bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bile acids inform about a sex‐specific resilience phenotype against Alzheimer’s disease implicating a role for the gut microbiome and the exposome
Authors: Kristal Bruce , Sniatynski Matthew J , MahmoudianDehkordi Siamak , Kastenmuller Gabi , Nho Kwangsik , Arnold Matthias , Borkowski Kamil , Jia Wei , Kaddurah‐Daouk Rima F. ,   for the Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium
Published: December 2023

AbstractBackgroundBile acids (BAs) are byproducts of cholesterol metabolism involved in lipid absorption, signaling and energy homeostasis. BA synthesis and metabolism, regulated by human and gut bacteria co‐metabolism, are influenced by the exposome. Our prior studies at a population level illustrated a correlation between altered BA profiles and cognitive and brain imaging changes in MCI and AD. More information is needed to determine if these are causal in sub‐populations, and if their modulation can impact disease course.MethodAbsolute serum levels of 33 primary, secondary, and conjugated BAs were measured on a targeted mass spectrometry‐based platform in 1117 fasted subjects (502 women) drawn from the AD Neuroimaging Initiative (ADNI‐1/GO‐2; AD (N = 180), MCI (N = 607) and CN (N = 330). Analysis centered on adjusted and/or stratified linear models with an interpretative focus emphasizing individual‐level granularity.ResultIn stratified analysis, men but not women showed strong association between levels and ratios of BAs and diagnosis. Inclusion of two (informative) bile acids and their ratios increases AUCs for AD vs control from ∼0.72 to ∼0.82‐0.85 (p<0.001) in APOEε4 genotype‐stratified analyses. Some specific associations were APOEε4 genotype‐dependent; some specific microbiome‐mediated ratios in BAs were associated with AD diagnosis in APOEε4− only and secondary bile acid synthesis was associated with AD diagnosis in APOEε4+ only. Other associations were APOEε4 genotype‐independent ‐ higher ratios of primary BAs to total BAs were associated with reduced AD prevalence. Levels of cholic acid below sharp thresholds 25 or 50 nM (in APOEε4+ and APOEε4−, respectively) at 24 months were associated with 5‐ to 7‐fold increased relative risk of MCI to AD progression, establishing a potential biomarker for a resilience phenotype.ConclusionLeveraging the combined power of ADNI and metabolomics with a focus on granularity and complementarity revealed previously unobserved relationships between BAs, sex, APOEε4 genotype, and AD etiology. These data identify a resilience class and provide a roadmap for stratifying subjects and targeting therapies in a precision medicine approach while gaining deeper insights linking peripheral‐central metabolism influenced by the exposome. BAs are a potential modifiable factor that mediates causal linkages between endogenous and exogenous factors in the susceptibility or resilience against AD.
Effect of calcineurin/NFAT inhibitors on biomarkers and cognition in a canine model of Alzheimer disease
Authors: Sordo Lorena , Ubele Margo F. , Boaz Kathy , Mefford Jennifer L. , Jones Erin D. , McCarty Katie , Smiley Jeffrey , Bailey Stasia A. Bembenek , Perpich Jessica A. , Meacham Beverly , Powell David K , Bresch Fred , Phelan Michael J. , Noche Jessica A. , Stark Craig E.L. , Puskas Laszlo G. , Norris Christopher M. , Head Elizabeth 
Published: December 2023

AbstractBackgroundCalcineurin/NFAT signaling increases in Alzheimer disease (AD) and is associated with neurodegeneration, neuroinflammation, amyloid‐β (Aβ) production, and cognitive decline. Hence, calcineurin/NFAT inhibitors (e.g., tacrolimus and Q134R) are attractive potential therapeutics to improve/prevent AD‐associated cognitive impairments. In AD mouse models, both tacrolimus and Q134R improved cognition and ameliorated neuroinflammation and synapse dysfunction.We hypothesized that 1) chronic low‐dose administration of tacrolimus and Q134R will delay cognitive decline over time in middle‐aged beagles, a model of human brain aging and AD; and 2) canine plasma and CSF biomarkers will be improved with treatment.MethodsCognitive outcomes were evaluated in 37 middle‐aged beagles at baseline and during follow‐up (years 1‐3) by assessing spatial learning [landmark‐discrimination (1, 2 and 4cm)], visual discrimination learning, reversal learning (executive