bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain vasculature influences local tau accumulation in the human inferior temporal gyrus
Authors: Hoglund Zachary T , Zwang Theodore J , Woost Benjamin , Bailey Joshua J , Hyman Bradley T. , Bennett Rachel E 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease that involves the accumulation of pathological tau protein. While the mechanisms behind tau accumulation are not well understood, they are pivotal to understanding the pathogenesis of AD. Because protein clearance in the brain is mediated in part by vasculature, we hypothesize that vasculature may direct the accumulation and distribution of tau pathology. In this study, we analyzed the spatial relationship between tau distribution and vasculature to elucidate vasculature’s role in tau clearance.MethodPost‐mortem human tissue samples (∼1 cm3) from the inferior temporal gyrus of 6 AD and 6 control donors were sliced at thicknesses of 500 µm to 1 mm. Tissue slices were prepared with tissue clearing. Cleared samples were stained with antibodies for tau (AT8), vasculature (GLUT1), nuclei (DAPI), and neurons (HUD). Images were collected using confocal fluorescence microscopy. A virtual reality tracing method was developed to segment individual blood vessels across large tissue volumes and 12‐21 individual vessels were isolated in each sample. Novel MATLAB scripts were developed to calculate the intensity of tau as a function of distance from the blood vessels’ surfaces.ResultIn AD samples, tau intensity varied along the length of the blood vessel and with distance from the blood vessel surface. Regions with high tau accumulation on the blood vessel surface exhibited elevated tau accumulation in the surrounding tissue. In regions with low tau accumulation on the blood vessel surface, tau intensity was observed to decrease near the vessel. The influence of blood vessels on tau intensity dissipated as distance from the vessel surface increased, where tau intensity approached the bulk value (average tau intensity across the entire image). Compared to AD samples, control tissue showed little AT8+ tau labeling and the relationship between tau and distance from blood vessels was not apparent.ConclusionThese results indicate that pathological tau accumulation is spatially related to blood vessels in AD. In addition, these data imply that blood vessels contribute to tau clearance and that vascular tau clearance is disrupted in regions with high tau accumulation.
Early identification of Alzheimer’s risk using anatomically interpretable estimation of brain age
Authors: Imms Phoebe , Kawamura Jaron , Yin Chenzhong , Amgalan Anar , Chowdhury Nahian F , Chaudhari Nikhil N , Irimia Andrei 
Published: December 2023

AbstractBackgroundNeuroanatomical aging patterns can be revealed by examining the discrepancy between brain age (BA) and chronological age (CA) – also known as age gaps (AGs). Older than expected BAs, as estimated using deep learning of magnetic resonance images (MRIs), are observed in patients with mild cognitive impairment (MCI) and Alzheimer’s Disease (AD) (Tseng et al., 2022). Our 3‐dimensional convolutional neural network (3D‐CNN) enhances the accuracy of BA estimation and employs saliency mapping to explore structural patterns of aging between persons with and without CI.MethodsMRIs and neurocognitive measures for 6,561 participants (5,851 cognitively normal ‘CN’, 351 MCI, 359 AD) were collated across online repositories (Downey & Peakman, 2008; Petersen et al., 2010; Van Essen et al., 2012). We constructed a deep learning regression model using a 3D‐CNN whose inputs are pre‐processed MRIs (Fischl, 2012) and whose outputs are estimated BAs and saliency maps (Yin et al., 2023). Spearman rank correlations between neurocognitive measures and BA and CA were calculated, then compared using Fisher’s z‐test. The ability of AGs to predict conversion from MCI to AD was examined using logistic regression.ResultsIn participants with CI, older BA (but not CA) is significantly correlated with worse neurocognitive function across all measures except delayed verbal recall and logical memory (Table 1, Fig 1). AGs are positively associated with MCI participants’ probability of conversion to AD (β = 1.417, t
343 = 2.240, p = 0.025). Saliency maps reveal that, in CI participants, the 3D‐CNN relies more on features of the cerebral white matter, the brainstem, medial aspects of the temporal lobes, and the caudal portions of the anterior cingulate when estimating age according to cognitive status (Fig 2).ConclusionsCompared to CA, our BAs are significantly more strongly associated with early signs of Alzheimer’s disease, possibly reflecting disease‐related structural alterations. Saliency maps conveying the importance of each brain region for estimating BA reveal differences in patterns of neurological aging between persons with and without CI. Our BA estimation tool enhances the interpretability of such models, potentially improving the ability to stratify people according to risk of CI.
