bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discriminating Alzheimer's Pathologic Changes from Dementias: A Multi‐Factor Blood Biomarkers Diagnostic Model Using the AT(N) System
Authors: Wang Tianyi , Shang Li , Mao Chenhui , Sha Longze , Dong Liling , Liu Caiyan , Lei Dan , Li Jie , Wang Jie , Huang Xinying , Li Bo , Huang Yixuan , Bao Jialu , Qiu Yuyue , Chu Shanshan , Jin Wei , Zhu Zhaohui , Sui Huimin , Hou Bo , Feng Feng , Peng Bin , Cui Liying , Wang Jianyong , Xu Qi , Gao Jing 
Published: January 2025

AbstractBackgroundTo assess the diagnostic efficacy of plasma biomarkers in distinguishing Alzheimer's pathologic changes from other forms of dementia, our study focused on examining plasma biomarkers in accordance with the AT(N) system.MethodA total of 156 participants were recruited from the PUMCH dementia cohort. This comprised 55 non‐AD (A‐) and 101 Alzheimer's pathologic changes (A+) individuals. Among the latter group, there were 40 AD‐like(A+T‐) and 61 AD(A+T+). Biomarker diagnoses were relied on cerebrospinal fluid (CSF) biomarkers and amyloid PET results. Plasma biomarkers were quantified using single molecule array (SIMOA).ResultPlasma Aβ40, Aβ42, GFAP, NfL, and pTau181 were compared among A‐, A+T‐, and A+T+ groups. Significant reductions in plasma Aβ42/40, along with elevated levels of plasma pTau181 and GFAP, were observed in both A+T‐ and A+T+ groups compared to the A‐ group. However, no significant differences were found between the A+T‐ and A+T+ groups. Additionally, plasma Aβ42/40, pTau181, and GFAP exhibited significant correlations with multiple CSF biomarkers, especially with CSF Aβ biomarkers, whereas plasma Aβ42, Aβ40, and NfL did not. None of the plasma biomarkers were indicative of disease severity in A+ dementia patients. Finally, a high accuracy diagnostic model in predicting Alzheimer's pathologic changes in dementia patients could be generated using plasma biomarkers.ConclusionPlasma levels of Aβ42/40, pTau181, and GFAP present valuable indicators in distinguishing Alzheimer's pathologic changes from other forms of dementia. The integration of multiple plasma biomarkers into a diagnostic model can significantly enhance diagnostic accuracy, thereby providing valuable support for clinical practice.
Cardiorespiratory Fitness Modifies the Association Between Cerebral Pulsatility on Amyloid Burden and Core CSF Biomarkers of Alzheimer’s Disease
Authors: Breidenbach Brianne M. , Brach Talia L. , Glittenberg Matthew P , Paulsen Adam J , Symanski Leah E , Naren Tarun , Driscoll Ira , Lose Sarah R , Gallagher Catherine L. , Johnson Sterling C. , Asthana Sanjay , Betthauser Tobey J. , Rivera‐Rivera Leonardo A. , Hermann Bruce P , Sager Mark A. , Blennow Kaj , Zetterberg Henrik , Carlsson Cynthia M. , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Cook Dane B. , Wieben Oliver , Okonkwo Ozioma C 
Published: January 2025

AbstractBackgroundIncreasing evidence supports the notion that vascular dysfunction contributes to the evolution of Alzheimer’s disease (AD). Cerebral pulsatility index (PI) is reportedly higher in AD and MCI compared to age matched controls and has been associated with greater beta‐amyloid (Aß) burden. Higher cardiorespiratory fitness (CRF) positively affects vascular function and is associated with lower PI in several large cerebral vessels. Our objective was to examine whether CRF modifies the relationship between PI, Aß burden, and core AD cerebrospinal fluid (CSF) biomarkers.MethodCognitively unimpaired adults (n=33, MeanAGE=64.0) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center who met study criteria were included. Aß burden was measured as global cortical PiB‐PET. CSF biomarkers were measured with the NeuroTookKit, a panel of robust prototype assays (Roche Diagnostics International Ltd). PI from bilateral MCA vessels were measured using 4D flow MRI and averaged (PI‐MCAAVG). CRF was indexed as VO2peak during a graded exercise treadmill test. A single multivariate regression, (covariate‐adjusted for sex, age, and APOE4) examined whether CRF modifies the impact of PI‐MCAAVG on Aß burden and core‐AD CSF biomarkers [phosphorylated Tau 217 (pTau‐217), total Tau (tTau), Aß42/Aß40, pTau/Aß42]. When significant, the PI*CRF interaction term would indicate a differential effect of PI on Aß burden or CSF biomarker as a function of CRF.ResultThere was a significant interaction between PI and VO2peak on PET Aß burden (ß = ‐0.05, p= 0.04), Aß42/ Aß40 (ß=0.006, p=0.03), pTau (ß= ‐3.4, p=0.03), tTau (ß ‐29.8, p=0.04) and pTau/Aß42 (ß= ‐0.006, p=0.02), indicating less Aß burden and more favorable profiles for all core CSF biomarkers with increasing VO2peak despite elevated PI.ConclusionOur findings support the hypothesis that greater CRF modifies the effect of cerebral PI on PET Aß burden and core AD CSF biomarkers, indicating that improved VO2 seems to be protective against cerebrovascular alterations known to contribute to AD‐related biomolecular changes.
Associations between blood‐based biomarkers, synaptic density and Alzheimer’s disease hallmarks in the brains of nondemented elderly
Authors: Meyer Steffi De , Alali Soha , Laroy Maarten , Casteele Thomas Vande , Cauwenberge Margot Van , Goossens Julie , Rocker Charlotte De , Vanbrabant Jeroen , Vanmechelen Eugeen , Dupont Patrick , Laere Koen Van , Vandenbulcke Mathieu , Emsell Louise , Poesen Koen 
Published: January 2025

