bluuebunny/crossref_metadata_2025_split huggingface dataset:
Precision estimates of Relative and Absolute Cerebral Blood Flow in Alzheimer’s disease and Cognitively Normal individuals
Authors: Heeman Fiona , Visser Denise , Yaqub Maqsood , Verfaillie Sander C.J. , Timmers Tessa , van der Flier Wiesje M. , van Berckel Bart NM , Boellaard Ronald , Lammertsma Adriaan A. , Golla Sandeep SV 
Published: December 2022

AbstractBackgroundAlzheimer’s disease is characterized by regional reductions in cerebral blood flow (CBF) and the gold standard for measuring CBF is [15O]H2O PET. Recently, proxies of relative CBF, derived from the early distribution phase of amyloid‐β and tau tracers, have gained attention. It has been hypothesized that relative CBF is likely to have higher precision (but not accuracy) than absolute CBF, as global variations in CBF are cancelled out. The present study assessed precision of [15O]H2O PET derived relative and absolute CBF measures, and compared them with relative CBF proxies estimated from [18F]florbetapir and [18F]flortaucipir scans.MethodDynamic [15O]H2O, [18F]florbetapir and [18F]flortaucipir test‐retest (TRT) PET datasets were included, consisting of eleven cognitively normal (CN) individuals for [15O]H2O, four CN and five AD participants for [18F]florbetapir, and six CN and eight AD participants for [18F]flortaucipir. [15O]H2O data were analysed using the standard single tissue compartment model and [18F]florbetapir and [18F]flortaucipir using the simplified reference tissue model (SRTM). Relative CBF (i.e. K1/K1’) was derived from absolute CBF (i.e. K1 of [15O]H2O) or estimated using SRTM (i.e. R1), in all cases using cerebellar cortex as reference tissue. CBF values were obtained for 22 cortical grey matter regions and TRT variability (eq.1) was calculated for all metrics. Differences (%) between test and retest measures were assessed using Bland‐Altman analysis and TRT variability for different tracers and between diagnostic groups were compared using Wilcoxon Signed‐Rank and Mann‐Whitney U‐tests.ResultAverage differences (M±SD) between test and retest measures were small for relative measures, [15O]H2O K1/K1’:‐2.0±7.8%, [18F]florbetapir R1:‐1.7±4.1%, [18F]flortaucipir R1:‐0.1±4.2%, but somewhat larger for [15O]H2O K1:‐5.7±14.6%,(Fig.1). In case of [15O]H2O, TRT variability was lower for K1/K1’ than forK1 (p<0.001). Furthermore, [18F]florbetapir and [18F]flortaucipir derived R1 showed lower TRT variability than [15O]H2O K1/K1’ (p<0.001). Only for [18F]flortaucipir, TRT variability was higher in the AD compared with the CN group.ConclusionRelative CBF has higher precision than absolute CBF derived from [15O]H2O PET scans. Furthermore, relative CBF proxies derived from commonly used amyloid‐β and tau tracers appear to have an even higher precision, possibly due to the compensatory effect of extraction fraction and/or the older scanner used for [15O]H2O scans.
Polyubiquitination of Tau Increases Across Braak Stages in Alzheimer’s Disease
Authors: Lee Yoo Bin , Kramer Jack , Oh Ian , Li Song Hua , Piergies Antonia M. H. , Xue Jie , Kumar Mukesh , Spina Salvatore , Steen Judith A , Grinberg Lea Tenenholz 
Published: December 2022

