bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of Native American ancestry in Alzheimer’s disease and related dementias
Authors: Sariya Sanjeev , Rentería Miguel Arce , Reyes‐Dumeyer Dolly , Arango Silvia Mejia , Obregon Alejandra Michaels , Samper‐Ternent Rafael , Wong Rebeca , Mayeux Richard , Barral Sandra , Tosto Giuseppe 
Published: December 2020

AbstractBackgroundDespite several genetic variants identified by large genetic studies, late‐onset Alzheimer’s disease and related dementias (ADRD)’s missing heritability remains extensive. Aging has accelerated globally and over 70% of the elderly population reside in developing countries; by 2050 people with dementia in Latin America is projected to increase 4‐fold. Hispanics are the largest ethnic minority in the US, and have a unique genetic background characterized by admixture of various proportions of European, African, and Native‐American ancestry. Although studies have reported higher incidence and prevalence of ADRD in Hispanics, there are limited investigations on the effect of ancestry on ADRD, in particular Native‐American ancestry.MethodThe analysis sample consisted of 1,702 Mexicans from urban and rural areas, part of the national sample of the Mexican Health and Aging Study (MHAS) for whom genotyping array, sociodemographic and clinical data were available (128 cases, 524 mild cognitive impairment [MCI], 1050 controls; 57% female; age 60‐98). Estimated proportions of European, African, and Native American ancestries were employed as predictors in regression and survival models (3‐year follow‐up) to study their associations with risk of ADRD or conversion from cognitively normal to MCI or ADRD.ResultThe MHAS sample exhibited a large Native‐American component (63%) followed by European (33%) and African (4%) (N = 1,702; Figure 1, right panel). For comparison purposes, we show Mexicans from the 1000genomes project (N = 66; Figure 1, left panel) which exhibited a larger European component (48%), and lower Native‐American component (48%). Regression analyses showed Native‐American ancestry to be significantly associated with higher risk of ADRD (OR = 1.19, 95%CI: 1.12‐1.28). Native ancestry also significantly predicted conversion from cognitively intact status to MCI or ADRD (HR = 1.11, 95%CI: 1‐1.24). APOE‐e4 was not associated with ADRD (OR = 1.5, p‐value = 0.720)ConclusionThe MHAS provides a true representation of the genetic landscape of Mexico yielding a Native‐American enriched cohort, compared to small, geographically‐limited studies such as the 1000 genomes project. Native‐American ancestry increases the risk for ADRD and might explain the observed higher frequency of ADRD among Hispanic populations. Lastly, we confirmed lack of association for APOE as previously reported in smaller investigations.
Transcriptomic profiling of brain amyloidosis using peripheral blood‐based gene expression
Authors: Sanjay Apoorva Bharthur , Svaldi Diana Otero , Apostolova Liana G. 
Published: December 2020

AbstractBackgroundIn an effort towards pre‐symptomatic risk assessment, precision medicine and biomarker development in AD, we evaluated the efficacy of characterizing and clustering peripheral blood transcriptomic data with respect to brain amyloidosis.Method356 participants were identified from the ADNI cohorts who had corresponding blood gene expression, Florbetapir SUVR, neurodegeneration measures and CSF measures (Table 1) (CN=120, EMCI=130, LMCI=72 and AD=34). Differentially expressed genes between diagnostic groups from ∼50,000 transcripts(p<0.001) were identified. Pairwise Euclidean distance between genes was used to construct a gene‐gene distance matrix followed by K‐means clustering to identify clusters of genes which shared similar transcriptomic profile (Figure 1). Gene enrichment analysis was performed to identify the most relevant biological process associated with each cluster. Principal component analysis was done to assign the weight of first principal component as the “eigen” gene; a data vector representing the whole cluster. The eigen genes were used to assess the association of the clusters with amyloid SUVR, hippocampal volume, entorhinal thickness, CSF Abeta and p‐tau measures. We defined driver genes, within each cluster, as transcripts whose correlation exceeded the eigen gene’s association with amyloidosis. Finally, classification algorithms (logistic‐regression and SVM) using the driver genes identified from ADNI were used to assess the diagnostic prediction (control vs amnestic MCI) in an external (ImaGene) dataset.ResultWe identified five clusters with overrepresentation of biological processes highly relevant to AD pathogenesis ‐ mitochondrial function, protein oligomerization, TGF beta signaling, protein autophosphorylation and MAPK activation. All five clusters were significantly associated with Florbetapir SUVR and CSF Abeta measures (p<0.05) (Figure 2). Many of the driver‐genes showed similar correlation with amyloid SUVR in ImaGene (Table 2). The SVM and logistic‐regression classifiers achieved an AUC of 0.81 and 0.82 respectively in predicting amnestic MCI from driver‐gene data in ImaGene (Figure 3).ConclusionWe identified five AD‐relevant clusters of transcripts from peripheral blood and validated this association in an independent dataset. Systems level genetic signatures from blood can serve as a highly important risk analysis and screening tool for amyloidosis.
Dietary intake of the bioactive pelargonidin may slow decline in multiple cognitive abilities
Authors: Holland Thomas Monroe , Agarwal Puja , Wang Yamin , Desai Pankaja , Dhana Klodian , Barnes Lisa L , Bennett David A , Booth Sarah , Morris Martha Clare 
Published: December 2020

