bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing flortaucipir tau‐PET deposition patterns across the Alzheimer’s disease spectrum: A comparison between regional and whole‐brain approaches
Authors: Chapleau Marianne 
Published: December 2021

AbstractBackgroundThe pattern of tau‐PET deposition might not always follow the classical post‐mortem Braak stages (Vogel et al, 2020). Yet, most current studies use a temporal meta‐ROI to calculate tau‐PET abnormality. We assessed inter‐individual patterns of tau binding across the spectrum of late‐onset Alzheimer’s disease (AD). We computed a score representing the spatial extent uptake of tau‐PET and compared it to a classical temporal meta‐ROI.MethodWe selected 766 ADNI participants along the AD spectrum (controls [CN], early mild cognitive impairment [eMCI], late MCI [lMCI] and AD patients) who underwent flortaucipir tau‐PET and had an available beta‐amyloid (Aβ)status (Table 1). We fitted 2‐distribution Gaussian mixture‐models to calculate thresholds of liberal and conservative tau retention (50% and 90% probability to be in the high SUVR distribution, respectively) in the classical Braak stages and all 70 FreeSurfer brain regions. Using this categorization, we defined positivity in the different Braak stages (Figure 1A‐C) and individual regions (Figure 1B‐D). We calculated a fine‐grained measure of spatial extent by summing the number of regions showing tau abnormality (Figure 1D and 2A). We also computed a temporal meta‐ROI SUVR (Figure 2B, Jack et al, 2018 regions).ResultIn Aβ‐positive participants 14% CN, 44% eMCI and 78% lMCI‐AD had elevated SUVRs in Braak stage 1 using the conservative threshold (Figure 1C, yellow). Participants who progressed to subsequent Braak stage(s), defined with conservative thresholds, were positive on all previous stages using a liberal or conservative threshold (Figure 1C yellow and green, 99% of the sample). Only the spatial extent of tau deposition was associated with worse cognition in CN individuals (Figure 3). In AD patients, both greater spatial extent of tau deposition and higher temporal meta‐ROI SUVR were associated with lower cognition, with the spatial extent index showing stronger associations (Figure 3). In AD, further widespread spatial extent and temporal binding was associated with younger age (Figure 4).ConclusionIn a typical amnestic cohort of late‐onset AD,the pattern of tau deposition follows the traditional Braak stages. Using a spatial extent index provides stronger results than a temporal‐meta ROI index in detecting associations with cognition.
The role of race/ethnicity, psychiatric history, and substance use in the risk of dementia subtypes: Findings from the NACC
Authors: Aranda Maria P , Liang Jiaming , Wang Xinhui , Chui Helena C , Schneider Lon S 
Published: December 2021

AbstractBackgroundDementia is characterized by significant declines in cognitive and physical functioning and includes multiple subtypes that differ in etiology. There is limited evidence of the influence of psychiatric and substance use history on the risk of dementia subtypes among underrepresented racial/ethnic minorities. The study explored the role of psychiatric and substance use history on the risk of etiology‐specific dementias: Alzheimer’s disease (AD) and vascular dementia (VaD), in the context of a racially and ethnically diverse sample based on national data in the US.MethodWe conducted secondary data analyses based on the National Alzheimer’s Coordinating Center Uniform Data Set (N = 17,592). Participants completed at least two visits and were dementia‐free at baseline, and were assessed for history of five psychiatric and substance use disorders (depression, traumatic brain injury, other psychiatric disorders, alcohol use, and other substance use). Cox proportional hazard models were estimated to examine the influence of psychiatric and substance use history on the risk of two dementia subtypes, and the interactions between psychiatric and substance use history and race/ethnicity with adjustment for demographic and health‐related factors.ResultIn addition to other substance use, having any one type of psychiatric and substance use history increased the risk of developing AD by 22‐51% and VaD by 22‐53%. The risk of other psychiatric disorders on AD and VaD risk varied by race/ethnicity. For Non‐Hispanic White, history of other psychiatric disorders increased AD risk by 27% and VaD risk by 116%. For African Americans, AD risk increased by 28% and VaD risk increased by 108% when other psychiatric disorder history was present.ConclusionThe findings indicate that having psychiatric and substance use history increases the risk of developing AD and VaD in later life. Preventing the onset and recurrence of such disorders may prevent or delay the onset AD and VaD dementia subtypes. Prevention efforts should pay particular attention to Non‐Hispanic White and African American older adults who have history of other psychiatric disorders.
Greater adolescent cognitive ability is linked to lower risk of cognitive impairment in later life
Authors: Gruenewald Tara L , Arpawong Thalida Em , Zavala Catalina , Grossman Molli , Walters Ellen E , Peters Kelly , Lapham Susan , Manly Jennifer J , Gatz Margaret , Prescott Carol Arlene 
Published: December 2021

