bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concordance of CSF AD biomarkers between intraventricular and lumbar CSF in iNPH
Authors: Lukkarinen Heikki , Vanninen Aleksi , Tesseur Ina , Pemberton Darrel , Van Der Ark Peter , Herukka Sanna‐Kaisa , Rauramaa Tuomas , Hiltunen Mikko , Zetterberg Henrik , Leinonen Ville 
Published: December 2022

AbstractBackgroundThe core Alzheimer’s Disease cerebrospinal fluid (CSF) biomarkers, amyloid β 1‐42 (Aβ42), total tau (T‐tau) and phosphorylated tau 181 (P‐tau181), have presented added value for differential diagnostics in the field of neurodegenerative diseases. Moreover, the concentration gradient of these biomarkers between intraventricular (V‐CSF) and lumbar region CSF (L‐CSF) has been partly established for idiopathic normal pressure hydrocephalus (iNPH) patients. In this study, we aim to provide conversion factors between V‐CSF and L‐CSF.MethodAltogether 138 patients were diagnosed for possible iNPH and received ventriculoperitoneal shunt. Lumbar CSF samples were obtained 3‐months prior shunt surgery. Additional intraoperative interventricular CSF samples were obtained from 97 patients. Furthermore, follow‐up samples of 41 patients were obtained 0‐, 3‐, 6‐ and 18‐months (0M, 3M, 6M, 18M) postoperatively by shunt valve and lumbar punctures. Aβ42, T‐tau and P‐tau181 CSF concentrations of samples collected were analyzed using Elecsys (Cohort of 97 patients) and Innotest (Cohort of 41 patients) assays.ResultPreoperative L‐CSF Aβ42, T‐tau and P‐tau181 associated to intraoperative V‐CSF (Sprearman ρ=0.54 Aβ42, r=0.34 T‐tau, r=0.55 P‐tau, all p<0.001). Strong associations were seen between postoperative L‐ and V‐CSF for all biomarkers in the every follow‐up sampling point (Spearman ρ Aβ42: 0M=.77, 3M=.88, 6M=.83, 18M=.84) (T‐tau: 0M=.92, 3M=.91, 6M=.92, 18M=.94) (P‐tau181: 0M=.96, 3M=.95, 6M=.94, 18M=.94) (all p<0.0001). Regression equations were determined for intraoperative V‐CSF and preoperative L‐CSF (Aβ42: V‐CSF=185+0.34*L‐CSF, T‐tau: Ln(V‐CSF)=3.11+0.49*Ln(L‐CSF) and P‐tau181: V‐CSF=8.2+0.51*L‐CSF, all p<0.01), and for postoperative V‐CSF and L‐CSF (Aβ42: V‐CSF=86.7+0.75*L‐CSF, T‐tau: V‐CSF=86.9+0.62*L‐CSF and P‐tau181: V‐CSF=1.9+0.75*L‐CSF all p<0.0001).ConclusionThe Aβ42, T‐tau and P‐tau181 showed linear dependency between ventricular and lumbar CSF for preoperative L‐CSF and intraoperative V‐CSF as well as for postoperatively collected L‐CSF and V‐CSF. The regression equations based on these findings provide a novel tool to use V‐CSF for diagnostics and prognostics entities that rely on the lumbar CSF concentrations.
Health‐Related Quality of Life Among Sexual and Gender Minority Older Adults Living With Cognitive Impairment
Authors: Kim Hyun‐Jun , Fredriksen‐Goldsen Karen , Jung Hailey H. 
Published: December 2022

