bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generalized q‐sampling imaging‐based fiber tracking measures of white matter tracts in cognitive impairment
Authors: Duran Tugce , Bateman James R. , Williams Benjamin J. , Hughes Tim M. , Barcus Richard A. , Peavey Jeremy J. , Okonmah‐Obazee Stephanie E. , Whitlow Christopher T. , Craft Suzanne , Lockhart Samuel N. 
Published: June 2023

AbstractBackgroundDiffusion magnetic resonance imaging (dMRI) is a non‐invasive technique for exploring white matter fiber organization of the brain. As traditional diffusion tensor imaging (DTI) methods may provide inaccurate descriptions of local crossing and diverging fibers, we examined generalized q‐sampling imaging (GQI), a novel method providing better directional and quantitative information using dMRI data from community‐dwelling older adults.MethodWe examined baseline dMRI data from 227 adults aged 71±8 on average from the Wake Forest Alzheimer’s Disease Research Center’s Clinical Core, who had baseline and year‐1 follow‐up global Clinical Dementia Rating (CDR) score of 0 (indicates normal cognitive function) and 0.5 (akin to MCI). The primary outcome measure was cognitive migration status determined by CDR increase/decrease between baseline and follow‐up (mean difference = 13.9 months), shown in Figure. We performed atlas‐based fiber tracking analysis using GQ in DSI Studio to generate normalized quantitative anisotropy (NQA), DTI fractional anisotropy (DTI_FA) and restricted diffusion (RDI) measures in several AD‐related white matter (WM) tracts: Corpus Callosum (CC), Fornix, Cingulum bundle/Parahippocampal tracts (see Table 2: CFP; CP; CPP), Uncinate Fasciculus (UF), Superior Longitudinal Fasciculus (SLF) and Inferior Fronto‐Occipital Fasciculus (IFOF). We performed multinomial logistic regression (MLR) models adjusted for age, sex, and education, using cognitive migration status as the outcome and standardized GQI‐based diffusion indices sNQA, sRDI, and sDTI_FA as predictors.Result
Table 1 lists the baseline demographics and biomarker characteristics for cognitive migration groups. MLR results in Table 2 show significant associations between diffusion indices and tracts for outcome 4 (Reversion) in reference to outcome 1 (stability of normal cognition). Decrease in sNQA in bilateral CP and right Fornix was significantly associated with higher odds of Reversion relative to the reference. Increase in sDTI_FA in left IFOF was associated with higher odds of reversion relative to reference. Decrease in sRDI in bilateral CFP, CPP, Fornix and UF and right CP was associated with higher reversion relative to reference.ConclusionIn early trajectories of cognitive impairment, RDI may be a sensitive diffusion marker for cognitive reversion in several AD‐related WM tracts. Future work will validate these markers in other cognitive migration groups (negative migration and MCI stability).
Ancestry‐Specific eQTL Associations in AA/NHW Alzheimer Disease Cohorts
Authors: Wheeler Nicholas R. , Benchek Penelope , Van Booven Derek , Gu Tianjie , Starks Takiyah D. , Byrd Goldie S. , Haines Jonathan L. , Beecham Gary W. , Pericak‐Vance Margaret A. 
Published: June 2023

AbstractBackgroundAlthough the genetic etiology of Alzheimer’s Disease (AD) has been shown to vary among ancestrally diverse populations, the influence of genetic variation on the transcriptome within these populations has not yet been extensively investigated. Multi‐ancestry AD datasets featuring both genetic information and gene expression measurements are needed to support expression quantitative trait loci (eQTl) studies in historically underrepresented populations. In this work, we have compared eQTL signals in case/control AD sample populations of both African American (AA) and non‐Hispanic white (NHW) ancestries.MethodWe analyzed cohorts of AA and NHW ancestries (Naa = 232, Nnhw = 241) with corresponding array‐based genotypes and RNA‐seq mRNA expression levels from whole blood, along with clinical AD diagnoses (Naa_case = 115, Naa_control = 117, Nnhw_case = 121, Nnhw_control = 120). Transcriptome‐wide eQTL associations between genetic variants and gene expression levels were assessed via regression across 17,638 gene units, adjusting for age, sex, experimental factors, and genetic principal components. This was repeated across all sample set combinations of ancestry‐AD pairings (ancestry = [aa, nhw, both] * AD = [case, control, both]).ResultThe number of significant (p‐value < 10e‐7) eQTL signals varied by ancestry, with the AA cohort showing 76,742 raw eQTL associations, the NHW cohort 19,734, and both ancestries combined 81,763. When further sub‐setting sample sets to AD cases only, 770 and 788 significant eQTL signals were observed for AA and NHW cohorts respectively, which impacted 135 (AA) and 130 (NHW) genes. Interestingly, these ancestry‐aware, case‐only eQTLs were remarkably distinct between the two ancestries, with only 71 (∼9.1%) of the eQTLs and only 19 (∼14.3%) of the impacted genes being shared by both ancestral cohorts. Of particular interest is the appearance of WWOX (a gene of wide neurological importance, and known AD risk loci), as differentially significant in the AA cohort (P = 8.07e‐7) as compared to the NHW cohort (P = 9.06e‐3).ConclusionWe have observed differences in eQTL signals relative to AD diagnosis status between AA and NHW sample populations, which may indicate the presence of novel ancestry‐specific effects impacting the genetic etiology of AD through changes in gene expression.
