bluuebunny/crossref_metadata_2025_split huggingface dataset:
MIND and Mediterranean diet association with Alzheimer’s disease pathology
Authors: Agarwal Puja , Wang Yamin , Aggarwal Neelum T , Cherian Laurel J , James Bryan D , Dhana Klodian , Leurgans Sue E , Bennett David A , Schneider Julie A 
Published: December 2021

AbstractBackgroundHealthy dietary patterns, primarily Mediterranean‐DASH Intervention for Neurodegenerative Delay (MIND), and Mediterranean diet (MedDiet) are related to slower cognitive decline and reduced risk for Alzheimer’s dementia. However, it is unknown if these diets and its primary food groups are associated with Alzheimer’s disease (AD) pathology in postmortem brains.MethodThe study was conducted in 459 deceased participants (age at death (91.0±6.3 years), 73% female, 20% with APO‐ε4 allele) of the Rush Memory and Aging Project (a clinicopathologic longitudinal cohort) with completed neuropathological evaluations, dietary data, and without mild cognitive impairment or dementia at first dietary assessments. Mean diet scores were obtained from a validated food frequency questionnaire administered annually over follow‐up years (6.8 ± 3.9 years). Multiple brain regions were assessed for percent cortical area occupied by amyloid‐beta and density of cortical phosphorylated tau (p‐tau) tangles. A global AD pathology score was computed, summarizing three pathologies (neuritic and diffuse plaques and neurofibrillary tangles) based on modified Bielschowsky silver‐staining. Linear regression models adjusted for age, sex, education, APO‐ε4 status, and total calories were used. We also assessed diet interaction with age, sex, education, and APO‐ε4 status. Diet was evaluated as continuous and in tertiles.ResultHealthy diet scores were associated with lower global AD pathology (MIND:β=‐0.028,p=0.02; MedDiet:β=‐0.011,p=0.006) and less amyloid load (MIND:β=‐0.077,p=0.04; MedDiet:β=‐0.040,p=0.001). However, when stratified by APO‐ε4 status, this association was significant only in non‐carriers, and diet was also associated with lower p‐tau tangles. Overall, higher fish (p trend=0.007) and green leafy vegetable (p trend=0.014) intakes were associated with less global AD pathology. Sweets and pastries intake was related to higher amyloid load (β=0.021,p=0.009). Those in the highest tertile of legumes/beans (β=‐0.032,p=0.03), and surprisingly, butter intake had fewer p‐tau tangles (β=‐0.030,p=0.04) compared to the lowest tertile group.ConclusionBoth the MIND and Mediterranean diets are associated with less AD pathology, primarily amyloid plaques. Dietary components, including green leafy vegetables, fish, legumes, butter, and sweets, were also related to AD pathology. These relationships were more significant in those without an APOE‐ε4 allele. Further studies with larger numbers should be explored in those with and without APOE‐ ε4 genotypes.
