bluuebunny/crossref_metadata_2025_split huggingface dataset:
White matter diffusion abnormalities observed in cognitively normal elderly before conversion to mild cognitive impairment
Authors: Zhang Linda , Medina Miguel , Strange Bryan A 
Published: December 2021

AbstractBackgroundDifferences in white matter (WM) microstructure, as measured with diffusion tensor imaging (DTI), have been observed between cognitively normal, mild cognitively impaired (MCI), and Alzheimer’s disease (AD) patient groups. With increased focus on early intervention for AD, detection of preclinical changes is paramount; however, due to difficulties in predicting future conversion, few studies have investigated WM deterioration prior to symptom onset. Using DTI data from the Vallecas project (an 8‐year longitudinal study of healthy elderly individuals), we determine if WM changes can be found in cognitively normal individuals before conversion to MCI.MethodsFrom a baseline cohort of 824 cognitively normal 70‐85 year olds, 65 individuals converted to MCI over the study duration (mean age 77.0±4.29 years, 58% female). 65 non‐converters were matched by age, sex, and years of education to act as controls. DTI scans from one year before conversion were analysed using tract‐based spatial statistics implemented in FSL. Fractional anisotropy (FA), mean diffusivity (MD), and mode of anisotropy (MO) were compared between groups using non‐parametric permutation tests. A second comparison between future converters and all 759 non‐converters (mean age 74.0±3.92 years, 65% female) was also conducted, using age, sex, and years of education as covariates.ResultsIn the unmatched comparisons, controls had higher FA in the left forceps minor (ForMin) and anterior corona radiata (CR) (p<0.05), and higher MO along the corpus callosum (CC) and ForMin (p<0.01). Future converters had higher FA in the left posterior CR and corticospinal tract (p<0.05), higher MD in the left anterior CR (p<0.05), and higher MO along the bilateral projection fibres (p<0.01). In the matched comparison, only MO differences were observed, with higher MO in controls along the body of the CC (p<0.05), and higher MO in future converters in the left projection fibres and the splenium of the CC (p<0.01). All significant results were FWE‐corrected.ConclusionsOur results suggest that frontal commissural fibres begin to deteriorate in cognitively normal subjects destined to convert to MCI, whilst also demonstrating selective preservation of projection fibres. We also find that MO is a sensitive measure of white matter microstructural changes presaging cognitive decline, even in preclinical populations.
Comparison of remote and in‐person digital speech‐based measures of cognition
Authors: Stegmann Gabriela M , Hahn Shira , Liss Julie , Berisha Visar , Mueller Kimberly D 
Published: December 2021

AbstractBackgroundNeuropsychological testing requires an in‐person visit with a trained administrator using standard/fixed materials. Speech‐based cognitive testing on mobile devices enables more frequent and timely test administration, but head‐to‐head comparisons of in‐person and remote versions of tests are rare. We compare responses to a well‐validated task conducted under supervised (in‐person) and unsupervised (remote) conditions.MethodWe used two data sets containing Cookie Theft picture descriptions (BDAE), one collected in‐person, under supervision (Wisconsin Registry for Alzheimer’s Prevention (WRAP); N = 912; age = 62.2 (SD = 6.7), 70% F) and one collected remotely, without supervision (participants online; N = 93, age = 36.5 (SD = 11.5), 65% F). WRAP participants were judged to be cognitively normal, and online participants self‐reported as healthy. Each participant provided one picture description, yielding 93 remote and 912 in‐person transcribed descriptions. Language metrics previously used in dementia research were extracted: word count (number of words spoken), MATTR (ratio of unique words to total number of words), pronoun‐to‐noun ratio, and semantic relevance. Comparing MATTR, pronoun‐to‐noun ratio, and semantic relevance values elicited in‐person and remotely is important because these characteristics have been found to be impacted by declines in cognition. Differences in word counts may reflect different levels of motivation in the two settings.ResultUsing Cohen’s d effect sizes, differences in mean word count between in‐person and remote participant transcripts was negligible (112 words in‐person and 118 words remote; d = .10, p = .21), the difference for semantic relevance was negligible (.19 in‐person and .18 remote, scale = 0 to 1; d = .14, p = .19), the difference for MATTR was small (.75 in‐person and .74 remote, scale = 0 to 1; d = .37, p<.05), and the difference for pronoun‐to‐noun ratio was moderate (.48 in‐person and .35 remote, scale = 0 to 1; d = .56, p <.05).ConclusionResults show that response length and semantic relevance of responses to the Cookie Theft picture description task are comparable under supervised, in‐person and unsupervised, remote conditions. Small to moderate differences in vocabulary (MATTR) and pronoun‐to‐noun ratio may be due to differences in age and merit further investigation.
Cognitive assessments in ADNI: Lessons learned from the ADNI psychometrics project
Authors: Crane Paul K. , Choi Seo‐Eun , Gibbons Laura E. , Mukherjee Shubhabrata , Zhu Ryoui , Scollard Phoebe , Lee Michael L. , Trittschuh Emily H. , Saykin Andrew J. , Mez Jesse , Mungas Dan M. , Wang Chun ,   ADNI Psychometrics Investigators
Published: December 2021