Impact of the COVID‐19 pandemic on moral distress of care home staff caring for people with dementia
Authors: Haslam‐Larmer Lynn , Grigorovich Alisa , Quirt Hannah , Pia Kontos , Astell Arlene J. , McMurray Josephine , Maxwell Colleen J , Rodrigues Kevin , Flint Alastair , Iaboni Andrea 
Published: June 2023

AbstractBackgroundHealthcare providers caring for people living with dementia may experience moral distress when faced with an ethically challenging situation, such as an inability to provide care that is consistent with their values. The COVID‐19 pandemic both created new and exacerbated pre‐existing factors which contributed to the experience of moral distress amongst healthcare providers in LTCHs.MethodWe conducted an online survey to examine changes in mortal distress during the first wave of the pandemic, its contributing factors and correlates, and its impact on the well‐being of LTCH staff. A total of 227 health care providers from LTCHs across Ontario, Canada completed the online survey. Using a Bayesian approach, we examined the associations between moral distress and staff demographics and roles, and characteristics of the LTCH in which they worked.ResultMore than 80% of LTCH healthcare providers working with people with dementia reported an increase in moral distress since the start of the pandemic. They frequently experienced physical and emotional symptoms related to moral distress more than once a week, with the most common symptoms being physical exhaustion (55%) powerlessness (39%), sadness/anxiety (38%) frustration/anger (31%), and difficulty sleeping (33%). There was no difference in the severity of distress by age, sex, role, or years of experience. The most common situations associated with moral distress were lack of activities and family visits, insufficient staffing and high turnover, and having to follow policies and procedures that were perceived to harm residents with dementia. Respondents working in not‐for‐profit or municipal homes reported less sadness/anxiety and feelings of not wanting to go to work than those in for‐profit homes. Front‐line staff were more likely to report not wanting to work than those in management or administrative positions. In the survey’s free‐text responses, respondents elaborated on the emotional impact of the change in care delivery for LTCH residents.ConclusionMoral distress increased during the pandemic, negatively affecting the well‐being of healthcare providers in LTCHs, with preliminary evidence suggesting that individual and systemic factors may intensify this negative effect.
Comparison of white matter hyperintensities between early‐onset Alzheimer’s disease participants and their cognitively normal and early‐onset nonAD peers from LEADS
Authors: Eloyan Ani , Vemuri Prashanthi , Gatsonis Constantine , Carrillo Maria C. , Rabinovici Gil D. , Apostolova Liana G. , Dickerson Bradford C. 
