bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic Differences in Endothelial Cells Across Five Brain Regions in Normal Aging and Alzheimer's Disease
Authors: Bryant Annie G , Li Zhaozhi , Serrano‐Pozo Alberto , Woodbury Maya E. , Wachter Astrid , Lin Gen , Kwon Taekyung , Talanian Robert V. , Biber Knut , Karran Eric H , Hyman Bradley T. , Das Sudeshna , Bennett Rachel E 
Published: December 2022

AbstractBackgroundAltered cerebral vasculature is recognized as a key feature of Alzheimer’s disease (AD) neuropathology, with current evidence suggesting a diverse collection of changes including aberrant angiogenesis, vascular pruning, inflammation, senescence, and other remodeling events. Previous studies examining the endothelial cell transcriptome in AD have been limited to 1‐2 brain regions and hampered by low numbers of isolated endothelial cell nuclei, potentially missing relevant regional heterogeneity. We hypothesized that such regional heterogeneity in endothelial cell gene expression in the normal aging brain may contribute to the varied vascular responses to AD neuropathology.MethodNuclei were isolated from five brain areas in subjects with increasing AD pathology (n=32 donors). The five brain areas chosen represent the hierarchical accumulation of tau pathology in AD: entorhinal cortex > inferior temporal gyrus > prefrontal cortex > secondary visual cortex > primary visual cortex. All subjects had detailed p‐tau, in vitro tau seeding, and amyloid‐beta plaque measurements available. Nuclei were FACS sorted to exclude NeuN+ and Olig2+ cells, and the resulting neuron‐ and oligodendrocyte‐depleted fraction was subject to single‐nucleus RNAseq. Endothelial cell nuclei were identified based on high von Willebrand factor expression and filtered to exclude contaminating glia, yielding a dataset comprised of 51,586 total nuclei.ResultTranscriptomic analysis confirmed that endothelial cells share a core set of commonly upregulated genes across the five brain regions compared to other cell types. However, there is also regional heterogeneity with 193‐311 differentially upregulated genes expressed in endothelial cells within each brain area relative to all other areas. Compared to normal aging brain, endothelial cells from AD donors downregulated 962 genes and upregulated 936 genes that are enriched in vasculogenesis, blood‐brain barrier maintenance, senescence, and leukocyte interactions. Further analysis indicates regional differences in upregulation of these pathways and highlights the relationship to disease burden.ConclusionThis dataset demonstrates a previously unrecognized regional heterogeneity in endothelial cell transcriptome in the normal aging human brain. These regional differences may impact the endothelial cell response to the local AD pathology. This dataset will inform ongoing research efforts to unravel the molecular underpinnings of AD‐induced endothelial cell dysfunction.
Modifying adult life course dementia risk: results from the Framingham Heart Study
Authors: Hwang Phillip H , Ang Ting Fang Alvin , Liu Xue , Liu Yulin , Gurnani Ashita S , Mez Jesse B. , Auerbach Sandford H , Joshi Prajakta S. , Yuan Jing , Devine Sherral A. , Au Rhoda , Liu Chunyu 
Published: December 2022