When is a biomarker an AD biomarker? Face versus construct validity and practical implications for differential application
Authors: Schöll Michael 
Published: December 2021

AbstractBackgroundTremendous recent developments have expanded the portfolio of biomarkers that have been described as directly specific for Alzheimer’s disease (AD) pathophysiology or assessing its consequences. This presentation will aim to provide a snapshot of the current validation and readiness status of imaging‐ and bodily fluid‐based AD biomarkers for different potential application scenarios.MethodAn overview of AD biomarker characteristics will be provided, focusing on established and emerging positron emission tomography (PET) and blood‐based biomarkers for amyloid‐β (Aβ) and tau pathology as well as glial activation and synaptic and neurodegeneration. Summarizing and discussing the foregoing talks in this session as well as reviewing relevant literature, emphasis will be placed on unique validation and application aspects of the respective biomarkers and on practical considerations.ResultAD‐related pathophysiology and its consequences can be assessed in vivo directly in the brain or in bodily fluids, most recently also in blood. The underlying modalities differ greatly in how their proposed face validity is confirmed, i.e. how specific the respective biomarker is to disease‐specific processes and how sensitive to longitudinal changes and different disease stages. Specifically, PET enables the direct mapping, quantification, and staging of regional pathology and related processes in the brain, while blood‐based measures generally provide information about peripheral, yet highly associated processes. Both yield continuous measures; however, this information is often discarded in favor of dichotomous, and global, biomarker classification. Novel blood‐based biomarkers have thus been claimed to have diagnostic and prognostic properties comparable with PET modalities. PET is limited to specialized centers, is resource‐hungry and involves radiation, while blood‐based biomarkers promise a scalable and accessible alternative or complement. However, the construct validity of blood biomarkers has hitherto mainly been established against relevant PET biomarkers. Finally, the various levels of harmonization and standardization of biomarker acquisition and analysis have major implications for their potential application.ConclusionThe field of AD biomarkers is more dynamic than ever. Snapshot evaluations of their current state of validity, their potential use and their practical limitations are needed to establish their potential differential, joint, and complementary roles in AD diagnostics, population screening, clinical trial enrichment, and use as trial outcome measure.
Randomized trial of n‐3 PUFA for cerebral white matter hyperintensities, medial temporal lobe atrophy and white matter integrity in older non‐demented adults: Per‐protocol and ApoE stratified results
Authors: Bowman Gene L , Murchison Charles F , Silbert Lisa C , Dodge Hiroko H , Hagen Kirsten , Lahna David , Harris William S , Kaye Jeffrey A , Quinn Joseph F , Shinto Lynne 
Published: December 2021

AbstractBackgroundBlood levels of marine n‐3 PUFA (20:5; 22:6) are inversely associated with cerebral white matter lesion volume (WML), suggesting that n‐3 may offer one approach to reduce this major vascular contributor to cognitive impairment and dementia. This trial determined whether n‐3 slows WML progression and sustains white matter integrity over 3‐years in older non‐demented adults with suboptimum n‐3 status and WML (NCT01953705).MethodsDouble‐blind, placebo‐controlled trial in non‐demented adults age 75 and older with plasma omega‐3 (20:5 + 22:6) < 110 ug/mL and total WML ≥ 5 cm3. Participants were randomized to 1.65 g of n‐3 (975 mg‐20:5, 675 mg‐22:6) or placebo. Primary outcome was the annual WML progression with biomarker‐based ITT, per‐protocol (PP) and APOE4 stratified analysis. Total brain, medial temporal lobe, and diffusion tensor imaging (DTI) of white matter integrity were secondary outcomes. Linear mixed‐effects models were used.Result102 participants randomized (51 per group; mean age 81; 60% female, 28% APOE4+), 78 completed 3‐year visit (39 per group). Under mITT, annual WML change was 1.34 cm3 (95%CI: 0.80‐1.88) vs. 1.19 (0.64‐1.74) (p = 0.303) and annual DTI fractional anisotropy (FA) change was ‐0.002718 vs ‐0.001352 (p = 0.069) in the placebo and active, respectively. PPA comparing participants with study exit plasma omega‐3 ≤ 110 ug/mL vs above this threshold exhibited WML change of 1.71 cm3 vs. 0.99 (p = 0.026) and DTI radial diffusivity change of 5.412e06 mm2/sec vs. 3.143e06 (p = 0.047). No effects on WML were observed by APOE genotype (e4 p = 0.196; non‐carriers p = 0.785), however, e4 carriers on placebo had annual DTI FA change of ‐0.005 vs. ‐0.002 in the active arm (p = 0.037).ConclusionOmega‐3 did not slow total WML progression in all randomized participants; however, those that superseded the plasma n‐3 threshold established in preliminary studies (110 ug/mL) had 50% and 43% reduction in annual WML and annual DTI RD progression, respectively. These results highlight responders and macro‐and microscopic structural features sensitive to omega‐3 that warrant more extensive studies powered to detect cognitive effects and dementia incidence.NIH‐National Institute on Aging R01 AG043398 (GLB).
