bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of BPSD and psychotropic drug therapy in patients with dementia
Authors: Pullia Rosanna , Rogani Sara , Bianco Maria Giovanna , Taverni Irene , Pardini Noemi , Maltese Leonarda , Giusti Andrea , Calsolaro Valeria , Virdis Agostino 
Published: January 2025

AbstractBackgroundDespite being off‐label, antipsychotics and antidepressants are widely prescribed to manage Behavioural and Psychological Symptoms of Dementia (BPSD). Aim of our study was to assess the evolution of BPSD and psychoactive pharmacological therapy in older patients with dementia.MethodIn this retrospective observational study, outpatients with dementia underwent a Comprehensive Geriatric Assessment (ADL, IADL, CFS and CIRS), at baseline, 6‐month and 12‐month follow‐up visits. Additionally, cognitive impairment (MMSE) and severity of BPSD (NPI) were determined.Result266 patients (mean age 82.69 ± 10.19; 69.58% female) were enrolled; 169 underwent a 6‐month follow‐up and 111 had a 12‐month follow‐up. We observed a progressive decline in MMSE [18.89 (±5.02), 17.69 (±5.72), 17.25 (±5.70); p<0.001], ADL [5 (±3), 4 (±3), 4 (±3); p<0.001], and CFS [5.44 (± 1.23), 5.67 (±1.78), 5.77 (±1.15): p<0.001]. No differences were found in the prescription of antipsychotics over 12 months. However, there was a notable increase in Trazodone prescription between baseline and 6‐month follow‐up (18.42% at baseline, 31.55% at six months, p>0.001), with consistent prescription rate at 12 months (32.43%). Among the neuropsychiatric symptoms (anxiety, agitation, sleep disturbances), there was a significant increase in agitation at the 6‐month follow‐up compared to baseline (p = 0.026). The prescription of antidepressants significantly increased between baseline and 6‐month follow‐up (p = 0.003), without a significant increase in symptoms like depression, anxiety, or eating behaviour disorders. Patients taking antidepressants at baseline were mostly female (p = 0.043), didn’t significantly differ in age and NPI scores both at baseline and six months, but showed lower frailty levels compared to non‐users (p = 0.009), higher prevalence of anxiety (p = 0.015), appetite disturbance (p = 0.017) and depression (p = 0.034). Antidepressants were more frequently taken by women (p = 0.03) and linked to clear depressive symptoms both at 6‐month (p<0.001) and 12‐month follow‐up (p = 0.025), with higher burden of psychiatric symptoms observed at six months and baseline.ConclusionIn older patients with dementia, BPSD gradually increased, together with functional and cognitive decline over 12 months. Managing agitation led to an increased prescription of trazodone, while antidepressant medications were used in follow‐ups for depressive symptoms; more importantly, prescription of antipsychotics did not increase, aligning with recommendations regarding their safety profile.
Pathological patterns of TDP‐43 in LATE, Alzheimer’s Disease and FTLD‐TDP
Authors: Tomé Sandra O. , Gawor Klara , Vandenberghe Rik , Nelson Peter T , Thal Dietmar Rudolf 
Published: January 2025

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy (LATE) has been recently recognized as a cause of dementia in the elderly. LATE and Alzheimer’s disease (AD) share similar clinical presentations, and their neuropathological changes—LATE‐NC and ADNC—commonly co‐occur in the brains of individuals with dementia. Frontotemporal degeneration (FTLD‐TDP) represents another group of TDP‐43‐associated neurodegenerative diseases. Still, the morphological and molecular features of TDP‐43 lesions in different diseases remain under‐researched. Here, we investigated distinct TDP‐43 lesions and immunoreactive species in cases of AD with LATE‐NC, pure LATE (ABC score < 1), and FTLD‐TDP.MethodWe performed immunohistochemistry in paraffin‐embedded tissue from the hippocampus, amygdala, temporal and frontal cortices of 22 non‐demented cases, 24 AD cases with comorbid LATE‐NC, 9 pure LATE and 22 FTLD‐TDP cases (subtypes A‐C). We semiquantitatively assessed the severity of neuronal cytoplasmic inclusions and dystrophic neurites using antibodies against different TDP‐43 epitopes: pS409/pS403, pS403/pS404 and non‐phosphorylated C‐ and N‐terminal TDP‐43. We also assessed general neuropathological parameters among the groups.ResultLATE cases were older at death and exhibited lower neuronal density in the hippocampus compared to the remaining groups, supporting the hypothesis of a slower disease course in LATE compared to AD. AD and LATE did not differ in LATE‐NC stages.Morphologically, pure LATE cases showed higher severity levels of hippocampal dystrophic neurites compared to AD with LATE‐NC and FTLD‐TDP cases. The severity of neuronal cytoplasmic inclusions was similar among groups. AD cases showed an overall predominance of pS409/pS410 TDP‐43 species, however LATE and FTLD‐TDP cases showed no significant differences in burden of all TDP‐43 species except N‐terminal TDP‐43, which showed lower severity in all groups. LATE cases also exhibited decreased burdens of TDP‐43 species in the frontal cortex compared to FTLD‐TDP.ConclusionThese results suggest that TDP‐43 assumes distinct patterns of immunoreactivity in dementia, especially in the hippocampus. LATE and FTLD‐TDP cases showed a similar, but non‐identical patterns of TDP‐43 immunoreactive species, patterns which were different in turn from LATE‐NC in ADNC. These data may also support the concept of LATE as a separate disease with high burdens of different TDP‐43 species restricted to the limbic system in the absence of moderate‐high ADNC.
Ten‐word Test:An Effective Tool to Differential Mild Cognitive Impairment from Subjective Cognitive Decline
Authors: Ren Hua , Dong LI , Liu Tiejun , Wang Ziqi 
Published: January 2025