AbstractBackgroundModifiable risk factors of dementia identified by the 2020 Lancet Commission, including less education, high alcohol intake, smoking, obesity, physical inactivity, social isolation, diabetes, and hypertension, measured at early adult life, midlife, and late‐life were analyzed for their associations with risk of incident dementia.MethodParticipants from the Framingham Heart Study Offspring cohort who attended the fourth examination cycle (1987‐1991) and were free of prevalent dementia were included in the study sample (n = 4,015). They were stratified into three age epochs: early adult life (<45 years, n = 1,079); midlife (45‐65 years, n = 2,476); and late‐life (>65 years, n = 460). Information on alcohol intake, smoking, body mass index, physical activity, and social network, as well as diabetes and hypertension status, were ascertained at the fourth examination cycle, while information on education was ascertained from the second examination cycle. Dementia diagnoses, including all‐cause dementia and Alzheimer’s disease (AD) dementia, were adjudicated by a multi‐disciplinary consensus committee through 2019. Cox proportional hazards models were used to examine associations between each risk factor and incident all‐cause dementia and Alzheimer’s disease (AD) dementia, stratified by age epoch.ResultOver an average of 21 years of follow‐up (early adult life = 24.0 years; midlife = 20.9 years; late‐life = 13.9 years), increased risk of all‐cause dementia was significantly associated with diabetes (HR = 1.62; 95% CI = 1.07‐2.46; p = 0.023) and physical inactivity (HR = 1.57; 95% CI = 1.12‐2.20; p = 0.009) in midlife, and with obesity (HR = 1.76; 95% CI = 1.08‐2.87; p = 0.024) in late‐life. Obesity in late‐life was associated with increased risk of AD dementia (HR = 2.19; 95% CI = 1.27‐3.77; p = 0.005). All other risk factors examined in early adult life, midlife, and late‐life were not significantly associated with risk of all‐cause dementia (Figure 1) or AD dementia (Figure 2).ConclusionResults suggest that modifiable risk factors individually may have modest to no impact across the adult life course on dementia risk. Additional studies are needed to determine if these risk factors in combination may have a more synergistic effect.
Identification of cognitive resilience through neuropsychological tests in the Framingham Heart Study
Authors: Hwang Phillip H , Amini Samad , Karjadi Cody , Lin Honghuang , Andersen Stacy L. , Paschalidis Ioannis , Au Rhoda , Mez Jesse B. 
Published: December 2022

AbstractBackgroundTo examine the predictive abilities of 1) traditional neuropsychological (NP) test summary scores, and 2) error and process scores in separating cognitively resilient individuals from those who exhibit cognitive decline.MethodA total of 69 participants from the Framingham Heart Study (FHS) Offspring and Omni 1 cohorts who had ≥1 NP assessment from 2011–2014 and at high risk for dementia were included in the sample. Participants also had to be ≥60 years of age and dementia‐free at the time of NP assessment. Being at high risk for dementia was determined using a cutoff score of ≥23 based on a published FHS dementia risk score algorithm. Dementia diagnosis was adjudicated based on DSM‐IV criteria by consensus. Participants completed 10 NP tests, which were scored using 11 traditional scores and 75 error and process scores. Supervised machine learning algorithms were used to classify individuals who were cognitively resilient, defined as not progressing to dementia within ≥5 years after the NP evaluation.ResultAmong the 69 participants in our sample, 10 were cognitively resilient while 59 developed dementia. Average area under the curve when using traditional NP metrics to predict cognitive resilience ranged from 90.5% to 95.7% across each supervised machine learning algorithm (logistic regression, random forest, support vector machines, and light gradient boosting machine) (Figure 1). Average accuracy ranged from 85.3% to 92.6%, while average sensitivity was 100% across all models and average specificity ranged from 82.7% to 91.4% (Table 1). Average area under the curve when using the error and process scores to predict cognitive resilience ranged from 93.2% to 98.3% across each supervised machine learning algorithm (Figure 2). Average accuracy ranged from 89.9% to 97.0%, while average sensitivity was also 100% across all models and average specificity ranged from 88.2% to 96.5% (Table 2). All performance metrics were calculated based on five‐fold cross‐validation.ConclusionResults from this pilot study suggest that use of NP tests may serve as an accurate method to identify individuals who are cognitive resilient, allowing for the study of genetic, lifestyle, and other factors that confer resilience among individuals with an elevated risk for dementia.
How e‐solutions can help to improve the AD diagnostic pathway
Authors: van der Flier Wiesje M. 
Published: December 2022

