bluuebunny/crossref_metadata_2025_split huggingface dataset:
Good plumbing for a healthy brain: new insights into the relationship between cerebral blood flow and tissue microstructural integrity
Authors: Bouhrara Mustapha 
Published: December 2023

AbstractAlzheimer’s disease (AD) has historically been regarded as a gray matter disease, with cortical atrophy on the macroscopic scale and development of amyloid‐β plaques and neurofibrillary tau tangles on the microscopic scale. However, this paradigm has been challenged mainly due to the continuous failure of anti‐amyloid interventions to stop cognitive decline. Researchers are now wondering whether these proteins aggregations are simply byproducts of other primary drivers of neurodegeneration. Based on these observations, a new paradigm put the myelination at the center of the pathophysiology of AD suggesting that alterations in myelin may lead to progressive disconnections of neural networks that could underlie age‐related cognitive decline and AD. Recent advances in quantitative MRI methodology have enabled probing tissue microstructure with exquisite sensitivity, particularly using diffusion tensor imaging and relaxation times, and has revealed nonlinear age‐related trajectories of cerebral tissues during aging. However, although sensitive to myelin, these MRI metrics are not specific precluding specific interpretation of the underlying mechanisms involved in these microstructural changes. To address this challenge, we have developed an advanced method, called BMC‐mcDESPOT, to measure myelin water fraction (MWF), a specific surrogate of myelin content, and provided the first in‐vivo evidence of myelin breakdown in mild cognitive impairment and dementias. Further, this method has opened the way to provide novel insights into the impact of vascular, genetic, and metabolic risk factors on myelination, as well as on the role of myelin in cognition and physical functioning. In this talk, we will present an overview of some of our recent improvements to further accelerate MWF imaging. We will also present results relating reversible risk factors, including cerebral blood flow, obesity and hypertension, to myelin integrity. Finally, we will discuss new results of the implication of cerebral myelination in longitudinal changes in cognition, including memory, executive function, attention, verbal fluency and processing speed, as well as in changes in gait speeds. Understanding the role of myelination in cognitive and physical functioning has the potential to provide a window into the underlying biology of age‐related brain diseases, and to nominate new MR imaging biomarkers for longitudinal assessment and targets for intervention.
Salivary tau as a probable diagnostic method for Alzheimer’s disease
Authors: Santos Gustavo A A , Vale Francisco Assis Carvalho , Fazan Valeria Paula Sassoli , Pardi Paulo Celso 
Published: December 2023

AbstractBackgroundBiomarkers can be detected in blood levels and, more recently, the feasibility of identifying TAU protein in salivary samples was verified.MethodThis is a case‐control study carried out in patients diagnosed with probable AD and cognitively healthy and non‐AD patients who had research centers in the cities of Ribeirão Preto, Jaboticabal, Louveira and São Paulo, Brazil. For the quantification of t‐Tau by the ELISA method in the saliva of research participants, we used the Kit MBS022635 Human Tau Protein ELISA. And for the quantification of phosphorylated TAU (pTAU), the Kit E‐EL‐H5314 Human pMAPT pTAU (microtubule‐associated phosphorylated tau protein) ELISA Kit was usedResultTotal TAU protein concentrations showed no evidence for differences in concentrations in the three groups of patients, with and without Alzheimer’s disease. However, the phosphorylated TAU protein brings a very interesting finding, as it showed variations between young and elderly patients with and without the disease.ConclusionTotal TAU protein does not seem to be a likely biomarker to aid in the diagnosis of the disease. However, our results show that phosphorylated TAU was elevated in the elderly and, in the elderly with AD, it was even higher.