AbstractBackgroundIdentifying the transition from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) is crucial for delaying the progression of dementia and enabling early intervention. In clinical practice, there are many deficiencies in the scale tools used to identify the two. We wanted to evaluate the application of the 10‐word test in identifying SCD and MCI.MethodsA total of 62 MCI and 203 SCD subjects were assessed and underwent multiple neuropsychological assessment, including the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐cog), Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment‐B (MOCA‐B), and Activities of Daily Living scale (ADL). We performed a statistical analysis on these assessments results.ResultsNeuropsychological assessment results of the MCI and SCD groups indicated significant differences in the scores of the ten‐word test (P< 0.001, figure 1), with the MCI group scoring higher. When the cut‐off value for the ten‐word test was set at 3.15, the sensitivity for differentiating MCI from SCD was 87%, and specificity was 61% (AUC 0.777, P< 0.001, figure 2). DeLong’s test revealed no statistically significant difference in the ability of the ten‐word test to distinguish between MCI and SCD compared to the total score of ADAS‐Cog (AUC 0.833) and MMSE (AUC 0.784) (P > 0.05), but a significant difference was observed when compared to MOCA (AUC 0.973, P < 0.001). In the population with an education level of ≤ 9 years, the optimal cut‐off value for the ten‐word test was 3.15, with a sensitivity of 91% and specificity of 45% (AUC = 0.674, P = 0.030, figure 3). In the population with an education level of > 9 years, the optimal cut‐off value was 3.63, with a sensitivity of 79% and specificity of 71% (AUC = 0.785, P < 0.001, figure 3).ConclusionMemory impairment is the most common complaint in MCI and SCD. The 10‐word immediate recall test from the ADAS‐cog may objectively reflect the short‐term memory level of subjects, with its simplicity and quick administration. It serves as an effective and convenient tool for rapid identification of mild cognitive impairment.
In vivo amyloid and tau metabolism in human brain tissue
Authors: Aslanyan Aram , Mukherjee Soumya , Dulewicz Maciej , Coyle Reid , He Yingxin , Sato Chihiro , Ghoshal Nupur , Ge Junyue , Moncur Eleanor , Koutarapu Srinivas , Camporesi Elena , Thorne Lewis , Toma Ahmed , Schwetye Katherine , Roberts Kaleigh F , Watkins Laurence , Elbert Donald L. , Bateman Randall J. , Hanrieder Jörg , Paterson Ross W. 
Published: January 2025

