bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of harmonized and co‐calibrated scores for memory, executive functioning, language, and visuospatial in the AIBL Study, ADNI, and NACC datasets
Authors: Crane Paul K. , Trittschuh Emily H. , Mez Jesse B. , Saykin Andrew J. , Sanders R. Elizabeth , Gibbons Laura E , Lee Michael L. , Scollard Phoebe , Choi Seo‐Eun , Rainey‐Smith Stephanie , Chooi Cheyenne K , Gavett Brandon E , Maruff Paul , Ames David , Culhane Jessica E. , Gauthreaux Kathryn , Chan Kwun Chuen Gary , Biber Sarah , Stephens Kari , Kukull Walter A. , Dumitrescu Logan , Hohman Timothy J. , Mukherjee Shubhabrata ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2022

AbstractBackgroundThe Australian Imaging, Biomarkers and Lifestyle (AIBL) Study is a prospective study collecting extensive cognitive, clinical, fluid, and imaging biomarkers data from older adults living in Australia. Integration of outcomes between large prospective studies of AD will provide greater precision in models of AD brain‐behavior relationships, so it is important to align composite scores for cognitive domains between such studies.MethodsDetailed methods for AIBL, the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the National Alzheimer’s Coordinating Center (NACC) have been published. Briefly, AIBL participants had cognition assessed with an extensive neuropsychological test battery alongside health and biomarker assessments at entry and each 18‐months thereafter. Granular‐level cognitive data were obtained and an expert panel of two neuropsychologists and a behavioral neurologist categorized each element as assessing memory, executive functioning, language, visuospatial, or none of these, exactly as we have done previously. We also identified elements we had previously calibrated from other studies; after careful quality control and confirmation these served as anchors enabling co‐calibration. We used confirmatory factor analysis bi‐factor models to calibrate the AIBL battery with other studies. We used those calibrations to obtain co‐calibrated scores for all AIBL participants at every study visit. Here we show descriptive statistics for baseline visits, separately by diagnosis (normal cognition, mild cognitive impairment (MCI), dementia) for two enrollment waves for AIBL as well as for each phase of ADNI and across the Uniform Data Set (UDS) 1 & 2 (UDS1/2) and UDS3 time periods for NACC.ResultsBox plots for memory, executive functioning, language, and visuospatial for people with normal cognition are in Figure 1, MCI in Figure 2, and dementia in Figure 3. These figures show there is substantial cognitive variation across waves within these disease stage groups and across studies.ConclusionCo‐calibrated neuropsychological domain scores provide a common metric for integrating cognitive data across studies. Co‐calibrated scores aggregated across large prospective AD studies such as AIBL, ADNI, and NACC provide a foundation for large‐scale models of the development of AD and can serve as phenotypes for genetics studies. Co‐calibrated scores are available from AIBL, ADNI, and from NACC.
Health behaviors and advanced planning in cognitively unimpaired older adults following amyloid PET disclosure: Preliminary findings from the Wisconsin Registry for Alzheimer’s Prevention
Authors: Clark Lindsay R. , Erickson Claire M , Basche Kristin E , Chin Nathaniel A. , Johnson Sterling C. 
