bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nanoscale imaging of pT217‐tau in aged rhesus macaque: Trans‐synaptic propagation and seeding of tau pathology in entorhinal cortex
Authors: Datta Dibyadeep , Mentone SueAnn , Morozov Yury , van Dyck Christopher H , Arnsten Amy F. T. 
Published: December 2022

AbstractBackgroundTau pathology in Alzheimer’s Disease (AD) targets higher cortical circuits, with evidence that phosphorylated tau propagates from the entorhinal cortex (ERC) to “seed” pathology throughout the neuronal network. Recent discoveries indicate that tau phosphorylated at threonine 217 (pT217‐tau) can be captured in cerebrospinal fluid (CSF) and plasma as an early biomarker of ensuing disease. However, the role of pT217‐tau in brain tau pathology is unknown, especially as soluble tau species are dephosphorylated postmortem in humans. Rhesus macaques naturally develop the same qualitative pattern and sequence of tau and amyloid pathology, with neurofibrillary tangles comprised of paired helical filaments, identical to human AD. Perfusion fixation of monkey tissue preserves phosphorylation state and allows imaging of molecular location and interactions with nanometer resolution not possible in humans due to postmortem degradation. The current study examined the ultrastructural localization of pT217‐tau in layer II ERC of the aged rhesus macaques, focusing on potential evidence of propagation between neurons, and exposure to the extracellular space.MethodWe used immunohistochemistry paired with high spatial‐resolution immunoelectron microscopy (immunoEM) in aged rhesus macaques (18‐31 years) to localize pT217‐tau in the stellate cell islands in ERC layer II, which show the earliest signatures of tau pathology in AD.ResultpT217‐tau immunolabeling was predominantly observed in postsynaptic compartments in macaque ERC layer II. pT217‐tau accumulated on the calcium‐storing smooth endoplasmic reticulum spine apparatus near axospinous asymmetric glutamatergic synapses in dendritic spines. We observed extensive, trans‐synaptic pT217‐tau trafficking between interconnected neurons within omega‐shaped bodies in ERC layer II, specifically near excitatory, but not inhibitory synapses. Within dendritic shafts, pT217‐tau aggregated on microtubules often in concordance with autophagic vacuoles indicative of neurite dystrophy.ConclusionpT217‐tau accumulates in ERC layer II subcompartments known to be the earliest to show pathology in humans. The data provide the first evidence of pT217‐tau trafficking between neurons to “seed” tau pathology in higher brain circuits, potentially interfacing with the extracellular space to become readily accessible and captured in CSF and blood as a robust AD biomarker. Illuminating patterns of neurodegeneration with pT217‐tau could potentially guide earlier intervention of therapeutics that might mitigate tau hyperphosphorylation in AD.
Case of Dementia with Lewy Bodies in Young Patient with Family History
Authors: Singh Neeraj , Ayyalu Tanesh , Fredrick Jason 
Published: December 2022

AbstractBackgroundDementia with Lewy bodies (DLB) is a neurodegenerative disorder characterized by cognitive decline, fluctuating attention, visual hallucinations, and sleep disorders, sometimes with signs of parkinsonism. Pathological evaluation reveals deposition of abnormally metabolized alpha‐synuclein, termed Lewy bodies. Clinical signs of DLB may be misdiagnosed in young patients with coexisting psychiatric disorders. A 43‐year‐old left‐handed man with a history of chronic paranoid schizophrenia, controlled with haloperidol, paroxetine, quetiapine, and clonazepam, presented with a 3‐year history of declining short‐term memory and concentration. He had a twin brother who was diagnosed with DLB and passed away at 40 years of age.MethodsThe patient was evaluated with serum laboratory tests to evaluate for metabolic abnormalities, infection, and heavy metal toxicity, including complete blood count, comprehensive metabolic panel, vitamin B12, folate, thyroid stimulating hormone, copper, and zinc. MRI Brain and subsequent PET‐FDG Brain were also conducted.ResultsThe results of the serum laboratory tests were all normal. MRI Brain was notable for bilateral parieto‐occipital atrophy and minimal chronic microvascular changes. PET‐FDG Brain revealed hypometabolism in bilateral parietal and occipital regions, with a cingulate island sign, indicative of advanced dementia with Lewy bodies.ConclusionDementia with Lewy bodies is a form of dementia that can sometimes present at an early age, and can be associated with psychological comorbidities and genetic risk factors. Further study of this case will include screening for mutations in the GBA gene, which encodes the enzyme beta‐glucocerebrosidease, which is the most frequent genetic association with dementia with Lewy bodies. Counseling on diagnosis and prognosis has been provided to the patient and his family, and he is being managed with rivastigmine 1.5mg twice daily to help slow down cognitive decline.
Causal Inference in Unrepresentative Databases: An Analysis of Vitamin E Supplementation in the National Alzheimer’s Coordinating Center Uniform Dataset
Authors: Morgan Olivia M. Bernstein , Vegetabile Brian G. , Gillen Daniel L. , Grill Joshua 
Published: December 2022

