bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of type 2 diabetes on the association between amyloid and 1‐year change in everyday functioning in older Veterans
Authors: Durazo Alin Alshaheri , Bangen Katherine J. , Weigand Alexandra J. , Membreno Rachel , Mudaliar Sunder , Thomas Kelsey R. 
Published: December 2023

AbstractBackgroundThe prevalence of diabetes in Veterans is 25%, which is double that of the civilian population. Type 2 diabetes (T2D) is associated with greater rates of dementia and has been shown to exacerbate the impact of Alzheimer’s disease (AD) risk factors including genetic risk and cerebrospinal fluid markers on declines in daily functioning. Amyloid‐β, a hallmark pathology in AD, consistently shows associations with future declines in cognition and everyday functioning. The goal of this study was to determine whether T2D moderates the association between amyloid positron emission tomography (PET) and 1‐year change in everyday functioning in older Veterans.MethodTwo‐hundred‐seven predominately male Veterans without dementia from the Department of Defense‐Alzheimer’s Disease Neuroimaging Initiative with (n = 75) and without (n = 132) T2D completed amyloid PET imaging and everyday functioning measures, including the Everyday Cognition (ECog) questionnaire and Clinical Dementia Rating–Sum of Boxes (CDR‐SB). Linear mixed effects models, adjusting for age, education, race/ethnicity, posttraumatic stress disorder, depressive symptoms, traumatic brain injury history, and Hachinski score, examined whether T2D moderated the association between amyloid PET and 1‐year change in everyday functioning.ResultNeither T2D nor amyloid PET were independently associated with change on the ECog or CDR‐SB (ps>.05). However, the T2D x amyloid PET x time interaction was significant for both the ECog (β = .118, 95% CI [.018, .217], p = .021) and CDR‐SB (β = .262, 95% CI [.147, .377], p<.001) such that greater amyloid burden was associated with greater increases in functional difficulties over time, but only in people with T2D. This pattern of results was also significant for the memory (β = .171, 95% CI [.065, .277], p = .002) and language (β = .141, 95% CI [.028, .255], p = .015) subscales from the ECog.ConclusionHigher amyloid is only associated with declines in everyday functioning over 1 year in people with T2D. On the ECog, these results were driven by memory and language domains, which may be consistent with AD‐related changes. Given that people with T2D are more likely to have co‐occurring cerebrovascular disease, the combination of multiple pathologies may result in faster declines. Future studies are needed to examine how diabetes duration, severity, and medications impact these associations.
Genomic atlas of human cerebrospinal fluid and brain metabolomics provides in‐depth understanding of cellular mechanism for neurodegeneration
Authors: Wang Ciyang , Western Daniel , Yang Chengran , Wang Lihua , Timsina Jigyasha , Ruiz Agustin , Pastor Pau , Fernandez Victoria , Sung Yun Ju , Cruchaga Carlos 
Published: December 2023

AbstractBackgroundBrain metabolism is critical for the pathological mechanism of neurodegeneration. However, most metabolite quantitative trait loci (MQTL) studies have used tissues other than brain or cerebrospinal fluid (CSF) and are not ideal for neurodegeneration. We therefore pursued a large‐scale brain and CSF study to identify metabolites contributing to 27 brain‐related diseases.MethodWe obtained 440 metabolites in 2311 CSF samples and 962 metabolites in 1016 brain samples (WashU, ROSMAP, MAYO). We identified MQTL and performed metabolome‐wide association study (MWAS) to identify metabolites affecting diseases. Mendelian randomization (MR) and colocalization was performed for causality and shared genetic regulations.ResultWe identified 192 associations for 144 CSFmetabolites at 102 loci. Of those, 122 associations and 24 loci were novel, indicating tissue specificity. The brain study found 35 associations at 27 loci. Through MWAS, we identified 57 metabolites associated with 17 traits, in which 21 colocalized. Of the eight metabolites