Published: June 2023

AbstractBackgroundThe Longitudinal Early‐onset Alzheimer Disease study (LEADS) aims to robustly characterize biomarkers of early‐onset AD (EOAD). Here we quantified white matter hyperintensities (WMH) in EOAD and compared the volume of WMH with that of cognitively normal (CN) and amyloid‐negative early‐onset dementia (EOnonAD) groups.MethodsWe compared WMH of 194 amyloid‐positive EOAD, 59 amyloid‐negative EOnonAD, and 88 cognitively normal participants. WMH in left and right frontal, temporal, parietal, and occipital regions was compared between the group, as well as the sum total in each hemisphere. For distributional considerations, the logarithm of the WMHs was used in the analyses. Group comparisons were performed using t‐tests. Analyses of variance were used to compare the groups after correcting for the effects of age, sex, and education. Linear regression analyses were used to investigate the association between cognitive impairment and WMH using age, sex, and education as covariates. Cognitive impairment was measured using the Mini‐Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) scale sum of boxes (CDR‐sb). All p‐values were corrected for multiple comparisons using the false discovery rate method.ResultsEOAD showed greater WMH compared with both CN and EOnonAD groups across all regions. This relationship holds after correcting for the effects of age, sex, and education (see Figure 1 and Table 1, all p‐values < 0.05). No significant differences were observed between WMHs of CN and EOnonAD groups. Higher WMH values were associated with greater cognitive impairment: MMSE (b = ‐1.69, p‐value <0.0001) and CDR‐sb (b = 0.45, p‐value <0.0001).ConclusionsEOAD consistently show higher WMH compared to their CN and EOnonAD peers. The extent of WMH in CN and EOnonAD groups is similar. No differences in regional distribution were observed, with EOAD having higher WMH across all brain regions. Higher WMHs were associated with worse cognitive impairment measured both using MMSE and CDR sum of boxes.
Blocking soluble TNF decreases diet‐induced hyperglycemia and modulates immune alterations in 5xFAD animal model of Alzheimer’s disease
Authors: de Sousa Rodrigues Maria Elizabeth , Blackmer‐Raynolds Lisa , Chang Jianjun , Sampson Timothy R. , Tansey Malu Gamez 
Published: June 2023

AbstractBackgroundRegulatory interactions between the gut and the brain are essential for energy homeostasis across systems. Current evidence indicates high‐fat, high‐carbohydrate diets (HFHC) impact Alzheimer’s disease (AD) pathophysiology, however, the mechanisms underlying this association are poorly understood. We hypothesize that (1) Tumor Necrosis Factor (TNF) mediates metabolic inflammation in an obesogenic environment with impacts across the gut‐brain axis and (2) that HFHC interacts with an AD‐relevant genetic background to promote metabolic and immune dysregulation that accelerates pathological and behavioral dysfunction in an animal model of AD.MethodTo investigate the effects of chronic systemic inflammation on AD‐associated pathology, 2‐month old female 5xFAD mice were fed HFHC or a control diets (CD) for 8 weeks. One month following dietary intervention, the brain‐permeant soluble TNF inhibitor XPro1595 or a brain‐impermeant pan (sol and membrane‐bound) TNF inhibitor Etanercept (Enbrel, Amgen‐Wyeth) or vehicle (saline) were dosed twice weekly for 4 weeks. Behavioral test were performed to assess cognitive parameters. Plasma, brain and gut were collected for evaluation of insulin impairment, metabolic and immune parameters. Cortical tissues were subjected to RNAseq analysis to determine gene pathways modified by interactions between diet, genotype, and TNF inhibition.ResultHFHC promoted metabolic syndrome features associated with increases in adiposity, body weight, and plasma glucose, cholesterol, leptin, and insulin. TNF inhibition did not rescue diet‐induced insulin increases, however XPro specifically reduced plasma glucose, while Enbrel increased HOMA‐IR in HFHC‐fed mice. HFHC diet increased circulating IL‐6, CXCL1, CXCL2 and CCL2 and TNF neutralization with either drug decreased IL‐6 in HFHC‐fed groups. In the colon, HFHC diet decreased CCL3 and TNF blockade increased colonic IL‐15 in HFHC‐fed mice. Ongoing behavioral assessment, cortical transcriptional analysis, and hippocampal protein profiles of insulin signaling and inflammatory markers will determine additional effects of TNF and HFHC in the 5XFAD animal model of AD.ConclusionCollectively, these results suggest that TNF modulates systemic metabolic and inflammatory pathways induced by HFHC consumption and associated with neurodegeneration and neuroinflammation. Blocking soluble TNF decreases hyperglycemia triggered during diet‐induce obesity. Future studies focusing on the impact of TNF on energy homeostasis and inflammation will provide targets for new therapeutics against neurological disease.
