bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between markers of left atrial cardiopathy and cognitive decline in the absence of atrial fibrillation
Authors: Li Zhe , Marion Danielle , Blair Jessica , Soliman Elsayed Z. , Gladstone David J. , Kamel Hooman , Manuel Doug , Edwards Jodi D. 
Published: December 2022

AbstractBackgroundWhether atrial cardiopathy is independently associated with cognitive impairment in the absence of atrial fibrillation (AF) remains unknown. This longitudinal cohort study aims to investigate associations between markers of left atrial cardiopathy and cognitive decline, and to identify longitudinal trajectories of cognitive decline in aging adults without AF over time.MethodA cohort of adults ≥45 years of age with no prior AF or cognitive impairment (N=21,869) was ascertained from the REGARDS (Reasons for Geographic and Racial Differences in stroke) prospective cohort study database. Markers of left atrial cardiopathy included atrial premature complexes (APCs) and N‐Terminal pro‐Brain Natriuretic Peptide (NTpro‐BNP). Cognitive status was measured using Six‐Item Screener (SIS) and an SIS score <5 was defined as cognitive impairment. Cox proportional hazards regression was used to estimate the cause‐specific hazard for primary (cognitive impairment) and secondary outcomes (stroke). Cognitive status trajectories were identified using latent class growth models. Baseline characteristics associated with each trajectory were identified using multinomial logistic regression.ResultDuring a mean follow‐up of 9.9 years, 6,060 participants had incident cognitive impairment and 876 had a stroke. APCs increased the hazard of cognitive impairment by 10% (hazard ratio [HR], 1.10, 95%CI: 1.00‐1.20) and stroke by 9% (HR, 1.09, 95%CI: 1.01‐1.18). Elevated NTpro‐BNP increased the hazard of cognitive impairment by 55% (HR, 1.55, 95%CI: 1.17‐2.04) and stroke by 35% (HR, 1.35, 95%CI: 1.13‐1.60). Three unique cognitive trajectories were identified: while 85% showed a normal and stable trajectory of SIS scores, 13% showed a progressively decreasing trajectory, and 2% showed a dramatic decrease in SIS scores. Age, coronary artery disease, diabetes, and NTpro‐BNP were all associated with worse cognitive trajectories.ConclusionWe showed that markers of left atrial cardiopathy including APCs and elevated NTpro‐BNP were associated with an increased risk of cognitive impairment and stroke in the absence of AF. Adults with these markers followed three unique longitudinal cognitive trajectories. These findings indicate that markers of left atrial cardiopathy (APCs and NTpro‐BNP) may have significant implications for early diagnosis and prevention of cognitive impairment.
Exercise‐Associated Signaling Reduces Tau Accumulation and Neuroinflammation in P301S MAPT Transgenic Mice
Authors: Cortes Constanza J , Birnbaum Allison , Nobles Amber C , Matthews Ian , McGraw Megan 
Published: December 2022

AbstractBackgroundSkeletal muscle has recently arisen as a novel regulators of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis and metabolism‐modifying functions in targeted tissues, including the CNS. Myokine secretion is heavily modified by exercise, suggesting that myokine signaling in the periphery may underlie the well document geroprotective benefits of exercise on the brain. The following studies address muscle proteostasis, a pathway highly activated during exercise, as a potential new regulator of the neurocognitive benefits of exercise.MethodWe have recently generated a novel transgenic mouse with enhanced muscle proteostasis via moderate overexpression of Transcription Factor E‐B (TFEB), a powerful master regulator of cellular clearance and proteostasis. We have discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity and reduce neuroinflammation in the aging CNS. To directly test the potential neuroprotective effectsof enhancing skeletal muscle proteostasisin AD‐associated pathologies, we derived cTFEB;HSA‐Cre transgenic mice in the P301S MAPT background. This is a well‐characterized model of fronto‐temporal dementia and neurofibrillary tangle toxicity and has been previously shown to benefit from exercise interventions.ResultWe detected a significant reduction in the accumulation of hyperphosphorylated tau [AT8 phospho‐tau antibody] in whole hippocampal lysates and in the dentate gyrus of cTFEB;HSACre;P301S mice compared to their single transgenic P301S littermate controls. Nanostring nCounter®AD panel analysis reveals displayed reductions in microglia activation modules in P301S MAPT/cTFEB:HSACre hippocampi, suggesting reduced neuroinflammation. We also determined that these CNS benefits in P301S MAPT/cTFEB:HSACre mice were accompanied by activation of exercise‐associated neurotrophic signaling and reduced markers of advancing tau‐associated pathologies in the hippocampus.ConclusionThese provocative results suggest that enhanced skeletal muscle proteostasis modifies the accumulation of pathogenic tau isoforms and reduces neuroinflammation in the CNS of P301S MAPT mice via activation of exercise‐associated signaling in the CNS.
Variability Independent of Mean Blood Pressure as an Electronic health record‐based Measure of Dementia Risk
Authors: Driver Matthew , Ebinger Joseph , Cheng Susan , Tan Zaldy S 
Published: December 2022