AbstractBackgroundThere have been few investigations of the role that adolescent cognitive ability might play in predicting who will later develop cognitive impairment. This is due, in part, to a lack of cohorts with early‐life cognitive assessment who have been followed to later adulthood. We capitalized on the 1960 Project Talent high school cohort to assess whether higher adolescent cognitive ability predicted lower risk of impaired cognitive function in older adulthood. A subsample of twin and non‐twin siblings allowed for assessment of whether these associations are due to shared family and genetic factors.MethodData come from the 1960 Project Talent (PT) baseline data collection (n>360,000) and two follow‐ups: the Project Talent Twin & Sibling (PTTS; n=2,491) Study and the Project Talent Aging Study (PTAS; n=6,421). The 1960 data collection assessed performance in multiple cognitive abilities (see Table 1). In 2018, participants/proxies reporting 2 or more symptoms of cognitive impairment on the AD8 Dementia Screener were classified as having a positive screen. Binary logistic generalized estimating equations assessed odds of a positive AD8 screen as a function of 1960 cognitive abilities. Models included age, race, sex, adolescent family SES, and adult educational attainment covariates. Co‐sibling control models examined whether associations remained when accounting for shared family and genetic characteristics.ResultsCovariate‐adjusted models indicated that each 1 SD higher adolescent cognitive ability predicted lower odds of a positive AD8 screen in later life for most ability domains (e.g., general cognitive ability OR = 0.86 (95% CI = 0.76, 0.98), see Table 1); associations were attenuated somewhat with inclusion of adult educational attainment in models. Preliminary co‐sibling control analyses indicated the persistence and strengthening of this association (OR = 0.57 (95% CI = 0.36, 0.91)).ConclusionFindings indicate that greater performance in multiple cognitive domains in adolescence predicts lower risk of cognitive impairment over 5 decades later. A co‐sibling control analysis indicated that the link between adolescent general cognitive ability and later‐life cognitive impairment is not simply due to shared family background and genetic factors. Ongoing analyses are assessing whether this is true for other cognitive domains and other indicators of cognitive function.
Methodological challenges across WW‐FINGERS Studies: Impact of COVID‐19 pandemic on statistical design and analysis plans for multidomain RCTs
Authors: Espeland Mark A , Roehr Susanne , Arai Hidenori , Mangialasche Francesca , Peltonen Markku , Raman Rema , Riedel‐Heller Steffi G , Snyder Heather M , Carrillo Maria C , Ngandu Tiia , Kivipelto Miia 
Published: December 2021

AbstractBackgroundThe coronavirus disease‐19 (COVID‐19) pandemic presents challenges to the conduct of randomized clinical trials of lifestyle interventions.MethodWorld‐Wide FINGERS is an international network of clinical trials to assess the impact of multidomain lifestyle intervention on cognitive decline in at‐risk adults. Individual trials are tailoring successful approaches from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) to local cultures and environments. The network convened forums for researchers to discuss statistical design and analysis issues they faced during the pandemic. We will provide an updated report on experiences of trials that, at various stages of conduct, altered designs and analysis plans to navigate these issues. We provide recommendations for future trials to consider as they develop and launch behavioral intervention trials.ResultThe pandemic led researchers to change recruitment plans, interrupt timelines for assessments and intervention delivery, and move to remote intervention and assessments protocols. The necessity of these changes add emphasis to the importance, in study design and analysis, of intention to treat approaches, flexibility, within site stratification, interim power projections, and sensitivity analyses.ConclusionRobust approaches to study design and analysis are critical to negotiate issues related to the intervention. The World Wide Network of similarly oriented clinical trials will allow us to evaluate the effectiveness of responses to the pandemic across cultures, local environments, and phases of the pandemic.
Metabolism in frontotemporal dementia
Authors: Ahmed Rebekah M 
Published: December 2021