“Probable 4R‐tauopathy” criteria in a Corticobasal Syndrome cohort: diagnostic accuracy, clinical, metabolic and volumetric patterns in a multimodal PET/MRI study
Authors: Parmera Jacy Bezerra , Carneiro Camila de Godoi , Neto Adalberto Studart , Ono Carla R , Barbosa Egberto Reis , Nitrini Ricardo , Buchpiguel Carlos A , Brucki Sonia Maria Dozzi , Coutinho Artur Martins 
Published: June 2023

AbstractBackgroundCorticobasal syndrome (CBS) is a neurodegenerative disease related to multiple underlying pathologies, including four‐repeat (4R) tauopathies, namely corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), Alzheimer’s disease (AD), among others. The Movement Disorders Society‐PSP clinical criteria proposed a diagnostic category “probable 4R‐tauopathy” to include the phenotypic overlap between PSP and CBD. These criteria were specific for 4R‐tauopathies in a previous post‐mortem validation study. We aimed to investigate this proposed criteria in a cohort of patients clinically diagnosed with probable CBS, comparing the CBS‐4R tau group regarding neurological assessment, brain atrophy patterns, functional and disease‐specific imaging biomarkers. Also, we compared this group with CBS patients that matched the clinical research (cr) criteria for CBD.MethodThirty‐two patients diagnosed with probable CBS were prospectively enrolled and clinically evaluated. They were split into those who fulfilled criteria for probable 4R‐tauopathy (CBS‐4RT = 12) and probable CBD (CBS‐CBD = 28). They underwent [18F]fluorodeoxyglucose‐positron emission tomography (FDG‐PET) and [11C]Pittsburgh Compound‐B (PIB‐PET) on a hybrid PET‐MRI to assess their amyloid status. PIB‐PET images were classified individually based on visual and 3D‐SSP semi‐quantitative analysis. Quantitative group analyses were performed with SPM12, to check both brain atrophy patterns using voxel‐based morphometry (VBM), and regional brain hypometabolism patterns with FDG‐PET. A healthy control group of 30 subjects, matched by age and education, was also included.ResultOnly one patient classified as CBS‐4RT was positive at PIB‐PET (p = 0.010), compared to 12 among 28 CBS‐CBD subjects (p = 0.458). The CBS‐4RT clinical classification had 52.6% sensitivity, 92.3% specificity, and 68.7% accuracy in predicting a negative PIB‐PET result. Also, CBS‐4RT patients presented dysarthria (p = 0.017) and motor perseveration (p = 0.032) more often than the whole group. CBS‐4RT patients showed asymmetric hypometabolism in the inferior, middle, and superior frontal gyri, supplementary motor area, and caudate compared to controls. They also demonstrated brain atrophy in the superior and inferior frontal gyri and basal ganglia.ConclusionThe new proposed clinical 4R‐tauopathies criteria demonstrated high specificity to detect amyloid‐negative CBS patients. Patients fulfilling the criteria presented specific metabolic and volumetric patterns. Moreover, they presented clinical characteristics such as dysarthria and motor perseveration previously related to tauopathies.
Tracking reactive astrocytes in autosomal dominant Alzheimer disease with plasma GFAP and multi‐modal PET imaging
Authors: Chiotis Konstantinos , Johansson Charlotte , Rodriguez‐Vieitez Elena , Pannee Josef , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Graff Caroline , Nordberg Agneta K 
Published: June 2023

AbstractBackgroundWe have proposed astrogliosis as a “first wave” of response to AD pathology with diverging longitudinal changes of reactive astrocytes and amyloid‐β positron emission tomography (PET) retention in pre‐symptomatic autosomal dominant AD (ADAD). It has been suggested that plasma glial fibrillary acidic protein (GFAP) could be a marker of neuroinflammation in AD brain, although this hypothesis remains unproven. We therefore compared plasma GFAP levels with 11C‐deprenyl (DED) with a multi‐modal PET design in ADAD mutation carriers (MC) and non‐carriers (NC).MethodTwenty‐three individuals from families with known ADAD mutations were included (MC = 9; NC = 14). All individuals underwent PET imaging with 11C‐DED, 11C‐PIB and 18F‐FDG, for assessing monoamine oxidase B as a marker of reactive astrocytes, amyloid‐beta deposition, and glucose metabolism, respectively. Plasma sampling was performed after a median of 3 (interquartile range 1.5‐5.5) months. GFAP levels were measured using single molecule array technology. Eleven individuals had follow‐up imaging investigations and plasma sampling after a median of 2.7 (interquartile range 2.5‐2.9) years.ResultPlasma GFAP levels and 11C‐PIB binding increased significantly from pre‐symptomatic to symptomatic stage while 11C‐DED binding and 18F‐FDG uptake significantly decreased towards estimated onset of clinical symptoms in MC. Cross‐sectionally, plasma GFAP showed negative correlations with [18F]FDG uptake in widespread cortical areas, in contrast to no correlations with 11C‐DED or 11C‐PIB binding. 