Published: December 2022

AbstractBackgroundAs biomarker testing becomes more widely available, people will have opportunities to learn their Alzheimer’s disease (AD) biomarker results. We developed an AD biomarker disclosure protocol to return results to research participants interested in learning this risk‐related information (Figure 1). This analysis assesses the effectiveness of a post‐disclosure dementia risk‐reduction counseling session and investigates health and advanced planning behaviors following amyloid PET disclosure.MethodCognitively unimpaired older adults enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) were recruited into the Amyloid Disclosure Study which provides education, amyloid PET results, and dementia risk‐reduction counseling. Participants rated their progress on a brain health goal set at the risk‐reduction visit and rated satisfaction and usefulness of this visit at follow‐up. Participants completed measures of health behaviors and planning at pre‐ and post‐disclosure (1 month, 7 months) visits. Linear mixed‐effects regression (LME) and t‐tests were used to assess outcomes over time and compare responses for amyloid elevated and non‐elevated participants.ResultAmyloid elevated (30%) and non‐elevated (70%) participants were similar in demographics and health/planning behaviors at baseline (n = 63; age = 71.3±4.5; 67% women; Table 1). 82% of participants recommended the risk‐reduction visits (Table 2). Goal attainment measures indicated 85% of participants made at least some progress on their brain health goal (55% met or exceeded goal at 7 month follow‐up; Table 3). Results from LME models demonstrated no main effects of time, biomarker result, or the interaction of time x biomarker result on health behavior or planning measures (Table 4). No differences in health behaviors or planning were observed between elevated and non‐elevated participants at follow‐up (p’s ≥ .05).ConclusionPreliminary analyses indicate that health behavior or advanced planning do not differ between participants receiving elevated or non‐elevated amyloid PET results at one or seven months following disclosure. However, participants endorse usefulness and satisfaction with a post‐disclosure dementia risk‐reduction visit, and a majority make progress on their personal brain health goal. As participants continue to enroll and complete follow‐up assessments, we plan to update results with a larger dataset and provide future directions regarding more personalized assessments of brain health and planning outcomes.
Longitudinal Qualitative Analysis of the Role and Perspective of the Care Partner During and Four Weeks Following Disclosure of Amyloid PET Scan Results
Authors: Kim Jeong Eun , Cheng Rebekah , Tamres Lisa K , Lingler Jennifer H 
Published: December 2022

AbstractBackgroundAmyloid PET scans allow for the visualization of amyloid plaque in the brain, which, in the context of mild cognitive impairment (MCI), signal heightened risk for progression to Alzheimer’s dementia (AD). Disclosure of such results can profoundly impact patients as well as their family care partners. The purpose of this study was to examine the role and perspectives of family care partners during and after the return of amyloid PET results.MethodWe used qualitative description to analyze transcripts of audio‐recorded results disclosure sessions and 4‐week follow‐up interviews of participants with MCI and their care partners who were randomized to the disclosure arm of the Return of Amyloid Imaging Scan Results (RAISR) trial. Focusing on care partners (n = 36), we conducted line by line coding and thematic analysis with the goals of 1) categorizing the frequency and nature of the questions raised by care partners during the open‐ended segment of the disclosure sessions, and 2) describing care partners’ perceptions of their loved one’s results in the month following disclosure.ResultAt disclosure, 13 families received positive for amyloid, and 21 received negative scan results. Care partners of those learning of amyloid positivity asked approximately twice as many questions as those receiving negative results (averaging 5.6 vs. 2.8 questions per session). Seven themes were identified in the questions: study logistics, AD/AD care, result clarification, next steps given result, outside resources, requests for scan images, and “other.” The vast majority of questions fell under AD/AD care (n = 47), followed by questions about study logistics (n = 24). The overarching theme of the week 4 interviews was a general sense of acceptance of the scan results. However, instances of inadequate comprehension of the scans’ implications were noted, particularly among partners of amyloid negative patients, some of whom interpreted the result to mean that their loved one’s MCI was nonprogressive.ConclusionFamily care partners play active roles in eliciting information and clarification during amyloid PET results disclosure. However, our findings regarding care partners of amyloid negative patients affirm that disclosing clinicians should not assume that those who ask fewer questions have an adequate understanding of the information presented.