Cognition may improve with medium‐chain triglyceride oil supplementation: A pilot study
Authors: Hillebrandt Heidi L , Dias Cintia B , Barin Edward S , Chatterjee Pratishtha , Shah Tejal M , Basci Ann M , Kaplan Jason , Sohrabi Hamid R , Martins Ralph N 
Published: December 2021

AbstractBackgroundMedium‐chain triglycerides (MCT), unlike other type of fats, are quickly digested into medium‐chain fatty acids (MCFA), which are metabolized by the liver into energy in the form of ketones. Ketones are then transported to the brain for energy supply. In Alzheimer’s disease (AD), the brain becomes less efficient in glucose uptake and metabolism, resulting in an energy deficiency. The only backup source of energy for the brain is ketones. In this study we examined the potential for MCT to serve as a fuel source during energy deprivation, such as what is observed in AD.MethodHealthy males and females aged 50 to 77 years old (n=19) consumed MCT oil (40% caprylic acid, 28% capric acid, 32% lauric acid) for 7 weeks. The National Institutes of Health (NIH) Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) neuropsychological battery was administered at baseline, midway and last appointment. Participants could discontinue at any time during the intervention period.ResultDescriptive statistics determined the data were not normally distributed, therefor a non‐parametric Wilcoxon Rank Test was performed to compare cognitive performance at baseline to mid‐way, and baseline to last appointment. Baseline to mid‐way analyses showed significant (α=.05) improvement in performance for the Continual Performance Task (CPT) (p=0.012), N‐Back‐2 (p=0.049), and anti‐saccade (p=0.036). Baseline to last analyses showed significant improvement (α=.05) in performance for the CPT task (p=0.034), N‐Back‐1 (p=0.027), N‐Back‐2 (p=0.038), and saccades (p=0.036). Both the N‐back‐1 and Saccades measures for baseline to mid‐way analyses approached significance. No significant changes were observed in the remaining tasks of the NIH EXAMINER.ConclusionMCT oil may improve working memory, inhibitory processing, problem solving, and motor control in older adults with no currently diagnosed memory problems. However, a further longitudinal study with a larger sample size is required to validate these preliminary results.
Relationship between amyloid and tau levels and its impact on tau spreading
Authors: Dore Vincent , Krishnadas Natasha , Bourgeat Pierrick , Huang Kun , Li Shenpeng , Burnham Samantha C , Masters Colin L , Fripp Jurgen , Villemagne Victor L , Rowe Christopher C 
Published: December 2021

AbstractBackgroundPrevious studies have shown that Aß‐amyloid (Aß) likely promotes tau to spread beyond the medial temporal lobe. However, the Aß levels necessary for tau to spread in the neocortex is still unclear.Method466 participants underwent tau imaging with [18F]MK6420 and Aß imaging with [18F]NAV4694 (Fig. 1). Aß scans were quantified on the Centiloid (CL) scale with a cut‐off of 25CL for abnormal levels of Aß (A+). Tau scans were quantified in three regions of interest (ROI) (mesial temporal (Me); temporoparietal neocortex (Te); and rest of neocortex (R)) and four mesial temporal region (entorhinal cortex, amygdala, hippocampus and parahippocampus) using the cerebellar cortex as reference region. Regional tau thresholds were established as the 95%ile of the cognitively unimpaired A‐ subjects. The prevalence of abnormal tau levels (T+) along the Centiloid continuum was determined.ResultThe plots of prevalence of T+ (Fig. 2) show earlier and greater increase along the Centiloid continuum in the medial temporal area compared to neocortex. Prevalence of T+ was low but associated with Aß level between 10‐40 CL reaching 23% in Me, 15% in Te and 11% in R. Between 40‐70 CL, the prevalence of T+ subjects per CL increased four‐fold faster and at 70 CL was 64% in Me, 51% in Te and 37% in R. In cognitively unimpaired (Fig. 3), there were no T+ in R below 50 CL. The highest prevalence of T+ was found in the entorhinal cortex, reaching 40% at 40 CL and 80% at 60 CL.ConclusionOutside the entorhinal cortex, abnormal levels of cortical tau on PET are rarely found with Aß levels below 40 CL. Above 40 CL prevalence of T+ accelerates in all areas. Moderate Aß levels are required before neocortical tau becomes detectable.