11C‐DED binding showed a positive correlation with 18F‐FDG uptake. Across the follow‐up interval, plasma GFAP levels showed a four‐fold greater intraindividual variation relative to 11C‐DED binding variation (longitudinal Δ variance = 1.67 vs 0.39 z‐scores, respectively). When averaging plasma GFAP values and tracer binding across consecutive time points for the same individual, strong negative correlations were found between plasma GFAP and 11C‐DED binding and 18F‐FDG uptake, but no significant correlation was found between plasma GFAP levels and 11C‐PIB binding in MC.ConclusionDivergent plasma GFAP levels and PET 11C‐DED brain binding in pre‐symptomatic ADAD carriers may reflect different but associated underlying processes, including different types of reactive astrocytes. However, the levels of plasma GFAP show large intraindividual variation over time and the assessment of reactive astrocytes based solely on cross‐sectional plasma GFAP levels poses great challenges and warrants further investigations.
Neuroimaging biomarkers of the Amyloid, Tau, Neurodegeneration and Vascular framework in association with sleep duration changes over time
Authors: Baril Andree‐Ann , Koijs Daniel , Himali Jayandra Jung , Decarli Charles , Sanchez Erlan , Himali Dibya , Cavuoto Marina G. , Pase Matthew P. , Beiser Alexa S. , Seshadri Sudha 
Published: June 2023

AbstractBackgroundBoth short and long sleep duration were previously associated with incident dementia, but underlying mechanisms of this association remains unknown. This project aims to evaluate how self‐reported sleep duration and its change over time associate with (A)myloid, (T)au, (N)eurodegeneration and (V)ascular neuroimaging markers of Alzheimer’s disease (AD).MethodWithin the Framingham Heart Study, two samples were studied: 271 participants (age:53.6±8.0 years; 51%M) who underwent 11C‐PiB amyloid (global, precuneus) and 18F‐Flortaucipir tau (several medial cortical limbic structures) PET imaging; and 2165 participants (age:61.3±11.1 years; 45%M) who underwent an MRI. To estimate neurodegeneration, total brain volume was extracted from MRI. Vascular MRI metrics included white matter hyperintensities (continuous, and dichotomous indicator for extensive for age), covert brain infarcts, and average free‐water. Self‐reported sleep duration was assessed both at the time of neuroimaging testing and around 15 years before, and split by categories (≤6h, 7‐8h, ≥9h). Sleep duration change over time was assessed by change between categories and by continuous delta change (split by negative and positive values for decreased or increased respectively). Logistic and linear regression models were tested between self‐reported sleep duration and neuroimaging metrics, adjusted for age and age2, sex, PET camera, APOE4 carrier status, depression, diabetes, hypertension, and prevalent cardiovascular diseases.ResultsNo association was observed between cross‐sectional self‐reported sleep duration and neuroimaging metrics. Transitioning to longer sleep over time (≤6h to ≥9h and 7‐8h to ≥9h as compared to consistently sleeping 7‐8h) was associated with higher white matter hyperintensities burden (extensive, OR[95%CI]:3.50[0.95‐12.92], p = 0.040;ß[SE]:0.25[0.10], p = 0.015) and higher free‐water (ß[SE]:0.021[0.007], p = 0.003;ß[SE]:0.009[0.002], p = 0.0002). When looking at continuous sleep duration change, increasing sleep duration over time was also associated with higher white matter hyperintensities burden (extensive, OR[95%CI]:1.26[1.02‐1.55], p = 0.032;ß[SE]:0.10[0.04], p = 0.007) and higher free‐water (ß[SE]:0.002[0.001], p = 0.031). Self‐reported sleep duration change was not associated with PET amyloid or tau outcomes.ConclusionVascular pathology in the brain as evidenced by higher white matter hyperintensities burden and free‐water is associated with sleep duration that is getting longer over time, thus potentially explaining its association with dementia risk. In fact, elongation of sleep duration may be an early change in the AD trajectory.