AbstractBackgroundThe proteolytic ubiquitin‐proteasome system (UPS) is a main control mechanism of tau degradation in eukaryotic cells. Although the UPS is an integral regulator for tau turnover in healthy neurons, preliminary data suggests that the pathological tau in Alzheimer’s Disease (AD) is polyubiquitinated. This is an intriguing conundrum where the polyubiquitinylation of tau does not result in the degradation of the protein by the UPS. This suggests that the capacity of the UPS is limited or that the UPS is unable to degrade this form of tau. In this study, we aim to validate this potential correlation between the polyubiquitination of tau and AD, which could perhaps provide more clarity on the specific mechanisms of toxicity for AD.MethodWe examined postmortem brain tissue (inferior temporal gyrus) of 11 cases across AD neuropathological spectrum (Table 1). All slides underwent multiplex immunofluorescence for four antibodies: NeuN (neurons), FK2 (to detect polyubiquitin), T231 (ptau), and GFAP (astroglia), followed by scanning and quantification on digital slides. We quantified the percentage of neurons positive for tau (T231) and polyubiquitination (FK2) and analyzed the spearman correlation and linear regression model (LRM) corrected by age on death and sex.ResultCases represent a spectrum of AD stage. As expected, the proportion of neurons with tau inclusions increase along AD progression. We failed to identify neurons positive for FK2 (polyubiquitination) in the absence of tau and neurons. Moreover, we observed a direct correlation between higher Braak Stages and proportion of neurons with polyubiquitin immunoprecipitations (Figure 1, ρ = 0.89, p = 2.33e‐4).ConclusionNeurons with polyubiquitin immunoprecipitations increase in number along the AD continuum. These neurons tend to accumulate phospho‐tau inclusions suggesting a polyubiquitination of tau in AD. Further studies are needed to identify the mechanisms underlying the lack of tau degradation by the UPS in this situation, which could lead to treatment opportunities for AD.
Cognitive Impairment in Older Adults with Type 1 Diabetes: Longitudinal data from the Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) Study
Authors: Fonseca Luciana Mascarenhas , Kanapka Lauren K , Miller Kellee M , Pratley Richard , Rickels Michael R , Chaytor Naomi S 
Published: December 2022

AbstractBackgroundAdults with type 1 diabetes (T1D) are at increased risk for cognitive impairment, accelerated brain aging, and Alzheimer’s disease and related dementias (ADRD). However, longitudinal data on cognitive aging, cognitive impairment and ADRD in adults with T1D are still scarce. The aim of this study was to characterize cognitive impairment in a longitudinal sample of older adults with T1D.MethodWe analyzed data collected as part of the Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) Study (Pratley et al., JAMA, 2020; 323(23):2397‐2406), in which 22 endocrinology practices in the United States participated. Participants with T1D ≥ 60 years of age who completed the NIH Toolbox Cognition Battery at two time points (baseline and one year follow up) were included in this study (n = 171). Cognitive impairment was classified using recommendations from Holdnack et al, 2017 (Holdnack et al., Arch Clin Neuropsychol, 2017; 32(5):574‐584).ResultAt baseline, 50% of the participants (N = 86/171) met criteria for cognitive impairment. Of those, 56% (N = 48/86) were still classified as having cognitive impairment a year later (28% of the total sample, N = 48/171). Conversely, 44% (N = 38/86) of the participants classified with impairment at baseline reverted to no impairment by a year. Of those classified as having normal cognition during the baseline assessment, 20% converted to impaired at the follow up (N = 17/85), while 80% (N = 68/85) remained normal.ConclusionThese data indicate that caution is warranted when assessing cognition in older adults with T1D, as a large percentage of those identified as having cognitive impairment at baseline reverted to normal after a year. Serial cognitive assessment is suggested. Longitudinal research with more diverse samples of older adults with T1D is needed to better understand the clinical utility of the NIH toolbox cognition battery and other neuropsychological assessments in older individuals with T1D.
Investigation of differentially expressed proteins through neurofibrillary tangle maturation in Alzheimer’s disease using NanoString’s GeoMx Digital Spatial Profiler
Authors: Moloney Christina M. , Liu Chia‐Chen , Wickland Daniel P. , Lesser Elizabeth R. , Kachergus Jennifer , Van Blitterswijk Marka M. , Graff‐Radford Neill R. , Dickson Dennis W. , Thompson E. Aubrey , Murray Melissa E. 
Published: December 2022