AbstractBackgroundThe AD diagnostic pathway is complex, with diagnosis often made in a relatively late stage. The field is moving quickly, with knowledge about the disease increasing and options for prevention by lifestyle modification and/or medication at the horizon. We need a paradigm shift, with a focus on stages before dementia, and taking into account that both underlying biology and preferences&wishes differ between patients. This will profoundly affect the patient journey.MethodsIn this presentation, I discuss examples of how e‐solutions can help to make the next step throughout different aspects of the patient journey.ResultsOnline cognitive tests, such as cCOG, could help in early detection of cognitive decline. cCOG was strongly correlated to paper&pencil tests, allowing for use in different contexts, and easy repeated assessment. ADappt.health provides a conversation starter which could be used to facilitate shared decision making in the context of AD diagnosis. Animations and a print page provide easily accessible information about the diagnostic pathway. Artificial intelligence solutions can help to combine and visualize different data sources and diagnostic tests. Such tools can provide automatic quantification of MRI images, integrating them with other sources of information, and support differential diagnosis of different types of dementia and promote individualized risk profiling for an individuals risk of future dementia. Finally, e‐solutions could provide easily accessible and easily scalable platforms for intervention, such as lifestyle interventions. In the Netherlands, the FINGER‐NL study is ongoing, entailing a hybrid lifestyle interventions, combining both on site and online meetings. Finally, when we surveyed end users, we found that the majority of both clinicians and patients and their partners is positive about the use of e‐solutions in the diagnostic pathway, provided they increase accuracy and are simple and easy to understand.ConclusionE‐solutions can help to improve the AD diagnostic pathway, by providing information, and tailor individually. They can help to make use of the increasing amount of available data, and create alignment across the entire patient journey. Finally, this type of solutions can help to keep healthcare affordable and accessible, and engage patients and their families more actively.
A Professional Musician with Sight‐Reading Difficulties: A Case Study
Authors: Tun Samantha M , Ficek‐Tani Bronte , Frolov Alexander , Sharp Emily , Fredericks Carolyn A 
Published: December 2022

AbstractBackgroundThere have been few reports of musical alexia in neurodegeneration. In this case report, we describe a professional orchestral musician who presented with a chief complaint of decline in performance accuracy. While he had previously been exceptional in sight‐reading, he was now making frequent mistakes and falling behind. He stated that performing a familiar piece was, “like reading it for the first time.” He later developed difficulties with visuospatial abilities and language.MethodsWe aimed to characterize his musical and cognitive symptoms using a battery that consisted of the Montreal Battery of Evaluation of Amusia, novel tasks to assess accuracy of music reading and music production, standard neuropsychological testing, and review of clinical imaging and CSF.ResultsThe patient completed the Montreal Battery of Evaluation of Amusia (MBAE) with no errors. His pitch, interval, auditory memory, rhythm perception, as well as basic note names and values were unaffected. (Fig.1). We had designed two novel measures to assess his ability to play unfamiliar music using a key signature task and a performance piece. (Fig 2,3,4). Results indicated that he was able to sight read familiar excerpts but not unfamiliar excerpts. On unfamiliar pieces, his sight reading, comprehension, and production showed marked impairment. He was unable to accurately reproduce note sequences in musical passages. On standard neuropsychological measures, he demonstrated impairment on tasks requiring mental rotation and figure discrimination as well as language measures including reading comprehension (BDAE), and confrontation naming (MINT). MRI (Fig 5) showed atrophy in the patient’s parietal lobes and CSF fluid analysis was positive for abnormal Aβ‐42 and normal tau (Aβ‐42:521.55, ptau:25.55).ConclusionOur novel tasks revealed specific deficits in music sight reading, echoed in impairment in visuospatial abilities and language on neuropsychological measures. The patient’s imaging, positive CSF amyloid testing and cognitive testing suggest that amusia was an early stage of a probable parietal variant of Alzheimer’s disease (i.e., PCA). His case highlights the importance of considering a neurodegenerative process in patients presenting with isolated deficits in music reading. Future studies will be needed for normative and validation studies of our novel tasks.
Sex differences in dementia risk and gray matter volume associated with hearing impairment
Authors: Fitzhugh Megan C , Pa Judy 
Published: December 2022