AbstractBackgroundSelf‐selection into research studies can lead to samples that are unrepresentative of the target population. For example, the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set is often used to identify risk factors of Alzheimer’s disease and overrepresents highly educated and non‐Hispanic White participants, relative to the US population. Sampling weights that are related to the self‐selection of enrolling in the NACC database can be used to estimate causal effects in the US population of older adults. We applied this strategy to estimate the effect of vitamin E supplementation on functional activities using NACC data and estimated sampling weights as proof of concept. A meta‐analysis found mixed evidence about the effect of vitamin E on functional outcomes in cognitively normal older adults (Browne et al. 2019).MethodsWe used baseline data for NACC participants who enrolled from 2005‐2021, were cognitively normal, and 65 or older. The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA‐funded ADCs. We estimated the probability of self‐selection into NACC relative to a nationally representative survey. We used the corresponding sampling weights to estimate weighted propensity scores and weighted propensity‐adjusted estimates of the effect of vitamin E supplementation on the Functional Activities Questionnaire (FAQ) and compared the results to unweighted models.ResultsAfter excluding 809 participants missing the FAQ, there were 14,358 participants. When incorporating sampling weights to obtain inference about the US population, we estimated that participants who take vitamin E supplements have a 0.29 point lower (95% CI: ‐0.54, ‐0.04) FAQ score, on average, compared to participants who do not. When failing to account for sampling bias and omitting sampling weights, we estimated that they have a 0.01 point lower (95% CI: ‐0.11, 0.09) FAQ score, on average (see figure).ConclusionWhen accounting for sampling bias we estimated that participants who take vitamin E supplements perform better on the FAQ compared to those who do not, but this effect was attenuated when failing to account for sampling weights. Incorporating estimated sampling weights allows for better isolation of causal effects in the population of interest.
Retromer subunit, VPS29, regulates vacuolar‐type ATPase and lysosomal acidification in the aging brain
Authors: Ye Hui , Bagchi Pritha , Wu Timothy , Dammer Eric B , Seyfried Nicholas T. , Shulman Joshua M 
Published: December 2022

AbstractBackgroundThe retromer, including VPS35, VPS26, and VPS29, is an evolutionarily conserved protein complex that retrieves cargoes from the endosome to the trans‐Golgi network or plasma membrane. Retromer regulates Tau phosphorylation and pathogenic processing of the amyloid precursor protein, both of which are neuropathological hallmarks of Alzheimer’s disease (AD). Previously, we found that loss of VPS29 in Drosophila causes progressive lysosomal dysfunction during aging, but the underlying molecular mechanism remains elusive.MethodTo investigate the molecular events in Drosophila heads caused by loss of Vps29, we performed quantitative proteomics on Vps29 mutants and age‐matched control animals, and identified 480 significant, differentially expressed proteins. To study the lysosomal acidity in fly Vps29 mutants, we neuronally expressed LAMP1‐GFP, a pH‐sensitive indicator that is localized to the lysosomal lumen. To evaluate the potential translational relevance of our findings, we knocked down retromer subunits in mammalian cell culture and examined levels of vacuolar‐type ATPase (v‐ATPase) subunits. We also interrogated available human postmortem brain proteomic data from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP).ResultUnbiased proteomics from VPS29 mutant flies revealed a sharp decline in subunits of the v‐ATPase, a multimeric proton pump that is primarily responsible for lysosomal acidification. Importantly, we obtained consistent evidence from mammalian cell culture. In aged Vps29 mutant fly brains, the LAMP1‐GFP pH sensor indicated impaired lysosomal acidification. Lastly, based on ROSMAP human brain proteomics, we found that VPS29 protein levels were significantly coexpressed with other proteins implicated in energy‐coupled proton transmembrane transport, including multiple subunits of the conserved v‐ATPase.ConclusionOur findings highlight a conserved role for retromer in regulating the v‐ATPase, possibly contributing to lysosomal acidification. Drosophila is a powerful model system for functional dissection of the retromer in the mammalian brains, including in AD pathogenesis.
Mitochondrial genome abundance is associated with Alzheimer’s disease neuropathological burden and cognitive function
Authors: Harerimana Nadia V. , Paliwal Devashi , Romero Carmen , Bennett David A , Pa Judy , Swerdlow Russell H , Goate Alison , Andrews Shea J 
Published: December 2022