Association between birth in the stroke belt and late‐life cognition with assessment of socioeconomic and cardiovascular risk factors: The Study of Healthy Aging in African Americans (STAR)
Authors: George Kristen M , Peterson Rachel L , Gilsanz Paola , Barnes Lisa L , Mayeda Elizabeth Rose , Glymour M Maria , Mungas Dan M , DeCarli Charles S , Whitmer Rachel A 
Published: December 2021

AbstractBackgroundThe Southeastern U.S. (“Stroke Belt”) is known for high rates of cardiovascular diseases and cognitive impairment. Due to the high proportion of Black Americans born in the Stroke Belt and their elevated risk of cognitive impairment, we examined the relationship of birth in a Stroke Belt state with late‐life cognition in The Study of Healthy Aging in African Americans (STAR).MethodSTAR evaluated cognition in African Americans (N=764) ages 50+ who were long‐term Kaiser Permanente Northern California members. Participants completed Multiphasic Health Check‐ups (1964‐1985) at which early adulthood cardiovascular risk factors (CVRF) of body mass index, blood pressure, glucose, and total cholesterol were measured. At STAR wave 1 (2018), participants self‐reported birth state (all participants resided in northern California by the 1980s), childhood and young adulthood socioeconomic status (SES), and completed cognitive assessments using the Spanish and English Neuropsychological Assessment Scales (SENAS). We used linear regression to estimate the association between Stroke Belt birth state with cognition adjusting for birth year, gender, and parental education and evaluating SES and CVRF as potential mediators.ResultAfter exclusions for missing data, 27% (n=197) of 728 participants were born in a Stroke Belt state and mean age at cognitive assessment was 69 years (SD=9). Birth in a Stroke Belt state was associated with worse late‐life executive function (β(95% CI): ‐0.18(‐0.33, ‐0.02)) and semantic memory (β(95% CI): ‐0.37(‐0.53, ‐0.21)), but not verbal episodic memory, compared to individuals born elsewhere. Having 2+ SES risk factors (β(95% CI): ‐0.77(‐0.97, ‐0.56)) or 2+ CVRF (β(95% CI): ‐0.20(‐0.37, ‐0.03)) was associated with significantly worse executive function compared to having no SES or cardiovascular risk factors, respectively. Additionally, having 2+ SES risk factors (β(95% CI): ‐0.64(‐0.85, ‐0.43)) was associated with worse semantic memory. Associations of birth in a Stroke Belt state with executive function (β(95% CI): ‐0.07(‐0.23, 0.08)) and semantic memory (β(95% CI): ‐0.30(‐0.47, ‐0.14)) were attenuated after adjusting for SES and cardiovascular risk factors simultaneously (as well as individually).ConclusionBirth in a Stroke Belt state has lasting influence on cognitive function that is only partially mediated by childhood and early adulthood SES and cardiovascular risk factors.