associated with AD, succinylcarnitine and adenine were causal. Succinylcarnitine was associated with AD risk gene LACTB, which product regulates lipid metabolism in mitochondrial, where succinylcarnitine generates energy. Both succinylcarnitine and LACTB have been implicated in obesity, a risk factor for AD. For Parkinson disease (PD), low galactosylglycerol level was causal, with signal colocalized at GALC with PD. The knockout of GALC gene prevented alpha‐synuclein accumulation in PD mice model, indicating that galactosylceramidase contributed to the development of PD. For cognitive performance, high levels of three metabolites (6‐oxopiperidine‐2‐carboxylate, 3‐hydroxyisobutyrate and argininosuccinate) were causal for low cognition, with additional support from colocalization and literature evidences. Pyridoxine‐dependent epilepsy patients, often with impaired cognition, had increased level of 6‐oxopiperidine‐2‐carboxylate. AD patients who underwent medium chain triglycerides treatment and improved cognition had changed level of beta‐hydroxybutyrate, related to 3‐hydroxyisobutyrate. Moreover, argininosuccinate lyase deficiency patients often develop severe cognitive impairment and seizures.ConclusionOur large‐scale CSF and brain MQTL study identified tissue‐specific MQTLs and multiple metabolites contributing to neurodegenerative disorders. Our results expand the knowledge on neurodegeneration, providing insights to neurodegeneration etiology, including AD, PD, and cognitive function.
Anticholinergic burden and cognitive impairment. Where do we stand?
Authors: García‐Lluch Gemma , Pardo Juan , García Hernán Ramos , Baquero Miguel , Peña‐Bautista Carmen , Cháfer‐Pericás Consuelo , Royo Lucrecia Moreno 
Published: December 2023

AbstractBackgroundPolypharmacy is commonly observed among elderly patients and may increase the risk of anticholinergic burden, which is associated with frailty and cognitive impairment, among other side effects. As the long period association between anticholinergics and cognitive impairment remains under study, the present work aims to assess whether a significative anticholinergic burden is associated with cognitive impairment diagnosis.MethodPatients between 50 and 80 years old were recruited at the Cognitive Disorders Unit from the Hospital Universitari I Politècnic La Fe of Valencia (Spain). Medical interviews, neurological examinations, neuropsychological tests, and CSF biomarkers were assessed to classify patients as Alzheimer’s Disease (AD) patients (based on the NIA‐AA criteria), other cognitive impairment (OCI) patients (when they had other cognitive impairments than AD), and controls (cognitively healthy patients without CSF biomarkers alteration). Pharmacological history was obtained throw medical history review and classified using the ATC/DDD classification (https://www.whocc.no/atc_ddd_index/). The CRIDECO Anticholinergic Burden Scale was applied to anticholinergic burden in all patients. A significant anticholinergic burden was considered when the overall punctuation was equal to or higher than 3 points. All the subjects signed the informed consent. This project was approved by an Ethics Committee (2020‐705‐1).ResultAn amount of 517 patients aged between 50 and 80 years participated in the present study. From them, 274 patients had AD, 192 were OCI, and 51 were control patients. Statistical differences were found between anticholinergic burden and diagnosis. The 24% of the cohort had a significant anticholinergic burden and were mainly AD and OCI patients. OCI patients had the highest rate of anticholinergic burden (29%), followed by AD patients (25%) and control patients (17%). Women showed a higher anticholinergic burden than men (p‐value <0.05). No differences were found between anticholinergic burden and CSF AD biomarkers.ConclusionAnticholinergic medication is more prescribed among patients with cognitive impairment, compared with control patients. As these drugs may promote the detrimental effects of anticholinergic burden on cognition, it is imperative to review the medications in patients at risk of dementia, especially women.
