bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic signatures of regional selective vulnerability in ALS and FTLD‐TDP
Authors: Spencer Barbara E , Phatnani Hemali , Lee Eddie B , Irwin David J. , McMillan Corey T ,   the NYGC ALS Consortium
Published: December 2023

AbstractBackgroundDifferential gene expression in the brain has been identified in both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP‐43 (FTLD‐TDP) relative to controls. However, direct comparisons of ALS and FTLD‐TDP are rare. We hypothesize that identification of distinct transcriptomic signatures between ALS and FTLD‐TDP may provide insight into regional selective vulnerability of TDP‐43. Here, we directly compare gene expression in frontal cortex between FTLD‐TDP and ALS cases, accounting for cell‐type proportion differences due to neurodegeneration.MethodFrontal cortex RNA‐seq samples passing extensive quality control metrics were downloaded from the New York Genome Center ALS Consortium, including non‐neurological controls (n = 42) and individuals with neuropathological diagnoses of ALS (n = 118) or FTLD‐TDP (n = 27). A total of 59,782 genes were quantified for each sample. Scaden was used to deconvolve this bulk RNA‐seq data into cell type proportions. Infrequently expressed genes were filtered and data was normalized by total count. Generalized linear model estimates of dispersion were calculated accounting for potential confounders including cell type proportions, RIN, contributing site, age at death, and sex to identify differentially expressed genes (DEGs) between ALS and FTLD‐TDP as well as each neurological group relative to controls. A gene ontology enrichment analysis for biological processes was performed for each DEG set. We report DEGs and enrichment surviving FDR p<0.05.Result653 DEGs were identified in FTLD‐TDP compared to ALS within the frontal cortex samples. The majority of these DEGs were also differentially expressed between only one of these neurological groups and controls. However, 281 of these DEGs were uniquely differentially expressed in ALS compared to FTLD‐TDP, not differentially expressed between either neurological group and controls. Gene ontology enrichment analyses for biological processes revealed that the 198 genes uniquely upregulated in FTLD‐TDP compared to ALS (not different from controls) mapped to pathway terms including those related to immune and inflammatory responses as well as vascular functions, while the 83 genes uniquely upregulated in ALS compared to FTLD‐TDP related to retina development.ConclusionThis case‐case comparative study will provide insight into the candidate mechanisms underlying regional selective vulnerability in FTLD‐TDP relative to ALS that may drive individual‐level cognitive/behavioral presentations of TDP‐43 proteinopathies.
Cerebrospinal Fluid Protein Levels in Patients with Neurodegenerative Diseases Correlates with Cognitive and Motor Function
Authors: Szabo Marcell P , Haselhuhn Taryn R , Kwan Justin Y , Snyder Allison 
Published: December 2023

AbstractBackgroundBlood brain barrier (BBB) dysfunction is suggested to have a causal role in neurodegenerative disorders. Cerebrospinal fluid (CSF) total protein (TP) is a proxy for CSF albumin quotient, which is an indicator of BBB breakdown. Normative values for CSF TP are based on young and healthy individuals, and there is a lack of understanding of how this biomarker changes with aging and neurodegeneration. The aim of this study is to examine the CSF profile in a cohort of patients with ALS‐FTD spectrum disorders and to determine relationship between the CSF profile and cognitive and motor measures in these patients.MethodCSF from participants with ALS‐FTD spectrum disorders enrolled in the NIH protocol “Investigating Complex Neurodegenerative Disorders related to Amyotrophic Lateral Sclerosis and Frontotemporal Dementia” were included (n = 63). We described the distribution of the CSF profile in these participants and compared the findings with existing literature. We then examined the relationship between CSF measures and functional rating scales and cognitive and motor measures.ResultThe average total protein was 47.77 mg/dL (SD = 38.29). The average CSF glucose was 66.00 mg/dL (SD = 12.80). There was a negative correlation (p = 0.0102) between CSF TP and the ALS Functional Rating Score. We will further investigate the relationship between the CSF profile and measures of cognitive and motor performance.ConclusionOur findings show that CSF TP is elevated in patients with ALS‐FTD spectrum disorders and higher CSF TP level correlated with greater disease severity in ALS. We will further investigate the relationship between CSF TP and other measures of cognitive and motor function.