AbstractBackgroundNeurofibrillary tangles are dynamic entities with a lifespan encompassing three maturity levels: intracellular pretangles, intracellular mature tangles, and extracellular ghost tangles. Proteins are suggested to be differentially expressed throughout the tangle lifespan; however, past studies may be limited by spatial expression or number of proteins investigated. We sought to assess differences in protein expression across the tangle lifespan using GeoMxTM Digital Spatial Profiler (DSP) by NanoString, a new technology allowing for spatially derived multiplex investigation.MethodWe used DSP to measure protein expression in hippocampi from Alzheimer’s disease (n=6) and nondemented controls (n=2) using the “Human Neural Cell Profiling Core” and “Alzheimer’s Pathology” module. Regions of interest (ROIs) were classified by the major tangle maturity level recognized by a primary fluorescent conjugated tau antibody. Protein expression was normalized to the geomean of the three housekeeping genes. The tau‐positive segment was specifically analyzed for comparisons. ANOVA was used for group‐wise comparisons and t‐test using the Benjamini‐Yekutieli adjustment for multiple tests was used for pair‐wise comparisons.ResultAs expected, cytoskeletal (e.g., MAP2, Tau) and neuronal (e.g., NeuN) markers generally decreased through the neurofibrillary tangle lifespan (Figure). Markers profiled as neurodegenerative (e.g., amyloid‐β1‐42, APOE, APP) generally increased through tangle maturity levels, except for TDP‐43 which decreased. Interestingly, there was no significant difference in ubiquitin expression. Astrocytic GFAP and S100B expression was significantly increased through each maturity level. Expression of microglial‐specific markers P2RY12 and TMEM119 was significantly elevated in ghost tangles compared to mature tangles. Additional microglial/macrophage markers including Iba‐1 and CD68 were generally increased as neurofibrillary tangles matured. Interestingly, APOE expression remained low in pretangles and mature tangles before dramatically increasing in ghost tangles (Figure).ConclusionOur findings suggest that proteins are differentially expressed throughout the tangle lifespan and the majority followed a monotonically directed pattern. Non‐monotonically directed protein patterns may reflect the death of the neuron during the ghost tangle maturity level. Future studies will test the hypothesis that the microenvironment of the hippocampus is altered with increasing vulnerability to tangle pathology.
O‐GlcNAcylation modulates GLUT1 levels at the blood‐brain barrier
Authors: Saiyasit Napatsorn , Bauman Allison J. , Nelson Amy R. 
Published: December 2022

AbstractBackgroundGlucose transporter 1 (GLUT1) at the blood‐brain barrier (BBB) is essential for glucose uptake into the brain. Previous studies have shown that GLUT1 levels are reduced at the BBB in Alzheimer’s disease (AD) post‐mortem brain, and perhaps explains the decreased glucose utilization observed in AD (Sweeney et al., Nat Rev Neurol, 2018). Individuals with a genetic reduction of GLUT1, known as GLUT1‐deficiency syndrome, were treated with increased blood glucose with no long‐lasting increase in brain glucose. Diabetes is a risk factor for AD and AD is sometimes referred to as Type‐3 diabetes due to elevated blood glucose levels. Taken together, these ideas provoked us to investigate connections between glucose and GLUT1 levels. Here, we tested if the glucose‐dependent post‐translational modification, O‐linked‐N‐acetylglucosaminylation (O‐GlcNAcylation), is the missing link. We hypothesized that increasing glucose concentrations will elevate O‐GlcNAcylation and decrease GLUT1 levels at the BBB. Furthermore, previous studies have shown that decreased GLUT1 levels result in reduced levels of the low‐density lipoprotein receptor‐related protein‐1 (LRP‐1) (Winkler, Nat Neurosci, 2015). Thus, we also are determining if altering glucose levels not only changes GLUT1 levels, but also other key BBB receptors implicated in AD.MethodsMouse brain endothelial (bEnd.3) cells were treated with vehicle (glucose 5.6 mmol), DMSO, the O‐GlcNAcase inhibitor Thiamet‐G (TMG, 1 µM), or the O‐GlcNAc transferase inhibitor OSMI‐1 (20 µM), for 24 and 48 hours. Next, the protein expression of O‐GlcNAc and GLUT1 were measured by western blot.ResultsAs previously reported, TMG increased and OSMI‐1 decreased O‐GlcNAcylation at both 24 and 48 h, compared to vehicle. Notably, TMG treatment significantly reduced and OSMI‐1 increased GLUT1 expression at both time points.ConclusionGLUT1 levels are modulated through O‐GlcNAcylation at BBB. When blood glucose levels are high, O‐GlcNAcylation will be high, thereby reducing GLUT1 at the BBB and brain glucose uptake. This is likely a homeostatic mechanism to prevent spikes in brain glucose levels when blood sugar levels are elevated.
Dual‐tracer assessment of CBF and early amyloid uptake of Alzheimer’s disease using 15O‐water and amyloid PET
Authors: Zhao Moss , Chen Kevin , Khalighi Mehdi , Mormino Elizabeth C. , Zaharchuk Greg 
Published: December 2022

