bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Liver Fibrosis with Cognitive Test Performance and Brain Volume Changes in the UK Biobank Study
Authors: Parikh Neal S , Kamel Hooman , Zhang Cenai , Rosenblatt Russell , Cohen David E , de Leon Mony J. , Gottesman Rebecca F , Iadecola Costantino 
Published: December 2022

AbstractBackgroundLiver fibrosis is a chronic liver condition that, though frequently subclinical, has widespread systemic effects. We hypothesized that liver fibrosis is associated with worse cognitive performance and corresponding brain imaging changes.MethodWe examined the association of liver fibrosis with cognition and brain volumes among adults in the UK Biobank study, which prospectively enrolled approximately 500,000 people starting in 2007 and subsequently collected cognitive test and brain MRI data for some participants. We included participants with available liver fibrosis, cognitive test, and brain imaging data. Liver fibrosis was defined at baseline using validated cutoffs of the Fibrosis‐4 (FIB‐4) liver fibrosis score. The primary cognitive test outcome was the Digit Symbol Substitution Test (DSST), a multidomain test. Secondary cognitive test outcomes were executive function tests (Trails A, Trails B, Reaction Time) and memory tests (Numeric Memory, Pairs Matching). The primary imaging outcome was white matter hyperintensity volume; secondary outcomes were hippocampal volume and total brain volume. We used multiple linear regression models to evaluate the association of liver fibrosis with cognitive test performance and brain volumes while adjusting for potential confounders.ResultsAmong 105,313 participants with cognitive test data, the mean age was 56.1 years and 56% were women. Standard liver chemistries were largely in the normal range. However, 2.0% (95% CI, 1.9‐2.1%) had liver fibrosis based on FIB‐4 scores. Cognitive tests were completed a median of 5.8 years after baseline liver fibrosis assessment. After adjusting for demographics, socioeconomics, education, body mass index, metabolic syndrome, hypertension, diabetes, dyslipidemia, and tobacco and alcohol use, liver fibrosis was associated with worse performance on the DSST (β = ‐0.40; 95% CI, ‐0.60, ‐0.20; P<0.001) (Figure). Liver fibrosis was associated with worse executive function but not memory test performance (Table). We included 34,730 participants with brain MRI, obtained a median of 9.3 years after baseline. In adjusted models, liver fibrosis was associated with lower hippocampal volume (β = ‐58.8; 95% CI, ‐94.7, ‐22.9; P = 0.001) and higher white matter hyperintensity volumes (β = 1142.8; 95% CI, 311.6, 1973.9; P = 0.007) (Table, Figure).ConclusionLiver fibrosis is associated with worse cognitive performance, perhaps explained by hippocampal volume loss and white matter hyperintensity burden.
Free Innovative Tool to Address Memory Concerns and Brain Health for All Communities
Authors: Kenny Brooks 
Published: December 2022

AbstractBackgroundOver 60% of dementia cases are undetected, often due to fear, stigma, and lack of education about memory and brain health. To address this unmet need, UsAgainstAlzheimer’s developed BrainGuide, a free, web‐based consumer education platform designed to empower individuals to take the best next steps in managing their own or a loved one’s brain health.MethodBrainGuide was built with nonprofit, advocacy, industry, medical and technology experts. It offers two memory questionnaires created with input from medical experts and adapted from validated tools in the healthcare community. The self‐assessment is based on MIS/MIS‐T and the caregiver assessment is based on the AD8. Both were adapted for use with a voice and web bot. BrainGuide is not intended to diagnose or provide treatments. Six personas representing individuals concerned about their or a loved one’s brain health, caregivers, and individuals living with Alzheimer’s, were created to curate resources for users to browse after completing a questionnaire. Twenty‐five original tailored factsheets and 70+ links to external resources are also available. BrainGuide’s development was informed by market research including qualitative and quantitative feedback from users. It runs on Amazon Web Services making it available to anyone with telephone or Internet access and was developed with in‐kind and financial support by Biogen.ResultSince launching in March 2021, over 283,000 individuals have visited BrainGuide and 160,000 have completed a memory questionnaire; 79% of users are women, 78% of users are 60+ years and 17% are non‐white. 79% of individuals are taking the memory questionnaire for themselves, and the platform generates a summary to bring to a provider. 74% of users who took the questionnaire indicated that they felt more prepared to discuss brain health with a doctor through our post‐experience user survey.ConclusionData collection is ongoing, to measure consumer engagement and behavior change. To date, we have collected data including consumer confidence in raising the topic of memory with loved ones and providers, the adoption among different audience segments and the ongoing engagement of users. This data provides insights for the field as we work to address challenges to early detection and diagnosis.