AbstractBackgroundSynaptic loss is a critical early pathological hallmark of neurodegeneration, in particular in Alzheimer’s disease (AD), as evidenced by in vitro as well as in vivo PET studies. To date, it is not clear how blood‐based synaptic and AD biomarkers relate to synaptic density in the brains of non‐demented elderly, including those diagnosed with depression.MethodThis cross‐sectional study included 61 older adults with no history of dementia (age [mean±SD] = 71±6 years, MMSE (median[IQR] = 28[3], 64% female, 38% late‐life depression) from the Leuven late‐life depression (L3D) study. Plasma as well as [11C]UCB‐J PET (synaptic vesicle protein 2A [SV2A]) were acquired from all participants. Subgroups underwent [18F]MK6240 (tau load, n = 51) and [18F]flutemetamol (amyloid‐β [Aβ] load, n = 48) PET. Plasma SNAP25, VAMP2 and pTau181 were quantified using Homebrew Simoa assays developed by ADx Neurosciences. Plasma GFAP, Aβ1‐42 and Aβ1‐40 were quantified using the Quanterix N4PE Simoa kit. Associations between biomarkers and SV2A density were evaluated using voxelwise regression models adjusted for age, sex and depression diagnosis at peak‐level Puncorrected <.05 and cluster‐level PFWE <.05. If significant clusters were detected, Spearman correlations were calculated across the identified clusters for each biomarker. Global brain Aβ and tau load were assessed in Aβ‐ and tau‐vulnerable regions and also correlated with plasma biomarkers.ResultHigh GFAP levels associated with low synaptic density within temporal regions (GFAP cluster 1) as well as the precuneus and cingulate gyrus (GFAP cluster 2) with ρGFAP = ‐0.39 (P =.002, Figure 1A). High VAMP2 levels were associated with lower synaptic density within temporal and frontal and – to a lesser extent – occipital regions (ρVAMP2 = ‐0.55, P <.001, Figure 1B). For the Aβ1‐42/Aβ1‐40 ratio as well as pTau181 and SNAP25 levels, no associations with synaptic density were observed. Of note, study participants overall demonstrated low global Aβ and tau pathology (Figure 2) and no correlations were found with global Aβ nor tau load for any of the plasma biomarkers.ConclusionPlasma levels of GFAP and VAMP2 reflect synaptic density independently of pathological AD hallmarks in nondemented elderly with low evidence of AD pathology.
Physical exercise prevents age‐related changes in [11C]PK11195 uptake in a mouse model of Down Syndrome
Authors: Righini Chiara Maria , de Souza Larissa Estessi , Brizola Jean Marques , Spelta Lidia Emmanuela Wiazowski , de Paula Faria Daniele de Paula 
Published: January 2025

