bluuebunny/crossref_metadata_2025_split huggingface dataset:
Duration of verbal fluency inter‐word intervals and risk of cognitive impairment
Authors: Ayers Matthew , Bushnell Justin , Gao Sujuan , Wadley Viriginia G , Unverzagt Fred W. , Clark David G. 
Published: December 2020

AbstractBackgroundVerbal fluency tasks have widely recognized value for dementia diagnosis. Some studies suggest that detailed analysis of verbal fluency word lists may aid in prediction of future cognitive decline or dementia.MethodWe identified 701 stroke‐free participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, all of whom performed in the normal range on a cognitive screening test at baseline, but who suffered from acute or progressive incident cognitive impairment (ICI) during subsequent years. These cases were matched with 701 controls who did not suffer subsequent cognitive decline. Baseline letter F and animal fluency recordings were automatically transcribed using Amazon Web Services’
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, then manually corrected using a Matlab‐based graphical transcription tool for precise capture of utterance latencies and durations. We performed two statistical analyses on the durations of inter‐word intervals (IWI). The first employed mixed‐effects linear models with IWI as the dependent variable and several lexical (e.g., frequency, edit distance from previous word, etc.) and demographic covariates. The second employed Cox proportional hazards (CPH) models, with time to ICI as the dependent variable and summary measures of IWI (sum of z‐scores) as key predictors of interest.ResultMixed‐effects models show that semantic similarity of consecutive words and overall within‐task latency of words are the strongest predictors of IWI, but that future progressive cognitive decline is associated with longer IWI on the animal fluency task. CPH models show significant independent contributions of animal fluency raw score and IWI summary score. Slowing of word retrieval reflected by the latter score was associated with greater risk for cognitive decline.ConclusionDetailed analysis of IWI measured during fluency tasks may enhance the prognostic value of verbal fluency tests. The effect appears to be strongest with animal fluency predicting progressive decline.
Cognitive decline prediction using an MRI‐based classifier of arteriolar sclerosis and small vessel atherosclerosis
Authors: Makkinejad Nazanin , Evia Arnold M , Tamhane Ashish A , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos 
Published: December 2020

AbstractBackgroundArteriolar sclerosis and small vessel atherosclerosis are two age‐related neuropathologies that are common in older adults and have been linked to cognitive decline and dementia. Definitive diagnosis of either pathology is only possible at autopsy. The purpose of this work was to develop a model that predicts the presence of arteriolar sclerosis or atherosclerosis based on in‐vivo MRI and basic demographic features. The model was first developed based on ex‐vivo MRI and pathology data from a large community‐based cohort of older adults and was then translated in‐vivo. The performance of the model was assessed both ex‐vivo and in‐vivo.MethodCerebral hemispheres were obtained from 727 participants of the Rush Memory and Aging Project (MAP) and Religious Orders Study (ROS), two longitudinal cohort studies of aging (Figure 1). A brain hemisphere from each participant was imaged ex‐vivo on a clinical 3T MRI scanner, while immersed in 4% formaldehyde solution. Following ex‐vivo MRI, all hemispheres underwent neuropathologic examination by a board‐certified neuropathologist blinded to clinical and imaging findings. The volume of white matter hyperintensities per lobe and regional white matter R2 values were extracted from the ex‐vivo MRI data and used as features in a logistic regression classifier to predict arteriolar sclerosis or small vessel atherosclerosis. The classifier was then translated to in‐vivo using linear mixed‐effects models, and was tested on in‐vivo 3T MRI of 405 ROS and MAP participants (Figure 2). In‐vivo assessment was performed by testing the association of the classification confidence score with the change in cognition two years after baseline MRI, using Pearson’s correlation.ResultThe ex‐vivo classifier of arteriolar sclerosis or small vessel atherosclerosis achieved an average area under the receiver operating characteristic curve AUC=0.73 (Figure 3). In‐vivo testing showed that the in‐vivo classification confidence score was associated with a two‐year decline in working memory (p=0.008), semantic memory (p=0.026), and perceptual speed (p=0.036) following baseline in‐vivo MRI.ConclusionA novel MRI‐based classifier was developed for predicting the presence of arteriolar sclerosis or small vessel atherosclerosis in‐vivo. This classifier may have broad clinical implications including refined participant selection and enhanced monitoring of the treatment response in clinical drug and prevention trials.
Evaluating pre‐screening tools for older Latino recruitment into preclinical Alzheimer’s disease studies
Authors: Muniz Martha C. , Martínez Jairo , Vila‐Castelar Clara , Pardilla‐Delgado Enmanuelle , Scott Matthew R. , Properzi Michael J. , Kirn Dylan , Rentz Dorene , Sperling Reisa A. , Quiroz Yakeel T. , Pruzin Jeremy J. , Ramirez‐Gomez Liliana A. 
Published: December 2020