AbstractBackgroundThe Alzheimer’s Disease Neuroimaging Initiative includes cognitive assessments at every study visit. We have had the opportunity to use modern psychometric approaches including confirmatory factor analysis (CFA) and item response theory (IRT) with these rich data. Here we discuss lessons learned from analyses of memory, executive functioning, language, and visuospatial functioning in ADNI.MethodWe analyzed data from all ADNI study waves. We considered granular data for each test. Our panel of experts considered each granular data element and assigned them to a single primary domain – memory, executive functioning, language, or visuospatial functioning – or to none of these. We then used CFA and IRT approaches to calibrate each domain separately. ADNI has extensive imaging and fluid biomarker data we used for validity assessments.ResultThe ADNI cognitive battery emphasizes memory assessment with multiple indicators. The assessment of language and executive functioning are less robust but are each measured with several indicators. The assessment of visuospatial functioning is much sparser. Assessment intensity is nicely reflected in measurement precision data, where standard errors of measurement are smallest for memory, intermediate for language and executive functioning, and largest for visuospatial functioning. Validity assessments were solid for all four domains. We have uploaded resulting composite scores (ADNI‐Mem, ADNI‐EF, ADNI‐Lan, and ADNI‐VS) to the Laboratory On Neuroimaging (LONI)‐hosted ADNI website.ConclusionThe composite scores we have developed will be useful for investigators integrating domain‐specific cognitive data in their analyses of ADNI data. The measurement precision findings have implications for future study design; for example, more robust measurement of visuospatial functioning may be a wise investment. Measurement precision findings also have implications for analytic strategies. Standard typical analyses ignore measurement precision and treat observed scores as if they were measured without error. We are developing hierarchical Bayesian modeling strategies that can incorporate both point estimates for domain scores along with standard errors of measurement. These models will account for measurement error, ensuring that inferences are valid across domains with very different measurement properties. We will make this code widely available as well.
A novel gut microbiome therapeutic derived from dietary polyphenols attenuates neuroinflammation in vivo in a model of C9orf72‐mediated frontotemporal dementia
Authors: Wu Henry , Smith Chad , Estill Molly , Sebastian Maria , Pasinetti Giulio Maria 
Published: December 2021