Modulation of cannabinoid receptor‐2 alters brain clearance of human tau
Authors: Joers Valerie L , Romero Julián , Hillard Cecilia , Tansey Malu Gámez 
Published: December 2023

AbstractBackgroundMultiple studies have demonstrated a strong neuroinflammatory response in the presence of Tau pathology, which is strongly associated with the clinical symptoms and cognitive decline found in Alzheimer’s disease (AD). The correlation between AD progression and tau pathologies, rather than Ab accumulation, suggests that targeting pathological tau may be a more effective therapeutic approach. Microglia have been implicated in tauopathies as they may contribute to tau phosphorylation and aggregation and the uptake and spread of seed‐competent tau to healthy neurons due to dysfunctional degradation. Cannabinoid type 2 receptors (CB2) are highly expressed in immune cells and upregulated in activated microglia under conditions of neurologic disease, such as AD. The pharmacological modulation of CB2 have demonstrated a reduction in inflammation and plaque deposition, suggesting a role of CB2 on the immune system to influence AD‐related pathologies and phenotypes. However, there are limited findings on the CB2 regulation of tau accumulation.MethodWe have generated organotypic brain slice cultures from CB2‐EGFP/f/f mice and transduced with rAAV‐P301L/S320F‐human tau, which previously has shown to accumulate total tau and develop insoluble tau species. Slices were treated with CB2‐selective compounds and evaluated for tau pathology and microglial phenotypes using real‐time imaging and biochemical analyses.ResultPrevious investigation in our lab of a synucleinopathy animal model revealed the capacity of CB2 signaling to alter the function of immune cells and reduce accumulation of phosphorylated human alpha‐synuclein. Furthermore, we have determined that treatment with a CB2 inverse agonist will increase phagocytosis of pHrodo E. coli bioparticles in microglia BV2 cultures stimulated by LPS. Our preliminary work in brain slices over‐expressing mutant human tau show a trend toward reduced ratio of phosphorylated tau (Ser202/Thr205) to total tau in the soluble protein fraction (p = 0.0549) in slices treated with CB2 inverse agonist SR144528 compared to vehicle. We are repeating the experiment and performing further evaluations in organotypic brain slice cultures from CB2‐KO mice.ConclusionThese studies will advance our understanding of the role of brain CB2 in pathologic tau removal and potentially highlight CB2 as a therapeutic target against tauopathies such as AD.
Sex differences in white matter bundle properties across menopausal transition states
Authors: Raikes Adam C. , Dyke Jonathan , Jett Steven , Williams Schantel , Pahlajani Silky , Brinton Roberta Diaz , Mosconi Lisa 
Published: December 2023

AbstractBackgroundWomen develop Alzheimer’s disease (AD) at a 2:1 rate compared to men. Changes associated with menopause exacerbate a midlife bioenergetic crisis that, when unsuccessfully resolved, leads to white matter degradation and ultimately brain atrophy. Understanding how white matter structural properties differ between sexes and evolve over midlife transitions may provide insight into the exacerbated AD risk for women. Here, we report differences in white matter bundle properties comparing pre‐ (n = 40, 44.1±3.34y), peri‐ (n = 60, 49.6±3.90y), and post‐menopausal women (n = 70, 56.0±4.12y) to age‐matched males.MethodDiffusion weighted MRI was acquired for each participant. Data were preprocessed with QSIPrep and analyzed using a fixel‐based approach implemented in MRtrix (v. 3.0.3). Fiber density (FD), cross‐section (FC), and a combined density/cross‐section metric (FDC) were compared between sexes after controlling for age, education, APOE ε4 carrier status, and total brain volume (FC and FDC only). Continuous covariates were standardized to 2 standard deviations. Analyses were conducted using connectivity‐enhanced fixel‐based permutation analyses and thresholded at family‐wise error corrected p<0.05.ResultPre‐, peri‐, and post‐ menopausal women exhibited greater FD and FDC in the corpus callosum, inferior occipto‐frontal fasciculus, cortico‐spinal, and cingulum bundles. By contrast, males had greater fiber cross section in the splenium of the corpus callosum (compared to pre‐), (compared to peri‐), and in fibers near the left uncinate fasciculus and inferior longitudinal fasciculus (compared to both peri‐ and post‐menopausal women). After controlling for age, education, total brain volume, and APOE ε4 carrier status, a smaller cluster of fibers in the left splenium survived multiple comparisons correction demonstrating greater fiber cross‐section in post‐menopausal women compared to peri‐menopausal women.ConclusionWomen across menopausal transition states exhibited greater fiber density than their age‐matched male counterparts in commissural and association tracts, which agrees with previous work demonstrating stronger inter‐hemispheric connections in women. However, peri‐ and post‐menopausal females exhibited 4‐8% decrease in fiber cross section in uncinate fasciculus fibers, which have been implicated in Alzheimer’s related cognitive decline. These findings suggest that reductions in white matter cross‐section, particularly in regions associated with Alzheimer’s disease, may begin for women in menopause and be an early indicator of neurodegenerative risk.