AbstractBackgroundMitochondrial DNA copy number (mtDNAcn) is a measure of mitochondrial genome abundance that is associated with age related diseases. mtDNA can also carry mutations that affect all copies of the mtDNA or only a fraction of the mtDNA molecules (heteroplasmy, mtHz) within an individual cell. To evaluate the role of mitochondrial dysfunction in Alzheimer’s disease (AD) we investigated the association of mtDNAcn levels and mtHz burden with AD neuropathological change and cognitive function.MethodsNeuropathology and genomic data were obtained from 1,381 non‐Hispanic white postmortem brain tissue samples from the Accelerating Medicines Partnership for Alzheimer’s disease (AMP‐AD). neuropathological AD was based on burden of amyloid plaques (CERAD) and neurofibrillary tangles (Braak). Relative mtDNAcn was estimated as the ratio of mtDNA to nuclear DNA, and mtHz burden was defined as the number of mtHz variants. The association of mtDNAcn and mtHz with ADNC was evaluated using logistic regression, and amyloid and tau burden using ordinal logistic regression, adjusting for mitochondrial haplogroup, age at death, sex, APOE, post‐mortem interval, study, and tissue. The association of mtDNAcn and mtHz with cognitive performance was evaluated using linear regression (n=785). As mtDNAcn levels estimated from bulk tissue can be influenced by cell type proportion, we conducted a sensitivity analysis adjusting for neuronal cell type proportion estimated from RNAseq (n=494).ResultsHigher mtDNAcn was associated with reduced risk of neuropathological AD and tau burden, but not with amyloid burden, and with higher cognitive performance for perceptual speed, episodic memory, working memory, global cognition, and semantic memory. In sensitivity analyses adjusting for neuronal cell type proportion, mtDNAcn remained significantly associated with neuropathological AD, perceptual speed, and working memory. mtHz was not significantly associated with neuropathology or cognition.ConclusionIncreased mtDNAcn levels estimated from postmortem brain tissue are associated with reduced risk of AD neuropathology and higher cognitive performance. This suggests that mitochondrial genome abundance is associated with AD pathogenesis, potentially by impairing mitochondrial bioenergetics and thereby impacting neuronal or microglia cell function. Drugs that upregulate total mitochondrial genome abundance or boost mitochondrial mass may ameliorate AD pathogenesis.
Assessment of gray matter microstructure and synaptic density in Alzheimer's Disease: a multimodal imaging study with DWI and SV2A PET
Authors: Salardini Elaheh , Silva‐Rudberg Jason A , O'Dell Ryan S. , Chen Ming‐Kai , Ra Jocelyn , Georgelos Jamie K , Morehouse Mackenzie R , Melino Kaitlyn P , Nabulsi Nabeel B. , Huang Yiyun , Carson Richard E. , van Dyck Christopher H , Mecca Adam P 
Published: December 2022