AbstractBackgroundFrontotemporal dementia (FTD) is a neurodegenerative disorder with various genetic etiologies, the most prevalent of which include G4C2 expansions in the c9orf72 gene. Expansions produce dipeptide repeat proteins (DPR), forming aggregates with deleterious impacts on cellular processes and correlating with neuroinflammation. Glycine‐Arginine (GR) aggregates are the only significantly correlated DPR found in clinically relevant neuroanatomical regions of the brain. Our current study investigates the contribution of innate immunity to FTD pathogenesis and the attenuation of neuropathologies with the brain bioavailable microbiome‐derived metabolite, 3‐hydroxybenzoic acid (3‐HBA).MethodMice were transfected via intracerebroventricular injection with AAV9‐GFP(GR)100 or AAV9‐GFP and treated starting on Day 28 with either PBS vehicle or 50 mg kg‐1 of 3‐HBA. At 14 weeks mice were sacrificed and prefrontal cortex (PFC), somatosensory cortex (CTX), and hippocampal (HIPP) tissue was dissected and prepared for RNA sequencing. Differentially expressed genes (DEGs) were identified using DESeq2 and pathway alterations were detected using Ingenuity Pathway Analysis. ELISA for IL‐1β was conducted on PFC, CTX, and HIPP tissue. To determine the ability of 3‐HBA to reduce secretion of IL‐1β, primary microglia pretreated with 3‐HBA were stimulated with LPS+ATP and IL‐1β concentration was analyzed by ELISA.ResultDEGs associated with FTD pathology, protein expression levels of the pro‐inflammatory cytokine IL‐1β, and subsequent amelioration via treatment with 3‐HBA were demonstrated to be a result of contributions from the innate immune system and inflammasome activation in microglia. Inflammatory pathways differentially enriched among treatment groups include TREM1 Signaling, the complement system, and NFκB signaling. GR‐100 Vehicle treated animals exhibited elevated IL‐β in cortical tissue. 3‐HBA was efficacious in vivo in rescuing IL‐1β levels in GR‐100 treated mice to levels of GFP animals. Primary microglia pretreated with 3‐HBA and stimulated with LPS+ATP significantly reduced IL‐1β release, signifying the efficacy of 3‐HBA in attenuating innate immune reactivity.ConclusionPathways and genes associated with the innate immune system show enrichment in a model of FTD and are rescued by administration of 3‐HBA. Overexpression of IL‐1β in the cortex of GR‐100 Vehicle animals is attenuated by the administration of 3‐HBA. Our data implicates a gut‐brain axis mechanism of treatment for key FTD associated neuropathologies.
Functional connectivity is altered by APOE4 carrier status in cognitively healthy older adults
Authors: Green Zachary D. , Honea Robyn A , Vidoni Eric D , Burns Jeffrey M. , Morris Jill K 
Published: December 2021

AbstractBackgroundResting‐state connectivity allows for investigating brain network changes in pathologic states of aging, such as Alzheimer’s Disease (AD). Recently, brain network changes have been associated with AD‐related risk factors in asymptomatic individuals. We explored how brain network connectivity is affected by one such risk factor, apolipoprotein e4 (APOE4) carrier status.MethodsIn a sample of cognitively healthy older adults (n=102), we acquired demographic information, APOE4 carrier status, and resting‐state fMRI scans. Individuals were designated as “APOE4 carrier” by the presence of at least one APOE4 allele. No APOE2 carriers were included in the analyses. Using independent component analysis approaches for both individual de‐noising and group‐level analysis, we identified key brain networks traditionally associated with AD‐related decline. Utilizing nonparametric permutation inference, we tested for differences in connectivity to these networks based on APOE4 carrier status.ResultsWe identified multiple networks with altered functional connectivity across groups, including networks associated with AD‐related decline. One key region, the anterior cingulate cortex, showed differences in connectivity with multiple resting state networks. Functional connectivity in these networks was decreased in APOE4 carriers compared to non‐carriers.ConclusionWe highlight changes in functional connectivity dependent upon genetic risk. Our results add to a growing body of evidence that APOE4 carrier status, along with other risk factors for AD, alter large‐scale functional networks. Additional characterization of the interaction of APOE4 status and other AD‐related biomarkers on functional connectivity is warranted.
Biomarker‐based polygenic risk scores for profiling genetic susceptibility in Alzheimer's disease
Authors: Chasioti Danai , Jacobson Tanner Y. , Nho Kwangsik , Risacher Shannon L. , Gao Sujuan , Yan Jingwen , Saykin Andrew J. 
Published: December 2021