AbstractBackgroundMetabolic changes incorporating changes in weight, insulin resistance and cholesterol levels have been identified across a number of neurodegenerative conditions. It remains unknown whether these changes represent the result of the process of neurodegeneration affecting critical brain regions involved in metabolic regulation, or are causative, driving the process. Changes in eating behaviour affecting metabolism have been incorporated into the diagnostic criteria for frontotemporal dementia (FTD), and have been shown to potentially effect disease progression, with the potential to aid in clinical phenotyping and early diagnoses.MethodsA number of studies will be reviewed examining changes in eating behaviour in FTD using ecological valid assessments including a test meal approach. The effect that these eating changes have on metabolism will be examined, including changes in cholesterol, and insulin levels and metabolic rate. The role of key brain regions including the hypothalamus will be explored through a number of studies incorporating brain imaging, neuropeptide examination and pathological analyses.ResultsPatients with FTD exhibit a strong fat and sucrose preference, that is not present in normal or Alzheimer’s disease controls. These changes result in increased cholesterol levels and a state of insulin resistance which has been associated with changes in disease progression. Patients with FTD have been found to be hypermetabolic, with increased cholesterol levels, from changes in eating behaviour, likely resulting in improved energy stores in a hypermetabolic state and potentially slowing disease progression. Changes in eating behaviour and metabolism have been linked to changes in key neural networks involving fronto‐insular‐ striatal networks, with connections to the hypothalamus. Changes in key hypothalamic peptides including agouti‐related peptide and leptin have also been implicated in mediating metabolic changes and changes in disease progression.ConclusionsGiven the spectrum of metabolic and eating changes observed in FTD, with emerging evidence that these changes may effect disease progression and prognoses, an understanding of metabolism in FTD may provide a model to better understand the pathophysiology of metabolic change and its complex interaction with the process of neurodegeneration.
Clinical characteristics and treatments in patients with chronic kidney disease and dementia
Authors: Xu Hong , Garcia‐Ptacek Sara , Eriksdotter Maria , Carrero Juan Jesus 
Published: December 2021