AbstractBackgroundResearch has demonstrated a positive relationship between cognitive abilities and dietary intake of flavonoids, bioactives found in foods that have known antioxidant and anti‐inflammatory characteristics. We advance past research by investigating the association of dietary intake of an anthocyanidin subclass constituent, pelargonidin, found in berries especially, strawberries, on change in global cognition, episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability.MethodsThis study was conducted in 961 Rush Memory and Aging Project (MAP), a prospective cohort study, consisting community‐dwelling participants in Chicago (aged 58 to 100 years), who were followed for an average of 6.3 (±2.7) years. MAP participants were asked to complete a validated semi‐quantitative food frequency questionnaire at baseline. Cognitive abilities were assessed annually using a battery of 19 standardized tests. Cognitive domain scores were regressed on baseline energy‐adjusted flavonoid pelargonidin, which was distributed into quartiles based on dietary intake in linear mixed models.ResultsOur analytical sample of 961 participants had an average age of 81.4 (±7.2) years, and 15 (±3) years of education, 74% were female, 22% had at least one APOE‐ɛ4 allele, and 42% had a smoking history. Higher intake of pelargonidin, intake was inversely associated with decline in global cognition and multiple cognitive domains. In models adjusted for age, sex, education, APOE‐ɛ4, late life cognitive activity, smoking and physical activity, dietary intake of the highest quartile versus lowest quartile of pelargonidin was associated with slower decline in global cognition (β estimate=0.02, p=0.03; p‐trend=0.02), episodic memory (β=0.03, p=0.045; p‐trend=0.03), semantic memory (β=0.03, p=0.02; p‐trend=0.02), perceptual speed (β=0.02, p=0.02; p‐trend=0.01) and visuospatial ability (β=0.03, p=0.02; p‐trend=0.050). Non‐significant working memory was suggestive (β=0.02, p=0.07; p‐trend=0.07).ConclusionDietary intake of the anthocyanidin subclass constituent, pelargonidin, may slow decline of cognitive abilities in multiple domains with older age.
Neuropsychological test performance among Hispanic and white older adults
Authors: Guerrero‐Berroa Elizabeth , Kluger Alan , Schmeidler James , Sailor Kevin , Lizardi Humberto , Phillips Ruby , Golomb James , Reisberg Barry 
Published: December 2020