AbstractBackgroundReduced CBF and amyloid update measured by PET imaging have been reported among Alzheimer’s disease (AD) patients. Evidence suggested that early amyloid update may reflect the underlying CBF information. In this pilot study, we aimed to compare whether early uptake amyloid PET images can be used to estimate CBF, by comparing them with gold‐standard 15O‐water PET CBF images.MethodData were collected from an AD patient (female, 74 years) and a normal subject (female, 75 years) using a simultaneous 3T PET/MRI system and injection of 775 MBq of 15O‐water followed by 330 MBq of the amyloid radiotracer 18F‐florbetaben. CBF was computed by fitting the reconstructed PET data to a one‐compartment pharmacokinetic model using an image‐derived AIF. The amyloid PET data were reconstructed from time of injection to 1 and 5 minutes post‐injection yielding two short early duration uptake images, with the OSEM reconstruction parameters set as 2 iterations, 28 subsets, and a 4mm Gaussian post‐reconstruction filter. All images were transformed to the MNI‐152 2mm standard space using non‐linear registration.ResultThe figure shows the measured CBF and amyloid PET maps of the patient and normal subject. In the AD patient, a CBF deficit is present in the posterior biparietal regions (indicated by the arrows), in contrast with other regions. This characteristic CBF deficit is not seen in the normal subject.ConclusionWith further investigation and quantification in various tracers and participant populations, using early dynamic data acquired with amyloid PET tracers could be a potential tool for measuring CBF
Distinctive age‐related longitudinal dementia progression patterns using a machine‐learning‐based MRI biomarker
Authors: Ma Da , Popuri Karteek , Wang Lei , Lockhart Samuel N. , Craft Suzanne , Gurcan Metin Nafi , Beg Mirza Faisal 
Published: December 2022

AbstractBackgroundDementia of Alzheimer’s type (DAT) is an age‐related neurodegenerative syndrome caused by Alzheimer’s disease. The risk of developing dementia increases with age, but also depends on disease trajectory. In this study, we aim to evaluate the effect of normal aging on the MRI‐derived dementia risk score and investigate the distinctive age‐related longitudinal dementia progression patterns among individuals with different dementia trajectories.MethodA total of 1609 participants with multi‐timepoint neuroimaging tests and diagnoses were recruited from the ADNI. Based on their dementia trajectories, the subjects were stratified into four groups: stable normal cognition (sNC=423), stable/progressive mild cognitive impairment (sMCI=535/pMCI=321), and stable dementia of Alzheimer’s type (sDAT=330). Brain structures were automatically segmented and harmonized to control the confounding effect of sex and scanner, and feed into an extensively‐validated kernel‐based ensemble classifier to derive the score, which we termed longitudinal MR‐DAT‐Score (MRDATS). The CSF‐based biomarker was derived as the ratio between the total tau and the amyloid beta (t‐tau/Aβ1‐42). We analyzed the effect of aging on the biomarkers’ distribution of each stratified group in terms of their empirical cumulative distribution function (ECDF). We also evaluated the difference in longitudinal MRDATS progression patterns among different groups.ResultCompared to the CSF biomarker, the MRDATS revealed a more distinctive age‐related risk increase among all stratified groups (Figure 1). In addition, the effect of aging persists across both the non‐progression groups (sNC and sMCI) and the progression groups (pMCI) except for the DAT group, where the age‐related effect is only observable for the 80‐90 years’ group. Distinctive longitudinal dementia risk progression patterns (in terms of MRDATS) were also observed for each stratified group (Figure 2). Specifically, for patients with mild cognitive impairment (MCI), distinctive patterns were observed between sMCI and pMCI across subjects across different aged populations.ConclusionOur study demonstrated the differential aging effect pattern as well as distinctive longitudinal patterns between AD‐progressive and non‐progressive subjects across different age groups. The results of this study emphasize the importance of disentangling the effect of aging with the disease‐driven brain atrophy patterns.
A qualitative study of older refugees’ perception and attitudes towards dementia and dementia risk reduction during the COVID‐19 pandemic
Authors: Al‐Rousan Tala , Awad Mina , Sideman Alissa Bernstein , Moore Alison A. 
Published: December 2022