Discovery of disease‐associated, tau, and inflammatory microglial subpopulations and molecular drivers in Alzheimer’s disease using network‐based deep learning integration of human brain single‐cell RNA‐sequencing data
Authors: Cheng Feixiong , Xu Jielin , Pieper Andrew A. , Cummings Jeffrey L. , Leverenz James B 
Published: December 2023

AbstractBackgroundMicroglia have been implicated in the pathophysiology of Alzheimer’s disease (AD) for over 100 years, and substantial progress has been made in characterizing microglial heterogeneities and biology, including disease‐associated microglia (or DAM, amyloid‐pathology related, neuro‐protective), tau microglia (tau‐pathology related), and inflammatory microglia (neuro‐toxic). However, the crucial next step knowing how to apply these findings to develop new treatments for AD, through uncovering the functional roles and molecular drivers of each microglial subtype, has not yet been accomplished.MethodIn this study, we conducted single‐cell RNA‐sequencing data integration analyses of ∼0.8 million cells/nuclei by leveraging frozen brain samples from AD subjects across different brain regions from The Alzheimer’s Cell Atlas (https://taca.lerner.ccf.org/) using a deep learning analytic approach. We annotated three microglial subtypes (including DAM, tau, and inflammatory microglia) using well‐established marker genes and then used a human protein‐protein interactome network‐based approach to identify potential molecular drivers of different microglial subtypes across the spectrum of AD. We also applied transition gene network analysis to characterize microglial subtype transition from non‐disease associated to disease‐associated stages at transcriptomic levels.ResultVia trajectory analysis we pinpointed the existence of three microglial subtypes across AD progression. We also identified that tau microglia were significantly associated with synaptic processes. Compared to DAM, upregulated genes within inflammatory microglia were more significantly enriched within key immune pathways (e.g., NF‐kappa B and toll‐like receptor signaling pathways). In addition, transition gene networks of inflammatory microglia and DAM were found to contain potential AD pathobiology regulators (e.g., SYK, LYN, IRF8, and CSF1R) and genetic risk genes (including INPP5D, PICALM, and MEF2A). We further conducted network‐based drug repurposing prediction by simultaneously activating DAM while inhibiting inflammatory microglia, which indicated that several predicted repurposable drugs (i.e., fluticasone and mometasone) are significantly associated with reduced risk of AD in large patient databases.ConclusionThis study identifies potential underlying mechanisms of microglial subtypes involved in human AD brains, leading to potential drug targets for future development of microglia‐targeted therapies for AD.
Effect of intra‐nasal insulin therapy on food intake among African American adults: the FIINAAL study
Authors: Goodson Mia M , Gwizdala Kathryn L. , Newton Robert L , Beyl Robbie , Firmin Simon , Rao Arushi , Salceanu Vanessa , Carmichael Owen T. , Martin Corby K 
Published: December 2023

AbstractBackgroundIntranasal insulin is a promising treatment for cognitive decline in Alzheimer’s Disease (AD) and mild cognitive impairment (MCI). However, intranasal insulin has been shown to promote weight loss, leading to concerns about decreased appetite, decreased food intake, and unintentional weight loss as negative side effects among metabolic and ingestive behavior effects of intranasal insulin sprays among AD and MCI patients. But, side effects related to food intake and appetite are not well studied, particularly among African American adults who are under‐represented in AD research.Method39 middle‐aged, cognitively normal, community‐dwelling African American adults (Table 1) were enrolled in the Food Intake and Intranasal Insulin in African American Adults (FIINAAL) study assessing effects of intranasal insulin on acute food intake and appetite ratings. This double‐blind, placebo‐controlled, randomized crossover study compared a single intranasal dose of 10 IUs of Novologã insulin, delivered with the Kurveã device, to an intranasal placebo. Participants ate a eucaloric, macronutrient‐balanced lead‐in diet for three days prior to each dose. The dose was administered in the morning following an overnight fast. An ad libitum test lunch followed the dose and participants rated their appetite immediately before and after each dose, and after the meal. Mixed effects linear model t‐tests were used to compare differences in food intake and appetite ratings between insulin and placebo conditions.ResultThere were no significant differences in test lunch energy (calories) or macronutrient intake between insulin and placebo conditions. However, fullness ratings increased significantly more after receiving a dose of insulin than after a dose of placebo (Figure 1). In addition, desire to consume sweet and fatty foods decreased significantly more after insulin than after placebo (Figure 2).ConclusionIn middle aged African American adults, acute intranasal insulin administration was associated with a reduced desire to eat palatable foods and with increased feelings of fullness, but not with reduced food intake at a test meal. Because reduced appetite appears to be an acute side effect of intranasal insulin administration, future work should study whether chronic intranasal insulin administration results in reduced appetite and, consequently, reduced food intake and body weight over time.