AbstractBackgroundDiffusion weighted imaging (DWI) is proposed to show alterations to microscopic barriers (O'Donnell, et al. 2011) associated with neurodegeneration (Jacobs, et al. 2013). Positron emission tomography (PET) imaging has also been used to measure synaptic density. Previously, we have shown that synaptic density is lower in Alzheimer's Disease (AD) participants (Mecca, et al. 2020) and is correlated with cognitive performance in patients with AD. Here, we aim to investigate the relationship between DWI metrics and synaptic density in gray matter in the hope of better understanding of AD neurobiology.MethodThirty‐four amyloid positive participants with clinical diagnosis of AD and 18 amyloid negative cognitively normal (CN) participants were included in this study. Early AD‐affected regions (entorhinal cortex, hippocampus, posterior cingulate, and precuneus) were chosen as the primary region of interest (ROI). Synaptic density was measured using [11C]UCB‐J PET where the distribution volume ratio in ROIs was computed using SRTM2 with cerebellum as reference region. Average axial diffusivity (AxD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) within each ROIs was computed using Freesurfer 6. Between group comparisons were performed using an unpaired t‐test. Association between gray matter DWI metrics and synaptic density was assessed using univariate regression analyses.ResultsAxD was significantly higher in AD participants in entorhinal cortex and hippocampus bilaterally as well as right posterior cingulate and left precuneus. FA was significantly lower in left hippocampus, and significantly higher in right hippocampus and right posterior cingulate in AD participants. MD was significantly higher in AD participants in bilateral entorhinal cortex, left hippocampus and left precuneus. RD was significantly higher in AD participants in left precuneus, bilateral entorhinal cortex and hippocampus. Within AD participants, synaptic density was inversely correlated with AxD, MD, and RD in the entorhinal cortex and hippocampus bilaterally and positively correlated with FA in the left precuneus. These associations were absent in the CN group.ConclusionWe found that DWI metrics had significant correlation with synaptic density in Early AD‐affected regions in participants with AD, but not in CN participants. We hypothesize that DWI outcome alterations is reflective of gray matter microstructural changes related to synaptic loss.
The effect of age on mnemonic discrimination is fully mediated by posterior cerebral artery‐defined white matter hyperintensities
Authors: Rizvi Batool , Sathishkumar Mithra , Larson Myra S , Tustison Nicholas J. , McMillan Liv , Greenia Dana E. , Corrada Maria M. , Kawas Claudia H. , Yassa Michael A. 
Published: December 2022

AbstractBackgroundPrevious work has observed a decline in memory performance with age on mnemonic discrimination tasks (MDT). Other studies have recognized the contributions of white matter hyperintensities (WMH), a marker of cerebrovascular disease, on age and Alzheimer’s disease‐related memory decline. Here, we asked whether WMH, defined within vascular territories, particularly the posterior cerebral artery (PCA) defined territory, would mediate the association between age and MDT performance.MethodA sample of 120 older adults (mean age (SD) = 76.6 (10.43) years, age range: 59‐98 years, 74 (61.7%) females) were included in these analyses. Regional WMH volumes were derived from T2‐FLAIR (Figure 1A) images using ANTs, a vascular territory atlas (Figure 1B) and manual editing. The MDT was administered to assess episodic memory and pattern separation ability within both the object (MDT‐O) and spatial (MDT‐S) domains. Adjusting for sex and education, we tested for associations among age, regional WMH volumes, MDT‐S, and MDT‐O scores, correcting for multiple comparisons. Results were then used to assess the mediating role of regional WMH on the relationship between age and MDT. Lastly, we compared the accuracy of the different vascular territory WMH volumes, along with total WMH volume, in classifying cognitive impairment (MCI, QCI, CIND) using area under the receiver operating characteristic curve (ROC).ResultAge was associated with MDT‐S (β=‐0.247, p=0.005), but not MDT‐O performance (β=‐0.130, p=0.177). Only PCA‐defined WMH volume was associated with MDT‐S (β=‐0.252, p=0.005) and MDT‐O (b=‐0.229, p=0.016). PCA‐defined WMH fully mediated the association between age and MDT‐S (indirect effect: β=‐0.001, 95% CI (‐0.003, ‐0.001); Figure 2A). Similarly, PCA‐defined WMH fully mediated the association between age and MDT‐O (β=‐0.001, 95% CI (‐0.002, ‐0.003); Figure 2B). PCA‐defined WMH volume more accurately classified cognitively impaired from non‐impaired (AUC=0.780, p<0.001; Figure 3) compared with total WMH (AUC=0.624, p=0.113), ACA‐defined WMH volume (AUC=0.618, p=.130) or MCA‐defined WMH (AUC=0.592, p=0.237).ConclusionPCA‐defined WMH mediate the relationship between age and memory performance and is a better diagnostic of cognitive impairment than whole brain or other vascular territory WMH volumes. This study demonstrates that defining WMH within vascular territories provides a useful way to characterize the impact of aging on memory impairment.
Qrater: collaborative imaging quality control tool
Authors: Fernandez‐Lozano Sofia , Dadar Mahsa , Morrison Cassandra , Manera Ana Laura , Fonov Vladimir S , Collins Louis D 
Published: December 2022