AbstractBackgroundDown syndrome (DS) is associated with mitochondrial dysfunction leading to higher levels of oxidative stress and cell degeneration. This fact, together with the overexpression of AD‐related genes in trisomy 21, increases the risk of developing Alzheimer's disease (AD). Thus, it is important to look for interventions that could prevent mitochondrial damage before symptoms occur. Physical activity is a non‐pharmacological intervention that provides an anti‐inflammatory response and increases the levels of neurotrophic factors that are beneficial for brain health. Therefore, the aim of this study is to evaluate the effect of physical activity on microglial function during the aging process in a transgenic mouse model of DS using [11C]PK11195 positron emission tomography.MethodTs65Dn male and female mice (euploid and trisomic) were used in this study (CEUA 1292/2019). Animals were subjected to physical activity on a treadmill from 2 to 20 months of age, 3 times per week. [11C]PK11195 PET images were acquired at 5, 14, and 20 months of age. For image acquisition, animals were injected intravenously with [11C]PK11195. Images were acquired in a small animal PET scanner 30 min after tracer injection, and acquisition took 20 min, with animals kept under anesthesia throughout the acquisition. PET images were co‐registered to a T2‐MRI template and the standardized uptake value (SUV) was calculated in the whole brain.ResultThroughout the aging process, a decrease in the [11C]PK11195 uptake was observed in the trisomic animals at 20 months of age, when compared to the age of 5 months (‐60.7%, 0.56±0.13 vs. 0.22±0.1, p<0.05); and 14 months (‐55.1%, 0.49±0.09 vs. 0.22±0.1, p<0.01). However, the exercised trisomic animals did not present a decrease in the [11C]PK11195 uptake at 20 months being comparable (no statistical differences) to the euploid animals (exercise and non‐exercise groups).ConclusionOur data suggest that physical activity could prevent a possible deleterious effect of accelerated aging in mitochondrial function, in the presence of the trisomy 21, since lower [11C]PK11195 uptake could be associated with mitochondrial dysfunction and reduced expression of the TSPO protein.
Multisensory stimulation in advanced dementia: Insights from a case study
Authors: Chrysostomou Savvina , Tziannarou Antonia , Hadjiloizou Andrea , Moza Sotiria 
Published: January 2025

AbstractBackground A 92‐year‐old retired seamstress, born in 1932, with 12 years of education, had been residing in a long‐term care facility since 2019, following a fall and hip fracture. Post‐admission, her cognitive function gradually declined and she did not participate in residential home activities. This study explores the outcomes of an 8‐month, multisensory remediation program. Methods The individual participated in bi‐weekly, multisensory, group therapy sessions spanning eight months from April to December 2023. The stimuli comprised a blend of visual, tactile, and auditory elements, such as constructive wooden puzzles, knitting wool, sensory balls, kinetic sand, exposure to fabric and clothing, classical music songs, language engagement through discussions, and reminiscence activities. Results Over the course of 8 months, the individual demonstrated qualitative improvements, including active participation in dialogues with neuropsychologists, expressing preferences for stimuli, and displaying increased engagement and willingness to attend sessions. Clinic personnel also noted positive changes in mood, cooperation, interest in interactive activities within the clinic, and enhanced language abilities. These improvements led to the patient relocating to a more team‐oriented table in the common area. As a result of these observed positive changes in the clinical profile, the Mini Mental State Examination (MMSE) was administered in December 2023, yielding a score of 6 out of 30 (points achieved in, naming, reading, orientation and following instructions). Discussion Multisensory therapy may show promise in regard to language and communication skills in elderly individuals with advanced dementia. These positive outcomes may contribute to the patients’ overall well‐being and serve as valuable indicators for treatment evaluation. The study is ongoing to explore long‐term effects and broader implications.
Contribution of White matter Hyperintensities Lesion Burden to Cognitive Impairment in Older Adults with Epilepsy
Authors: Reyes Anny , Prabhakaran Divya , Farid Nikdokht , Punia Vineet , Struck Aaron F , Wang Irene , Ferguson Lisa , Almane Dace , Jones Jana , Busch Robyn M , Hermann Bruce P , McDonald Carrie R 
Published: January 2025