Change in life space is associated with cognitive decline and increased risk of incident Alzheimer’s and Parkinson’s disease in older men
Authors: Bock Meredith A , Hoang Tina D , Patel Sheena , Yaffe Kristine 
Published: December 2023

AbstractBackgroundLife space measures the range of geospatial movement through one’s environment during daily functioning. Prior studies on the association of life space and cognitive change are mostly cross‐sectional and have mixed results. To clarify this association, we prospectively evaluated change in life space with cognitive decline and incident Alzheimer’s disease (AD) and Parkinson’s disease (PD).MethodWe studied 1,684 men enrolled in a prospective study of aging. We excluded individuals with probable dementia or PD at baseline (Study Year 7). Life space was evaluated with the self‐reported University of Alabama at Birmingham Life Space Assessment at Year 7 and Year 14. The composite life space score ranges from 0 (most restricted) to 120 (least restricted). Incident AD or PD was defined as a self‐reported physician diagnosis or medication use at Year 14. We conducted logistic regression analyses examining change in life space with the odds of our outcomes unadjusted and adjusted for age, clinic site, race, education, living arrangement, vascular risk factors, and depression. We also conducted mixed linear effects models to evaluate the association between change in life space and change in 3MS and Trails B score.ResultOf 1,684 men (mean age 77.1 +/‐ 18.7 SD) in our analytic cohort, 80 (4.8%) developed incident AD and 23 (1.4%) developed PD over 7 years. The mean (SD) life space score at baseline was 92.9 (18.7) and change over 7 years was ‐9.9 (22.3). In the fully adjusted model, each 1 SD decrement in life space was associated with increased odds of AD (OR 1.6, 95% CI 1.3, 2.0) and PD (OR 1.6, 95% CI 1.1, 2.5). For each 1 SD decline in life space, men worsened by 20.6 seconds in their Trails B score and 1.15 points in their 3MS score over 7 years (p<0.001 for both).ConclusionIn this novel longitudinal analysis, decline in life space is associated with cognitive decline and incident AD and PD. Future studies should examine whether decline in life space is a sensitive and practical way to identify older individuals at risk for cognitive dysfunction and neurodegenerative disease.
Alzheimer’s disease genetics and real‐world patient data fuel target and drug discovery in European and African American ancestries
Authors: Hou Yuan , Zhang Pengyue , Fan Fan , Bekris Lynn M. , Haines Jonathan L. , Pieper Andrew A. , Hammock Bruce D. , Leverenz James B , Cummings Jeffrey L. , Cheng Feixiong 
Published: December 2023

AbstractBackgroundTranslation of massive genetic and genomic data into Alzheimer’s target and drug discovery has not materialized. One challenge in this process is ethnicity‐based differences in the field of Alzheimer’s disease (AD). For example, African Americans (AAs) and European Americans (EAs) differ in AD prevalence, risk factors, and symptomatic presentation, and AAs have historically been less frequently enrolled in AD clinical trials.MethodWe conducted ancestry genetic‐specific target and drug discovery by gathering large genetic data from a diverse population with real‐world patient data to boost the likelihood of identifying disease‐modifying drug targets and treatments for AD. We analyzed genetic data from 275,540 AD cases and 1.55 million controls across 7 AD genome‐wide association studies (GWAS) datasets for both EA and AA ancestries, using Mendelian randomization. We utilized the genetic instruments from 9 expression quantitative trait loci (eQTL) and 3 protein quantitative trait loci (pQTL) datasets from three large human brain biobanks: a) Mount Sinai Brain Bank (MSBB), b) Mayo clinic (Mayo), and c) Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP) (ROS/MAP).ResultWe identified 25 drug targets in EAs and 6 new drug targets in AAs among 1,176 investigated druggable targets. Notably, the inflammatory target of epoxide hydrolase 2 (EPHX2) emerged as a potent AD target in EAs, and treatment of transgenic TgF344‐AD rats with an EPHX2 inhibitor was therapeutic. Among 6 AA‐specific targets, we identified that TRPV3 is a potent drug target for AA individuals with AD, and further replicated our finding in AA‐specific eQTL data. We additionally identified 23 candidate drugs associated with reduced risk of AD in mild cognitive impairment (MCI) patients after analysis of ∼80 million electronic health records. Using a propensity score‐matched design, we identified that usage of either apixaban (hazard ratio [HR] = 0.74, 95% confidence interval [CI] 0.69 – 0.80) or amlodipine (HR = 0.91, 95% CI 0.88 – 0.94) were both significantly associated with reduced progression to AD in people with MCI.ConclusionCombining genetics and real‐world patient data has identified ancestry‐specific therapeutic targets and medicines for AD.