Regional cerebral blood flow is associated with PET and plasma biomarkers of tau pathology in middle age
Authors: Houck Alexander L , Lao Patrick J. , Alshikho Mohamad J , Turney Indira C , Pyne Jeffrey , Benavides Andrea , Hale Christiane , Gutierrez Jose , Simoes Sabrina , Manly Jennifer J. , Brickman Adam M. 
Published: December 2023

AbstractBackgroundCerebrovascular dysfunction and vascular brain injury are associated with risk and progression of clinical Alzheimer’s disease (AD), but it is unclear whether they contribute directly to disease pathogenesis. Animal models of small vessel cerebrovascular disease suggest that transient cerebral hypoperfusion may promote tau pathology independent of amyloidosis. In the current study, we used pulsed arterial spin labeling (PASL) magnetic resonance imaging (MRI) to examine the association of regional cerebral blood flow (CBF) with two biomarkers of tau pathology, plasma phosphorylated tau 181 (ptau181) concentrations and PET MK6240 SUVR, in middle aged adult participants from the Offspring Study of Mechanisms for Racial Disparities in Alzheimer’s Disease.MethodAt the time of analysis, 469 Offspring Study participants (54.0±10.6‐years‐old; 64% women; 67% Latinx, 22% non‐Latinx Black, 6% non‐Latinx white) had available PASL and ptau181 plasma concentrations (Quanterix Simoa HDx platform). Sixty‐four participants (59.9±5.4‐years‐old age; 67% women; 64% Latinx, 22% non‐Latinx Black, 8% Latinx white) with PASL CBF data received tau PET imaging with MK6240 and mean SUVR was computed across all grey matter regions for each participant. Voxelwise correlational analyses were run to examine the relationship between ptau181 concentrations and regional CBF and between tau PET SUVR and regional CBF.ResultIncreased ptau181 concentrations were associated with clusters of decreased CBF in frontal grey matter, striatum, hippocampus, and periventricular white matter. These correlations were asymmetrical, with the largest clusters found in the left hemisphere. Higher PET SUVR was associated with clusters of lower CBF in frontal, parietal, and occipital grey matter.ConclusionThese findings demonstrate a codependency between regional blood flow and tau pathology, indexed by fluidic and imaging biomarkers. Future studies will clarify the directionality and possible causality of these associations, but these cross‐sectional findings are consistent with a hypothesis that subtle diminished blood flow gives rise to tau abnormalities.
APOE4 affects cortical microstructural alterations in Alzheimer’s disease: evidence from an autopsy‐confirmed cohort.
Authors: Torso Mario , Ridgway Gerard R , Valotti Michele , Hardingham Ian , Chance Steven A ,   National Alzheimer’s Coordinating Center and Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundApolipoprotein E ε4 (APOE4) is one of the most studied genetic risk factors for developing Alzheimer’s disease (AD). However, it is still not fully understood how APOE4 contributes to cortical neurodegeneration. We investigate ante‐mortem cortical microstructural changes in carrier and non‐carrier patient MRIs with autopsy‐confirmed Alzheimer’s disease neuropathological changes (ADNC).MethodForty‐nine participants with ADNC and ante‐mortem MRI were obtained from the National Alzheimer’s Coordinating Center (NACC; n = 34) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 15). Participants were grouped based on APOE4 presence (22 non‐carriers and 27 carriers). Thal phase, CERAD neuritic plaque assessment, Braak NFT, and combined ABC score, were used as AD neuropathological hallmarks.Structural and diffusion MRI (dMRI) were used to calculate cortical diffusivity measures in five different functional macroregions: Primary Sensory, Unimodal, Limbic/Proisocortex, Heteromodal and Primary Motor (Ffytche & Wible 2014, PMID:24936089; Mesulam 1998, PMID:9648540). For each macroregion, cortical mean diffusivity and three neuropathology‐inspired cortical diffusivity measures were calculated: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+) (Torso et al. 2022, PMID:36281682).Clinical, demographic and neuropathological data were used to characterize groups (Table). Group differences in diffusion metrics were tested with GLM adjusting for ABC score, interval between MRI scan date and autopsy date, scanner manufacturer, dMRI b‐value, age and sex, with false discovery rate correction (pFDR<0.05).ResultThe cortical diffusivity investigation revealed higher Primary Sensory (auditory, visual, sensory) AngleR values in APOE4 carriers (Figure). The APOE4 carrier group was significantly younger and showed higher Thal phase, CERAD neuritic plaque, Braak stage and ABC scores.ConclusionCortical diffusivity measures can detect differences in cortical microstructure of APOE4 Carrier and Non‐carrier patients, suggesting a wider pattern of cortical damage in APOE4 carriers that involves Primary Sensory areas (lateral occipital, postcentral, pericalcarine, transverse temporal).Consistent with previous findings, the diffusion‐derived metric AngleR appears particularly sensitive to subtle effects, such as the early cortical changes associated with amyloid deposition and neuroinflammation (Torso et al. 2022, PMID:36281682), perhaps linked to the APOE4 modulation of the pattern of cortical microstructural neurodegeneration.