AbstractBackgroundWhile sexual and gender minority (SGM) older adults are found to be at heightened risks of cognitive impairment, they may face unique challenges in health‐related quality of life (HRQOL) due to bias, social isolation, and other SGM‐related risks. This study examined risk and protective factors predicting HRQOL among SGM older adults living with cognitive impairment.MethodA subset of longitudinal survey data collected over three time points (2014, 2016, 2018) was drawn from the Aging with Pride: National Health, Aging, and Sexuality/Gender Study. Participants were 855 people who were born in 1964 or earlier and self‐reported having cognitive impairment at Wave 1 (2014). We employed multilevel modeling to investigate the effects of risk and protective factors on the overall levels of physical and psychological HRQOL and their longitudinal changes.ResultLifetime SGM‐related discrimination and victimization (b = ‐0.17, p < .001; b = ‐0.22, p < .001, respectively), identity stigma (b = ‐0.91, p < .05; b = ‐2.97, p < .001), and insufficient food intake (b = ‐2.70, p < .001; b = ‐3.69, p < .001) were associated with lower physical and psychological HRQOL. Having more chronic conditions (b = ‐1.52, p < .001) was associated with lower physical HRQOL. Factors positively associated with physical and psychological HRQOL were physical activity (b = 0.12, p < .01; b = 0.19, p < .001), outdoor leisure activity (b = 3.57, p < .001; b = 5.40, p < .001), optimal sleep (b = 3.47, p < .001; b = 2.32, p < .001), and social network size (b = 0.19, p < .01; b = 0.66, p < .001).ConclusionThe results of this study have important implications for further research. Most research on cognitive impairment has previously adopted a disease and deficit‐focused model rather than investigating the resilience and quality of life of people living with cognitive impairment. It is critical to further identify ways to help SGM older adults with cognitive impairment adhere to health‐promoting behaviors and to foster and maintain social resources as we develop targeted and culturally responsive interventions that support their optimal aging.
Identifying Latent Patterns and Predictors of Health Behaviors and Healthcare Barriers among LGBT Older Adults
Authors: Jung Hailey H. , Kim Hyun‐Jun , Fredriksen‐Goldsen Karen 
Published: December 2022

AbstractBackgroundHealth behaviors are multi‐dimensional and associated with various barriers to healthcare. With no previous research having investigated patterns of health behaviors in conjunction with healthcare barriers among lesbian, gay, bisexual, and transgender (LGBT) older adults, we aim to identify latent classes of the behavior and barrier patterns, to examine differences in physical and psychological health‐related quality of life (HRQOL) by the specified latent classes, and to explore predictors of the class membership.MethodThree‐step latent class analysis with survey weights was conducted using baseline data of the Aging with Pride: National Health, Aging, and Sexuality/Gender Study (NHAS, N = 2,450). Health behavior and healthcare barrier indicators were analyzed in four dimensions: risk‐taking behavior, health‐promoting behavior, preventive care, and healthcare barriers.ResultThe best empirical and substantive fit was determined with four classes consisting of (1) healthy behaviors and minimal barriers (C1, 39%), (2) unhealthy behaviors and high barriers (C2, 31%), (3) healthy behaviors and healthcare system barriers (C3, 19%), (4) Very healthy self‐care behaviors, low preventive care use, and moderate barriers (C4, 11%). Compared to C1, C3 had lower physical HRQOL and C2 had lower physical and psychological HRQOL. C4 did not differ in HRQOL from C1. Modifiable predictors of C2 include more day‐to‐day discrimination and lower mastery and social support.ConclusionEfforts to lower healthcare barriers are warranted in addition to interventions to strengthen social support and to reduce marginalization. Positive relationships between LGBT older adults and healthcare need to be established via trust‐building and cultural competency.
White matter health in the context of Alzheimer’s disease pathophysiology
Authors: Raghavan Sheelakumari , Przybelski Scott A. , Reid Robert I. , Lesnick Timothy G. , Ramanan Vijay K , Botha Hugo , Matchett Billie J , Murray Melissa E. , Reichard Ross R. , Knopman David S. , Radford Jonathan Graff , Jones David T. , Lowe Val J. , Mielke Michelle M. , Machulda Mary M. , Petersen Ronald C. , Kantarci Kejal , Whitwell Jennifer L , Josephs Keith A , Jack Clifford R. , Vemuri Prashanthi 
Published: December 2022