AbstractBackgroundThe risk of developing Alzheimer’s Disease and Related Dementias (ADRD) is associated with visit‐to‐visit blood pressure (BP) variability, including variability independent of the mean (VIM).1,2 The association between ADRD and VIM has primarily been evaluated using standardized BP measurements from clinical trials and cohorts, rather than utilizing measurements from clinical practice, potentially limiting generalizability to the real‐world context. As such, we sought to evaluate the relationship between ADRD and BP VIM utilizing real‐world data collected from the electronic health record (EHR).MethodWe studied all patients with repeated BP measurements and without a prior diagnosis of ADRD across ambulatory visits within a high‐volume academic healthcare system from 2013 to 2016. Using EHR data, we calculated BP VIM for all patients during the first 4 years of the study period and followed all patients through the end of 2019 or most recent office visit, whichever came first. The primary outcome of interest was incident ADRD, defined by presence of ICD‐10 codes for ADRD or prescription for dementia medication. We used multivariable adjusted Cox proportional hazards models to examine risk of incident ADRD associated with increasing BP VIM.ResultWe identified 46,703 patients with repeated BP measurements over 730,721 ambulatory visits between 2013 and 2016. In multivariable analyses, higher levels of both systolic (HR, 95% CI: 1.26, 1.15‐1.38) and diastolic (1.15, 1.04‐1.27) BP VIM were positively associated with risk of incident dementia (Figure A). In subgroup analyses, results were similar when stratified by age, diabetes, prior stroke, renal disease, and hypertension (Figures B‐D). For both systolic (p = 0.036) and diastolic (p = 0.043) BP VIM, risk of incident dementia was higher among patients below the age of 60 compared to those 60 and older.ConclusionVisit‐to‐visit variability in BP, a measure readily ascertainable from the EHR, is associated with increased risk for incident dementia independent of mean BP in the context of a high‐volume, real‐world patient care setting. These findings indicate the EHR derived VIM may serve as an additional tool in risk assessment for incident ADRD. Future research is needed to determine efficacy of targeted interventions aimed at lowering BP variability in clinical practice.
Biomarker modelling of Alzheimer's disease using in vivo Braak staging
Authors: Therriault Joseph , Pascoal Tharick A , Lussier Firoza Z , Tissot Cécile , Bezgin Gleb , Servaes Stijn , Benedet Andréa Lessa , Ashton Nicholas J. , Karikari Thomas K , Rodriguez Juan Lantero , Wang Yi‐Ting , Arias Jaime Fernandez , Massarweh Gassan , Soucy Jean‐Paul , Saha‐Chaudhuri Paramita , Blennow Kaj , Zetterberg Henrik , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2022