Co‐Creating an AI Virtual Assistant Prototype with People Living with Dementia
Authors: Fournier Lisa 
Published: December 2022

AbstractBackgroundJoi is an Artificial Intelligence (AI) Virtual Assistant prototype to improve emotional well‐being for people living‐in‐place with dementia. The Virtual Assistant creates personalized joy pops for the person with dementia within a smart‐home living environment. The joy pops by the VA are triggered based on input from sensors in the smart home, including motion, sound, temperature, and light. The prototype is designed and personalized for the person to provide a moderately stimulating environment to reduce agitation, apathy, and anxiety.MethodBased on reminiscence therapy intervention and a smart home environment, the prototype was co‐created with input from people living with dementia and their care partners. A literature review on stress‐related risk reduction strategies between people with dementia and their care partners was completed for input into the system philosophy. Surveys were used to gather the information from people living with dementia and their care partners, including the current and future state of the home environment and an assessment of meaningful objects.ResultA personalized memory box was developed for each individual to house meaningful objects, such as photos, music, or other items deemed meaningful by the participants in the survey. In addition, the prototype was integrated into a smart home environment to show how smart technologies can be used for conversation prompts with AI versus a name prompt to initiate the AI instance.ConclusionThe prototype can be used for continued development and testing to explore possibilities for living‐in‐place with dementia. This type of co‐creation encourages dementia citizenship and well‐being as well as values user input for prototyping from a vulnerable population.
Synthesizing Images of Tau Pathology from Images of Glucose Utilization
Authors: Lee Jeyeon , Burkett Brian J , Min Hoon‐Ki , Senjem Matthew L. , Mester Carly T. , Wiste Heather J. , Lundt Emily S. , Corriveau‐Lecavalier Nick , Dicks Ellen , Botha Hugo , Radford Jonathan Graff , Barnard Leland R , Gunter Jeffrey L. , Schwarz Christopher G. , Kantarci Kejal , Knopman David S. , Boeve Bradley F. , Petersen Ronald C. , Jack Clifford R. , Jones David T. 
Published: December 2022

AbstractBackgroundIn vivo tau‐positron emission tomography (PET) is an attractive biomarker for Alzheimer’s disease (AD) diagnosis and treatment. However, tau‐PET is less widely available than other modalities. In this study, we tested cross‐modality synthesis of tau‐PET brain images from fluorodeoxyglucose F‐18 (FDG)‐PET using a deep convolutional neural network (CNN).MethodParticipants (n=1,192) who had brain FDG‐PET with 18F‐FDG and tau‐PET with Flortaucipir (F‐18‐AV‐1451) were included for training and testing. This cohort spanned normal aging (ages 26‐98), pre‐clinical, and clinical AD and related disorders including the FTD and DLB spectrum. External validation was done using ADNI (n=288). The PET scans were co‐registered to the corresponding MRI and subsequently warped to Mayo Clinic Adult Lifespan Template (MCALT) space. Tau‐PET images were SUVR‐normalized to the cerebellar crus, and FDG to the pons. A 3D dense‐U‐net model was utilized as an architecture. Cross‐validation experiments were conducted using 5‐fold validations (60% training set, 20% validation set, and 20% test set) with mean squared error as the loss function.ResultOur dense‐U‐net