AbstractBackgroundMulti‐compartment modelling of white matter (WM) microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) can provide information on WM health through the neurite (axons and dendrites) density index and free water measures. We hypothesized that cerebrovascular disease (CVD), Alzheimer’s disease (AD), and an FDG pattern suggestive of TDP‐43 proteinopathy would be associated with distinct NODDI readouts of WM damage which would be informative for identifying the substrate for cognitive impairment.MethodWe identified two independent cohorts with multi‐shell diffusion MRI, amyloid and tau PET, and cognitive assessments. One, were participants from the Mayo Clinic Study of Aging, a population‐based cohort of 347 elderly randomly sampled from the Olmsted county, Minnesota. The second were 61 amyloid positive AD participants from the Mayo AD Research Center.ResultWe observed an increase in free water and decrease in neurite density in the genu of the corpus callosum associated with vascular risk factors, which we refer to as vascular WM component (Figure 1). Tau PET signal reflective of 3R/4R tau deposition was associated with worsening neurite density index in the temporal WM where we measured parahippocampal cingulum and inferior temporal WM bundles. Worsening temporal neurite density was associated with (antemortem confirmed) FDG TDP‐43 signature. Post‐mortem neuropathologic data on a small subset (n=9) of this sample lend support to our findings. In the population‐based cohort where vascular disease was more prevalent, the vascular WM component explained variability in global cognition (partial R2 of free water and neurite density = 8.3%) and MMSE performance (8.2%) which was comparable to amyloid PET (7.4% for global cognition and 6.6% for memory) (Table 1). In the AD dementia clinic‐based cohort, tau deposition was the greatest contributor to cognitive performance (9.6%), but there was also a non‐trivial contribution of the temporal WM component (8.5%) to cognitive performance. The differences observed between the two cohorts were reflective of their distinct clinical composition.ConclusionWhite matter microstructural damage assessed using advanced diffusion models may add significant value for distinguishing the underlying substrate (whether CVD versus neurodegenerative disease caused by tau deposition or TDP‐43 pathology) for cognitive impairment in older individuals.
Single Cell Approaches Reveal Perturbed Brain Vascular Molecules in Alzheimer’s Disease
Authors: İş Özkan , Wang Xue , Reddy Joseph S. , Patel Tulsi , Min Yuhao , Quicksall Zachary , Heckman Michael G. , White Launia , Kouri Naomi , Deniz Kaancan , Tutor‐New Frederick Q , Carnwath Troy , Oatman Stephanie R , Carrasquillo Minerva M. , Nguyen Thuy , Petersen Ronald C. , Kantarci Kejal , Nho Kwangsik , Saykin Andrew J. , Dickson Dennis W. , Murray Melissa E. , Allen Mariet , Ertekin‐Taner Nilufer 
Published: December 2022

AbstractBackgroundInter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, maintenance of the blood‐brain‐barrier (BBB) properties, and brain energy metabolism. Although numerous cell biology studies demonstrate the role of the GVU for BBB breakdown in Alzheimer’s disease (AD), the precise molecular changes contributing to its pathophysiology are unclear.MethodWe performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in 24 AD and control brains to understand the transcriptional changes in the cells of GVU. We acquired the snRNAseq profile of 79,751 total brain cells that comprise 6,541 astrocytes and 2,210 vascular cells. The latter formed three distinct vascular clusters characterized as activated pericytes, endothelia and resting pericytes. We identified differentially expressed genes (DEGs) and their enriched pathways in these clusters and detected the most transcriptional changes within activated pericytes. Using our data and a knowledge‐based predictive algorithm, we discovered and prioritized molecular interactions between vascular and astrocyte clusters, the main cell types of the GVU of the BBB.ResultsVascular targets predicted to interact with astrocytic ligands have biological functions in signalling, angiogenesis, amyloid ß metabolism and cytoskeletal structure. Top astrocytic and vascular interacting molecules include both novel and known AD risk genes such as APOE, APP and ECE1. We validated gene expression changes using qPCR. We are in the process of evaluating these gene expression changes in antemortem blood from AD and control participants.ConclusionOur findings provide valuable information into the transcriptional changes in predicted vascular‐astrocytic partners at the GVU, highlighting insights into the molecular mechanisms of BBB breakdown in AD.
Obstructive sleep apnea risk is associated with decreased executive processing speed in older women but not in men: A longitudinal analysis of the Canadian Longitudinal Study on Aging
Authors: Legault Julie , Thompson Cynthia , Moullec Grégory , Baril Andree‐Ann , Martineau‐Dussault Marie‐Ève , André Claire , Carrier Julie , Gosselin Nadia 
Published: December 2022