Association Analysis of Common Structural Variants in the Alzheimer’s Disease Sequencing Project
Authors: Lee Songmi , English Adam C , Xia Rui , Peloso Gina M. , Bis Joshua C , Lin Honghuang , Choi Seung Hoan , Heard‐Costa Nancy , DeStefano Anita L. , Sedlazeck Fritz J , Fornage Myriam 
Published: December 2023

AbstractBackgroundStructural variants (SV), genomic rearrangements of >50 base pairs, are an important source of genetic variation and have a great impact on gene expression and protein function. However, their contribution to the genetic architecture of Alzheimer’s Disease (AD) has not been comprehensively investigated. Identification of SVs by short‐read alignment can be inaccurate and biased. We used a novel SV calling pipeline that leverages assembly‐based methods and graph‐based representation, to identify SVs with high accuracy in the diverse sample of the Alzheimer’s Disease Sequencing Project (ADSP). We further examined the association of common SVs with AD.MethodsWe applied Biograph for SV calling on the ADSP 17K whole genome sequence data. After filtering out low‐quality SVs and performing sample‐level quality control, we identified 222,956 deletions, 177,139 insertions, and 10,558 inversions in 12,908 individuals (6,304 AD cases; 6,604 controls). We performed association analyses of common SVs (MAF > 1%) with AD using a logistic mixed‐effects model adjusting for sex, technical covariates, principal components, and relatedness. Statistical significance was evaluated using a Bonferroni‐corrected threshold (P< 9.19.x10−7).ResultsThere were 28,634 deletions, 25,522 insertions, and 198 inversions with MAF > 1%. We identified 2 intronic deletions significantly associated with AD. The first deletion is located in CCDC88B, encoding a protein that regulates T‐cell maturation and inflammation. The second deletion is located in CCDC11, predicted to be part of the spliceosomal complex. Among 11 insertions significantly associated with AD, 3 mapped to exonic sequences. A relatively common insertion located in an exon of FOXO6 showed the most significant association with AD (P = 1.41×10−12). FOXO6 is a member of Forkhead transcription factors that have been implicated in aging. Along with its high level of expression in the hippocampus, mice lacking FOXO6 had impaired memory consolidation. We identified one inversion suggestively associated with AD (P = 3.32×10−6) and located in an intron of PDE5A. PDE5A inhibitors have been reported as potential therapeutic targets for AD.ConclusionUsing novel data structures and algorithms to call SV, we discovered 14 SVs significantly associated with AD. Validation and gene prioritization of these findings are warranted.
Alzheimer’s disease blood tests of amyloid‐β 42/40, p‐tau217, p‐tau181 and p‐tau205 ratios in a diverse community‐based population: Preliminary results from SEABIR
Authors: Bateman Randall J. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) blood tests that can identify and quantify amyloid plaques, tau tangles, and cognitive and clinical decline are needed in clinical practice, including primary care. However, these tests require validation in diverse groups and real‐world settings. The goals of the Study to Evaluate Amyloid in Blood and Imaging Related to Dementia (SEABIRD) were to enroll 1120 participants to determine the accuracy and validity of blood amyloid‐β (Aβ) and phosphorylated tau (p‐tau) tests in a diverse, community‐based sample of older adults compared with amyloid PET, and to explore the impact of key factors (age, race, years of education, cognition, APOE genotype, and medical conditions) on validity estimates.MethodSEABIRD measured blood plasma Aβ42/40 ratio and ratios of phosphorylated to non‐phosphorylated p‐tau217, p‐tau181, and p‐tau205 (%p‐tau) in a diverse population of older adults. In addition, cognitive screening with the AD8® dementia screen and Montreal Cognitive Assessment (MoCA) were obtained. Approximately 25% of participants were selected for amyloid PET and CDR as a reference standard.ResultOf the 859 participants enrolled in this ongoing study, 20.6% self‐identified as Black or African American and the percentage of APOE ε4 carriers was 30.2%, as expected for a population‐based sample (Table 1). For a subset of 76 participants with completed amyloid PET and all blood measures, plasma Aβ42/40 had ROC‐AUC with amyloid PET status of 0.85, %p‐tau217 of 0.97, %p‐tau181 of 0.83, and %p‐tau205 of 0.81 (Figure 1). Spearman correlations with amyloid PET SUVR were ‐0.59 for plasma Aβ42/40, 0.69 for p‐tau217 ratio, 0.43 for p‐tau181 ratio and 0.48 for p‐tau205 ratio.ConclusionThese preliminary results demonstrate that AD blood tests have similar accuracies in a diverse population‐based sample to those reported in AD research cohorts. These findings suggest that rapid screening and diagnosis of amyloid pathology with AD blood tests is possible in a broader population with higher comorbid disease burden and greater diversity than typical AD research cohorts. Screening with AD blood tests could accelerate clinical trial recruitment and increase the representativeness of clinical trial populations, which may improve the generalizability of clinical trial results.