Genetics and diet explain sex differences in glucose metabolism and cognitive function
Authors: Litkowski Elizabeth M , Dai Miko , Dunn Amy R , Bridges Dave , O'Connell Kristen MS , Kaczorowski Catherine C. 
Published: December 2023

AbstractBackgroundDiabetes and cognitive impairment occur together more often than would be expected by chance [1–6]. Individuals diagnosed with type 2 diabetes have a 1.4–2.2‐fold higher risk of dementia than those without diabetes [2,6,7]. Epidemiological research has demonstrated shared risk factors, metabolic disorders, and comorbidities[5,8], shared genetics[9], and evidence of causality assessing glycemic traits [4,10–12]. We set out to determine how glucose metabolism modifies normal aging‐related cognitive decline in comparison to Alzheimer’s Disease (AD)‐related decline, given genetic diversity and controlled diet (GxD).MethodWe studied an innovative, genetically diverse mouse population (AD‐BXDs, Fig. 1) to determine GxD effects on metabolic function and the transition to cognitive impairment [13]. The data were collected longitudinally from a cohort of ∼650 AD‐BXD mice (39 unique strains) fed either a low‐fat chow diet or a high‐fat, high sucrose diet (HFD:45% fat,17.5% sucrose). Glucose metabolism was assessed by measuring the area under the curve of an intraperitoneal glucose tolerance test (IPGTT). In general, faster clearance of glucose (smaller area under the curve) reflects better glycemic control. Contextual fear memory (CFM) at 6 and 14 months of age was the measure of cognitive function. We used multivariable linear regression to model the relationship between overall CFM and an IPGTT by strain effect.ResultWe found that there was heterogeneity in IPGTT by sex, strain, and diet, accounting for more than 50% of the variation explained (Fig. 2). Females generally exhibit faster glucose metabolism than males (Fig.2, left), while the magnitude of the effect of sex and diet on IPGTT differs by strain (Fig. 2, x‐axis). For our research question of how glucose metabolism affects cognitive function, we identified strains that exhibited resilience to cognitive dysfunction as predicted by their glucose metabolism, with a broad‐sense heritability of 0.81 (Fig. 3). These early findings establish a foundation to identify quantitative trait loci (QTLs) and GxD‐type QTLS based on glucose tolerance and cognitive function associations.ConclusionBy examining the effect of diet on AD‐BXD strains and incorporating metabolic measures associated with diabetes, we will be able to evaluate and validate cause in these relationships for the first time.
Vascular contribution to the relationship between cerebrovascular reactivity and cognition
Authors: Kim Donghoon , Hong Sarah Y. , Hughes Timothy M. , Lipford Megan E. , Lockhart Samuel N. , Craft Suzanne , Baker Laura D , Whitlow Christopher T , Okonmah‐Obazee Stephanie E. , Hugenschmidt Christina , Bobinski Matthew , Jung Youngkyoo 
Published: December 2023

AbstractBackgroundBrain vascular health is closely related to cognitive performance, and cerebrovascular reactivity (CVR), an indicator of cerebral blood flow (CBF) compensatory capacity in response to vasoactive stimuli, may help elucidate this relationship. Arterial spin labeling (ASL) and blood‐oxygen‐level‐dependent (BOLD) are two representative methods for measuring CVR, although BOLD is a complex combination of CBF, cerebral volume, and cerebral metabolic rate of oxygen. This study aimed to investigate the relationship between cognition and two different CVR methods.MethodSeventy‐nine subjects (age: 68.7±7.2 years) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core underwent MRI, including both dynamic pseudo‐continuous ASL (PCASL) under a hypercapnic respiratory challenge and multi‐TI PCASL for resting CBF and ATT mapping. The dynamic PCASL with a longer TE (20ms) provided simultaneous acquisition of ASL and BOLD. CVR was obtained by calculating CBF or BOLD signal changes during a hypercapnic period. Voxel‐wise multiple linear regression analyses were performed to examine the relationship between CVR and mild cognitive impairment (MCI), adjusting for age, sex, glycemic status, APOE e4 allele, hypertensive status, and years of education. False positive cluster thresholding was applied for each modality. Additional statistical analyses were conducted to investigate differences in baseline CBF and ATT between cognitively healthy and MCI groups within the voxel clusters that showed significantly different CVR values.ResultIn the BOLD‐based CVR analysis, two voxel clusters in the white matter (WM) of superior temporal and parietal lobes showed lower CVR in the MCI group compared to the cognitively healthy group (Figure 1). Additionally, reduced CBF and prolonged ATT were observed within the clusters (Figure 2 and 3).ConclusionSubjects with MCI exhibited lower BOLD‐based CVR in WM, while no association was found between ASL‐based CVR and MCI. BOLD‐based CVR may be a more sensitive measure than ASL‐based CVR in association with cognition, particularly in WM where optimization of ASL acquisition is challenging. The impaired CVR in the MCI group may be due to cerebrovascular impairments, such as reduced CBF and prolonged ATT.