AbstractBackgroundNeuropsychological tests are useful in the assessment of cognitive functioning, but whites have consistently performed better than other racial/ethnic groups. The utility of some of these tests has not been fully established for Hispanic elderly, and especially among relatively highly educated Spanish‐speaking Hispanics.MethodSeventy‐five pairs of Spanish‐speaking Hispanics and whites with normal to moderately impaired cognitive functioning (Global Deterioration Scale [GDS] were matched on sex, GDS rating, and clinical diagnosis; and strongly overlapped on age (Mean±SD, Spanish‐speaking Hispanics = 67.7±10.1, whites = 68.2±10.4) and years of education (Mean ±SD, Spanish‐Speaking Hispanics = 12.4±3.8, whites = 13.3±3.5) in a cross‐sectional study. Repeated measures analyses of covariance (ANCOVA) compared performance on seven neuropsychological tests in the two ethnic groups. Additional analyses compared English‐speaking Hispanics to whites (GDS 4).ResultSpanish‐speaking Hispanics performed more poorly than whites on the WAIS‐Digit Symbol Substitution subtest (p< .001), a task of executive function and psychomotor speed. This result was significant after adjustment for multiple comparisons (seven neuropsychological tests).Two other tests showed significantly poorer performance (p< .05) in the Hispanics, delayed recall of the NYU‐Guild Paragraph Test (p= .029) and delayed recall of the Guild Paired Associates subtest (p= .010). For all seven neuropsychological tests,nondemented (GDS 3) Spanish‐speaking Hispanics tended to have lower scores than matched whites. In contrast, Spanish‐speaking Hispanics with dementia (GDS ≥ 4) showed relatively similar (and sometimes better) performance than their white counterparts on some of the tasks. There were no significant differences in performance among English‐speaking Hispanics and matched whites on any neuropsychological tests.ConclusionCareful interpretation of test scores on tasks of executive function/psychomotor speed should be considered for Spanish‐speaking Hispanics without AD. These results extend others’ findings by demonstrating that executive function/psychomotor speed is compromised even among relatively highly educated Spanish‐speaking Hispanics compared to whites. These findings highlight the potential influence of acculturation on these tasks and the importance of using appropriate group norms. Future studies should be aimed at examining the longitudinal associations of neuropsychological test scores with cognitive decline in cognitively normal Spanish‐speaking Hispanics.
[18F]Flortaucipir PET to autopsy pathology comparisons in Alzheimer’s disease and other neurodegenerative diseases
Authors: Soleimani‐Meigooni David N. , Iaccarino Leonardo , La Joie Renaud , Baker Suzanne L. , Bourakova Viktoriya , Boxer Adam L. , Edwards Lauren , Eser Rana A. , Tempini Maria Luisa Gorno , Jagust William J. , Janabi Mustafa , kramer Joel H. , Lesman‐Segev Orit H. , Mellinger Taylor J. , Miller Bruce L. , Pham Julie Q. , Rosen Howard J. , Spina Salvatore , Seeley William W. , Strom Amelia , Grinberg Lea Tenenholz , Rabinovici Gil D. 
Published: December 2020

AbstractBackgroundFew studies have evaluated the relationship between in vivo [18F]Flortaucipir (FTP) PET and post‐mortem pathology.MethodWe sought to compare antemortem FTP‐PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative diseases. 80‐100 min FTP‐PET standardized uptake value ratio (SUVR) images were created using an inferior cerebellar gray matter reference. W‐score maps were generated to highlight areas of increased tracer retention compared to cognitively normal controls, adjusting for age as a covariate. Autopsies were performed blinded to PET results. Mean SUVRs were calculated for Braak stage regions of interest (ROIs), and these values were compared to SUVRs derived from young, non‐autopsy, cognitively normal controls used as a standard for tau negativity.ResultNineteen patients were included (mean age at PET 61 [range 34‐76]; 8 female; mean PET‐to‐autopsy time of 30 months [range 4‐59 months]; Table 1). Eight patients had primary Alzheimer’s disease (AD) pathology, 9 had non‐AD tauopathies (progressive supranuclear palsy [PSP], corticobasal degeneration [CBD], argyrophilic grain disease [AGD], and frontotemporal lobar degeneration [FTLD] with tau inclusions), 2 patients had non‐tau related FTLD. There was excellent correspondence between areas of FTP retention and neurofibrillary tangle (NFT) distribution in patients with primary AD neuropathology. Patients with non‐AD tauopathies showed a range of tracer retention that was less than AD and more than age‐matched, cognitively normal controls, with CBD and FTLD due to MAPT mutations showing the most extensive and distinct binding patterns (Figure 1). Patients with non‐tau related FTLD also showed small areas of tracer retention (Figure 1). Overall, binding across both tau‐positive and tau‐negative non‐AD disorders did not reliably correspond with post‐mortem tau pathology. Quantification of FTP‐PET SUVR images at Braak stage ROIs reliably detected high Alzheimer’s Disease Neuropathologic Change (Braak VI) pathology. However, patients with earlier Braak stages did not show elevated tracer uptake in these regions compared to young, tau‐negative controls (Figure 2).ConclusionIn summary, PET‐to‐autopsy correlations confirm that FTP‐PET is a reliable biomarker of advanced tau pathology in AD. The tracer cannot reliably differentiate non‐AD tauopathies and may not detect early Braak stages of NFT pathology.
What’s the cut‐point? A systematic review of tau pet thresholding methods
Authors: Weigand Alexandra J. , Eglit Graham M.L. , Maass Anne , Bondi Mark W. 
Published: December 2020