AbstractBackgroundRecruitment for preclinical Alzheimer’s disease clinical trials and observational studies in the Latino population continues to increase as researchers aim to diversify their samples. The Telephone Interview for Cognitive Status modified version (TICS‐m) is a pre‐screening tool that has shown to have high diagnostic validity for identification of dementia in mostly Caucasian samples. The TICS‐m cut‐off currently used for screening out cognitive impairment in older individuals is ≥26. We aimed to 1) determine whether currently used TICS‐m cut‐offs are appropriate for pre‐screening clinically normal older Latinos, and 2) assess the relationships among the TICS‐m score and outcome measures typically used in clinical trials, such as Mini Mental State Exam (MMSE), Logical Memory Delayed Recall, and Clinical Dementia Rating (CDR).MethodsTwenty‐nine older Latino adults (mean age= 68.7, mean education=15.6, and mean TICS‐m= 33.4/40) from the Harvard Aging Brain Study (HABS) were included in this study. Participants completed the pre‐screening TICS‐m over the phone, followed by an in‐clinic screening neuropsychological battery, which included the MMSE, Logical Memory Delayed Recall, and CDR, administered in Spanish. Linear regression models controlling for age, sex, and education were used to assess the relationships between TICS‐m score and performance on the neuropsychological measures.ResultsTICS‐m scores were positively correlated with years of education (r=0.54, p=0.002). No significant associations were observed among TICS‐m scores and other cognitive measures, after adjusting by age, sex, and education (MMSE: r=0.04, p=0.82; Logical Memory Delayed: r=0.10, p=0.62; and CDR sum of boxes: r=‐0.03, p=0.86).ConclusionPreliminary results suggest that in this sample of largely cognitively normal Latino adults, TICS‐m score is not associated with performance in other cognitive outcome measures typically used in clinical and observational trials for preclinical Alzheimer’s disease. These findings also suggest that the TICS‐m may not accurately reflect actual cognitive function in older Latino participants. However, we do not know if we are inadvertently screen‐failing participants using TICS‐m as a pre‐screening tool. Further research is needed to assess whether this pre‐screening tool is adequate in the pre‐screening process for preclinical Alzheimer’s disease in older Latino adults.
External validation of an MRI‐based classifier of arteriolar sclerosis
Authors: Makkinejad Nazanin , Evia Arnold M. , Tamhane Ashish A. , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos 
Published: December 2020