function), and spatial working memory (20‐, 70‐, and 110‐second delays). Dogs were ranked for cognition at baseline and randomized into treatment groups: Control (n = 12; placebo), Q134R (n = 12; 8mg/day), and tacrolimus (n = 13; 0.075mg/kg/day). Concentrations of Aβ40, Aβ42, and NfL in plasma and CSF were measured using the Quanterix SIMOA.ResultsAccuracy at all landmark‐discrimination distances declined significantly among controls 20% faster than tacrolimus, and 15% faster than Q134R dogs, at the most difficult distance of 4cm. Accuracy on spatial working memory task declined 21% faster/year among controls than tacrolimus (years 2&3); and 18% faster than Q134R dogs (year 1). Performance on visual discrimination and reversal tasks declined with age but there was no treatment effect.Biomarkers in plasma tended to increase over time with no significant differences between treatment groups. In CSF, relative decreases in Aβ40 and Aβ42 in tacrolimus (2.9 and 2, respectively) and Q134R (5.4 and 3.7, respectively) were less than in control dogs. Finally, relative increases of NfL in tacrolimus and Q134R were less than in control dogs (2.3 and 3.7, respectively).ConclusionBoth tacrolimus and Q134R showed beneficial preventative effects on age‐related decline in spatial functions and memory but not on associative learning nor executive function in a canine model of AD. Finally, only CSF biomarkers tended to improve relative to treatment and are suggestive of less Aβ deposition in brain and higher clearance.
Comparison of Expert Reads vs. Local Clinical Reads of Amyloid PET Scans in IDEAS
Authors: Windon Charles , Zeltzer Ehud , Hanna Lucy , Carrillo Maria C. , Iaccarino Leonardo , La Joie Renaud , March Andrew , Mejía Jhony Alejadro , Mundada Nidhi , Arora Anupa , Bullich Santiago , Sherwin Paul , Siegel Barry A , Gatsonis Constantine , Rabinovici Gil D. 
Published: December 2023

AbstractBackgroundAmyloid‐directed therapies will increase the clinical use of amyloid PET. IDEAS captured >17,000 clinical scan interpretations from local radiologists and nuclear medicine physicians. This study aimed to establish accuracy of these interpretations by comparison to expert readers across identical scans.MethodRandomly selected amyloid PET/CT scans performed using one of three FDA‐approved agents [18F‐Florbetaben (FBB), 18F‐Florbetapir (FBP), 18F‐Flutemetamol (FMM)] and previously interpreted by local readers from the Imaging Dementia ‐ Evidence for Amyloid Scanning (IDEAS) study were assigned to vendor‐selected panels of 3 expert readers for interpretation; 500 scans per agent and 1 panel per agent. Scans were stratified to match frequencies observed in the overall study by 1) participant age; 2) MCI vs dementia; 3) positive/negative interpretation; and 4) type of PET facility. Respective vendors performed quality control on attenuation‐corrected PET/CT images.Visual interpretations (positive or negative for Aβ cortical deposition) were performed according to agent‐specific validated interpretation criteria. Expert panel readers were blinded to clinical and demographic data. Cohen’s kappa statistic with two‐sided 95% confidence interval estimates examined agreement between local reader and majority expert panel visual interpretation.ResultExpert panel readers’ visual interpretations totaled 4489. Median age for scanned participants was 75 (range 65‐96), 51.4% were female and 60.5% had MCI. Local readers interpreted 60.9% of scans positive and 39.1% negative (Table 1).Across all radiotracers, agreement between majority expert read and local readers was excellent (k coefficient 0.76; 95% CI 0.73 – 0.80, p<.0001) with 86.6% (791/913) agreement for positive scans and 90.9% (532/585) agreement for negative scans (Figure 1). Agreement by individual radiopharmaceuticals was good to excellent: k coefficient 0.78 (95% CI 0.72 – 0.83, p<.001) for FBB, k coefficient 0.72 (95% CI 0.66 – 0.78, p<.001) for FBP, and k coefficient 0.78 (95% CI 0.73 – 0.84) for FMM (Figure 1). Agreement levels between local readers and individual experts varied from good to excellent (Figure 2).ConclusionWe found good to excellent agreement between local readers and majority assessment of three‐member expert panels for all combined scans and scans by individual agents. Visual interpretation of Aβ PET can be performed in a clinical setting with high reliability.
