biopsychosocial dysfunction. Patient had hypothyroidism for 6 years and was on irregular medication. History suggested major neurocognitive disorder in multiple siblings with both parents being cognitively normal. During the initial presentation, he had agitation, poor speech output, irritable affect, soft neurologic signs like Marfanoid habitus, albinotic eyes, hypotonia and high arched palate and no cerebellar signs. Pathway to care was complicated with magico‐religious model of illness accepted by the family members, stigma and fear of ostracization by society. Psychoeducation of the family about medical model and ensuring cooperativeness for evaluation was the initial challenge followed by diagnosis and management of behavioural problems. In addition to the routine dementia workup, CSF study, autoimmune panel and paraneoplastic panel was carried out. Elevated Anti‐TPO suggested possible Hashimoto’s encephalitis. After liaison with neurologist, pulse steroid courses were administered which initially resulted in transient speech improvement and emotional reactivity, but worsening of behavioural symptoms occurred subsequently. Patient required two further admissions during which ECT was administered resulting in significant improvement in aggression and improved fluency of speech, improvement in food intake and selfcare. MRI brain showed mild cerebellar atrophy, hypointense thalami,volume loss in the entire cortex, minimal T2 FLAIR hyperintensities periventricularly.Suspecting familial frontotemporal dementia, genetic counselling and testing was done .It reported positive for a novel splice region deletion variant in CTSF gene of autosomal recessive inheritance suggestive of Kufs disease. Psychoeducation, genetic counselling for other family members, psychosocial and supportive interventions for long‐term care were provided.