AbstractBackgroundWith increasing use of Alzheimer’s disease (AD) biomarker staging schemes, derivation of thresholds to determine biomarker positivity is becoming a critical methodological step. Recent advances in tau PET have made this modality a primary method for in vivo assessment of tau pathology. Given the heterogeneity in methodological decisions around tau PET positivity thresholding across studies, we conducted a systematic review of articles deriving tau PET thresholds to chronicle and compare these methods.MethodStudies were excluded if they used animal models, included non‐AD and related dementias patients (e.g., Parkinson’s disease), used cerebrospinal fluid data, used a tracer other than flortaucipir, or included tau PET as a continuous variable only. Search terms included “tau PET positivity,” “tau PET threshold,” “tau PET cutoff,” and “tau PET cutpoint,” with these searches then repeated after replacing “tau PET” with “flortaucipir.” Of the 405 studies reviewed, a total of 19 studies were identified that matched inclusion criteria for the review.ResultOf the 19 studies identified, 7 thresholded tau positivity in a manner conditional on amyloid positivity (e.g., maximally discriminating amyloid‐negative and amyloid‐positive), leading to SUVR cut‐points ranging from 1.19 to 1.33. The other most used method involved thresholding at 2‐2.5 SDs above the SUVR for young (n = 6) or old (n = 1) controls (cut‐points from 1.17 to 1.36). Other approaches included using conditional inference regression discriminating clinical diagnoses or global cognition (n = 4; cut‐points from 1.13 to 1.40) and clustering into high and low tau (n = 1; cut‐point = 1.25). Regions used differed greatly between studies, ranging from individual cortical regions (n = 5) to a temporal meta‐ROI (n = 10) to PET‐recapitulated Braak stages (n = 4).ConclusionThere exists significant variability in tau PET cut‐points derived even within a particular thresholding method, which may be attributable to differences in sample composition, preprocessing methods (e.g., normalization, partial‐volume correction), or regions selected. Notably, although a large proportion of studies thresholded tau conditionally upon amyloid status, this may lead to bias in the estimated proportion of AT(N) groups. Consensus in thresholding methods, and particularly those that threshold tau and amyloid independently of the other, are needed given the increasing use of biomarker cut‐points within AD diagnostic frameworks.
Association of brain copper with cognitive decline in a community‐based neuropathologic study
Authors: Agarwal Puja , Dhana Klodian , Schneider Julie A. , Ayton Scott , Wang Yamin , Agrawal Sonal , Bennett David A. , Barnes Lisa L. , Leurgans Sue E. , Bush Ashley I. , Morris Martha Clare 
Published: December 2020

AbstractBackgroundCopper (Cu) is an essential metal for brain health. Limited studies reported no association of plasma Cu and inverse association of Cu in human hair with cognitive abilities in older adults. However, no study investigated the association of Cu levels in the human brain with the long‐term change in cognitive functioning before death. Thus, we aim to examine the association of brain Cu with cognitive decline in a community‐based cohort study.MethodUsing data from 625 deceased participants from the Rush Memory and Aging Project. Brain copper levels were measured using ICP‐MS in gray matter from inferior temporal, mid frontal, anterior cingulate, and cerebellum. Composite global cognition and specific domains were derived from z‐scores of a 19‐panel cognitive tests that were performed annually for up to 14 years proximate to death. We used linear mixed‐effects models to examine associations of Cu (grouped in tertiles) in the brain with cognitive decline. All the models were controlled for age at death, sex, education, late‐life cognitive activity, physical activity, smoking, and APOE‐ɛ4 status.ResultThe mean age at first cognitive assessment was 82.7 (±5.8) years, 71% were women, and 25% carried an APOE‐ɛ4 allele. Participants in the highest and the middle tertile of Brain Cu in the inferior temporal region had a slower annual rate of cognitive decline (T3 vs. T1:β= 0.027; T2 vs. T1: β= 0.032; p for trend= 0.007). Similar associations were found for specific domains, including episodic memory (T3 vs. T1: β= 0.027; T2 vs. T1: β= 0.033; p for trend= 0.03), semantic memory ((T3 vs. T1:β= 0.040; T2 vs. T1: β= 0.050; p for trend= 0.001) and perceptual speed (T3 vs. T1:β= 0.024; T2 vs. T1: β= 0.035; p for trend= 0.03). Concentrations of Cu in the other brain regions were not associated with cognitive decline.ConclusionThe association of higher brain copper levels in the vulnerable region of Alzheimer’s disease, such as the inferior temporal region with slower cognitive decline, supports the role of copper dyshomeostasis in the disease process.
Precision Functional Assessment for Alzheimer’s disease (PFA‐AD): A pilot study framework
Authors: Lopez Claudia M. , Hernandez Gerson D. , Wang Yiwei , Wershiner Dana , Gisler Trang , Seyfert‐Margolis Vicki , Brinton Roberta Diaz 
Published: December 2020