AbstractBackgroundArteriolar sclerosis is a common age‐related neuropathology that has been associated with lower cognition and higher risk of dementia. Definitive diagnosis of arteriolar sclerosis is only possible at autopsy. We recently introduced an MRI‐based classifier of arteriolar sclerosis [1]. In the present work, we tested this classifier for prediction of pathology in‐vivo, and also validated it on external datasets.MethodIn‐vivo 3T MRI and pathology data were available on participants of the Rush Memory and Aging Project (MAP) and Religious Orders Study (ROS), two longitudinal cohort studies of aging used in training of the classifier. We first assessed the performance of the classifier in predicting arteriolar sclerosis based on in‐vivo MRI of MAP and ROS participants that had not been included in the training sample. The generalizability of the classifier was then evaluated in the Minority Aging Research Study (MARS), and Alzheimer's Disease Neuroimaging Initiative (ADNI), by testing the association of the classification confidence score with change in cognition two years after baseline MRI, using Spearman’s rank correlation.ResultThe area under the receiver operating characteristic curve for in‐vivo classification of arteriolar sclerosis in MAP and ROS data not used in training of the classifier was 0.77. Also, the classification confidence score showed significant association with two‐year decline in perceptual speed (p=0.027) in the MARS dataset, and with Trail Making Test Part A (p=0.027), and Trail Making Test Part B (p=0.046) in the ADNI dataset.ConclusionOur previously introduced classifier of arteriolar sclerosis was shown to have a high performance in prediction of the pathology based on in‐vivo MRI, illustrating its significance. Testing in MARS and ADNI showed that the classifier generalizes to other cohorts and demonstrated its clinical utility in predicting cognitive decline two years after baseline MRI. References: [1] N. Makkinejad, A.M. Evia, A. Tamhane, D.A. Bennett, J.A. Schneider, K. Arfanakis, A Novel MRI Classifier of Arteriolar Sclerosis in Aging: Prediction of Pathology and Cognitive Decline, Proc. Int. Soc. for Magn. Reson. in Med. 2019.
Differential associations between PET and CSF Alzheimer's disease biomarkers and cognition among cognitively normal older adults
Authors: Oh Hwamee , Correia Stephen , Salloway Stephen P. 
Published: December 2020

AbstractBackgroundThe presence of brain β‐amyloid (Aβ) plaques among cognitively normal older adults has been related to steeper cognitive decline and an increased risk of Alzheimer’s disease (AD). The co‐presence of tau pathology in these individuals, however, makes it challenging to link AD pathologies to changes in specific cognitive function and brain structure. In addition, it remains unclear whether AD pathologies in the brain and their increased concentration in the cerebrospinal fluid (CSF) have similar effects on cognition.MethodWe assessed the relationship between Aβ and tau pathology, gray matter atrophy, and cognition among cognitively normal older adults in the Alzheimer's disease neuroimaging initiative whose brain Aβ deposition and tau‐protein neurofibrillary tangles were detected by 18F‐Florbetapir and 18F‐Flortaucipir, respectively. Within a subset of the sample, CSF measures of amyloid (Aβ40 and Aβ42) and tau (t‐tau and p‐tau) pathologies were assessed in relation to cognition and cortical thickness. Multiple regression models were applied to assess the relationships between AD pathologies, gray matter atrophy, and cognition using region‐of‐interest and whole‐brain surface‐based approaches.ResultHigher entorhinal tau PET counts corresponded to greater gray matter atrophy in the entorhinal cortex and hippocampus and poorer executive function performance, controlling for age, sex, and whole‐brain amyloid load. In the subset of the sample, whole‐brain amyloid load related to poorer memory and executive function performance, controlling for age, sex, and CSF total tau. Age was associated with memory and executive function performance, independent of entorhinal tau PET counts, CSF total tau, and whole‐brain amyloid load. Entorhinal tau PET counts did not correlate with CSF total tau or p‐tau among cognitively normal older adults.ConclusionAmyloid and tau pathology differentially influence cognition and brain structure. A low correlation between tau PET and CSF total tau measures in cognitively normal older adults may warrant further investigation on the source of discordance in these measures.
Decreased complexity and increased variability in systolic blood pressure are associated with elevated long‐term risk of dementia: The Rotterdam Study
Authors: Ma Yuan , Zhou Junhong , Kavousi Maryam , Lipsitz Lewis A , Raso Francesco US Mattace , Westerhof Berend E , Wolters Frank J , Wu Julia W , Manor Brad , Ikram M Kamran , Goudsmit Jaap , Hofman Albert , Ikram M Arfan 
Published: December 2020