AbstractBackgroundKnowledge of the chemical composition of amyloid plaques and tau tangles at the earlier stages of Alzheimer’s disease (AD) pathology is sparse. This is due to limited access to human brain during life and at the earlier stages of AD pathophysiology and technical limitations in quantifying amyloid and tau species at a subcellular level. Understanding the chemical composition of plaques and tangles, how rapidly they grow and what factors drive growth is important for developing and refining therapeutics. We access in vivo cortical brain biopsy samples from individuals undergoing surgery, aiming to provide detailed characterisation of pathology with spatial and temporal resolution.MethodWe collected in vivo brain biopsies with matched ventricular and lumbar cerebrospinal fluid samples from individuals with suspected Normal Pressure Hydrocephalus (NPH) undergoing ventriculoperitoneal shunt surgery. All participants were labelled with intravenous 13C6 Leucine as per Stable Isotope Labelling Kinetics protocol. We used immunohistochemistry, immunoprecipitation‐mass spectrometry (IP‐MS) and Matrix Assisted Laser Desorption Ionization (MALDI) mass spectrometry‐based imaging (MSI) to characterise amyloid and tau and their common post‐translational modifications. We calculate the tracer‐to‐tracee ratio of labelled to unlabelled amyloid and tau to determine rate of pathological accumulation of these proteins. Using a 2‐compartment model we establish the half‐life of tau in brain tissue.ResultWe collected cortical brain biopsies from individuals with suspected NPH (n = 6), labelled between 4.25 hours to 133 days prior to surgery; 4 out of 6 individuals had amyloid plaques (range 1‐25 plaques/mm2). These individuals had mild cognitive impairment. Cored plaques showed characteristic localization of Aβ1‐40 and Aβ 3pE‐40 in the core while x‐42 species including 1‐42, 4‐42 and 3pE‐42 showed a more homogenous distribution across both plaque core and diffuse/immature plaque periphery (Figure 1, 2). We did not detect incorporation of labelled amyloid in any subject using IP‐MS or MALDI. We detected labelled tau in brain homogenate as early as 4.25 hours after label administration. The half‐life of tau in human brain was calculated to be 26.85 days.ConclusionOur study provides the first detailed chemical characterisation of AD pathology in living human brain giving insights into plaque composition, age and tau dynamics.
Contributions of heavy metal exposure to late‐onset Alzheimer’s disease
Authors: Kotredes Kevin P , Minaeva Olga , Pandey Ravi S , Moncaster Juliet A , Lamb Bruce T. , Carter Gregory W , Goldstein Lee E , Howell Gareth R 
Published: January 2025

AbstractBackgroundLate‐onset Alzheimer’s disease (LOAD) is the leading cause of dementia and a major contributor to increased mortality. Recent human datasets have revealed many LOAD genetic risk factors that are correlated with the degree of AD burden. Further, the complexity and heterogeneity of LOAD appears to be promoted by interactions between genetics and environmental factors such as diet, sedentary behavior, and exposure to toxicants, like lead (Pb), cadmium (Cd), and arsenic (As). While the neurotoxicants‐LOAD association is known, the molecular mechanisms modulated by these gene‐environmental interactions are unknown. Here we test the hypothesis that heavy metal exposure induces cerebrovascular deficits, neuroinflammation, and brain biometal dyshomeostasis which exacerbate AD‐associated brain pathologies in next‐generation mouse models of LOAD. Examination of these gene‐environmental (“exposome”) interactions provides essential insight into the heterogeneity observed in human disease and may uncover potentially modifiable mechanisms that mediate AD pathogenesis.MethodYoung and aged mice from novel polygenic strains expressing LOAD risk alleles (APOE4, Trem2, APP, Mthfr, Abca7) were exposed to heavy metal toxicants in drinking water. Toxicants and endogenous biometals were assayed by ICP‐mass spectrometry in the brain, blood, and urine. Transcriptional profiling of brains revealed specific changes in human‐aligned, LOAD‐related gene expression networks indicating mechanisms of disease progression. Neuropathology was evaluated with LOAD‐relevant phenotypes, including amyloid burden, glial activity, and neuron loss.ResultNeurotoxicants were detected in all tissue samples collected. Pb, Cd, and As accumulated in the brain and altered expression of LOAD‐relevant genes in a toxicant‐specific manner, including a decrease in Vgf and an increase in App. Reduced VGF expression has been observed and reported in all four independent AMP‐AD studies and nominated as a key therapeutic target in each and APP encodes amyloid precursor protein (APP) from which the Aβ peptides are generated.ConclusionPb, Cd, and As exposure is common, especially in disadvantaged populations (urban, rural), raising concern about LOAD risk disparities, socioeconomic/racial inequities, and environmental justice. These experiments provide critical feedback related to the impact of the “exposome” in the aging, disease progression, and gene expression of novel preclinical LOAD models. Collectively these data suggest a direct effect of neurotoxicant exposure related to LOAD progression.
Prioritization of polygenic combinations for LOAD mouse models from ensemble machine learning on cross‐species transcriptomic signatures
Authors: Cary Gregory A. , Pandey Ravi S , Uyar Asli , Spruce Catrina , Haber Annat , Carter Gregory W ,   The IU‐JAX‐PITT MODEL‐AD Center
Published: January 2025