AbstractBackgroundCurrent clinical trial assessments of cognitive function and activities of daily living are based on periodic assessments conducted under controlled clinical conditions using standardized measures. This approach is highly correlated with diagnosis of Alzheimer’s disease (AD) but has varied relevance to the real‐life challenges of those living with the disease and their caregivers. The use of digital technologies in clinical trials is actively encouraged. The opportunity to embed these tools in clinical trials in parallel with traditional measures is needed to move the field forward. This pilot study provides a framework to build on this approach and expand its use in research and patient care management. PFA‐AD will enable: 1) identification of key behavioral challenges that are relevant to the person with AD and their caregivers; 2) assessment of therapeutic effect in real time across multiple domains of behavioral function; and 3) innovate clinical trial measures of daily activities that are personalized and relevant to the patient and caregiver.MethodPFA‐AD proof‐of‐concept development was embedded as part of a clinical trial (Clinicaltrials.gov: NCT03748303) to further develop allopregnanolone, a first‐in‐class regenerative therapeutic for AD. This study is enrolling 12 persons with AD to assess the intramuscular formulation of allopregnanolone. Participants are being asked to download the “Allo IM app” and interact with it daily during 12‐weeks. The platform/app created by MyOwnMed,Inc supports simple digital measures of lifestyle and daily function defined by the team interacting with patients. Content is personalized for each patient/caregiver based on their input. Wearable technologies have been integrated to capture physical activity and sleep, using available interfaces that will be seamlessly integrate into the app.ResultAnalysis of PFA‐AD data will include: 1) App usability; 2) Fidelity of personalized measures; 3) Correlation of personalized measures with standardized assessments; 4) Feasibility for inclusion in clinical trials.ConclusionAD is personal and assessment of functional capacity can be too. The PFA‐AD application brings the power of precision analytics to those living with AD and their caregivers. Outcomes of this research will advance the development of a technology‐based tool to enable assessments of real‐life function that really matters, in real‐time.
Reported chronic high glycemic diet intake predicts amyloid deposition in the precuneus of cognitively normal older adults over one year
Authors: Taylor Matthew K , Sullivan Debra K , Vidoni Eric D , Burns Jeffrey M 
Published: December 2020

AbstractBackgroundWe previously reported that high glycemic diet (HGD) was related to cerebral amyloid deposits, a pathologic hallmark of Alzheimer’s disease (AD), in multiple highly metabolic regions of interest (ROI). The purpose of this study was to test high glycemic diet’s relationship with longitudinal change in cerebral amyloid deposition in older adults.MethodsThis longitudinal study included 106 cognitively normal older adults with elevated (n=72) and non‐elevated (n=34) amyloid participating in a one‐year exercise intervention trial. Habitual dietary intake was collected at baseline using the National Cancer Institute’s Diet History Questionnaire (DHQ II) and intake was quantified using Diet*Calc software. We derived a HGD pattern using principal covariates regression (PCovR). Amyloid PET (Florbetapir F18) scans were obtained on a GE Discovery ST‐16PET/CT scanner at baseline and 52‐weeks. MIMNuero software was used to standardize the PET images to the whole cerebellum and calculate tracer standard uptake value ratios (SUVR) in 6 ROIs. One‐year regional SUVR delta scores were calculated. We constructed ordinary least squares regression models to assess HGD’s relationship with continuous regional delta SUVR scores controlling for age, sex, and intervention group assignment. Statistical analyses were performed using R (v. 3.6.2; R Foundation, Vienna, Austria). Statistical significance was set at p < 0.05.ResultsThe participants were 68% female with a mean age of 71.1 ± 5.2 years. In the precuneus, higher intake of the derived HGD pattern (β=0.23, p=0.02), sugar (β=0.24, p=0.01), and total carbohydrate (β=0.22, p=0.03) correlated with more amyloid accumulation. Higher reported intake of carbohydrate as a percentage of total energy was related to more amyloid accumulation in the inferior medial frontal gyrus (β=0.20, p=0.04), posterior cingulate gyrus (β=0.20, p=0.04), precuneus (β=0.21, p=0.04), and superior parietal lobule (β=0.21, p=0.03).ConclusionThe results of this study corroborate our previous findings and suggest a physiological role for HGD in amyloid pathology prior to onset of AD‐related symptoms.