Detecting Unrecognized Cognitive Impairment and Dementias Using Clinical Health Systems Bioinformatics and Electronic Health Records from a National Population
Authors: Khachaturian Ara S , Beeri Michal S , Li Gang , Ravona‐Springer Ramit 
Published: December 2023

AbstractGlobally there are upwards of 35 million people living with dementia and other cognitive impairments, with total annual costs of approximately US$ 1 trillion by 2025. Yet, this estimate does not consider the impact due to the lack of specialized personnel and health care infrastructure to provide timely access for dementia diagnosis, treatment, and care. These factors are complicated by the lack of valid and equitable means for detecting signs of impending cognitive impairment or dementia. Also, these same symptoms are not easily recognized by many primary care physicians who do not make referrals to specialists. These negative dynamics on access to quality brain healthcare may impact under‐represented, underserved, and vulnerable populations at disproportionately greater levels. Although more AD/ADRD interventions will be approved, this will not assure equal market access.There is an immediate need to provide accurate, affordable, appropriate, and equitable clinical care profiles. One approach is to develop digital tools to access electronic health record (EHR) data. Yet, generic EHR data on dementia status are limited to people who have received a formal diagnosis. Worse, in the community setting, most people enduring cognitive impairment or living with dementia will not receive generally a timely diagnosis to support useful clinical care decision‐making.Fortunately, several international health data reservoirs exist that integrate routine EHR data with dementia research‐driven cohort studies with affiliated biobanks, including Sheba Medical Center (SMC) with its ongoing ‐omics and neuroimaging research. As Israel has socialized medicine, and all residents have healthcare provided through the Israeli National Health Insurance law, the Sheba data offers a unique opportunity to develop
valid
,
reliable
, and
transportable
EHR derived assessment tools for cognitive impairment and dementia.The project in collaboration with SMC and Maccabi Healthcare Service—one of four national Israeli medical service providers—demonstrates the advanced capabilities to use electronic medical records linked with a national network of primary care physicians, and the ability to conduct deep‐source data mining in the absence of a clinical diagnosis of cognitive impairment or dementia. The project reports the performance characteristics (i.e., sensitivity and specificity) of assessment tools to detect cognitive impairment or dementia.
Inhibition of EV biogenesis reduces tau propagation in Alzheimer’s Disease mouse models
Authors: Huang Meixiang , Tallon Carolyn , Bell Benjamin J , Kapogiannis Dimitrios , Haughey Norman J , Rais Rana , Slusher Barbara S 
Published: December 2023

AbstractBackgroundMounting evidence correlates the propagation of hyperphosphorylated tau (pTau) along synaptically connected networks in the brain with progressive cognitive decline in Alzheimer’s Disease (AD). Recent findings have highlighted extracellular vesicle (EV)s in enabling transcellular transmission of pathological tau and identified the partial inhibition of EV biogenesis via small‐molecule inhibitors of nSMase2 as a potential therapeutic avenue. However, there are no suitable compounds for clinical development so far.MethodThrough high‐throughput screening, we identified PDDC, a highly selective and potent nSMase2 inhibitor with excellent brain penetration and oral bioavailability. To evaluate PDDC’s effect on tau propagation in vivo, we chronically administered PDDC‐containing chow to PS19 transgenic mice and measured brain ceramides, nSMase2 activity, tau levels, glial activation, hippocampal neuronal cell layer thickness, and mossy fiber synaptophysin staining. In addition, neuronally‐derived EVs from plasma were isolated and characterized. To directly monitor the effect of PDDC on tau propagation, we developed a murine model where an AAV encoding for P301L/S320F double mutant human tau was stereotaxically‐injected unilaterally into the hippocampus and transfer to the contralateral dentate gyrus (DG) was monitored ± PDDC treatment.ResultPS19 mice exhibited robust elevation of multiple ceramide species and nSMase2 enzymatic activity in the brain, both of which were normalized by PDDC treatment. PS19 mice treated with PDDC had significantly reduced hippocampal total tau and Thr181 pTau, reduced glial activation, protected synapses, and improved pyramidal and granule cell layer thickness. Plasma NEVs of treated mice were fewer in number and had lower p181‐Tau levels than the untreated group; FCA confirmed the decrease of NEVs carrying p262‐Tau at the single EV level. Similarly, the AAV‐hTau‐seeded mice treated with PDDC had reduced tau staining intensity in the contralateral DG.ConclusionData in two AD models using PDDC provides strong preclinical support for using nSMase2 inhibition as a therapeutic strategy to slow tau propagation in AD.