AbstractBackgroundThe genetic etiology of late‐onset Alzheimer’s disease (LOAD) is complex, with over 75 identified loci contributing to disease risk. Recent efforts of the MODEL‐AD consortia have yielded several dozen mouse strains harboring variation designed to model LOAD risk alleles. Given the complex genetic architecture of LOAD, developing animal models that combine multiple risk alleles is likely essential to improving the fidelity of these models to human disease. However, it is not clear which combinations of risk alleles are optimal for modeling disease features in mice. In this study we utilize transcriptome data from existing strains to prioritize which variants should be combined in future model development.MethodWe estimated the effects of genetic variants and environmental perturbations on gene expression using multiple linear regression. The computed gene‐level effects were used as features in separate regression models fit to changes in human transcriptomes from AMP‐AD cohorts and previously described disease subtypes. To mitigate multicollinearity and allow for non‐linear relationships, we employed both regularized linear models (LASSO, SVM) and non‐linear models (Random Forest, Neural Network). Variable importance was extracted from the fit models for each regression analysis. We evaluated the importance of each feature (e.g. genetic variant) across models in an ensemble approach.ResultThe top mouse features prioritized by the different regression models were largely similar. Moreover, similar features were also prioritized across the different human cohorts. The top mouse features included a humanized Aβ and variants in SPI1, ABCA7, Epha1, and Sorl1. Intriguingly there were distinct sets of strains prioritized for different disease sub‐types. Looking across cohorts there were generally a typical (i.e. inflammatory) sub‐type and a non‐inflammatory sub‐type. The inflammatory subtypes prioritized similar features to the overall cohorts, while the priorities for non‐inflmmatory subtypes included Cd2ap, Shc2, and Mtmr4.ConclusionWe identified consistent predictions regarding which mouse factors are most influential in modeling disease across model classes and human cohorts. Ensembling the models was a useful approach for feature selection. These priorities informed the selection of mouse strains to breed in the development of polygenic LOAD mouse models by the IU‐JAX‐PITT MODEL‐AD center.
Large‐scale Genome‐wide Investigation of Short Tandem Repeats Associated with Alzheimer’s Disease Risk
Authors: Küçükali Fahri , Sleegers Kristel ,   EADB
Published: January 2025

AbstractBackgroundClassical genome‐wide association studies (GWAS) of Alzheimer’s disease (AD), which successfully identified over 75 risk loci to date, are limited to the content of the imputation panels that typically do not cover all types of genetic variation, e.g., tandem repeats encompassing >55% of human genome. Recent advances in the imputation panels with short tandem repeats (STRs; repeated motifs of 1‐6 bp in tandem, accounting for 10% of all repetitive elements) pave the way for large‐scale STR GWAS opportunities for complex diseases with substantial missing heritability such as AD. In this study, we investigated the contribution of STRs to AD risk.MethodWe leveraged a publicly available STR imputation reference panel to impute over 440,000 multiallelic STRs in the European Alzheimer & Dementia Biobank (EADB) core cohort of 20,301 AD cases and 21,839 controls. After converting multiallelic STRs and applying filters of imputation quality score (R2≥0.3) and minor allele counts (≥20), imputed dosages from ∼2.35 million biallelic STRs were included in GWAS where the results were adjusted for the first 20 genetic principal components and genotyping center. We ran conditional analyses to determine independent risk loci driven by STRs. Furthermore, we constructed brain expression and splicing STR (eSTR & sSTR) catalogues for accurate mapping of non‐coding STRs to prioritized risk genes.ResultWe identified 410 significant biallelic STR associations at P<1 × 10‐5, of which 194 were passing the stringent genome‐wide significant threshold, originating from 50 risk loci. ∼8% of the associations were rare (minor allele frequency <1%), while ∼10% of them were positioned outside of previously identified AD GWAS loci. One of these new association peaks was positioned near the promoter of a novel candidate gene, which was prioritized also by the eSTRs regulating the expression of this gene in the locus.ConclusionOur first biallelic STR GWAS results demonstrate the power of our approach, and together with the complementary subsequent analyses (e.g., multiallelic length‐based STR GWAS method, conditional analyses, e/sSTR integration analyses, and additional replication and meta‐analyses), it has the potential to unravel and characterize AD‐associated STRs, towards a full characterization of all types of understudied genetic variation for AD in the future.
Biological pathway‐based Alzheimer’s Disease polygenic risk score and proteinopathy
Authors: Katsumata Yuriko , Wu Xian , Aung Khine Zin , Tsuchiya Inori , Shade Lincoln MP , Karanth Shama D , Gauthreaux Kathryn , Mock Charles , Kukull Walter A. , Abner Erin L. , Nelson Peter T , Fardo David W. 
Published: January 2025