Moderate‐Severe Traumatic Brain Injury History and Chronic Traumatic Encephalopathy Neuropathology in Brain Donors Exposed to Repetitive Head Impacts
Authors: Culhane Julia E , Abdolmohammadi Bobak , Nair Evan S , Saltiel Nicole , Tripodis Yorghos , Martin Brett M , Palmisano Joseph , Katz Douglas I , Dwyer Brigid , Daneshvar Daniel H , Goldstein Lee E , Dams‐O'Connor Kristen , Kowall Neil W , Stern Robert A , Huber Bertrand R. , Stein Thor D. , Mez Jesse B. , McKee Ann C. , Alosco Michael L 
Published: December 2022

AbstractBackgroundRepetitive head impacts (RHI) from American football and other sources are associated with the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Moderate‐to‐severe traumatic brain injury (msTBI) has been suggested to be sufficient to precipitate CTE. Yet, this evidence is based on small case series of msTBI and the interplay between msTBI and RHI on CTE risk is unknown. We modeled the associations between msTBI history and years of American football play (proxy for RHI exposure duration) on CTE neuropathology among deceased American football players.MethodsThe sample included 471 deceased male football players from the UNITE brain bank, all 40+ years old. Informants of donors were administered the Ohio State University TBI Identification Method to assess TBI history. Loss of consciousness (LOC) for 30+ minutes defined msTBI. CTE was neuropathologically diagnosed and staged using published criteria. Outcomes included CTE status, CTE severity (low vs high), and cumulative p‐tau burden—summary of semi‐quantitative ratings of p‐tau severity across 11 brain regions (n = 402). Binary or linear regressions tested the association between msTBI and each outcome, controlling for age and years of football. A years of play x msTBI history interaction term was examined.ResultsTables 1‐2 shows sample characteristics (mean age = 67.89, SD = 12.70; 15.7% Black). Of the sample, 114 (24.2%) had a msTBI history. Years since last TBI with LOC was 37.16 (SD = 18.66) years. 344 (73.0%) had autopsy‐confirmed CTE. There was no association between msTBI and CTE status (OR = 1.38, 95% CI = 0.81,2.33, p = 0.24), CTE severity (OR = 0.77, CI = 0.41,1.44, p = 0.41), or cumulative p‐tau burden (beta = ‐1.03, 95% CI = ‐2.77,0.71, p = 0.25). In contrast, years of football play was associated with CTE status (OR = 1.15, 95% CI = 1.10,1.21, p<0.01), CTE severity (OR = 1.14, 95% CI = 1.08,1.21, p<0.01), and cumulative p‐tau burden (beta = 0.44, 95% CI = 0.32,0.56, p<0.01). There were no years of play x msTBI interaction effects (ps>0.05).ConclusionsmsTBI history was not associated with CTE neuropathology, nor did it modify the effect of years of football play on CTE status and severity. These findings argue against msTBI as a contributor to CTE in the setting of RHI. Examination of age at msTBI and msTBI frequency, as well as non‐CTE neuropathological correlates of msTBI are next steps.
Regional white matter hyperintensities in posterior cortical atrophy and logopenic progressive aphasia
Authors: Pham Nha Trang Thu , Radford Jonathan Graff , Machulda Mary M. , Spychalla Anthony J. , Schwarz Christopher G. , Senjem Matthew L. , Lowe Val J. , Vemuri Prashanthi , Jack Clifford R. , Josephs Keith A , Whitwell Jennifer L 
Published: December 2022

AbstractBackgroundWhite matter hyperintensities (WMH) are markers of cerebral small vessel disease and have been associated with higher risk of typical amnestic Alzheimer’s disease (AD), however, little is known about the role of WMHs in atypical variants of AD. This study aimed to determine the frequency and distribution of WMH in two atypical variants of AD: logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA), and determine whether WMH are associated with demographic and clinical outcomes in these cohorts.MethodSeventy‐five LPA and 39 PCA patients were recruited by the Neurodegenerative Research Group and underwent two‐ dimensional fluid‐attenuated inversion recovery (FLAIR) MRI and Pittsburgh Compound B (PiB) PET. All patients were PiB‐positive. All FLAIR images were segmented using an in‐house software, then were manually edited by a trained imaging analyst. WMH volume was scaled by total intracranial volume to correct for differences in head size. Adjusted WMH burdens were compared between LPA and PCA, and associations were assessed between WMH burden and age, global PiB standard uptake value ratios (SUVRs), and clinical metrics, including tests of general cognitive impairment, executive function, naming, repetition, visuospatial and visuoperceptual function, and parkinsonism. Associations between WMHs and clinical scores were adjusted for age and brain volume to correct for atrophy.ResultTotal WMH burden was similar in PCA and LPA, however, regional differences were identified with PCA having greater subcortical WMH burden in right occipital, parietal, and temporal lobes compared to LPA, and LPA having greater WMH burden in left deep grey and white matter and greater subcortical burden in left parietal lobe compared to PCA. Total WMH burden was greater with older age in both groups but was not related to global PiB SUVR either globally or locally. Greater total WMH was associated with visuoperceptual performance in both cohorts after correcting for atrophy. When assessed regionally, visuoperceptual performance was associated with right subcortical occipital WMH across the cohort.ConclusionRegional distribution of WMHs differ across clinical variants of atypical AD and WMHs may impact clinical outcomes, although further work is needed to determine whether they reflect cerebrovascular disease or regionally specific neurodegenerative changes.