AbstractBackgroundHearing impairment is highly prevalent in older adults and was recently recognized as a modifiable risk factor for dementia. However, it is unknown if risk differs by sex and whether other issues associated with hearing, like social engagement or depression, impact these associations.MethodUK Biobank data was used to identify 165,471 participants (57±8 years, 55% female) without dementia who had a hearing assessment at baseline. Hearing was assessed using a speech reception threshold task, with scores grouped into good, insufficient, and poor severity levels based on previously derived cut‐offs (Dawes et al., 2014). Cox proportional‐hazard models were used to investigate sex differences in the association between hearing impairment and dementia risk. Sensitivity analyses were conducted to determine if social engagement or depressive symptoms mediated these associations. In a subset of participants with MRI data (n = 2,322, 62±7 years, 52% female), linear mixed models stratified by sex were conducted to examine if development of impaired hearing from baseline was associated with gray matter atrophy in auditory and limbic regions.ResultInsufficient and poor hearing were associated with increased risk for dementia compared to good hearing (HR = 1.76, 95%CI 1.43‐2.18 and HR = 2.13, 95%CI 1.46‐3.11, respectively), but differed by sex. Women with insufficient (HR = 1.73, 95% CI 1.25‐2.40) and poor (HR = 3.08, 95%CI 1.80‐5.28) hearing had the greatest risk of dementia, whereas only men with insufficient hearing had increased risk (HR = 1.78, 95%CI 1.34‐2.35; poor HR = 1.60 95%CI 0.94‐2.73). These relationships were not mediated by social engagement or depression. In the MRI subset, women who developed or maintained impaired hearing had greater atrophy over 2.29 years in auditory pathway (e.g., primary auditory cortex, thalamus) and limbic (e.g., hippocampus, parahippocampus, amygdala) regions compared to women with good hearing. Men who developed impairment exhibited decreases over 2.30 years in a secondary auditory region only.ConclusionWomen with impaired hearing have greater risk of dementia compared to men. These sex differences are not mediated by social engagement or depression. Women with impaired hearing exhibit greater atrophy in auditory and limbic regions, while men do not. Sex differences in gray matter atrophy may explain why women with impaired hearing are at greater risk of dementia.
Usability and acceptability of wearable technology in the early detection of dementia
Authors: Wilson Sarah , Ardle Ríona Mc , Tolley Clare , Slight Sarah 
Published: December 2022

AbstractBackgroundThe Early Detection of Neurodegeneration (EDoN) is a global initiative that aims to explore the potential of wearable technologies and smartphone applications to detect preclinical dementia, with aspirations to validate a digital toolkit for clinical practice. To enhance the development of an inclusive digital toolkit, we conducted a study to assess the usability and acceptability of different digital devices in people with cognitive impairments and their carers.MethodRecruitment was conducted across various UK networks such as Join Dementia Research. Participants received the EDoN toolkit, which includes a smartwatch (Fitbit Charge 4), EEG headband (Dreem 3) and two smartphone applications (Longevity and Mezurio). Guides were provided to support the setup process. Initial interviews were conducted approximately three days after the participant received the devices, to explore initial perspectives regarding the toolkit and experiences of the setup process. Follow‐up interviews were conducted two weeks later to explore the acceptability and usability of the toolkit. NVivo was used to thematically analyse the interview transcripts. Emerging themes were discussed and refined by the research group.ResultSixteen semi‐structured interviews were conducted with nine participants, at two‐time points. Four participants had mild cognitive impairment, two had frontotemporal dementia, one had Alzheimer’s and two were carers. We identified three key themes, which centred around usability, acceptability and inequity. Participants expressed the wearable devices were comfortable but individuals with physical disabilities or cognitive impairments struggled to use some devices. Participants valued the feedback the devices provided such as information on sleep and heart rate, although some information was not fully understood. Participants also shared their concerns around detecting preclinical dementia and the increased anxiety around the consequences of this such as "being put in a home”. Various inequities of the toolkit were uncovered such as digital exclusion relating to a lack of access to strong WiFi connection, compatible smartphones and poor digital literacy.ConclusionThese results are informative for the further development of user‐friendly digital tools for the early detection of dementia. Further work is required to ensure a digital toolkit is inclusive and provides information that can be understood by the user.
Functional profiles of older adults from the dementia continuum: Analyzing critical errors that occurred during an IADL ecological evaluation
Authors: Yaddaden Amel 
Published: December 2022