Transforming genetic data for a convolutional neural network using genotype posterior probability: Algorithm for handling incorrectly imputed multiallelic variants for multiple genetic datasets
Authors: Bae Jinhyeong , Nudelman Kelly N. H. , Apostolova Liana G. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) genetic research utilizing genome‐wide association study data often requires imputation. Genotypes are imputed probabilistically by the Hidden Markov Model and converted into one‐dimensional categorical variables for a convolutional neural network (CNN). Such a conversion, however, contains uncertainty, which can mislead CNN in determining AD‐risk factors when added up. Also, the imputed genotypes are quality‐controlled (QCed) by using PLINK, a widely used whole genome data analysis toolset. However, the QC process of PLINK cannot exclude all incorrectly imputed multiallelic genetic variants (IMGs). To address such issues, we proposed a post‐quality control algorithm to transform the genetic dataset into three‐dimensional one‐hot encoding weighted by genotype posterior probabilities.MethodWe collected 1876, 173, and 384 participants from the Alzheimer’s Disease Neuroimaging Initiative, Imaging and Genetic Biomarkers for AD, and Longitudinal Early‐Onset Alzheimer’s Disease Study, respectively. Genotypes were imputed through Markov Chain Haplotyping and QCed using PLINK (Fig. 1). Then the data was transformed into 5×2xN three‐dimensional one‐hot encoding; 5 indicates the number of nucleotides (4) including insertion (1), 2 indicates genotype copy, and N indicates the number of all available markers. One‐hot encoding data was weighted by genotype posterior probabilities obtained by Genome Analysis Toolkit. The weighting algorithm also re‐imputes IMGs based on their genotype posterior probabilities (Fig. 2).ResultAll genotypes were successfully transformed into one‐hot encodings composed of genotype posterior probabilities. Each participant had about 6,980 IMGs with a standard deviation of 822 (Fig. 3). The percentage of IMGs for each chromosome was about 0.274% with a standard deviation of 0.234 (Table 1). All IMGs were corrected based on genotype posterior probabilities and transformed into one‐hot encodings (Fig. 4).ConclusionThe QC process is essential for minimizing possible bias and errors that would be imposed on computational models. Transforming genetic data into one‐hot encodings weighted by genotype posterior probability can present genotypes with their imputation quality. Furthermore, it can fully utilize CNN’s capacity by allowing it to determine various features.