Simulation‐based effect size analysis in the absence of drug effects to inform the design of clinical trials in Alzheimer’s disease
Authors: Andrews Daniel , Arnold Douglas L , Bzdok Danilo , Ducharme Simon , Chertkow Howard , Collins D Louis ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundRandomized clinical trials of Alzheimer’s‐modifying drugs typically report a clinical effect as the final observation difference in means for a cognitive endpoint between treated and placebo groups. However, randomization of subjects naturally following different cognitive decline trajectories could produce a between‐group endpoint difference even when a drug has no disease‐modifying effect. Recent work used data from ADNI subjects matching trial inclusion criteria to simulate patient trajectories [Jutten et al. (2021). https://doi.org/10.1212/WNL.0000000000012022]. We build on such simulations by incorporating a trial’s specific design parameters, including multiple visits, visit time windowing, dropout rate, and measurement noise using jittering. We estimate treatment‐independent group differences in a cognitive endpoint’s rate of change in simulations of the Phase 3 aducanumab and lecanemab trials.Method563 ADNI subjects matched inclusion criteria for the identically designed Phase 3 aducanumab trials EMERGE and ENGAGE [clinicaltrials.gov/ct2/show/NCT02484547]. We fitted a continuous time linear mixed effect model tracking CDSRB change from baseline (CDRSBΔbl). ADNI subjects’ baseline data were resampled and jittered, generating data for 1,070 synthetic subjects total while preserving the real trials’ baseline Alzheimer’s stage distribution. Subjects were randomized 1:1 to “treated” and “placebo” groups, but without any treatment effect. We simulated 4 visits, ∼26 weeks apart, with 30% dropout. Our sample size and visit scheme matches the real trials’ Statistical Analysis Plans. We generated 10,000 simulated trials, each a unique randomization of subject trajectories. The “treated” vs. “placebo” CDRSBΔbl linear slope difference was extracted from each simulation. We repeated this procedure for the demographics and design of lecanemab’s Phase 3 trial Clarity AD [clinicaltrials.gov/ct2/show/NCT03887455].ResultHistograms of simulated slope differences differ between the trial designs (see Figures). Averages are zero because there is no simulated treatment effect. Each successful trial’s real‐world difference (EMERGE high dose: –22%, Clarity AD: –27%) corresponds to a statistically significant reduction in cognitive decline rate for treated subjects vs. placebo.ConclusionOur results suggest low false positive probabilities for the successful trials. Cohort composition, sampling, and other trial characteristics might influence treatment‐independent group difference in cognitive decline rate. With our method, future trials could target treatment effects outside the target population’s false positive range.