Friends with benefits: Sharing large‐scale transcontinental brain MRI databases in LatAM‐FINGERS and US POINTER
Authors: Da Graça Morais Martin Maria , Landau Susan M. , Damian Andres , Vemuri Prashanthi , Bérgamo Yanina , Suemoto Claudia Kimie , Calandri Ismael Luis , Caramelli Paulo , Lopera Francisco , Allegri Ricardo Francisco , Lovato Laura , Delgado Carolina , Nitrini Ricardo , Brucki Sonia Maria Dozzi , Duque Lissette , Baieti Ana Charamelo , Custodio Nilton , Leon‐Salas Jorge M , Acosta Daisy M , Velazquez Ivonne Z. Jimenez , Cusicanqui María Isabel , Sosa‐Ortiz Ana Luisa , Vellila Lin , Salinas‐Contreras Rosa Maria , Espeland Mark A. , Snyder Heather M , Carrillo Maria C. , Kivipelto Miia , Baker Laura D , Crivelli Lucía ,   US POINTER and LatAm‐FINGERS
Published: December 2023

AbstractBackgroundMulticentric initiatives to study brain cognition in the elderly offers us a unique collection of brain imaging data accompanied by detailed neuroclinical and neuropsychological evaluations. U.S. POINTER and LatAm‐FINGERS, part of the World Wide FINGERS, are both large‐scale investigations of lifestyle interventions and its impact on cognitive function. These large‐scale detailed data may offer an unprecedented opportunity to compare diverse populations.MethodBaseline MRI of subjects from multiple US centers (POINTER‐US), distributed in 5 geographical regions, and from 9 latin‐american countries (LatAm‐FINGERS). The protocols vary from basic (3D T1, 3D FLAIR,T2* GRE, Cor T2 hippocampus, DWI) to advanced which also included ASL, rs‐FMRI and DTI. Demographic information and clinical, cognitive and neuropsychological assessment were also included.ResultMRI data was collected from 662 participants in the United States (about 65% of the total anticipated U.S. POINTER neuroimaging sample) and from 542 subjects from 9 countries in latin‐america (about 80% of the total anticipated LatAm‐FINGERS neuroimaging sample), with around 1200 participants scanned (table1).All participants have 3D T1, 3D FLAIR, T2* GRE images and either DWI or DTI images.Comparative demographics from the 2 datasets shows similar mean age, a predominance of females, and slight differences in education (table 2). This will allow us to compare multiethnic and multicultural volumetric and functional brain MRI information, as well as disease markers, associated with thorough neurological and clinical assessment. Reasons for not acquiring MRI were mainly due to claustrophobia or scanner unavailability.ConclusionThis is an exceptional opportunity to have comparative large‐scale databases, with anatomical and functional brain imaging from different populations, allowing us to study real world diverse brain data and better understand its relationships with demographics, health and risk characteristics, and cognition.