model successfully synthesized tau‐PET from metabolic images with good correlation and low prediction error for regional SUVRs (Figure 1A‐C). The model showed a robust prediction ability, performing accurately in an independent, external ADNI cohort (Figure 1D‐F). The model‐imputed tau‐PET significantly improved performance in classifying tau positivity (mean AUROC(±SD)=0.78±0.04 and 0.85±0.03 for FDG‐PET and synthesized tau‐PET, respectively) and diagnostic groups (cognitively unimpaired with abnormal amyloid‐PET vs. cognitively impaired with abnormal amyloid‐PET) compared to the original input FDG data (mean AUROC(±SD)=0.89±0.04, 0.85±0.05 0.91±0.04 for actual tau‐PET, FDG‐PET and synthesized tau‐PET, respectively) (Figure 2), suggesting enhanced clinical utility for metabolic images. The ADNI cohort also showed similar results (for tau positivity: AUROC=0.66 and 0.78 for FDG‐PET and synthesized tau‐PET, respectively; for CU A+ vs. CI A+: AUROC=0.86, 0.62, and 0.73 for actual tau‐PET, FDG‐PET, and synthesized tau‐PET; Figure 3).ConclusionWe showed that using a CNN model to predict tau‐PET from FDG‐PET is feasible. The synthesized tau‐PET can augment the value of FDG‐PET, facilitating the multi‐modal diagnosis of AD.
Alzheimer’s Disease Proteinopathy and Synaptic Integrity: The Protective Role of Physical Activity
Authors: Lee Shannon Y. , Paolillo Emily W , VandeBunte Anna M. , Brinkmalm Ann , Blennow Kaj , Zetterberg Henrik , Kramer Joel H. , Casaletto Kaitlin B 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) proteinopathy levels are associated with greater synaptic dysfunction markers in brain tissue and cerebrospinal fluid (CSF). However, it is less well known how physical activity (PA) affects this relationship. We aimed to examine the moderating role of PA on AD proteinopathy and synaptic marker outcomes in typically aging adults.Method43 cognitively normal older adults from the UCSF Memory and Aging Center (Meanage = 72.82; SDage = 6.51; 56% women; 83.7% non‐Hispanic White) self‐reported their physical activity levels via the Physical Activity Scale for the Elderly (PASE) questionnaire and completed lumbar punctures during their annual research visit. CSF was analyzed for p‐tau181 and Aβ42, as well as presynaptic (SNAP‐25, synaptotagmin‐1), postsynaptic (neurogranin‐36), and synaptic growth (GAP‐43) proteins in picograms per milliliter (pg/ml). Separate linear regression models assessed the interactive effect of PA and p‐tau181/Aβ42 ratios on levels of each synaptic marker, covarying for participant demographics.ResultGreater p‐tau181/Aβ42 ratios correlated with worse synaptic integrity (r = 0.364‐ 0.412). Adjusting for age, body mass index, and education, there was a significant interaction between p‐tau181/Aβ42 and physical activity on synaptotagmin‐1 (p = 0.0065), neurogranin‐36 (p = 0.0318), and GAP‐43 (p = 0.0321) CSF protein levels, with SNAP‐25 approaching interaction significance (p = 0.0699). Probing the interaction by tertiles, at higher levels of physical activity, the negative relationships between AD proteinopathy and synaptic integrity outcomes were significantly attenuated.ConclusionPhysical activity significantly moderates the relationship between AD proteinopathy and CSF biomarkers of synaptic integrity. Higher PA engagement may attenuate the adverse link between AD proteinopathy and synapse dysfunction. Our findings highlight the importance of exercise and active lifestyles in promoting and maintaining synapse function regardless of neuropathological burden.