AbstractBackgroundQuality control (QC) is particularly important in vulnerable populations like patients with dementia where movement artifacts as well as registration failures may be more prevalent. From our need to review the quality of tens of thousands of raw MR images and reviewing the steps of our pre‐ and post‐processing pipelines, we developed Qrater. Qrater is a web‐based application installed centrally on a server where our data is stored. We can then rate the images and access the database of our team’s stored ratings (QC status and potential comments for each image).MethodIn Qrater the images are uploaded as datasets that can be restricted to specific users (Fig. 1). Each image is viewed and rated with available features such as a magnifying glass, seeing other users’ ratings, adding specifying comments, moving between images, and rating with key bindings to store QC outcomes other than pass/fail/warning (Fig. 2.). Looking for a specific image or rating is made easier by the search and sorting features (Fig. 3). Four experienced researchers rated three different datasets of MRI (A: 1275 unprocessed T1w brain images; B: 1623 unprocessed T1w brain images; C: 3000 preprocessed T1w brain images non‐linearly registered to a standard template). We looked at timing from the ratings’ timestamps to determine how much time it took to rate the datasets. All analyses were done in R v 4.1.ResultOn average, it took between 10 and 25 seconds to rate each image (14.2 s dataset A, 25.5 s dataset B and 14.1 s dataset C. Figure 1); less than 10 seconds to mark a clearly failed image for both raw acquisition and registration tasks, while the more questionable images (marked as Warning) took between one and two minutes (Table 1, Fig. 4).ConclusionOur team has found Qrater’s usability to be a significant improvement over previous quality control methods. The built‐in SQL database supports thousands of images without affecting its performance, and the web‐based interface enables remote QC. Since Qrater belongs to the initiative towards a more open and reproducible science, the code is currently available for download in GitHub [https://github.com/soffiafdz/Qrater].
Emergence of visual artistic creativity in frontotemporal dementia
Authors: Friedberg Adit , Pasquini Lorenzo , Diggs Ryan T. , Glaubitz Erika Alma , Lopez Lucia , Brown Jesse A. , Rankin Katherine P , Allen Isabel Elaine , La Joie Renaud , Iaccarino Leonardo , Mundada Nidhi S. , Illán‐Gala Ignacio , Bonham Luke W. , Yokoyama Jennifer S. , Miller Zachary A. , Rabinovici Gil D. , Kramer Joel H. , Rosen Howard J. , Tempini Maria Luisa Gorno , Seeley William W. , Miller Bruce L. 
Published: December 2022

AbstractBackgroundEmergence of novel visual artistic skills has been described in neurodegenerative disorders, particularly in the frontotemporal dementia – amyotrophic lateral sclerosis (FTD‐ALS) spectrum, but associated clinical and genetic features and the underlying neural mechanisms have not been systematically examined. We aimed to address these gaps.MethodWe performed comprehensive chart review of all 734 participants in the University of California San Francisco FTD Program Project Grant who had a clinical syndrome within the FTD‐ALS spectrum. This review allowed us to ascertain subjects meeting current FTD‐ALS clinical research criteria who had: (1) an emergence of novel visual artistic skills or (2) a change in the style of visual art produced or (3) a significant increase in quantity of visual art produced. Clinical data, imaging studies, and genetic information were collected and analyzed.ResultAmong the 734 patients screened, 45 were excluded due to lack of available research notes. We identified a change in visual artistic creativity in 17/689 patients (prevalence 2.5%). Mean age of FTD symptom onset was 57.4 (±10.4), and the visual artistic creativity (VAC) change was reported an average of 0.7 years (±10.1) prior to FTD symptom onset. Of the 17 patients with VAC, 8 exhibited no prior interest in art, 2 were professional visual artists who experienced a change in artistic style, and 7 reported some prior interest in art but a substantial change of style or quantity. Artistic output was diverse however bright colors and non‐human subjects were prominent. VAC occurred in patients with semantic variant primary progressive aphasia (8), behavioral variant FTD (3), nonfluent variant primary progressive aphasia (2), progressive supranuclear palsy ‐ Richardson’s syndrome (2), corticobasal syndrome (1), and ALS (1). None carried a common pathogenic variant in a FTD gene.ConclusionChange in VAC is an uncommon but early positive symptom that occurs in patients across the FTD‐ALS clinical spectrum but appears most common in patients with anterior temporal lobe degeneration. We are pursuing the neural mechanisms of VAC through structural and functional neuroimaging studies.