Novel characterization of Alzheimer’s disease genetic loci using long‐read sequencing
Authors: Talozzi Lia , Chemparathy Augustine , Jensen Tanner D. , Gorzynski John , Belloy Michael E , Guen Yann Le , Kasireddy Nandita , Dailey Maddie , Stewart Ilaria , Ashley Euan , Greicius Michael D 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is up to 60‐80% heritable, but less than ∼20% is explained by studies analyzing single nucleotide variants (SNVs). One limitation of short‐read whole‐genome sequencing (SRS) is the standard read length of 150 base pairs, which does not enable the detection of longer structural variants (SVs). Here we sequenced individuals using long‐read sequencing (LRS), which can sequence reads with an average length of ∼20 kilobases, allowing us to identify SVs previously uncaptured.MethodAll participants underwent whole‐genome LRS (∼15x coverage) and a subgroup (84%) underwent SRS. Out of 576 participants (47% males, age = 70.6±7.9 y.o.), 115 were diagnosed with AD or mild cognitive impairment, 365 were healthy controls, and 96 were diagnosed with a synucleinopathy (either Parkinson or Lewy Body disease). Eighty‐three index SNVs from loci associated with AD risk through GWAS (Bellenguez et al., Nature Genetics 2022) were genotyped with 30x coverage SRS, in addition to APOE2‐4. A 1Mbp window was defined around these SNVs to construct the discovery range for SVs (Sniffles2 population mode). Linkage disequilibrium (LD) was assessed between SNVs and SVs (CubeX).ResultA total of 14854 SVs were found across the AD risk loci (Figure1). After LD calculation, N = 197 SVs had a R2>0.1 (Figure2). The SVs with the highest LD (R2>0.7) are reported in Table1, among which there is a 322 bp deletion in the 3’ UTR region of the TMEM106B in high LD (R2 = 0.918) with the intronic SNV rs13237518. This TMEM106B locus has been previously associated with the risk of frontotemporal lobar dementia with TDP‐43 pathology in addition to AD, but the causative SNV has not been identified yet. This large deletion may mediate TMEM106B’s risk‐modulating role in AD and FTLD‐TDP (Chemparathy et al. medRxiv 2023). At the complex MAPT locus, three SVs showed a high LD with rs199515.ConclusionInsights into the role of SVs in neurodegenerative disorders have been hampered due to limitations with SRS. Using LRS in a large AD‐related sample, we characterized for the first time the genetic variation of SVs in known AD risk loci and provide a roadmap to identify potential causal SVs driving the AD association signal.