AbstractBackgroundStudies investigating the possible links between obstructive sleep apnea (OSA) and cognitive dysfunction have yet led to heterogenous results. Individual characteristics, such as sex and age, could moderate this association and explain part of this heterogeneity. Here, we characterized the sex‐ and age‐specific association between OSA risk and cognitive performance using longitudinal data from the community‐based Canadian Longitudinal Study on Aging (CLSA) comprehensive cohort.MethodOur sample included 25,393 participants aged 45 to 85 years at baseline (mean = 63 years; 51% women; 78% with post‐secondary degree), recruited between 2011 and 2015 across Canada. Participants with Alzheimer’s and Parkinson’s diagnosis or with history of stroke and of traumatic brain injury were excluded. Participants’ risk for OSA was measured at baseline using the STOP‐B questionnaire, based on risk factors and symptoms of OSA. Participants scoring ³ 3/5 were classified as being at high‐risk for OSA. Neuropsychological tests assessed memory (Rey Auditory Verbal Learning Test), executive functioning (Mental Alternation, Animal Fluency, Controlled Oral Word Association and Stroop tests) and psychomotor speed (Choice Reaction Time) at baseline and at 3‐year follow‐up. We calculated changes (follow‐up – baseline) in each cognitive continuous score and conducted sex‐specific age‐stratified (45‐59; 60–69; 70–85 years) analyses of covariance (ANCOVAs) to estimate the predictive role of baseline OSA risk, adjusting for socio‐demographic, lifestyle and medical comorbidities. The level of significance was set at p<0.05, after false‐discovery rate correction.ResultsIn the whole sample, results show a decline over time only for executive functioning (Mental Alternation, Animal Fluency and Stroop) at 3‐year follow‐up. When analyses were performed according to age and sex, being at high‐risk for OSA was associated with increased reaction times only in women aged 70–85 years (Stroop word: [F = 12.486; 95%CI ‐5.440 to ‐1.554]; Stroop color: [F = 7,870; 95%CI ‐9.843 to ‐1.738]).ConclusionAlthough changes in executive functioning were noted over time in the whole sample, being at high‐risk for OSA only increased the risk of slower processing speed for older women. These findings suggest that the possible detrimental effects of OSA on cognitive health depend on participants’ age and sex.
Memorability of Word‐Pairs: Developing a Method for Generation of Calibrated Stimulus Sets for Repeat, Remote, Automated Testing
Authors: Kaula Alexander J , Cormack Francesca K , Taptiklis Nick 
Published: December 2022

AbstractBackgroundVerbal‐Paired Associates (VPA) is widely used measure of memory. However, the memorability characteristics of the word‐pairs are not well‐understood, and the task currently suffers from ceiling effects (Uttl et al. 2002). Here we describe a data driven process for word‐pair selection, yielding precise estimates of memorability at the item and list level. This allows tuning of task difficulty to participant characteristics, and the development of many well‐calibrated parallel forms for longitudinal automated testing.MethodFor model development we recruited a total of 185 participants aged 18‐40 years without psychiatric diagnoses, chronic medication, or historical head injury using the Prolific online testing platform. We used Cambridge Cognition’s NeuroVocalix software to automatically deliver and score Learning and Recall phases of VPA.In a series of experiments, we explored the contributions of item‐level, pair‐level, list‐level, and study‐level properties to the probability of subsequent recall. At the item‐level, we considered word‐concreteness and word‐frequency. To capture the semantic relatedness of word‐pairs, we trained the GloVe neural network model (Pennington et al, 2014) to predict the co‐occurrence of words from a corpus of transcribed English. This yields high‐dimensional vectors, from which we could calculate the semantic cosine distance between items in a word‐pair. At the list‐level we considered order effects (primacy and recency), and at the study level we considered practice effects.Data from these experiments was combined in a linear mixed effects logistic regression model to yield predicted memorability estimates for new sets of word‐pairs. These test sets were then deployed with a cohort of 43 older adults (aged 55 years and upwards) to evaluate this prediction.ResultModelling showed significant contributions of item‐level, pair‐level, list‐level, and study‐level factors to probability of recall. When applied to the new set of words and tested with our older cohort, we found that this model‐derived measure was a robust predictor of recall (r = .931, p < 10‐6).ConclusionWe have a robust method of predicting, for a given word‐pair, what the likelihood of recall will be. This enables the generation of sets of word‐pairs with well‐understood memorability characteristics, for use in automated, repeat, remote assessment.
Latent profiles of physical actigraphy patterns among older adults: Differential relationships with cognition and vascular burden by sex
Authors: Paolillo Emily W , Lee Shannon Y. , Djukic Nina , VandeBunte Anna M. , Saloner Rowan , Kramer Joel H. , Casaletto Kaitlin B 
Published: December 2022