White matter hyperintensities are an early marker for cognitive decline in cognitively healthy older adults
Authors: Morrison Cassandra , Dadar Mahsa , Villeneuve Sylvia , Collins Louis D 
Published: December 2022

AbstractBackgroundPrevious research suggests that white matter hyperintensities, amyloid, and tau contribute to cognitive decline. It remains unknown as to how these factors relate to one another and how they jointly contribute to cognitive decline in normal aging. The goal of this study was to examine the association between these pathologies and their relationship to cognitive decline.MethodsCognitively normal older adult data from the Alzheimer’s Disease Neuroimaging Initiative were examined. Participants were included if they had no subjective cognitive decline, had baseline white matter hyperintensity measurements, CSF Aß42, CSF pTau181, and cognitive scores. WMHs were segmented using a previously validated automatic technique (Dadar et al., 2018). Of the 230 participants included, only 199 had follow‐up cognitive scores. Linear regressions examined the influence of white matter hyperintensities, amyloid, and tau on baseline and follow‐up cognitive scores. Linear regressions also examined the association of amyloid and tau on white matter hyperintensities and between tau and amyloid.ResultsIncreased baseline WMHs were associated with increased baseline ADAS‐13 scores (t=2.59, p=.01) and lower follow‐up executive functioning (t= ‐2.84, p=.005). Lower baseline Aß42 was associated with lower baseline (t=3.58, p<.004) but not follow‐up executive function. Baseline pTau was not associated with decline in cognition at baseline or follow‐up. At baseline, WMHs were not associated with pTau but were inversely related to lower baseline Aß42 (t=‐4.20, p<.001). Aß42 and pTau were not associated (t=0.51, p=.61).ConclusionWhite matter hyperintensities may be one of the earliest pathologies observed in healthy older adults that contribute to cognitive decline. The inclusion of white matter hyperintensities as an additional marker for early cognitive decline may improve our current understanding of age‐related changes in cognitively healthy older adults.
Amyloid status prediction by combining plasma p‐tau181 and NfL cut‐offs
Authors: Bun Shogyoku , Ito Daisuke , Sato Yoshiaki , Tezuka Toshiki , Takahata Keisuke , Yamamoto Yasuharu , Sano Yasunori , Kubota Masahito , Tabuchi Hajime , Mimura Masaru 
Published: December 2022

AbstractBackgroundPlasma biomarkers have emerged as a promising tool for screening Alzheimer's disease(AD). However, no externally defined cut‐off values for any plasma biomarkers yet to exist to predict amyloid β (Aβ) status.MethodTaking advantage of the different plasma p‐tau181 and NfL increase profiles, we used the two plasma biomarkers to establish preliminary cut‐off values (two cut‐offs for p‐tau181, one for NfL) for screening Aβ positivity. Participants with a clinical diagnosis of AD(N=20), mild cognitive impairment(MCI)(N=12), other neurodegenerative disorders(N=19), psychiatric disorders(N=3 with depression, N= 1 with delusional disorder), and healthy controls(N=37) were recruited from the Memory Clinic at Keio University Hospital. Static 18F‐Florbetaben (FBB) PET was conducted on all the participants. A trained neuroradiologist visually assessed the acquired images to determine Aβ positivity. Each participant's p‐tau181 value was plotted against NfL values. After visualizing their distribution stratified by the Aβ status, we conducted an exhaustive search to predict Aβ positivity. We first created a ROC curve for p‐tau181 alone and then made a 'quasi‐ROC' curve by combining two p‐tau181 cut‐offs(i.e., the higher and lower cut‐offs) and one NfL cut‐off. The optimal cut‐off values for each ROC curve were determined by the Youden Index.ResultOf the 92 participants, 30(32.6%) were Aβ‐positive(Aβ+). Mean ages were 68.7 years(SD8.2) for Aβ‐ and 72.4(SD9.3) for Aβ+ group (p=0.02). Mean p‐tau181 values were 1.72pg/ml (SD0.75) for Aβ‐ and 3.58pg/ml (SD1.09) for Aβ+ group (p<0.001), whereas mean NfL values were 24.47pg/ml(SD13.77) vs 27.24(SD9.96) (p=0.01). The ROC curves yielded each found the optimal cut‐off values as follows: for plasma p‐tau181 alone, ptau‐181 value, true positive rate(tpr) and false positive rate(fpr) were 5.8 pg/ml, 0.767 and 0.065, respectively. For a combination of higher and lower p‐tau181 cut‐offs and one NfL cut‐off, each biomarker value and the corresponding tpr and fpr were 3.0pg/ml, 2.0/g/ml, 35pg/ml, 0.933, and 0.177, respectively.ConclusionOur results suggest combining two cut‐off values for plasma p‐tau181 and one cut‐off for NfL may yield an excellent discriminant capacity for Aβ positivity. Further research is needed to validate the result.