AbstractBackgroundGold standard diagnostic methods for AD rely on staging systems to measure disease severity, which have not yet been incorporated into the in vivo biological research framework for AD. The topographical information conferred by tau‐PET offers the potential to translate the gold standard histopathological Braak staging system to living individuals.MethodUsing the topographical information from [18F]MK6240 tau‐PET, we applied the Braak tau staging system to 324 living individuals. We used PET‐based Braak stage to model the trajectories of amyloid‐b, phosphorylated tau in cerebrospinal fluid (pTau181, pTau217, pTau231, pTau235) and plasma (pTau181, pTau231), neurodegeneration and cognitive symptoms.ResultPET‐based Braak stages were We identified nonlinear AD biomarker trajectories corresponding to the spatial extent of tau‐PET, with modest biomarker changes detectable by Braak stage II and significant changes occurring at stages III‐IV, followed by plateaus. Early Braak stages were associated with isolated memory impairment, while Braak stages V‐VI were incompatible with normal cognition. Follow up tau‐PET scans indicated sequential progression of in vivo Braak stages over time, with progression beyond Braak stage III requiring the presence of amyloid‐beta abnormality.ConclusionOur results support PET‐based Braak staging as a framework to model the natural history of AD, as well as monitor AD severity from presymptomatic to clinical dementia phases.
Tau‐Neurodegeneration mismatch reveals vulnerability and resilience in Alzheimer’s continuum and Non‐Alzheimer’s pathophysiology
Authors: Lyu Xueying , Duong Michael Tran , Xie Long , Richardson Hayley , de Flores Robin , DiCalogero Michael , McMillan Corey T , Robinson John , Trojanowski John Q , Grossman Murray , Lee Eddie B , Irwin David J. , Dickerson Brad C. , Xie Sharon X , Nasrallah Ilya M. , Yushkevich Paul A. , Wolk David A. , Das Sandhitsu R. 
Published: December 2022

AbstractBackgroundIn previous work (Das et al., 2021), we exploited the non‐specific nature of neurodegeneration by investigating the amount and spatial pattern of deviation from the level of neurodegeneration (N) expected for a given level of tau (T). Using a data‐driven clustering approach based on T‐N mismatch, we found phenotypes that had greater N than expected for T (“vulnerable”) and phenotypes with less N than expected for T (“resilient”) in specific patterns. Here we extend this work to include amyloid positive (A+) and negative (A‐) participants. The logic of inclusion of A‐ individuals is that areas of mismatch in A+ individuals is likely driven by factors outside of AD pathology, which can be present in the absence of AD pathology.MethodWe employed cortical thickness to represent N and 18F‐flortaucipir tracer uptake as T for 104 bilateral cortical regions of interest (ROI) in 343 symptomatic individuals including both A+ and A‐ from ADNI. We established T‐N robust regression and partitioned participants based on thresholded residuals. Longitudinal trajectories of cognitive scores were assessed with linear mixed‐effects model effect models using CDRSB as the dependent variable.ResultWe replicated prior work and obtained clusters with distinct T‐N mismatch patterns. We defined the largest group as “canonical”, as it displayed typical T‐N relationships (N∼T, low residuals). The limbic vulnerable cluster displayed N>T (negative residuals) in limbic regions, while diffuse vulnerable group displayed N>T throughout the cortex. Alternatively, the resilient (N<T, positive residuals) clusters were classified as limbic resilient or prefrontal resilient based on the pattern of this relationship. Note the highly similar regional patterns of the A+ and A‐ subgroups, supporting our hypothesis that this residual reflects non‐AD related phenomenology which could be present irrespective of amyloid status. Phenotypes differed in longitudinal cognitive trajectories. The vulnerable clusters declined significantly faster than the canonical cluster regardless of amyloid status likely attributable to the presence of non‐AD pathologies. The resilient groups tended to progress less than the canonical group.ConclusionOur findings suggest T‐N mismatch depicts vulnerability and resilience likely attributable to non‐AD factors. This may provide an approach for detecting co‐pathologies in AD continuum and benefiting therapeutic management.
Canada’s changing dementia landscape: Preliminary findings from The Landmark Study
Authors: Armstrong Joshua J. , Stiff David , Baraké Evelyn , Smetanin Paul , Guimond Josée , Sivananthan Saskia 
Published: December 2022