Amyloid‐mediated TRAIL DRs activation leads to progressive degeneration of cerebral vascular smooth muscle cells
Authors: Anzovino Amy , Fossati Silvia 
Published: December 2022

AbstractBackgroundVascular accumulation of amyloid beta (Ab) leads to loss of vascular smooth muscle cells (VSMC) in cerebral arteries via unknown mechanisms, promoting cerebral blood flow alterations and contributing to cognitive impairment. Ab species with different lengths or mutated familial variants may have differential effects on VSMC. Ab1‐42, the main pathogenic form of amyloid in the AD brain with the highest propensity to form aggregates, increased apoptosis in brain vascular cells whereas Ab1‐40 was found to be less toxic. By comparison, the familial Ab variant E22Q, induced the most cell death of all the amyloid variants tested. However, there has been little progress in defining the pathways leading to VSMC degeneration in AD and related disorders. The aim of this study was to identify Ab‐mediated cell death mechanisms in VSMC.MethodHuman cerebral VSMC were treated with pre‐oligomerized variants of Ab for 2‐8hrs (acute treatment) and 24‐72hrs (chronic treatment). Analysis of fragmented nucleosomes and visualization of cytochrome c (Cyt. C) expression by immunocytochemistry were used to measure apoptosis. Activation of intrinsic and extrinsic apoptotic pathways were examined by western blot and caspase‐glo assays. The effects of Ab on mitochondrial function were examined using a Seahorse XF96 Analyzer and TMRM fluorescent dye in live cells.ResultsAcute Ab treatment in VSMC up‐regulated tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) death receptors DR4 and DR5 with activation of caspase 8 and transient activation of Nuclear Factor k B (NF‐kB). DR4 and DR5 expression remained high with chronic Ab treatment and lead to caspase activation followed by Cyt. C release and apoptosis. 24hrs of Ab treatment also decreased mitochondrial membrane potential and significantly impaired mitochondrial respiration.ConclusionAcute exposure of VSMC to Ab causes up‐regulation and activation of DR4/DR5, that, over time, results in mitochondrial dysfunction, caspase activation and apoptosis. Our data suggests that an early and transient activation of NF‐kB may also contribute to the toxic effects of Ab, possibly by inducing pro‐inflammatory pathways in the neurovascular unit.
Harmonizing machine learning imaging biomarkers – CDESH and the case for harmonization in both MR image and low‐dimensional (scalar) output space
Authors: Gunter Jeffrey L. , Cogswell Petrice M , Senjem Matthew L. , Kantarci Kejal , Knopman David S. , Petersen Ronald C. , Graff‐Radford Neill R. , Radford Jonathan Graff , Jack Clifford R. 