AbstractBackgroundWe recently reported genetic associations with dementia‐related proteinopathies. Using multidimensional generalized partial credit modeling, we constructed three continuous latent variables, corresponding to TDP‐43, Aβ/Tau, and a‐synuclein related neuropathology endophenotype scores.MethodParticipant data were drawn from the National Alzheimer’s Coordinating Center (NACC) neuropathology (NP) data (from the September 2023 data freeze) linked to Alzheimer’s Disease Genetics Consortium (ADGC) genotype data. ADGC genotype data were imputed by TOPMed Imputation Server (https://imputation.biodatacatalyst.nhlbi.nih.gov/). The AD summary statistics were obtained from GWAS Catalog (https://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90027001‐GCST90028000/GCST90027158/) created by Bellenguez et al. We calculated biological pathway‐based PRS by Gene Ontology (GO) terms listed for Homo sapiens from Ensembl (http://www.ensembl.org/biomart/martview/) with the subset of retained SNPs based on r2 = 0.1 with a physical distance threshold of 250 kb and p‐value < 0.0001 using PRSice‐2 (https://www.prsice.info/). We then estimated the associations between each of the PRS scores and each of the three latent proteinopathy scores adjusting for age at death, sex, the top three principal components, and the two non‐outcome latent scores than the outcome. We adjusted the p‐values using the Bonferroni correction.ResultThe total 19,596,813 single nucleotide variants (SNVs) or short indels were overlapped in ADGC imputed genotype and the GWAS summary statistics. We extracted 1,850 biological process, 542 molecular function, and 405 cellular component GO terms that were constructed of 5 or more SNVs. The AD PRSs in “membrane” cellular component and “protein binding” molecular function were strongly associated with the Ab/Tau pathology related latent score (Bonferroni corrected p‐value = 1.7 × 10‐6 and 0.00011, respectively). There was no biological pathway‐based AD PRS associated with TDP‐43 and α‐synuclein pathology‐related latent scores.ConclusionThe biological pathway‐based AD PRSs were associated with only Aβ/Tau pathway related latent proteinopathy score. We will explore PRSs for other diseases that are potentially related to AD etiology including Parkinson’s disease linked to α‐synuclein pathology, amyotrophic lateral sclerosis (ASL) with TDP‐43 aggregation, cardiovascular diseases, cardiovascular risk factors, and psychiatric diseases.
Clinical profile and serum Vitamin D level among dementia patients: An Insight from Ethiopia
Authors: Zewde Yared Z 
Published: January 2025

AbstractBackgroundVitamin D deficiency is linked with the risk of developing dementia and Alzheimer disease. There is paucity of data on serum vitamin D level among patients from tropical countries such as Ethiopia. The objective of this study is to determine the prevalence of vitamin D deficiency and associated factors among Alzheimer disease and related dementia patients in Ethiopia.MethodAn institution‐based cross‐sectional study was conducted among patients presented with cognitive complaints and diagnosed with Alzheimer’s disease or Alzheimer’s disease related dementia at Lancet General Hospital in Addis Ababa, Ethiopia from November 1 – August 30, 2023. Sociodemographic and clinical data were obtained at presentation with serum vitamin D level determined subsequently. Cognitive test was assessed using the Montreal Cognitive Assessment‐Basic (MOCA‐B). Descriptive and inferential statistical analysis were done and measures of estimated crude and adjusted odds ratio with95% CI were constructed and a p value <0.05 was considered statistically significant.ResultA total of 60 adult patients with dementia were enrolled. The mean (SD) age of dementia patients was 69.4 (1.56) years and 56% were male. The prevalence of vitamin D deficiency was 70% and the mean serum vitamin D level was 23.94 (1.55) ng/ml. Amnestic variant AD was detected in 45% of the participants followed by vascular dementia (35%) and Parkinson disease dementia (10%). HIV associated dementia was diagnosed in 6% of the participants. Hypertension was the most prevalent (45%) comorbidity reported in our dementia cohort. Severe vitamin D deficiency (serum vitamin D level < 10 ng/ml) was negatively association with disease severity (p = 0.01) and increased age (p = 0.003).ConclusionVitamin D deficiency was prevalent in Ethiopian dementia patients. There were strong associations between severe vitamin D deficiency and dementia severity and increment in age.