Semi‐quantitative [11C]PiB and [15O]H2O PET measures of cerebrospinal fluid dynamics discriminate amyloid load but not cognitive status
Authors: Minhas Davneet S , Laymon Charles M , Lopresti Brian J , Cohen Ann D , Tudorascu Dana L , Mason Neale S , Lopez Oscar L. , Villemagne Victor L , Aizenstein Howard J , Mathis Chester A , Klunk William E 
Published: December 2021

AbstractBackgroundAltered interstitial and cerebrospinal fluid (CSF) dynamics have been linked to impaired amyloid clearance in animal models of Alzheimer’s disease (AD). Recent dynamic PET studies using tau and amyloid PET tracers [18F]THK5117 and [11C]PiB have sought to quantify CSF dynamics in humans [de Leon 2017, Schubert 2019]. The aim of this work was to examine the relationships between [11C]PiB and [15O]H2O semi‐quantitative measures of CSF dynamics, efflux and influx, respectively; amyloid load; and cognitive status.MethodNineteen participants consisting of n=5 cognitively normal (CN; 71.6±8.9 years, 3 female), 9 mild cognitive impairment (MCI; 68.6±9.9 years, 2 female), and 5 Alzheimer’s disease (AD; 67.0±9.0 years, 0 female) subjects underwent [11C]PiB PET (0‐90min post‐injection, 34 frames), [15O]H2O PET (0‐3min post‐injection, 20 frames), and 1.5T T1 MR imaging. MR images were processed using FreeSurfer 7.1 (FS). Amyloid load status (PiB‐/+) was assessed using a FS Global [11C]PiB 50‐70min SUVR (cerebellar gray matter [GM] reference) and a cutoff of 1.35 SUVR. FS lateral ventricle ROIs were eroded using a 5mm kernel to minimize partial volume contamination from neighboring tissue and used to calculate three semi‐quantitative ventricular CSF outcomes: [11C]PiB ventricular SUVR50‐70 (cerebellar GM reference), [11C]PiB ventricular AUC35‐90 (cerebellar GM reference), and [15O]H2O ventricular influx ratio (IR; 1.0‐3.0min, whole brain reference). Relationships between PET outcomes were assessed using Spearman’s correlations, and group differences across cognitive and amyloid statuses were assessed using the Mann‐Whitney U test.ResultEleven subjects were classified as PiB+ (1/5 CN, 5/9 MCI, 5/5 AD). Both [11C]PiB ventricular outcomes were significantly correlated with [15O]H2O IR ([11C]PiB SUVR50‐70 p<0.001; [11C]PiB AUC35‐90 p<0.001). In this population, no significant differences were observed across any pair of diagnostic groups for any of the three ventricular outcome measures (Figure 1). However, significant differences were observed between PiB‐ and PiB+ groups across all three ventricular CSF outcomes (Figure 2; [11C]PiB SUVR50‐70 p=0.033; [11C]PiB AUC35‐90 p=0.041; [15O]H2O IR p=0.001).ConclusionThe results observed in this population suggest CSF dynamics are altered early in the AD pathophysiological spectrum and are associated with amyloid load. In addition, ventricular CSF dynamics measured using [15O]H2O IR provided greater discriminatory power than [11C]PiB CSF outcomes.
Differentiating memory clinic patients and healthy volunteers using machine‐learning analysis of speech and eye movements during a reading task
Authors: Soroski Thomas , Barral Oswald , Jang Hyeju , Newton‐Mason Sally May , Shajan Sheetal , Tutt Pavan , Granby Saffrin , Rizzo Matteo , Chui Diego , Teng Minnie Y , Chatterjee Atri , Hsiung Ging‐Yuek Robin , Nygaard Haakon B. , Conati Cristina , Carenini Giuseppe , Field Thalia S. 