Published: December 2022

AbstractBackgroundIn 2018 we presented the Computational DESH (CDESH) metric (DOI:10.1016/j.nicl.2018.11.015), a machine learning measure of abnormal CSF space patterns commonly observed on MRI in Disproportionately Enlarged Subarachnoid‐space Hydrocephalus (DESH‐type) NPH. We have shown that CDESH positive individuals often have discordant CSF and PET amyloid measures (DOI:10.1016/j.jalz.2019.06.4921). Positive CDESH scores are predictive of cognitive decline (DOI:10.1016/j.neuroimage.2021.117899, DOI: 10.1212/WNL.0000000000008616). The score is calculated from regional CSF volumes in a sulcal atlas and within the ventricles using a support vector machine (SVM). The Mayo Clinic Study of Aging (MCSA) changed scanner platforms (GE to Siemens) and T1‐weighted image resolution (1.2mm x 1.05mm x 1.05mm to 0.8mm isotropic) in 2017. We refer to these as “isotropic” or “anisotropic” scans. Our objective was to assess the dependence of a machine learning method (specifically CDESH) to image input variation and, if necessary, determine what needed corrections.MethodAll data considered is from the MCSA or Mayo Clinic ADRC. The SVM was trained on anisotropic images with laboriously labelled ground truth. We resampled the isotropic data from a crossover study (N=112, typically scanned same‐day with both platforms/resolutions) to match the anisotropic resolution. Two approaches to correction were evaluated (Figure 1). In Figure 2 we compare of the score with and without correction cross‐sectionally in 998 MCSA participants. In Figure 3 we present longitudinal series from 23 participants with multiple scans using the isotropic resolution protocol and at least one prior anisotropic image.ResultsComparisons of data from the crossover study are presented in Figure 1. Matching voxel resolution to the data used to train the SVM is critical and a subsequent mild linear score adjustment may be warranted. Cross‐sectional comparisons (Figure 2) confirm improvement matching voxel resolution with a possible mild linear score adjustment. After matching voxel resolution CDESH score trajectories (Figure 3) are markedly more stable across this scanner/protocol change.ConclusionThe SVM‐based CDESH score is sensitive to voxel resolution. Corrections are needed in image processing and possibly in the scalar output score to achieve stability across protocol and scanner changes. The resulting correction supports coherent long timeseries data and longitudinal extension of previous work.
Evaluation of novel data‐driven metrics of amyloid β deposition for longitudinal PET studies
Authors: Bollack Ariane , Cash David M , Markiewicz Pawel J , Wink Alle Meije , Prosser Lloyd , Coath William , Pemberton Hugh , Farrar Gill , Barkhof Frederik 
Published: December 2022

AbstractBackgroundPositron emission tomography (PET) provides in vivo quantification of amyloid‐β (Aβ) pathology. The most common method for assessing PET is standardized uptake value ratio (SUVr), which can be affected by physiological and technical factors. Novel, data‐driven metrics have been developed to address these sources of variability. We evaluate cross‐sectional and longitudinal performance of four data driven metrics.MethodThree cohorts were used for evaluation: Insight 46, a neuroimaging sub‐study of the 1946 British birth cohort, Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing, and a test‐retest flutemetamol dataset (Table 1). Data from participants were included if good quality volumetric MRI and amyloid PET, using florbetapir (Insight 46) or flutemetamol (AIBL and test‐retest data), was available. No partial volume correction was applied. Four data driven metrics were extracted: the Centiloid derived from non‐negative matrix factorisation (CLNMF), the Aβ PET pathology accumulation index (Aβ‐index), amyloid load (Aβ‐load), and amyloid pattern similarity score (AMPSS). These data‐driven metrics were compared to a global composite SUVr, with either a pons (flutametamol) or cerebellar grey matter (florbetapir) reference region, and a Centiloid (CL) score. They were evaluated by measures of repeatability in test‐retest data, associations with non‐displaceable binding potential (BPND, computed from Logan graphical analysis), sample size estimates to detect a 20% slowing in Aβ accumulation with 95% significance and 80% power, and accuracy in predicting the second follow‐up visit.ResultAll metrics show good to excellent reliability. The repeatability is highly influenced by the amyloid burden, the range, and the offset of each metric. (Table 1) All metrics are strongly correlated to the BPND (R
2: 0.8 to 0.94), with SUVr and CL explaining more variance in BPND than the data‐driven metrics. (Figure) Sample size estimates were lowest in CL and CLNMF compared to the SUVr. (Table 2) The Aβ‐index had the best predictive power over ∼3 years while the other metrics were comparable. (Table 3)ConclusionNovel data driven metrics provide comparable performance in terms of accuracy and performance to more established quantification methods of Aβ PET tracer uptake, but with additional benefits, such as being MRI‐free, reference region independent, or more robust to change in tracer.