AbstractBackgroundThere is limited information on clinical features and treatments of patients with chronic kidney disease (CKD)–associated dementia. In this study, we assessed the difference in dementia diagnoses, cognitive function, and dementia treatment among patients with and without CKD.MethodWe included 20,032 patients with newly diagnosed dementia from the Swedish Dementia Registry (SveDem) within the region of Stockholm during 2006‐2018. Patient baseline kidney function was extracted from the Stockholm CREAtinine Measurements (SCREAM) project, and categorized by estimated glomerular filtration rate (eGFR) as ≥60, 30‐59, 15‐29, and <15 ml/min/1.73m2 or dialysis. Dialysis patients were identified via linkage with Swedish Renal Registry. The difference in dementia diagnosis, cognitive function, dementia treatment among patients with different eGFR strata were examined. Confounders included demographics, living conditions, comorbidities, and therapies.ResultAmong the dementia patients 70% had GFR≥60ml/min, 27% GFR 30‐59ml/min, 2% GFR 15‐29ml/min and 1% <15 % ml/min or with dialysis. The proportion of vascular dementia increased across lower eGFR categories, while Alzheimer’s and mixed dementia, dementia with Lewy Bodies and Parkinson's disease dementia decreased. Patient diagnosis in nursing home, the use of renin‐angiotensin‐system‐inhibitors, calcium‐channel‐blockers, and statins increased while antipsychotics and antidepressants decreased. Compared with eGFR ≥60 ml/min, lower eGFR strata were associated with worse cognitive function (MMSE unit, adjusted β coefficient, ‐0.69, 95% confidence interval [‐1.22,‐0.17] for eGFR 15‐29ml/min and ‐1.50, (‐2.66,‐0.34) for eGFR<15ml/min or dialysis). After adjustment for patient demographics, living conditions, comorbidities, MMSE and therapies, lower eGFR strata were significantly associated with less prescription of acetylcholinesterase inhibitors (aChEIs) and memantines [Odds ratio 0.91(0.84‐0.99) in eGFR 30‐59ml/min and 0.20 (0.09‐0.46), in eGFR<15ml/min or dialysis for aChEIs; 0.91(0.83‐0.99) in eGFR 30‐59ml/min, 0.37 (0.25‐0.55) in eGFR 15‐29ml/min and 0.14(0.03‐0.58), in eGFR<15ml/min or dialysis for memantine use].ConclusionPatients with advanced chronic kidney disease had worse cognitive function and less prescribed anti‐dementia drugs. Since we have previously shown that aChEI treatment is associated with lower mortality, the relationship between anti‐dementia medication, renal function and cognition must be further investigated.
Disease progression models of familial frontotemporal lobar degeneration and the temporal ordering of biomarker changes in an international cohort
Authors: Staffaroni Adam M. , Quintana Melanie , Wendelberger Barbara , Russell Lucy L. , Petrucelli Leonard , Gendron Tania F. , Goh Sheng‐Yang Matthew , Cobigo Yann , Wolf Amy , Heuer Hilary W. , Cash David M. , Ong Elise , Forsberg Leah K. , Brushaber Danielle , Bahl Riley , Heller Carolin , Bouzigues Arabella , Swift Imogen J. , Peakman Georgia , Bocchetta Martina , Todd Emily G. , Convery Rhian S. , Boeve Bradley F. , Rosen Howard J. , Rohrer Jonathan D. , Boxer Adam L. ,   ALLFTD and GENFI
Published: December 2021

AbstractBackgroundClinical trials are underway to treat familial frontotemporal lobar degeneration (f‐FTLD). This is a rare disease, and a limited number of mutation carriers have been identified; thus, efficient trial design is critical. Multimodal, latent disease progression models (DPM) can estimate time to symptom onset and define the temporal ordering of biomarker changes. DPMs can also be leveraged to select endpoints and potentially supplement analyses by integrating historical data. Recent draft FDA guidance for gene therapy trials in neurological disease supports these novel approaches to clinical trials.MethodParticipants included 1,049 members of families affected by f‐FTLD, due to mutations in GRN, MAPT, or C9orf72 genes, who were enrolled in ALLFTD or GENFI. A Bayesian repeated measures model incorporated multimodal data to estimate disease progression, conditional on latent disease age (proximity to symptom onset), in 677 mutations carriers (GRN (n=233), MAPT (n=151) and C9orf72 (n=293)). Family members without pathogenic mutations were used as the reference group. Mean follow‐up was 1.1 (SD=1.1) years. Jointly modeled longitudinal variables included neuropsychological scores, CDR®+NACC‐FTLD Box Score, MRI volumes of brain regions affected by f‐FTLD, and plasma levels of neurofilament light chain (NfL).ResultDisease progression curves were similar across ALLFTD and GENFI cohorts. Plasma NfL elevations occurred earliest, up to 10 years before symptom onset, and NfL was the most powerful endpoint in the asymptomatic stage. MRI abnormalities occurred next, closer to symptom onset. The earliest MRI changes relative to symptom onset were observed in C9orf72+. GRN mutation carriers showed the most rapid acceleration in all biomarkers, and this acceleration occurred in close proximity to symptom onset. Neuropsychological measures and CDR®+NACC‐FTLD Box Score were among the most promising endpoints in the symptomatic stage. Trial simulations indicated that using latent disease age as an enrollment criterion would allow some asymptomatic mutation carriers to be enrolled without sacrificing power.ConclusionSimilarity in disease progression across ALLFTD and GENFI participants suggests these models will apply to international trials. Model‐derived estimates of disease progression curves indicate that endpoint selection should be specific to disease stage and mutation, and DPMs would facilitate greater participant enrollment.
The joint effects of audio and linguistic markers for early identification of mild cognitive impairment
Authors: Tang Fengyi , Chen Jun , Dodge Hiroko H , Zhou Jiayu ,   I‐CONECT
Published: December 2021