Longitudinal Trajectories of Normal versus Abnormal Cognitive Aging in the SIU Longitudinal Cognitive Aging Study as measured by the original Alzheimer’s disease Assessment Scale and a novel extended version
Authors: Trivedi Mehul Alkesh , Botchway Albert , Scaife Steven , McGinity Sean , Porter Nicholas , Zec Ronald F , Ala Thomas A , Hascup Erin R. 
Published: December 2023

AbstractBackgroundThe original Alzheimer’s disease Assessment Scale‐cognitive subscale (oADAS) is a common measure of cognition used in Alzheimer’s disease (AD) clinical trials. The oADAS may not be sensitive to pre‐dementia syndromes such as mild cognitive impairment (MCI), possibly due to ceiling effects for many of the subtests. However, little is known about the trajectories of cognitive aging on the oADAS in cognitively‐normal individuals who decline over time. We used Linear Mixed Effects Modeling to examine trajectories of cognitive aging on the oADAS, a novel extended version (eADAS), and the MMSE. We hypothesized that, compared to non‐decliners, individuals who declined from normal to MCI and/or AD (decliners) would demonstrate increased error scores on the ADAS and lower scores on the MMSE over time.MethodsWe included data from 608 older adults (72% female, mean age = 69.0 years) who were enrolled in SIU Longitudinal Cognitive Aging Study (LCAS). Total years of educational attainment ranged from 8‐26 years. The vast majority of the participants were White/Not‐Hispanic. There were 50 decliners and 558 non‐decliners included in the present analysis. The eADAS included short‐delay recall/recognition trials for the first word list, a short‐delay true‐false word recognition trial for the second word list, a letter‐digit d psychomotor test, supermarket fluency, spontaneous clock drawing, three additional items to the object naming subtest, three additional figure copies, and a similarities test. All analyses were completed after controlling for gender, education, age at first visit, time between visits, and number of visits.ResultsThere was no significant difference between the groups for age at first visit. Greater age at first visit and lower education were associated with increased error scores for both ADAS versions and MMSE in the decliner group (p’s <0.001). There was no significant effect of the number of days between visits. The mean coefficients for the change in error score over time between visits for the oADAS, eADAS, and MMSE was 2.84, 10.30, and ‐1.09, respectively.ConclusionOur results indicate that the oADAS and eADAS are useful measures for examining trajectories of cognitive decline in cognitively‐normal individuals at increased risk for AD.