Published: December 2021

AbstractBackgroundClinical trials investigating novel disease‐modifying therapies for Alzheimer’s disease (AD) are increasingly targeting participants with preclinical or early‐stage neurodegeneration. Artificial intelligence may improve ascertainment of these individuals and thus enrich clinical trial cohorts. We examined classification accuracy of machine learning analysis of speech and gaze data to distinguish memory clinic patients from controls.MethodWe recruited individuals with a clinical diagnosis of AD, mild cognitive impairment (MCI), and subjective memory complaints (SMC) from a subspecialty memory clinic, and controls from the community. Clinical diagnosis was ascertained by trained Behavioural Neurologists aided by cognitive tests and neuroimaging. Participants read a paragraph from the International Reading Speed Texts (IReST). Speech was recorded, automatically transcribed, and manually verified. Eye movements were recorded with an infrared eye‐tracker. Features extracted included lexical and acoustic parameters for speech, fixation and saccade‐related features from gaze, and novel multimodal features leveraging speech and gaze signals in combination. We explored predictive models combining using logistic regression, Gaussian Naïve Bayes classifiers, and Random Forests.ResultHere we report baseline IReST task data from 60 clinic patients (12% SMC, 30% MCI, 58% AD, mean age 73 ± 9, 52% female) and 66 controls (mean age 65 ± 9, 68% female). Best speech‐based models distinguished patients from controls with an Area Under the ROC Curve (AUC) of 0.75 (95% CI 0.72‐0.78). Best gaze models yielded an AUC of 0.73 (0.71‐0.75). Models integrating speech and gaze data yielded best results with AUC 0.78 (0.76‐0.80). We have previously reported data from a separate task where participants describe the Cookie Theft photo from the Boston Aphasia Battery while undergoing infrared eye‐tracking; the best AUC model combining speech and gaze was 0.80 (0.78 ‐ 0.92).ConclusionMachine‐learning based analysis of speech and gaze data demonstrates promising classification accuracy in distinguishing memory clinic patients from healthy controls, particularly when leveraging speech and gaze data in combination. We will explore the additional classification accuracy of combining data from multiple tasks.
Does clinical data capture modifiable midlife risk factors for Alzheimer’s disease?
Authors: Shaaban C Elizabeth , Taneja Sanya B , Witonsky Kailyn F , Malec Scott A , Karim Helmet T , Pratt Sheila , Levine Arthur S , Munro Paul , Boyce Richard D , Albert Steven M 
Published: December 2021

AbstractBackgroundThe 2020 Lancet Dementia Commission Report highlighted 5 modifiable midlife risk factors for dementia across multiple datasets: hearing loss, traumatic brain injury (TBI), hypertension, alcohol use, and obesity. We tested associations of these risk factors with Alzheimer’s disease (AD) 10 or more years later within clinical care data from a large health system.MethodWe used University of Pittsburgh Medical Center electronic health record data including diagnoses, demographics, social history, and medications from inpatient, outpatient, and emergency visits. Cases were aged 50‐75 at the time of a first ICD‐9 or 10‐based diagnosis of AD between 2016‐2020. Controls were age‐matched to cases 4:1, selected with replacement; they were free from neurodevelopmental, neurodegenerative, or demyelinating disorders, and had a visit from 2016‐2020. Cases and controls had at least one visit 10+ years prior (“early visit”). Risk factors from the early visit were defined as follows: hearing loss and TBI were based on diagnoses; obesity and hypertension were based on diagnoses or 2 measures of body mass index ≥ 30 or systolic blood pressure (BP) ≥ 140 and diastolic BP ≥ 90, respectively; alcohol use was based on diagnoses or self‐reported use ≥ 21 drinks/week. We tested associations of risk factors with AD using logistic regression models; results are presented as unadjusted odds ratios [95% confidence intervals].ResultParticipants had a mean age of 67 in 2016‐2020; N=2382 cases (56% female, 80% white, 19% Black) and N=9528 controls (58% female, 88% white, 10% Black). All midlife risk factors were associated with significantly increased odds of AD. In order of largest to smallest effect size: TBI, 4.5 [4.1, 5.0]; alcohol use, 3.5 [3.0, 4.0]; hypertension 2.6 [2.4, 2.9]. hearing loss, 1.9 [1.7, 2.1]; and obesity, 1.2 [1.1, 1.4]. Narrower definitions of alcohol use and TBI only slightly altered their respective effect sizes.ConclusionIn agreement with the Lancet Report, we find that these modifiable factors in late‐early to midlife are associated with AD. Information about these risk factors is already captured in clinical electronic health records and should be used to guide dementia risk reduction beginning early in midlife.