Speech and Language characteristics of Kannada and Hindi speaking individuals with Primary Progressive Aphasia
Authors: J Darshini K. , Kumar S Sandeep , Arshad Faheem , P Vandana V. , Philip Mariamma , Paplikar Avanthi , Ramakrishnan Subasree , Alladi Suvarna 
Published: December 2023

AbstractBackgroundLinguistic typology plays an important role in identifying clinical markers of language deficits that characterise Primary Progressive Aphasia (PPA). The current International criteria to diagnose PPA were primarily developed for English. Typological characteristics of Indian languages however differ from English in their morpho‐syntactic complexity, a flexible‐word order, richer morphology, ‘pro‐drop’ languages with absence of prepositions and transparent orthography. We aimed to develop a novel test in Kannada (Dravidian) and Hindi (Indo‐Aryan) to identify language deficits in Indian language speakers with PPA.MethodThe speech‐language test systematically developed for Kannada and Hindi consisted of unique tasks for syntax, semantics, phonology, motor speech and working memory. Participants underwent assessment of cognition and language with Addenbrooke’s Cognitive Examination‐III, Western Aphasia Battery‐Revised and Indian Semantic Memory Battery (ISMB) in addition to the novel test.ResultsOf 26 patients with PPA (Kannada 13, Hindi 13), 15 had non‐fluent variant (nfvPPA), 8 semantic variant (svPPA) and 3 logopenic variant (lvPPA). On the novel test, PPA had higher phonological, motor speech, syntactic and semantic errors compared to 60 controls. nfvPPA had higher phonological, motor speech and syntactic errors and lesser semantic errors compared to svPPA. Semantic and working memory errors discriminated between nfvPPA and svPPA. On qualitative analysis, 5 patients of nfvPPA had significant apraxia of speech. The other 10 had a unique syntactic profile: agrammatism was not prominent in their spontaneous speech and picture description. Sentences were relatively fluent, complete and sufficient for functional communication. The consistent abnormality observed was a reduction in overall length of utterance. Agrammatisms such as inappropriate use of case markers were restricted to specific tests of syntax. svPPA patients had increased verbal output and prominent paragrammatisms. Testing for surface dyslexia was not relevant due to the orthographic transparency of Indian languages.ConclusionThe novel language test for evaluation of Indian speakers of PPA revealed unique findings for diagnosis of nfvPPA. Reduction in length of utterances and lack of prominent agrammatism was a consistent clinical marker and owes itself to morpho‐syntactic complexity of Indian languages. Our study emphasises the need to account for linguistic typology in diagnosis of PPA.
NFL and pTau species from plasma neuronal and astrocyte exosomes correlate with neuropathological development and neurodegeneration in Down Syndrome
Authors: Sukreet Sonal , Kim Elise K , Nauss Sophie N , O'Bryant Sid E. , Rafii Michael S , Rissman Robert A 
Published: December 2023

AbstractBackgroundIndividuals with Down Syndrome (DS) develop Alzheimer’s disease (AD). Plasma Neurofilament (NFL), phospho tau181, and 231 (pTau181 and 231) are currently considered promising blood‐based biomarkers of brain tau pathology in AD. However, it is still unknown whether the use of exosomal NFL and different pTau epitopes offers overlapping or complementary information about tau pathology information in this population. Using biobanked DSBI plasma samples, we aimed to understand the relationship between blood‐based exosome derived NFL, pTau181 and 231 with age, brain amyloid and tau pathology, APOE status, as well as cognitive and functional performance in non‐demented DS individuals. We hypothesized that the relationship between NFL, pTau‐181, and 231 derived from plasma neuronal and astrocyte exosomes (NDEs/ADEs) with that of other fluid and imaging biomarkers might help to accurately assess brain AD pathology in DS adults.MethodExosomes were isolated from the plasma of adult DS individuals who were enrolled in DSBI. Exosomes were precipitated and isolated using an ExoQuick kit. Isolated exosomes were enriched for NDEs and ADEs using antibodies against neuronal (L1CAM) and astrocyte (GLAST), respectively, followed by magnetic immunocapture and fluorescence‐activated cell sorting. NDEs and ADEs were assessed for their size and marker proteins by Nanosight, electron microscopy, and ELISA. NFL was quantified by SIMOA assays, while pTau epitopes 181 and 231 were quantified by MSD assays in NDEs and ADEs. We compared the diagnostic accuracy of exosomal p‐tau epitopes with NFL levels. We analyzed imaging data and cognitive measures in relation to NFL, pTau181, and pTau231 of NDEs and ADEs in adults with DS.ResultBlood‐based NDEs and ADEs showed expected exosomal size, shape, and distribution. ELISA showed the presence of exosome marker proteins on NDEs and ADEs. The p‐tau epitopes showed correlations with each other. We showed significant correlations of exosomal NFL and pTau epitopes with age, brain amyloid, tau pathology, APOE status, and cognitive and functional performance.ConclusionThe correlations reported here lay a foundation to study the use of plasma‐derived exosomal NFL and pTau181, and pTau231 as a “combination biomarker” in clinical trials and to better understand the neurodegenerative trajectories in DSAD.