AbstractBackgroundIn recent years, speech‐related behavioral markers such as spoken language and lexical preferences have been studied in the early detection of mild cognitive impairment (MCI). While the combination of linguistic and acoustic signals has been shown to be effective in detecting MCI, they have generally been restricted to structured conversations in which the interviewee responds to fixed prompts. In this study, we propose a stratification scheme that proves to be effective in extracting quality linguistic and acoustic MCI markers in semi‐structured more natural conversational settings.MethodWe obtained transcripts and audio recordings from an ongoing single blind randomized controlled clinical trial NCT02871921. Briefly this clinical trial aims to improve psychological well‐being and cognitive functions of the non‐demented (normal or MCI) older adults aged 75 and older by enhancing their social interactions. The experimental group receives 30 minutes of semi‐structured conversations (video chats) with interviewers four times per week, for up to one year. Recruitment started in July 2018 and we used the data from the first 39 participants enrolled in the experimental group with audio and transcribed data as of March 2020 in the current analysis. Our stratification scheme eliminates drastic train‐test distribution mismatch, allowing for apples‐to‐apples comparison across participant conversations, despite drastic variations in word choices, sentence structure and length of conversations – obstacles that typically present challenges to the semi‐structured conversational setting for automatic acoustic marker extraction.ResultsFigure 1 gives an overview of our MCI prediction pipeline. The combination of linguistic and audio features achieve a mean AUC of 82.7, significantly (p<0.01) out‐performing linguistic‐only (AUC = 74.9) or acoustic‐only (AUC = 65.0) detections on hold‐out data. Our subtopic stratification method identifies several conserved clusters (Figure 2) in interview structure, allowing more balanced train‐test split in terms of linguistic properties, despite the semi‐structured nature of conversations.ConclusionA combination of linguistic and audio features improves the ability to detect MCI beyond that achieved by each feature alone in semi‐structured conversation. Our method provides a potentially valuable approach for using speech for early detection of MCI and clinical trials enrichment.
Characterizing blood‐based, microglial derived exosomes (MDEs) as biomarkers for Alzheimer’s disease
Authors: Winston Charisse N. , Sarsoza Floyd , Spencer Brian , Rissman Robert A. 
Published: December 2021

AbstractBackgroundRecent studies suggest neuronal and astrocyte‐derived exosomes may serve as the source of biomarkers for many neurodegenerative diseases, include AD. However very few studies have characterized the biomarker potential of microglial derived exosomes.MethodPlasma exosomes were extracted and precipitated from AD patients and age matched controls. Extracted exosomes were enriched against a microglial source (TMEM119) using magnetic immunocapture and fluorescence‐activated cell sorting (FACS) sorting. MDEs were characterized by size (Nanosight) and shape (TEM). Exosome marker profiling was done by western blot. MDE cargo proteins will be quantified to identify biomarkers for stages of AD using ELISA.ResultBlood‐based MDEs demonstrate similar size distributions and shape to previously reported exosome preparations. Western Blot demonstrated that MDEs were positive for exosome marker Flotilin‐1; microglial markers CD68 and IBA1 and negative for astrocyte marker, GLAST. Further characterization of MDE protein cargo levels, which include AD‐related (Aβ and p‐tau) and inflammatory markers, will be analyzed and presented.ConclusionMDEs can be successfully isolated from human blood with the hope that they also demonstrate biomarker potential for AD, akin to other CNS‐derived exosomes.