AbstractBackgroundOlder adults with epilepsy represent the largest and fastest‐growing segment of individuals with epilepsy and harbor risk factors for pathological aging, including cerebrovascular risk factors (CVRFs) and Alzheimer’s disease (AD)‐related pathology. In fact, several community‐based studies have reported up to a 3‐fold increased risk for dementia including AD among individuals with epilepsy. Despite this, identification of risk factors for AD and related dementias (ADRD) remains largely unexplored in epilepsy, which has critical implications for patient care and dementia risk stratification. Here, we examine the relationship between white matter hyperintensities (WMH) as a marker for vascular brain injury, a common contributor to the ADRD spectrum (i.e., biomarker of non‐AD co‐pathology), and sociodemographic, clinical, and cognitive profiles in older adults with epilepsy.MethodForty‐nine older adults with epilepsy without dementia (average age=66.6, average education=15.1, 52.8% female, 86.8% non‐Hispanic white) completed cognitive testing, a comprehensive lipid panel, and MRI that included 3D FLAIR. The 3D FLAIR was analyzed to quantify WMH lesion burden (LB) using the LesionQuant software. Stepwise regressions were used to examine the contribution of sociodemographic, clinical, and vascular risk factors to WMH‐LB. The association between cognitive scores and WMH‐LB was analyzed with Spearman rho.ResultOlder age, male sex, non‐White race, hypertension, and diabetes were associated with increased periventricular (adjusted R2= .518, p=.016) and whole brain WMH‐LB (adjusted R2= .456, p=.025). Smoking was associated with increased juxtacortical WMH‐LB (β= .684, p=.025). Higher juxtacortical WMH‐LB was associated with poorer performance on measures of visual immediate (rho=‐.374, p=.010) and delayed memory (rho=‐.408, p=.004), delayed list recall (rho=‐.363, p=.011), processing speed (rho=‐.364, p=.010), confrontation naming (rho=‐.314, p=.010), and lower scores on the MoCA (rho=‐.350, p=.014) and more errors on the ADAS‐Cog (rho=.372, p=.008).ConclusionIn a group of older adults with epilepsy, greater WMH burden was associated with a worse cognitive profile and with the presence of CVRFs. The etiology of dementia in epilepsy remains understudied, and here, we provide evidence for WMH burden as a potential contributing factor to cognitive decline in this population. Older adults with epilepsy with evidence of vascular pathology would benefit from targeted interventions focused on the management of modifiable vascular risk factors.
Intersection of co‐occurring α‐synuclein and tau seeds in Lewy body and other neurodegenerative diseases
Authors: Zamore Hannah , Manca Matteo , Coughlin David G , Standke Heidi , Browne Danielle F. , Smirnov Denis , Thomas Olivia R. , Swanberg Caitlin , Galasko Douglas R. , Hiniker Annie , Kraus Allison 
Published: January 2025

AbstractBackgroundDistinct amyloid structures characterize specific proteinopathies, including tau and α‐synuclein based neurodegenerative diseases. However, how protein seed co‐occurrence and other pathologic features account for clinicopathological heterogeneity observed within and between proteinopathies is unclear. Here, we quantify α‐synuclein and isoform‐specific tau seeds across neurodegenerative diseases, including in Lewy body disease (LBD), AD neuropathologic change (ADNC), and 4R tauopathy cases to inform how co‐occurring seeds may impact disease presentation and trajectory.MethodReal‐time quaking‐induced conversion (RT‐QuIC) assays with fM sensitivity were used to estimate α‐synuclein and tau isoform specific seeding doses in LBD (n=21), ADNC (n=47) across a range of Braak stages, and in 4R tauopathy (CBD=6; PSP=15) in mid‐frontal lobe and hippocampus.Resultα‐synuclein seeding doses were observed in the mid‐frontal lobe of all LBD cases, increasing with Lewy body stage (F=69.8, p<0.001) and reaching up to 105 and 106 seeding doses. Co‐occurring α‐synuclein seeding was noted as prevalent (50%) in AD, albeit typically at multi‐log lower levels than that quantified in LBD. 100% of AD with amygdala‐predominant α‐synuclein (N=4) and 30% of AD cases without Lewy bodies (N=10) had detectable α‐synuclein seeding. 3R/4R tau seeds were nearly ubiquitously detected well before overt neuropathology across all cases, and α‐synuclein seeding was also observed occasionally without α‐synuclein neuropathology. Markedly, 3R/4R tau and α‐synuclein seeding activities correlated in LBD while controlling for Braak stage (R2=0.72, p<0.001). 4R tau seeds confirmed 4R tauopathy and occurred to some extent, albeit with lower frequency than 3R/4R tau, in non‐4R tauopathy.ConclusionProtein seed co‐occurrence is prevalent, including at early stages of both tau and α‐synuclein based disease. RT‐QuIC assays can selectively amplify, with multi‐log differentiation, α‐synuclein or tau seeds related to distinct α‐synuclein or tau structures characteristic of LBD, AD, and 4R tauopathies. Pervasive, but quantitatively distinct α‐synuclein seeding activity occurred in frontal cortex in LBD and AD, including detectable α‐synuclein seeds in some AD cases without identifiable Lewy body neuropathology. Regression analysis of seeding activities revealed quantitatively similar levels of α‐synuclein and tau seeding in LBD suggesting a possible novel role for α‐synuclein‐tau interaction in LBD, which we will explore in future studies.
Joint Contribution of NfL and PSMD for Improved Risk Stratification of VCID
Authors: Luckey Alison M. , Beiser Alexa S , Himali Jayandra J. , Gaona Carlos A. , Zeynoun Joy , Rodriguez Luis A. Mendez , Habes Mohamad , Kautz Tiffany F. , Seshadri Sudha , Aparicio Hugo J. , Satizabal Claudia L 
Published: January 2025