Hypertension predicts lower cerebral blood flow and fluid cognitive scores after a lipid challenge in older adults
Authors: Ashford Nathanial K , Miglani Jasroop K , Farris Kristen M , Levendovszky Swati Rane , Hanson Angela J 
Published: December 2023

AbstractBackgroundHypertension (HTN) is a modifiable risk factor for AD. We previously reported an association with high systolic blood pressure (SBP) and lower cerebral blood flow (CBF) using ASL MRI at AAIC 2022. Here we reproduce and expand on those findings in a new cohort of participants.MethodAfter fasting, 29 older adults (age = 66.9±7.3, 20 females) underwent ASL MRI two hours after ingestion of 1/2 cup heavy cream to mimic an oral triglyceride tolerance test (OTTT). At three hours, participants underwent a cognitive assessment using the NIH Toolbox as well as several blood pressure assessments. We used 3D pCASL MRI with background suppression to measure CBF in ml/100g/min using label duration = 1.8 s, post‐labeling delay = 2 s, labeling offset = 25‐30 mm, slices = 30, resolution = 2×2×4 mm3, SENSE‐factor = 2, TR/TE = 5000/18 ms. Finally, we acquired a reference scan (M0, 1 minute) identical to the above scan but with TR = 10,000 ms and no labeling or background suppression. CBF was measured in AD‐vulnerable regions (posterior cingulate, temporal cortex, angular gyrus, and hippocampus). Statistical analyses included Pearson correlation using SAS Studio.ResultOverall, SBP tended to drop at one hour following lipid drink and returned to baseline around 2‐3 hours; around 30% of participants had a higher SBP at 2 or 3 hours compared to fasting levels. Systolic but not diastolic blood pressure negatively correlated with global CBF as well as CBF in all four prespecified regions of interest, with strongest correlations at the 3‐hour time point. When the group was split into those with and without HTN (≥130), those with HTN scored lower on fluency composite of NIH Toolbox (110.5±4.3 vs 98.8±3.2, p = 0.037) whereas no differences were noted for the crystallized composite (125.3±4.6 vs 122±3.5, p = 0.58) or MoCA at screening visit (27.9±1 vs 26.7±0.8, p = 0.37).ConclusionBuilding on our pilot work, we continue to find a strong negative correlation between SBP and CBF. Individuals that met criteria for HTN after ingestion of lipids had lower fluid composite scores on NIH Toolbox, suggesting that maintaining a normal blood pressure helps prevent cognitive decline.
Comparative analysis of types according to activities and social participation of the Oldest‐old
Authors: Lim Young Myoung , Kim Ah‐Ram , Lim Seungju , Park Ji‐Hyuk 
Published: December 2023

AbstractBackgroundUsing the Korean Longitudinal Study of Ageing(KLoSA), we tried to classify the clusters according to the activity and social participation of the oldest‐old and analyze the differences in characteristics between the clusters.MethodData from 682 people aged 85 years or older were included in the analysis using the KLoSA cross‐sectional data. Data extracted factors related to demographic characteristics, activities of daily living, social participation, lifestyle‐related factors, and successful aging. Cluster analysis was conducted focusing on activity and social participation variables. A chi‐square test was performed to determine the differences between demographic characteristics and variables for successful aging between clusters. In addition, ANOVA and Welch’s robust were performed according to the homogeneity of variance, and Scheffe and Dunnett T3 were performed for post hoc analysis.ResultAs a result of Cluster analysis, ‘Active participation’ (4%), ‘Dependent daily life’ (27.1%), and ‘Passive participation’ (68.9%) were clustered. Differences in demographic characteristics between clusters showed high rates in all clusters for women, the level of education below elementary school, and the number of household members of 2∼4. For related‐factors to successful aging, cognitive, perceived health status, depression, and satisfaction of life all showed differences between cluster, and the active participation group showed the most positive results in the post‐hoc analysis.ConclusionThe cluster according to the activities and social participation of the oldest‐olds confirmed the difference in the factors related to successful aging. This is significant in that it was an empirical analysis focused on successful aging for the older aged 85 years and over, and it can be used as a useful basic data for access to health promotion for the super‐aged society in Korea.