AbstractBackgroundThe COVID‐19 pandemic continues to worsen economic inequality, political unrest and violence resulting in unprecedented numbers of refugees and asylees globally. Various stressors related to forced displacement may impact cognitive function as refugees age in hosting countries. However, little is known about how forced displacement impacts perceptions and attitudes towards dementia and dementia risk reduction.MethodIn‐depth interviews with 61 older refugees aged 55‐86 who were resettled in San Diego, California from Iraq and Syria, conducted between April‐December of 2021. A phenomenological long‐table approach was used to identify themes and categorize data on dementia knowledge, risk and attitudes.ResultThe mean age of participants was 64.61 (SD: 7.19), 50.82% were female, 14.75% were employed, Median income was USD $15,001 ‐ %25,000, median years since resettlement was 8 (SD7.06), 32.79% reported they could read and write English, 81.97% were Iraqis, 80.33% were married was. 16.39% have contracted COVID‐19, and 85.25% reported being more forgetful since the pandemic started. Participants' responses about their attitudes about dementia were classified into three distinctive thematic domains: fear, acceptance, and practical challenges. Participants identified fear of developing dementia and the need to improve dementia knowledge as major motivators towards adopting healthier lifestyle and health behaviors. Acceptance emerged in relationship to the following areas: 1) religious; aging mentioned in the holy books as an experience associated with feelings of humiliation and helplessness, 2) cultural; dementia as an unavoidable part of normal aging, 3) experiential; displacement and war‐related trauma increase risk of dementia. Practical challenges included the lack of age‐friendly and trauma‐informed care and services available for refugees which were identified as a major barrier for preventive, behavioral and lifestyle change.ConclusionThese findings can be used to develop effective and refugee‐focused interventions that increase motivators and reduce barriers by tailoring interventions to refugees’ dementia risk reduction literacy and motivations to change behaviors.
Worse objective and subjective sleep‐wake metrics are associated with locus coeruleus hypopigmentation: a retrospective post‐mortem study
Authors: Van Egroo Maxime , Jacobs Heidi I.L. 
Published: December 2022

AbstractBackgroundThe brainstem locus coeruleus (LC) was recently put forward as a key nucleus to connect early sleep‐wake disruption and Alzheimer’s disease (AD) pathophysiological processes. Here, we sought to investigate the relationships between post‐mortem LC hypopigmentation, reflecting LC neurodegeneration, and retrospective subjective/objective sleep‐wake regulation metrics in two longitudinal datasets.MethodLC pigmentation ratings were extracted from autopsy data across 517 Rush Memory and Aging Project (MAP) and 637 National Alzheimer’s Coordinating Center (NACC) cases. Actigraphy‐derived intradaily variability, an objective measure of rest‐activity rhythm fragmentation, was obtained in the MAP dataset, and subjective evaluations of sleep quality were retrieved from the NACC cohort. For both studies, sleep‐wake measures were extracted at the furthest and closest available time points, on average 6.8 y. and 2.5 y. before death, respectively. Logistic regressions adjusted for age at death, sex, race, and post‐mortem interval were used to assess whether sleep‐wake variables could predict post‐mortem LC pigmentation ratings. In the next step, additional models including AD‐related variables of APOE genotype and cortical neuropathology (amyloid‐beta and tau burden) were further performed to test for independence in the relationships between sleep‐wake measures and LC pigmentation.ResultsIn the MAP cohort, higher rest‐activity rhythm fragmentation at both time points was significantly associated with greater odds of LC hypopigmentation at autopsy (Table 1). In models considering additional AD‐related variables, these relationships remained significant independently of the effects of APOE and cortical AD neuropathology (Table 1). In the NACC dataset, worse subjective sleep quality at the closest time point, but not at the furthest, was significantly linked to greater odds of LC hypopigmentation at autopsy (Table 2). Likewise, additional models indicated that this relationship is independent of APOE and cortical AD neuropathology (Table 2).ConclusionThese findings highlight the utility of evaluating sleep and wakefulness, especially with objective measurements, to predict LC neurodegenerative processes in older populations, as far as 6.8 years before death and beyond the effects of APOE genotype and cortical AD neuropathology. Our results thus have implications for improved detection of at‐risk individuals.