Intersecting PTMS regulate clearance of pathogenic tau by the CHIP ubiquitin ligase
Authors: Nadel Cory M , Gestwicki Jason E. 
Published: December 2022

AbstractBackgroundBiochemical and cellular models of tau post‐translational modifications (PTMs) were generated to understand how pathogenic tau species evade the protein quality control machinery during the pathogenesis of neurodegeneration.MethodA pathogenic fragment of 0N4R tau representing the species derived from caspase‐cleavage at Asp421 (tauC3) bearing native PTMs was purified from Sf9 insect cells, and its binding to the ubiquitin ligase CHIP was analyzed by ELISA. Differential scanning fluorimetry and fluorescence polarization assays were used to identify relevant sites of modification that alter the affinity of CHIP for tauC3. X‐ray crystallography was employed to define the molecular details of the interaction of the CHIP TPR domain with tauC3.ResultPhosphorylation of tauC3 was shown to reduce the affinity of the CHIP‐tauC3 interaction and attenuate ubiquitination of tauC3 by CHIP. Phosphorylation of tauC3 at Ser416 was shown to be sufficient to significantly reduce the affinity of CHIP‐tauC3 interaction and promote tauC3 accumulation in cells. Introducing specific mutations into CHIP rescued binding to phosphorylated tauC3 and improved ubiquitination and clearance of tauC3.ConclusionC‐terminal phosphorylation at Ser416 of caspase‐cleaved tau inhibits tau clearance by the CHIP ubiquitin ligase and represents a targetable modality to promote clearance of pathogenic tau species during the pathogenesis of neurodegenerative diseases.
Novel Loci for Alzheimer Disease Identified by Genome Wide Association Study in Ashkenazi Jews
Authors: Li Donghe , Farrell John , Mez Jesse B. , Martin Eden R. , Bush William S. , Mayeux Richard , Haines Jonathan L. , Pericak‐Vance Margaret A. , Wang Li‐San , Schellenberg Gerard D. , Lunetta Kathryn L. , Farrer Lindsay A. 
Published: December 2022

AbstractBackgroundPrevious studies identified associations of Alzheimer’s disease (AD) risk primarily in outbred European ancestry (EA) populations. We focused on Ashkenazi Jews (AJs) who descended from a founder population in eastern Europe.MethodWe discriminated AJs in the multiethnic Alzheimer’s Disease Genetic Consortium (ADGC) TOPMed imputed GWAS dataset (n = 53,502) and whole genome sequencing (WGS, n = 16,815) and whole exome sequencing (WES, n = 20,504) datasets assembled by the Alzheimer’s Disease Sequencing Project using a reference GWAS dataset including persons with four AJ grandparents (n = 3,435). Principal component (PC) analysis was performed for each AD dataset combined with the AJ reference data, and a Gaussian mixture model was applied for population clustering. GWA analyses were performed by combining AJs discriminated from the ADGC and WGS subjects (G1) using genome‐wide data and from all three datasets using variants called from exome capture (G2). Separate analyses of individual common (MAF≥1%) and rare (MAF<1%) variants and gene‐based analyses including rare variants were performed using models adjusting for age, sex, and PCs.ResultTotals of 2,956, 738 and 1,062 unique AJs were identified in the ADGC, WGS and WES datasets, respectively. After filtering duplicate and closely related individuals, the sample sizes were 1,355 cases and 1,661 controls for G1 and 1,504 cases and 2,047 controls for G2 analyses. Excluding the APOE region, G1 analyses revealed a genome‐wide significant (GWS) association (P<5.0×10−8) with the TREM2 R47H missense mutation (P = 9.66×10−9) and suggestive associations with rs541586606 near RAB3B (P = 5.01×10−8), rs545690149 near ZNF890P, (P = 5.77×10−8) and rs1225737296 near ANXA10 (P = 6.32×10−8). In G2 analyses, we obtained GWS associations with GBA intronic SNP rs3115534 (P = 3.20×10−13) and TREM2 R47H (P = 2.64×10−10), and suggestive associations with rs1003710 in SMAP2 (P = 1.91×10−7) and rs200698976 in ZNF890P (P = 3.49×10−7). No GWS rare variant associations were identified. Significant gene‐based association was identified with GIPR (7.34×10−7).ConclusionAmong the novel findings, GBA was previously associated with Parkinson disease and Lewy body dementia (LBD). Remarkably, rs3115534 is located 35 bp from, but not in linkage disequilibrium with, N370S that is associated with LBD in AJs. Moreover, rs3115534 (MAF = 0.027 AJ controls) is rare in EAs (MAF = 0.0015). Our results highlight the efficacy of GWAS in founder populations.
Computerized cognitive interventions for preventing dementia in people with mild cognitive impairment: A systematic review with meta‐analyses
Authors: Zuschnegg Julia , Schoberer Daniela , Häussl Alfred , Russegger Silvia , Ploder Karin , Fellner Maria , Hofmarcher‐Holzhacker Maria , Roller‐Wirnsberger Regina , Paletta Lucas , Koini Marisa , Schüssler Sandra 
Published: December 2022

AbstractBackgroundPeople with mild cognitive impairment (MCI) are faced with a higher risk of developing dementia, but with a “window of opportunity” for prevention and treatment. Computerized cognitive interventions (CCIs) might constitute a beneficial non‐pharmacological treatment approach. This systematic review evaluated evidence of CCIs performed individually with a computer, tablet‐PC, game consoles, virtual reality (VR), or augmented reality (AR) on cognition in community‐dwelling people with MCI.MethodA systematic review and meta‐analyses of randomized controlled trials (RCTs) was performed. The systematic literature search was conducted in MEDLINE, CINAHL, Embase, Cochrane CENTRAL, IEEE Xplore Digital Library, ISI Web of Knowledge, Scopus and PsycINFO, and included an additional search for gray literature. The search was completed by backward citation tracking. The methodological quality of the included RCTs was independently assessed by two reviewers. Comparable studies were pooled using the random‐effects model.ResultA total of 18 randomized controlled trials (RCTs) were identified. 12 RTCs were used for conducting meta‐analyses which showed significant effects of CCIs for people with MCI in memory (SMD 1.12, CI 95% [0.08, 2.16]), working memory (SMD 0.85, CI 95% [0.32, 1.38]), attention/concentration/processing speed (SMD 0.61, CI 95% [0.21, 1.02]), executive functioning (SMD 0.96, CI 95% [0.26, 1.66]), and language (SMD 1.63, CI 95% [0.20, 3.06]), but no significant improvement in global cognition. Pooling follow‐up evaluations was not possible, but one of two studies showed continuing significant differences for the intervention group after 6 months post intervention in memory and working memory. CCIs were conducted predominantly with computers, followed by tablet‐PCs, VR, AR, and mixed reality.ConclusionThis review demonstrated beneficial effects of CCIs on domain‐specific cognition in people with MCI. Therefore, CCIs might be a valuable treatment option to maintain cognition and prevent progression to dementia. However, further research is necessary, especially on CCIs applied with emerging technologies like VR or AR. Furthermore, various outcome measurements used in the studies were challenging for the pooling of study results, which highlights the need for a predefined set of important cognitive outcomes and tools for future RCTs.