AbstractBackgroundOlder adults with Alzheimer disease (AD) or mild cognitive impairment (MCI) experience challenges that affect their independence. Instrumental activities of daily living (IADLs) are critical in assessing the independence. Single errors can have considerable impact, as they can lead to institutionalization. Thus, optimal recommendations regarding independence depends on an accurate analysis of IADL, including a fine grain analysis of the type of critical errors. Our study aim to describe the errors produced by older adults from the dementia continuum (AD, MCI and older adults living in the community with no dementia) when performing IADL. More specifically, our objectives are to understand: (1) What are the main types of errors occurring during IADL and (2) When are these errors more likely to occur.MethodWe conducted a performance based IADL assessment with older adults (n = 24), including 7 with AD, 8 with MCI, and 9 without dementia. We used the IADL Profile[1], which is a standardized assessment based on ecological observation of 8 IADL tasks. For each task, observations of performance are grouped into 4 operations: (1) formulate a goal, (2) plan, (3) execute, and (4) achieve the goal. Based on video recordings of the sessions, participants performances were transcribed into verbatim reports of all the errors that occurred. Deductive qualitative analysis and descriptive statistical analysis (standard deviation and correlation) were used to categorize/count the main type of errors for each task.ResultOur results highlighted that (1) older adults make several errors while performing IADLs, with a higher occurrence according to the advancement along the dementia continuum and some of which may be crucial to the person’s independence; (2) the most frequent errors for all participants were in formulating a goal and in planning a task and (3) these errors are likely to occur during grocery shopping and meal preparation.ConclusionThe fine grain analysis of errors during the performance of IADL allows us to better identify the needs of older adults from the dementia continuum that can service to guide the selection of effective strategies that can optimize their safety and functional independence.[1] Bottari et al. (2009)
The potentially protective role of an understudied tau isoform in Alzheimer’s disease
Authors: Chung Dah‐eun Chloe , Revelli Jean‐Pierre , Richman Ronald , Yalamanchili Hari K. , Kang Myoung‐Goo , Han Alexander , Zoghbi Huda Y. 
Published: December 2022

AbstractBackgroundAs Alzheimer’s disease (AD) progresses, tau becomes abnormally aggregated and hyperphosphorylated in selective brain regions such as the cortex and hippocampus. Surprisingly, the cerebellum remains spared from tau pathology. Given this observation, we proposed to examine possible differences in the level of various tau isoforms in the cerebellum compared to the forebrain.MethodsWe first compared the transcript and protein levels of tau isoforms between the cerebellum and other brain regions (e.g., the cortex and hippocampus) using both mouse and human brain samples. Here, we discovered that “big tau”, an understudied tau isoform previously reported to be specifically expressed in the periphery, is highly elevated in the cerebellum compared to other brain regions. Next, we performed detergent fractionation using cells expressing mutant big tau or tau441 (the longest one of six major tau isoforms) to compare the aggregation propensity between the two tau isoforms. Lastly, to test this in an animal model, we injected a newborn wild‐type mice with adeno‐associated viruses (AAV) that express either mutant big tau or tau441. After aging the mice for 6 to 9 months, we examined their brains to analyze pathological changes associated with either of these two tau isoforms.ResultsWe found that the transcript level of big tau is significantly higher in the mouse cerebellum compared to the cortex and hippocampus. Using the total tau antibody and the novel mouse big tau‐specific antibody that we generated, we confirmed that big tau protein level is also significantly elevated in the cerebellum. We obtained similar results in human tissues as both the transcript and protein levels of big tau were higher in the cerebellum than the cortex. Interestingly, our fractionation experiment using cells revealed that big tau protein is significantly less likely to aggregate compared to tau441. Consistent with these results, big tau did not become pathologically aggregated or phosphorylated compared to tau441 in the AAV‐based mouse model.ConclusionBig tau has a substantially lower tendency to become pathologically aggregated or hyperphosphorylated. The higher level of big tau in the cerebellum may potentially protect this brain region from developing tau pathology in AD.