AbstractBackgroundPhysical activity (PA) is well‐known to benefit cognition and vascular health, yet it is less clear how specific PA patterns relate to cognitive and vascular outcomes and whether these relationships differ by person‐specific factors. Thus, we characterized empirically‐derived latent profiles of PA among older adults and examined their associations with cognition, vascular burden, and person‐specific factors (e.g., sex).Method124 older adults from the UCSF Memory and Aging Center (Meanage = 72.2; SDage = 8.4; 54% women; 83% non‐Hispanic White) wore a FitbitTM during waking hours for 30 days. Minute‐level Fitbit data were used to calculate daily averages for three distinct PA metrics: step count, sedentary time (0 steps/minute), high‐intensity time (≥120 steps/minute). Composite memory and executive functioning z‐scores were calculated for a subset of participants (n = 86) who completed neurocognitive testing. Vascular burden was estimated via a count of vascular conditions. Homogenous subgroups with similar PA patterns were identified via latent profile analysis (LPA). ANCOVAs and Poisson regression examined independent and interactive effects of PA group and sex on cognition and vascular burden, respectively, covarying for age and education.ResultLPA identified 3 latent PA classes: Class1 (high overall activity but low intensity; n = 59), Class2 (low overall activity and low intensity; n = 49), and Class3 (high overall activity and high intensity; n = 16). PA class membership was associated with executive functioning and vascular burden, driven by better outcomes in Class3 than Class2 (executive: mean difference = 0.59, p = 0.013; vascular: b = ‐0.84; p = 0.028). PA class was not related to memory (p = 0.32). There was an interaction between class and sex on executive functioning (F2,78 = 3.20; p = 0.046) and vascular burden (b = 2.37; p = 0.032). In males, Class3 demonstrated the best executive functioning (vs. Class1 p = 0.038; vs. Class2 p = 0.057) and the least vascular burden (vs. Class1 p = 0.025; vs. Class2 p = 0.022). In contrast, there was no clear relationship between PA class and cognition or vascular burden among women (ps>0.05).ConclusionDifferential PA patterns relevant to cognitive and vascular health can be identified using actigraphy in older adults. Sex‐differences emerged suggesting men may require higher intensity PA to improve cognitive and vascular health, whereas specific PA patterns did not significantly predict outcomes in women.
Improved automated cerebral microbleed (CMB) detection
Authors: Mead Aaron K , Bermudez Camilo L , Cogswell Petrice M , Wiste Heather J. , Gebre Robel K , Vemuri Prashanthi , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Graff‐Radford Jonathan , Gunter Jeffrey L. 
Published: December 2022

AbstractBackgroundCerebral Microbleeds (CMBs) are tracked in anti‐amyloid drug safety monitoring. T2*GRE or SWI MRI images are visually assessed for the presence of CMBs. Automated methods tuned for sensitivity often have unacceptably high false positive rates requiring extensive human cleanup.MethodAssume contemporaneous T2*GRE and T1‐weighted images. CMB detection (Figures 1,2) has three steps: 1) Segmentation outputs from the T1‐weighted image are resampled into the T2*GRE image voxel raster; 2) Normalized cross‐correlation of the T2*GRE with a CMB template identifies “candidate CMBs”; 3) a neural network using voxel patches centered on each candidate CMB rejects false positives. Patches presented to the network are 4D and include five contrasts drawn from the T2*GRE, correlation, T1‐weighted, WM probability and CSF probability images. The simple network architecture consists of convolutional blocks followed by dense blocks. The system is trained using images from ADNI, ARIC, MCSA, and the Mayo Clinic ADRC that have been previously visually graded for CMBs (Table in Figure 3). Importantly, we include participants with and without CMBs in our data reflecting the fact that the majority of people (even the elderly) have no CMBs. Data is split 70:10:20 by subject for training, validation, and testing. Various network configurations were evaluated.ResultHigh candidate detection sensitivity can be achieved at the expense of presenting hundreds to thousands of false positive candidates per input image to the rejection network. Our best performing network configuration to date has AUC 0.982 (95% bootstrap CI 0.971 to 0.990 based on the 10% validation subset). Choosing an operating point with 95% sensitivity in the validation set and admits, on average, 0.6 false positive CMB candidates per input T2*GRE image. Sensitivity is hindered by a small number of obvious errors in the ground truth visual assessment. Validation loss tracks training loss with no indication of over‐fitting. Example patches are shown in Figure 4.ConclusionExcessive false positive detection requires significant human correction and effort, preventing automated CMB detection from being widely adopted. We have an automated detection system that is sensitive (95%) and provides excellent false positive rejection (<1 false positive CMB/input image) reducing needed human effort.