AbstractBackgroundBlood pressure (BP) is a key player in the vascular etiology of dementia, but their relationship is not fully elucidated. The current BP control paradigm focuses on BP levels, but real‐time BP is highly dynamic, involving simultaneous interactions of numerous neural and vascular feedback mechanisms. We hypothesized that early subclinical disruption in BP dynamics, captured by decreased complexity and increased variability, contributes to dementia risk, above and beyond BP levels.MethodIn a prospective cohort study since 1997 involving 1,877 dementia‐free community‐based older adults, we investigated whether BP variability and complexity were associated with the risk of dementia. The primary exposures were BP complexity (quantified by sample entropy) and BP variability (quantified by coefficient of variation) derived from continuous beat‐to‐beat BP series of 300 beats. The primary outcome was incident dementia during follow‐up until January 1, 2016.ResultOf 1,877 participants (59% women; mean [SD] age, 70.9 [6.3] years), 333 developed dementia over 20 years. Reduced systolic BP (SBP) complexity was associated with a higher dementia risk (HR comparing extreme quintiles: 1.53 [95%CI: 1.08, 2.17], P=0.008). Increased SBP variability was also associated with a higher risk of dementia (HR comparing extreme quintiles: 1.57 [95% CI: 1.11, 2.22]; P=0.017). When considered jointly, individuals with both high variability (within the top quintile) and low complexity (within the bottom quintile) had a significantly higher risk of developing dementia compared with those with both high complexity and low variability in SBP (HR: 2.16; 95%CI: 1.28‐3.65, P=0.003). These findings were observed after adjusting for age, sex, APOE genotype, mean SBP, and traditional vascular risk factors. Consistent findings were observed for variability but not complexity of diastolic BP.ConclusionDecreased complexity and increased variability of beat‐to‐beat systolic blood pressure are potential novel risk factors for dementia. Our findings suggest that maintaining complexity and limiting variability in systolic blood pressure may provide new opportunities to prevent dementia.
Serum NFL as a predictor of disease progression in dementia with Lewy bodies
Authors: Pilotto Andrea , Imarisio Alberto , Conforti Francesca , Lupini Alessandro , Giannì Giuliana , Gipponi Stefano , Cottini Elisabetta , Masciocchi Stefano , Nocivelli Sara , Grasso Roberto , Turrone Rosanna , Borroni Barbara , Rizzetti Maria Cristina , Bonanni Laura , Pizzi Marina , Bellucci Arianna , Garrafa Emirena , Zetterberg Henrik , Hye Abdul , Ashton Nicholas J. , Padovani Alessandro 
Published: December 2020

AbstractBackgroundCSF and plasma neurofilament light chain (NfL) levels have been consistently proposed as reliable markers of neurodegeneration able to discriminate between Parkinson’s disease (PD) and atypical parkinsonisms. Increased Serum NfL might predict worse motor and cognitive progression in PD patients at single subject level.Methodplasma NfL was assessed in a longitudinal study including 93 patients with Parkinson’s disease and 27 patients with DLB who underwent an extensive motor and cognitive assessment and after 2 years of follow‐up. The study evaluated the correlation between NfL plasma levels and motor, non‐motor symptoms, cognitive and behavioral abnormalities in the two cohorts, as well as benignant/malignant phenotypes and motor/cognitive progression in PD after 2 years of follow‐up.ResultSerum NfL correlated with age and age at onset in the cohort. In DLB, NfL correlated with disease duration, hyposmia and neuropsychiatric symptoms, but not with motor function assessed by UPDRS‐III. We found no significant associations between NfL and disease progression in DLB patients. In PD, higher NfL levels correlated with hyposmia (p=0.01), total UPDRS‐II and UPDRS‐III scores (0.001), gait speed (0.04) and several disability milestones, including mild cognitive impairment (0.001), symptomatic dysautonomia (0.001), loss of independency in activities of daily living (p=0.01) and instrumental daily living (p=0.001). At two years of follow‐up, NfL was the best marker in multivariate regression analyses for both motor and cognitive progression beyond malignant/benignant phenotypes.ConclusionElevated serum NfL levels are associated with fast progression in PD patients and could thus represent target of interventions in specific subpopulation of patients.
Magnetic nanoparticles as MRI contrast agents for the diagnosis of Alzheimer’s disease
Authors: Ulanova Marina , Gloag Lucy , Bongers Andre , Gooding Justin , Biazik Joanna , Tilley Richard , Sachdev Perminder S. , Braidy Nady 
Published: December 2020