Who benefits from MRI in memory clinics? A clinical and research perspective from the Oxford Brain Health Clinic
Authors: Griffanti Ludovica , Dembele Mohamed , Gillis Grace , Mitchell Robert , Pretorius Pieter M , O'Donoghue M Clare , Blane Jasmine , Martos Lola , Raymont Vanessa , Mackay Clare 
Published: December 2023

AbstractBackgroundWith the advent of disease modifying treatments for dementia, it is essential to restructure memory clinic services to provide accurate and early diagnosis to enable precision therapies and recruitment to clinical trials. The Oxford Brain Health Clinic (BHC) offers a comprehensive clinical and embedded research assessment in the patient pathway, including a research‐quality brain MRI scan (using the UK Biobank protocol), well‐tolerated by patients (Griffanti et al., 2022, Neuroimage:Clinical). In this study we investigated whether the images obtained from BHC patients were of sufficient quality for clinical/diagnostic purposes (i.e. to provide a radiology report) and research purposes (i.e. suitable to extract quantitative measures with automated software) and whether the scan quality was related to patients’ characteristics (capacity, frailty, anxiety, cognitive impairment ‐ CI), to inform future triage to Brain Health Clinics.MethodT1 and FLAIR scans from 138 BHC patients were reported by a radiologist and independently rated as high, medium or low quality for research purposes (consensus between 2 raters). The following patients’ characteristics were evaluated: capacity (yes/no), Rockwood Clinical Frailty Scale (more frail if 5 or more), anxiety before/during the scan (low/not‐low), Addenbrooke’s Cognitive Examination III (ACE‐III, score above or below 82). A two‐sided Fisher‐Freeman‐Halton test was run to test the association between scan quality (3 classes) and patients characteristics (2 classes for each independent variable). Bonferroni‐adjusted post‐hoc comparisons were performed between scan quality classes using 2×2 Fisher’s Exact Tests.ResultThe radiologist was able to provide a clinical report for all scans. Over 90% of scans were rated high or medium quality for research purposes (Fig.1). No significant associations were observed between patients’ characteristics and FLAIR quality. T1 quality was significantly associated with patients’ capacity (p = 0.001, more low‐quality images from patients lacking capacity, Fig.2) and frailty (p = 0.014, more low‐quality images from frailer patients, Fig.3).ConclusionResearch‐quality MRI scans in memory clinic are useful for both clinical and research purposes. For research comprised of high‐quality MRI, relatively generous thresholds relating to frailty and capacity could be considered to balance the trade‐off between inclusivity (i.e. increasing representativeness) and adherence to protocols.
Describing the effects of iron dyshomeostasis on cognitive function and dementia in UK Biobank
Authors: Winchester Laura M , Newby Danielle , Sproviero William , Gallacher John , Bauermeister Sarah , Nevado‐Holgado Alejo J 
Published: December 2023

AbstractBackgroundIron dyshomeostasis is a feature of neurodegenerative disease. In circulating blood, changes in iron are associated with dementia disease phenotypes, while in brain tissue increased iron is associated with dementia progression. In UK Biobank, whole body imaging includes variables derived from the brain swMRI data which are indicative of iron in brain tissue. Complete blood counts per participant include hemoglobin concentration indicative of iron in oxygen transportation. Using the cognitive assessment and participants with all‐cause dementia we aimed to understand how measured changes in iron would affect dementia in a large UK‐based cohort.MethodUsing cross–sectional analysis at shared time points in UK Biobank data collection we compared both the iron phenotypes with cognitive measures. Firstly, the baseline values at the primary assessment centre visit where 478,082 participants were tested for cognitive function and red blood cell measures. Secondly, at Visit 2 (n = 5861), where brain imaging derived T2* measures and complete blood count (hemoglobin concentration) were captured alongside the repeated cognitive measures. Each linear regression model includes cognitive function (outcome) and iron measures (exposure) with correction for age and sex. Adjusted models include correction for education years, assessment centre and ethnicity.ResultWe found association between low hemoglobin and all‐cause dementia (beta = ‐0.125, p <0.001). This association was replicated with poorer cognitive function and low haemoglobin analysing cognitive function tests (including verbal and numerical reasoning and reaction time) and mean corpuscular hemoglobin, (p<0.05). Using quantile sets of hemoglobin concentration we found a non‐linear effect, whereby both high and low iron had a negative association on cognitive outcome (verbal reasoning ‐0.029,‐0.019, p’s = 0.002,0.049). Using MRI T2* we found associations between newer cognitive function tests, matrix pattern puzzles and symbol digit substitution (p <0.0001) as well as verbal reasoning (p = 0.015). These cognitive function measures were strongly associated with the T2* hippocampus region.ConclusionWe have shown an association between dementia and low hemoglobin concentration. We have demonstrated the complexities of this iron homeostasis relationship, showing how lower cognitive function is associated with both increased and reduced iron concentration in blood and how iron changes in brain effect different cognitive traits.