Beyond the hippocampus: amygdala and memory functioning in older adults
Authors: Bookheimer Tess Helen , Ganapathi Aarthi S. , Iqbal Fatima , Mattinson Jenna M , Popa Emily S. , Glatt Ryan M. , Merrill David A. , Porter Verna R. , Bookheimer Susan Y. , Bramen Jennifer E. , Lampa Melanie G. , Kim Mihae , Bookheimer Austin , Panos Stella E. , Siddarth Prabha 
Published: December 2023

AbstractBackgroundMedial temporal lobe atrophy has been linked to decline in neuropsychological measures of explicit memory function. While the hippocampus has long been identified as a critical structure in learning and memory processes, less is known about contributions of the amygdala to these functions. We sought to investigate the relationship between amygdala volume and memory functioning in a clinical sample of older adults.MethodsA serial clinical sample of older adults that underwent neuropsychological assessment at an outpatient neurology clinic was selected for retrospective chart review. Patients were included in the study if they completed a comprehensive neuropsychological assessment within six months of a volumetric MRI scan. Each subject underwent scans conducted on a GE 3.0 Tesla scanner, and volumetric analyses were performed using imaging software which quantifies regional brain volumes. We used bilateral hippocampal and amygdala volumes in our analyses. Associations between these volumes and memory scores, derived from immediate and delayed recall conditions of a verbal story learning task and a nonverbal design reconstruction task [1], were examined using mixed‐effects general linear models, controlling for total intracranial volume, age, sex and education. Partial correlation coefficients, controlling for these covariates, were calculated to estimate the strength of the association between volumes and memory scores.ResultsA total of 68 (38F, 29M) participants were included in the analyses, with a mean (SD) age of 80.1 (6.0) and educational level of 15.9 (2.5) years. Controlling for age, sex, education, and total intracranial volume, greater amygdala volumes were associated with better verbal and nonverbal memory performance (p<.001), comparable to hippocampal volume. The interaction term of hemisphere and memory was not significant for any of the models, indicating no lateralized effects. Partial correlation coefficients ranged from 0.45 to 0.31.ConclusionThese findings contribute to a growing body of knowledge highlighting the amygdala as a target for further research in memory functioning through the adult lifespan, supporting a holistic understanding of limbic system operations in which multiple subcortical structures contribute synergistically to memory processes and decline in older adults.
References
[1] Wechsler, D. (2009). Wechsler Memory Scale fourth edition. San Antonio, TX: Pearson.
Heart Rate Variability during Slow Wave Sleep is Linked to Resting‐state Functional Connectivity in the Central Autonomic Network among Older Adults ‘at‐risk’ of Dementia
Authors: Kong Shawn Dexiao , Gordon Christopher J , Hoyos Camilla M , Wassing Rick , D’Rozario Angela L , Mowszowski Loren , Ireland Catriona , Palmer Jake R , Grunstein Ronald R , Shine James M , McKinnon Andrew C , Naismith Sharon L ,   Healthy Brain Ageing Research Clinic
Published: December 2023

AbstractBackgroundReduced heart rate variability (HRV) can be an early sign of autonomic dysfunction in neurodegenerative diseases, and may be related to brain dysfunction in the central autonomic network (CAN). As yet, such autonomic dysfunction has not been examined during sleep – which is an ideal physiological state to study brain‐heart interaction as both the central and peripheral nervous systems behave differently compared to during wakefulness. Therefore, we aimed to examine whether nocturnal HRV, especially slow wave sleep (SWS), is associated with CAN functional connectivity in older adults ‘at‐risk’ of dementia.MethodOlder adults (n = 78; age range = 50‐88 years; 64% female) attending a memory clinic for cognitive concerns underwent resting‐state functional magnetic resonance imaging and an overnight polysomnography. From these, CAN functional connectivity strength and HRV data during sleep were derived, respectively. High‐frequency heart rate variability (HF‐HRV) was extracted to index parasympathetic activity during distinct periods of sleep, including SWS as well as secondary outcomes of non‐rapid eye movement sleep, wake after sleep onset, and rapid eye movement sleep. General linear models were used to examine associations between CAN functional connectivity and HF‐HRV.ResultAnalyses revealed that increased HF‐HRV during SWS was associated with stronger functional connectivity (F = 3.98, p = 0.022) in two core brain regions within the CAN, the right anterior insular and posterior midcingulate cortex, as well as stronger functional connectivity (F = 6.21, p = 0.005) between broader CAN brain regions – the right amygdala with three sub‐nuclei of the thalamus. There were no significant associations between HF‐HRV and CAN functional connectivity during wake after sleep onset or rapid eye movement sleep.ConclusionThese findings show that in older adults ‘at‐risk’ of dementia, parasympathetic regulation during SWS is uniquely linked to differential functional connectivity within both core and broader CAN brain regions. It is possible that dysfunctional brain‐heart interactions manifest primarily during this specific period of sleep known for its role in memory and metabolic clearance. Further studies elucidating the pathophysiology and directionality of this relationship should be conducted to determine if HRV drives neurodegeneration, or if brain degeneration within the CAN promotes aberrant HRV.