AbstractBackgroundNanoparticle‐based magnetic contrast agents have opened the potential for Magnetic Resonance Imaging (MRI) to be used for early non‐invasive diagnosis of Alzheimer’s disease (AD). Current methods for clinical diagnosis in the early stages of the disease, such as Positron Emission Tomography imaging of amyloid build‐up, are limited by their availability and cost. The aim of this research is to develop a novel non‐toxic amyloid targeted nanoparticle which can successfully permeate the blood brain barrier and bind amyloid plaques resulting in enhanced contrast in the MR image and improved diagnostic sensitivity.MethodsTargeted iron nanoparticles were assessed using a U‐251 cell line to determine their in vitro toxicity. Transmission electron microscopy was used to determine the movement of the nanoparticles within the cell and in vitro binding to amyloid fibrils. APPSwe/PSEN1 mice were treated with increasing doses of targeted and non‐targeted nanoparticles to evaluate acute in vivo toxicity, in addition to nanoparticle biodistribution and MRI contrast enhancement.ResultsThe novel targeted nanoparticles have demonstrated no significant in vitro toxicity and electron microscopy results show their movement through the endocytic cycle within the cell, demonstrating an effective degradation and clearance pathway (Figure). No acute toxicity was observed in the animal model. In addition, immunohistochemistry demonstrated nanoparticles to co‐localise with plaques on ex vivo brain sections.ConclusionThe present work shows promising preliminary results in the development of a targeted non‐invasive method of early AD diagnosis using contrast enhanced MRI.
Study design and clinical characteristics of the LEADS cohort
Authors: Apostolova Liana G. 
Published: December 2020

AbstractBackgroundThe Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS) is a 2‐year observational study designed to look at disease progression in adults with early‐onset Alzheimer's disease (EOAD). To move toward more effective treatments, scientists need to understand the genetic, biological and clinical processes involved in EOAD. Compared to LOAD, patients with sporadic EOAD are believed to show more rapid clinical decline, higher prevalence non‐amnestic phenotypes, greater impairment in non‐memory domains, as well as more severe and widespread neurodegeneration.MethodThe over‐arching goals of the LEADS are to: (1) Compare the baseline and longitudinal cognitive, functional imaging and fluid biomarker characteristics of EOAD vs. LOAD; (2) Develop sensitive clinical and biomarker measures for future clinical and research use; (3) Develop composite clinical and biomarker outcome measures for implementation in clinical trials; (4) Establish a network of EOAD sites ready to launch interventional studies in this population; and (5) Explore possible genetic susceptibility factors through WGS. LEADS will recruit and longitudinally follow approximately 400 EOAD, 200 amyloid‐negative cognitively impaired subjects (EOnonAD) and 100 age‐matched controls. Participants will undergo clinical and psychometric assessments, MRI, amyloid ([18F]Florbetaben) and tau ([18F]AV1451) PET, CSF, DNA, RNA, plasma, serum and peripheral blood mononuclear cells collection at three time points. Methods are harmonized with ADNI and DIAN to facilitate scientific comparisons.ResultThe latest enrollment data including the demographic, clinical and biomarker characteristics of the LEADS cohort to date will be presented at the meeting. We will include data on disease subtypes, biomarker collection, genetic screening and counseling and results disclosure.ConclusionLEADS will develop a publicly available natural history biomarker and clinical dataset in EOAD and will enable future planning and implementation of clinical trials in EOAD. Successful completion of this project will address several substantial gaps in our understanding of EOAD and AD research in general.