AbstractBackgroundAdvancing therapeutic and prevention strategies for vascular contributions to cognitive impairment and dementia (VCID) warrants identifying novel biomarkers. However, due to the high heterogeneity underlying dementia pathology, a single marker may not fully risk‐stratify for VCID. A blood‐based biomarker of neuroaxonal injury, neurofilament light chain (NfL), and a neuroimaging‐based biomarker of white matter microstructural damage on diffusion weighted imaging, peak width of skeletonized mean diffusivity (PSMD), have been related to worse general cognition and proposed as robust biomarkers for cerebral small vessel disease (cSVD). We investigated the joint contribution of NfL and PSMD for improved specificity/sensitivity to identify persons at risk for VCID.MethodDementia‐free participants from the Framingham Offspring Study with cognitive, neuroimaging, and NfL data were included (N=969). NfL was measured in plasma, and PSMD was derived from MRI diffusion weighted imaging. Executive function and general cognitive function were assessed from a neuropsychological battery. NfL and PSMD were dichotomized by the top quartile and combined to indicate a high cSVD burden. The high NfL‐PSMD risk category was related to cognitive function using linear regression adjusting for age, age‐squared, sex, education, renal function (eGFR), and total intracranial volume. Additional analyses incorporating amyloid PET uptake in 64 participants were performed to discern Alzheimer’s disease pathology from VCID.ResultHigher NfL‐PSMD was significantly associated with worse executive (Beta±SE, ‐0.06±0.02, p=0.002) and general cognitive function (‐0.15±0.07, p=0.02). Additionally, amyloid PET over‐predicted NfL levels in those with PSMD below the median (observed<predicted, Mean(SD), ‐0.06(0.31)) and under‐predicted NfL in those with PSMD above the median (observed>predicted, 0.06 (0.33)). Although results were not significant (p=0.15) due to the limited sample, they suggest that amyloid pathology does not explain cSVD burden measured with NfL and PSMD.ConclusionOur findings suggest combining NfL and PSMD can better risk‐stratify those with VCID and poorer cognitive function. This NfL‐PSMD multi‐biomarker has potential to discriminate vascular dysfunction from Alzheimer’s pathology, improving identification of persons better suited for VCID clinical trials. Utilizing a multi‐biomarker approach may improve accuracy for risk stratification of persons bearing covert cerebral vascular injury. Further studies are underway to confirm these findings in larger, diverse samples.
Gut microbiome features co‐occur in different groups of Alzheimer’s disease phenotypes and genotypes
Authors: Kang Jea Woo , Khatib Lora A. , Dilmore Amanda H. , Heston Margo B. , Ulland Tyler K. , Johnson Sterling C. , Asthana Sanjay , Carlsson Cynthia M. , Chin Nathaniel A. , Knight Rob , Kaddurah‐Daouk Rima , Rey Federico E. , Bendlin Barbara B. ,   Alzheimer's Gut Microbiome Project Consortium (AGMP)
Published: January 2025

AbstractBackgroundGut microbiome features are known to be different in Alzheimer’s disease (AD) patients compared with cognitively normal. Evidence suggests that the gut microbiota may be related to the pathology of AD. We examined the association between the gut microbiome and AD phenotypes and genotypes.MethodCross‐sectional analysis was performed on the filtered microbiome count table including 246 participants from the Microbiome in AD Risk Study. The filtered taxonomic count table was used to analyze differential abundance using the BIRDMAn pipeline. To determine the differences in the microbiota features derived from each cognitive, amyloid, and ApoE4 group, we implemented statistical models that had microbiome features as outcome variables and each cognitive, amyloid, and ApoE4 group as predictor variable adjusting for covariates including age, sex, BMI, Bristol type, and age difference between fecal collection and measurements of each predictor variable.ResultEach cognitive, amyloid, and ApoE4 group showed differentially abundant microbiota features. Top microbial features (more abundant in AD, amyloid +, ApoE4 +) that co‐occurred with all three groups were mostly Bacteroides spp., Collinsella spp., and Fusobacterium spp. Bottom microbial features (less abundant in AD, amyloid +, ApoE4 +) that co‐occurred with all three groups were mostly Dialister spp. and Prevotella spp.ConclusionThe same microbial species were more abundant and less abundant in clinical, preclinical, and genetic risk groups. These results suggest candidate microbes that can be stratified in analyses that involve associations between gut microbiome and AD pathology.