Multiomics Blood Test for Increasing Asymptomatic AD Patients Proportion in Preventive Clinical Trials
Authors: Souchet Benoit , Michaïl Alkéos , Heuillet Maud , Dupuy‐Gayral Aude , Haudebourg Eloi , Pech Catherine , Berthemy Antoine , Billoir Baptiste , Autelitano François , Fortea Juan , Fowler Christopher J , Jayadev Suman , Lleo Alberto , Masters Colin L , Mouton‐Liger Francois , Paquet Claire , Braudeau Jerome 
Published: December 2023

AbstractBackgroundWith the first positive phase III trials for anti‐amyloid approaches in MCI participants, the drug evaluation during the asymptomatic Alzheimer’s disease (AD) stage is now more relevant than ever. Currently, cognitively unimpaired participants are included in preventive trials based on risk factors such as amyloid positivity. The lifetime risks for an individual without cognitive impairment does not exceed 30% for a 65‐year‐old with amyloidosis alone (Brookmeyer et al., 2018). Based on this risk factor, most participants included will never develop AD and therefore will not respond to anti‐AD therapies. There is a need to develop new biomarkers with high specificity predicting which individuals in the cognitively unimpaired population will exhibit AD symptoms and which will not to conduct effective preventive clinical trials.MethodTargeted mass spectrometry assays were developed for 81 blood biomarkers (45 proteins and 36 metabolites) pre‐identified in AAV‐AD rats (Audrain et al. 2018). 287 participants were collected in plasma at baseline and followed clinically from 1 to 18 years. Participants’ diagnosis (AD, or Healthy Controls) was established at the last clinical visit based on reference diagnosis standard. 73.9% of participants had available amyloid status, 42.9% were determined as amyloid positive. Predictive machine learning models for asymptomatic AD participants (n = 48, followed for an average of 6.1 years) among individuals without cognitive decline (HC, n = 239, followed for an average of 4.6 years) was developed. The training dataset (70%) aimed to select the biomarkers subset, train the algorithm, and define the cut‐off. External test dataset (30%) aimed to validate in blind the locked predictive model.ResultWith 20 blood biomarkers and 2 covariates (age and gender), the model predicted asymptomatic AD (n = 16) from HC participants (n = 72) with 81.9% specificity and 56.3% sensitivity during external validation (AUROC = 69.1%, p = 0.02). When current amyloid tests (CSF or PET) and this predictive ML model were applied in series, and participants positive for both were predicted as asymptomatic AD, 90.9% specificity and 54.5% sensitivity were achieved.ConclusionMultiomics blood peripheral biomarkers predict asymptomatic AD patients among cognitively unimpaired individuals with high specificity. This could constitute an additional tool for the inclusion of participants in preventive clinical trials.
Atrophy of hypothalamic subunits in Alzheimer’s disease
Authors: Quattrini Giulia , Saglia Silvia , Agosta Federica , Bagattini Chiara , Bulgari Martina , Canu Elisa , Delai Mara , Ferrari Elisabetta , Filippi Massimo , Fracassi Claudia , Pievani Michela , Bortoletto Marta , Marizzoni Moira 
Published: December 2023

AbstractBackgroundNon‐cognitive deficits (e.g., sleep‐cycle and neuroendocrine alterations) are commonly observed in Alzheimer’s disease (AD) and are suggestive of hypothalamic (HPT) dysfunctions (Ishii and Iadecola., 2015). However, studies on the HPT involvement in the early stages of the disease are limited. Here, we compared the volumes of HPT and its subunits in cognitively unimpaired (CU), mild cognitive impairment (MCI), and AD.MethodTwenty‐nine cognitively unimpaired (CU), 21 MCI, and 21 AD participants were enrolled and underwent 3T MRI and neuropsychological exams. 3D T1‐weighted images were processed using the standard FreeSurfer v7.2 pipeline, and the newly released tool for the automated segmentation of HPT and its subunits (Billot et al., 2020). After normalization to the total intracranial volume, whole and subunits HTP volumes were compared among groups using the Kruskall‐Wallis test with Dunn‐Bonferroni correction.ResultMCI and AD showed lower left (p<.001) and right (p = .013) whole HPT volume than CU. Furthermore, lower volumes were detected in both the hemisphere for the anterior (p<.011) and posterior (p<.001) subunits in AD, and for right anterior posterior (p = .025) and for the superior tubular (p = .045) subunits in MCI, as compared with CU. No HPT differences were observed between AD and MCI patients.ConclusionPosterior HPT subunit atrophy was detectable since MCI stage and increased according to the disease progression. These results suggest a possible involvement of hypothalamus in early AD phases.