Morphometric Differences in Hippocampal Shape Across the Alzheimer’s Disease Spectrum
Authors: Madi Kedar V , Kawas Mohammad I , Lockhart Samuel N. , Barcus Richard A. , Hudson Jeremy Patton , Bateman James R. , Craft Suzanne , Wolfe Stacey Q , Whitlow Christopher T 
Published: December 2023

AbstractBackgroundPrior studies have demonstrated that shape analysis of the hippocampus may provide a more accurate prognostic prediction of cognitive decline than simply volume. Here we deploy a novel automated pipeline for hippocampal morphometry to elucidate the surface regions sensitive to shape change along the AD spectrum.MethodsHippocampal volumes were segmented from 186 T1 images obtained from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort including cognitively normal (CN, n = 62, mean age = 72.1, males = 29), mild cognitive impairment (MCI, n = 62, mean age = 73.2, males = 29), and dementia participants (DEM, n = 62, mean age = 73.4, males = 28). All chosen participants were matched for age, sex, and education. Correspondent surface meshes of each hippocampus were generated via spherical harmonics (SPHARM‐PDM) in SlicerSALT. Hippocampal mesh models were incorporated into a Multivariate Functional Shape Data Analysis (MFSDA), a linear model paradigm that builds associations between shape measurements, demographic information, and other clinical variables to determine if there exists a statistically significant morphological difference caused by variables of interest. Results were mapped onto a template hippocampus to visualize surface regions significantly associated with cognitive diagnosis. Adjudication of cognitive diagnosis by expert panel consensus occurred in accordance with NIA‐AA guidelines.ResultsFigure 1 displays surface regions of left hippocampus that significantly differed between DEM and CN participants. Figure 2 displays surface regions of left hippocampus that significantly differed between MCI and CN participants. Significant regions (p ≤ 0.05) are yellow‐red, while non‐significant regions (p > 0.05) are blue. Similar results were observed in right hippocampus (not shown).ConclusionShape differences between DEM and CN subjects are significant across the majority of the hippocampal surface, while shape differences between MCI and CN subjects appear significant primarily at the posterior portions of CA1/CA3 and prosubiculum subregions, suggesting these particular regions may be vulnerable to atrophic shape change during the early stages of AD, consistent with previous findings.
High expression of Alzheimer’s disease‐related metabolic brain pattern is predictive of conversion to mild cognitive impairment or dementia and faster cognitive decline
Authors: Perovnik Matej , Jamšek Jan , Trošt Maja ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundAlzheimer’s disease‐related pattern (ADRP) is a metabolic brain biomarker of Alzheimer’s disease (AD), which was previously identified and validated. Its utility for differential diagnosis is known. Here, we aimed to explore its predictive value for conversion from cognitively normal (CN) to mild cognitive impairment (MCI), from MCI to dementia and for the rate of cognitive decline.MethodsWe analysed 609 participants followed for up to 15 years and their FDG PET scans from ADNI database (CN = 133, MCI = 352, dementia due to AD = 124) and 56 participants from University Medical centre Ljubljana (MCI = 22, AD = 34). ADRP expression was calculated from pre‐processed FDG PET scans. CN and MCI participants were stratified according to their conversion status and cerebrospinal fluid biomarkers. Amyloid positivity (A+) was defined as Aβ42 < 880 pg/mL and tau positivity (T+) as pTau > 21.8 pg/mL. AD patients were stratified into slow (< 2 points/per year decline on mini mental state examination (MMSE)) and fast (> 2 points/per year decline on MMSE) progressors.ResultsA+T+ cCN had higher baseline ADRP expression than A–T– (p<0.001), A+T– (p = 0.003) and A+T+ (p = 0.01) stable CN corrected for age, while the groups did not differ in gender, education or baseline MMSE scores. A+T+ cMCI had higher baseline ADRP expression than A–T– (p<0.001), A+T– (p = 0.001) and A+T+ (p<0.001) stable MCI, corrected for baseline age and MMSE. A+T– stable MCI had higher baseline ADRP expression than A–T– stable MCI (p = 0.02). ADRP was a predictor of conversion to dementia in survival analysis (HR = 4.5[2.4‐8.7]). Similarly, in the UMCL dataset A+T+ cMCI had higher baseline ADRP expression than A–T– stable MCI (p = 0.03). Fast progressing AD patients had higher baseline ADRP expression than slowly progressing AD patients (p<0.001). Similarly, in the UMCL dataset fast progressing AD patients had higher baseline ADRP expression than slowly progressing AD patients (p = 0.02). In neither dataset, AD groups differed in age, sex or baseline MMSE scores.ConclusionADRP expression levels can be used to predict conversion from CN to MCI and from MCI to dementia in A+T+ individuals. AD patients with high ADRP expression are at an elevated risk for faster progression of cognitive decline.