AbstractBackgroundPrecision medicine is designed to resolve heterogeneity in complex diseases such as Alzheimer’s (AD) to deliver timely and tailored treatment. Using ADNI data, we developed endophenotype‐specific polygenic risk scores (PRS) to assess the AD risk and to identify distinct genetic risk profiles among the converters.MethodWe used ADNI genetic, clinical and biomarker data for PRS development. We derived four ADRD endophenotype components including Amyloid (A), Tau (T), Neurodegeneration (N) and Vascular (V), by applying PCA on 11 phenotypic variables. Four individual biomarker PRSs (A, T, N, V) were obtained and combined into a single PRS (PRSATNV). Penalized regression (Lasso) applied for SNP selection and weight re‐estimation. Bootstrapping was used to minimize possible overfitting. On the ADNI test set, after removing participants with mild cognitive impairment (MCI), we estimated the odds and hazard of AD among the extreme PRSATNV quartiles (Q1,Q4). To identify biomarker‐specific genetic risk profiles among LMCI/AD participants, we performed K‐means clustering using the 4 biomarker PRSs (PRSA, PRST, PRSN, PRSV). Clustering was done based on APOE groups.ResultThe odds for AD individuals in the Q4 of PRSATNV was double those in Q1 (p=2.2e‐06, AUC=80%). On the same participants, we obtained a significant difference of 5 years in the AD onset between Q1 and Q4 (HR=2.2, p=6.9e‐03). Clustering restricted to LMCI/AD yielded 2 PRS clusters for ε3/ ε3 and ε3/ ε4 and 3 for ε4/ ε4 (Figure 1). In general, genetic risk profiles differed among the clusters for all APOE groups (PRSATNV in Table 1). The main difference was amyloid‐related for ε3/ ε3 carriers, neurodegeneration‐related for ε3/ ε4 and tau‐related for ε4/ ε4 (Table 1).ConclusionThe combined biomarker PRS we developed successfully identified individuals in high risk for AD. Using clusters derived from endophenotype‐specific genetic information we were able to identify distinct biomarker‐related genetic profiles among converters. Endophenotype‐based PRS may be useful for risk stratification and development of genetically tailored therapeutics as different mechanisms may contribute to AD onset for a given individual. Validation in independent samples is a critical next step.
Effect of temporal meta‐ROI and Braak1&2 ROI on the dissociation between plasma pTau181 and PET statuses
Authors: Tissot Cécile , Kunach Peter , Therriault Joseph , Lussier Firoza Z , Benedet Andréa Lessa , Chamoun Mira , Pascoal Tharick A. , Servaes Stijn , Bezgin Gleb , Arias Jaime Fernandez , Wang Yi‐Ting , Stevenson Jenna , Rahmouni Nesrine , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2021

AbstractBackgroundTau is usually assessed through cerebrospinal fluid or Positron Emission Tomography (PET). However, those methods are expensive and not readily available. Research is now focusing on cost‐effective blood‐based biomarkers to assess Alzheimer’s disease (AD) pathophysiologies. A novel immunoassay for plasma pTau181 has been created, and even though there are strong associations between plasma pTau181 and PET, no study has yet investigated which cortical area better reflects plasma tau.MethodWe assessed 269 individuals from the TRIAD cohort (164 CU, 60 MCI and 45 AD) that underwent plasma pTau181 assessment, [18F]MK6240 tau‐PET scan, [18F]AZD4694 amyloid‐PET scan to assess their amyloid‐b (Ab) status, an MRI and a neuropsychological evaluation. We conducted statistical analyses using R, first to calculate the threshold values for positivity in both tau assessing methods and to make comparisons between the groups. SUVR values for [18F]MK6240 were either based on Braak1 SUVR or temporal meta‐ROI SUVR.ResultUsing Receiver Operating Characteristic (ROC) curves, we established that the cut‐off for positivity for plasma pTau181 was 11.1060 pg/mL. When using Braak1 mask, the cut‐off for positivity was 1.040 SUVR (B1+/‐), while with temporal meta‐ROI it was 1.1827 (TMR+/‐). In both cases, we observed a majority of concordant individuals. However, we obtained 87 discordant individuals in the plasma/TMR, mostly plasma+/TMR‐, and 78 in the plasma/B1 analyses, mostly plasma‐/B1+ (Figure 1). Concomitant status of plasma/TMR was usually accompanied by a similar Ab status. However, in the Braak1 analyses, Ab status seemed to closely follow the PET status (Figure 2).ConclusionThe cut‐off values for positivity using Braak1 mask is significantly smaller than when using temporal meta‐ROI. Using the temporal meta‐ROI mask, we had more discrepant individuals that were plasma+/TMR‐, with plasma‐/TMR+ individuals close to the threshold values. It was accurate at predicting negative biomarker statuses in CU participants, and positive in AD participants. Conversely, we had more plasma‐/B1+ individuals when using Braak1 mask, with values more spread around the plot. Due to low threshold values, portion of CU and MCI individuals were categorized as positive to both biomarkers. Finally, B1 status seemed to follow closely the Ab levels. Plasma pTau181 thus seems to reflect better temporal meta‐ROI tau.
Factors associated with early and late onset Alzheimer disease in Down syndrome
Authors: Lai Florence , Wang Cassandra , Mercaldo Nathaniel , Rosas H Diana 
Published: December 2021

AbstractBackgroundAlzheimer disease (AD) onset in adults with Down syndrome (DS) typically occurs in the early 50s; however, the wide range from 40 to 70 years of age is poorly understood. Adults with DS commonly have co‐existing medical conditions which could influence age of onset and shed light on both risk and mitigation of AD in DS.MethodA 12‐year retrospective chart review was conducted on 350 adults with DS, of whom 219 had AD, with mean onset age of 52.51 years and one standard deviation (SD) of 6.07. This AD cohort was divided into three age‐of‐onset groups: Typical Onset (TO) within 1 SD of the mean, Early Onset (EO) with >1 SD below the mean, and Late Onset (LO) with >1 SD above the mean. We analyzed factors hypothesized to influence dementia: sex, level of intellectual disability (LID), Apolipoprotein E (APOE) status, obstructive sleep apnea (OSA), and presence and onset age of hypothyroidism, seizures, and menopause. Analysis of variance or the chi‐square test of independence was used to assess differences amongst the three groups for continuous and categorical variables, respectively.ResultsAs we hypothesized, medical co‐morbidities influence AD onset age in DS. Significant differences across the groups, particularly in the EO‐AD group included: greater percentage with OSA (p=0.015); younger age of hypothyroidism onset (p<0.001); greater percentage with seizures (p=0.018); and seizure onset age (p=0.001). We were unable to detect differences with respect to sex, menopause age, presence of APOE E4 or baseline LID.ConclusionsAge of onset of medical co‐morbidities in DS, and not just their presence, is an important risk factor for dementia. Autoimmune/inflammatory processes in hypothyroidism could contribute to AD pathophysiology. Hypoxemia or hypercarbia from OSA may be risk factors for developing dementia. Proper screening and rigorous mitigation of hypothyroidism and OSA at their inception could possibly influence the course of AD in DS. Greater incidence of seizures may indicate that EO‐AD is more aggressive. The proximate timing of seizures and AD onset suggests that seizures may herald imminent dementia. Understanding the pathophysiology of these conditions could elucidate mechanisms in AD.
Outreach and recruitment of African Americans for Alzheimer’s disease studies during the COVID‐19 pandemic
Authors: Starks Takiyah D , Caban‐Holt Allison M , Williams Kelvin , Adams Larry D , Haines Johnathan L , Beecham Gary W , Reitz Christiane , Cuccaro Michael L , Vance Jeffery M , Pericak‐Vance Margaret A , Byrd Goldie S 
Published: December 2021

AbstractBackgroundRecruiting African Americans in AD studies remains a challenge, particularly during a pandemic, where major health disparities in this population are illuminated. The recruitment literature suggests myriad factors that contribute to the underrepresentation of AAs, including, but not limited to “mistrust” in researchers and their institutions. Maintaining a continuous presence in the AA community builds trust even when traditional outreach methods are not allowed. We continued to provide outreach and recruitment opportunities through COVID education and food for families as we educated them about AD, and opportunities for study participation.MethodWhile our traditional outreach methods for recruiting AAs were interrupted, we continued to conduct AD outreach using virtual platforms, mobile phone calls, family conference calls and food distributions. We hosted nine webinars on COVID‐19 to maintain a presence in local and national AA communities and to remain connected to existing AD participants. We reached over 160,000 persons through webinars and social media. We established new relationship new faith leaders in the AA community who co‐hosted COVID‐19 webinars and also expressed interest in forming partnerships on AD education. In addition, we hosted food drives in AA communities that not only addressed food insecurity and COVID prevention, but also AD education and AD research opportunities. At the food drives we distributed bags with masks, hand sanitizers, AD brochures, booklets and study participation information.ResultBetween October and December of 2020, 64 AAs who attended food drives expressed interest in AD studies that required blood draws and cognitive testing. Fifteen enrolled in our genetic study, 15 requested additional follow‐up and 13 expressed interest in participating in more than one study.ConclusionPrior research suggests that recruiting AAs into AD studies requires continuous engagement. We used multiple strategies to maintain contact with the AA community and existing research participants, and successfully increased enrollment in the last quarter of the year. Maintaining consistent and continuous engagement facilitates trustworthiness with AAs and yields positive recruitment outcomes, even in a pandemic where traditional recruitment methods are limited.