AbstractBackgroundAs with many nations, the prevalence of dementia in Canada is expected to rise dramatically in the upcoming decades as the population ages. The Landmark Study is aimed at updating these estimates and the broader population changes associated for the Canadian population made in the 2010 Rising Tide Report.MethodUsing the Canadian Centre for Economic Analysis’s socio‐economic statistical analysis platform, a simulation model was developed using demographic characteristics (age, sex, ethnicity) and risk factors for dementia to forecast the burden of dementia in Canada over the next 30 years. This approach allows for comparisons across sex, ethnicity, provinces, while accounting for population dynamics including immigration. The model was also used to examine how a delay in incidence (1‐year, 5‐years, 10‐years) would impact prevalence and incident cases.ResultAs expected, the model forecasts the number of Canadians with dementia to more than double in the next 30 years: 493,718 (2020; 59.6% female) to 1,296,707(2050; 61.2% female; Figure 1). With changing immigration patterns, the ethnic background of people with dementia will be quite different than today. People with Asian origin could increase from 8% of people with dementia today to 24% by 2050 (Figure 2). The changes are driven both by future immigration, and people who have already immigrated to Canada in the past. Delays in onset of 1 year would avoid over 300K cases, whereas a deferred incidence of 10 years would bring Canadian dementia rates to lower than where it is today (Figure 3). With the increase in prevalence of dementia, comes an increase in the number of informal caregivers and the number of hours providing care to persons living with dementia. The number of informal caregivers in 2020 (349,551; 472.6 million hours/year) is projected to increase in 2050 to 1,005,815 (1,386 million hours/year; Figure 4).ConclusionThis study forecasts rising dementia prevalence in Canada, illustrates the changing landscape of ethnicity in Canadians living with dementia, and estimates the population‐level impacts of interventions that delay onset of dementia would have on prevalence, incidence, and informal care.
Diagnosing Alzheimer Disease: Which Dementia Screening Tool to Use in Elderly Puerto Ricans with Mild Cognitive Impairment and Early Alzheimer Disease?
Authors: Rodriguez‐Santiago María A. , Sepulveda Vanessa , Valentin Eric Miranda , Arnold Steven E. , Jiménez‐Velázquez Ivonne Z. , Wojna Valerie 
Published: December 2022

AbstractBackgroundMost of the time, Alzheimer Disease (AD)’s diagnosis is not made at its earliest periods and prodromal stages, for instance at Mild Cognitive Impairment (MCI) and Early Alzheimer Disease (E‐AD) stage. Commonly, AD’s diagnosis is made when significant impairment interferes with the habitual daily activities (1). Our pilot study, serves to demonstrate a correlation between the screening tools, including the Mini‐mental Status Exam (MMSE), Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating Scale (CDR), and the biological biomarkers in the cerebral spinal fluid (CSF) (Amyloid Beta 1‐42 (Aβ42 pg/mL), Tau proteins (tTau (pg/mL) and tTau/Aβ42 ratio in Puerto Ricans > 55 years old with MCI and E‐AD. To our knowledge, this is the first study trying to create a correlation between memory tests scores and underlying AD pathology to improve early detection in elderly Puerto Ricans.MethodThirty participants were evaluated including, demographics, clinical characteristics, memory scales and CSF biomarkers. CSF biomarkers (Aβ42, tTau protein, and tTau/Aβ42 ratio) were determined using the Meso Scale Discovery Platform (MSD). Associations between memory scales (MOCA, MMSE, CDR) and CSF markers were performed using Spearman’s rho correlation.ResultOur study revealed statistical association in favor of a direct relationship between MMSE and tTau/Aβ42 ratio in CSF (p= .022, 95.00% CI = [‐.69, ‐.07] (Figure 1). We found a trend towards significance with an inverse relationship with MMSE and Aβ42 (p=.069) (Figure 2) and a direct relationship with MMSE and tTau (p= .098) (Figure 3). Besides, MoCA and tTau/Aβ42 ratio had a statistically significant direct relationship (p = 0.035) (Figure 4). There was no significant statistical association between CDR test with CSF biomarkers in elderly Puerto Ricans.ConclusionMMSE was the dementia screening test consistently identifying a statistically significant or a‐trend‐towards a significant association with the CSF Alzheimer Disease’ s biomarkers (Aβ42, tTau protein, and tTau/Aβ42 ratio) in elderly Puerto Ricans with MCI and E‐AD. Clinically, > 55 y/o Puerto Rican patients with MCI and E‐AD should be screened with MMSE for a higher likelihood of earlier detection and, thus, initiation of disease‐modifying treatment.
Comparing neuroimaging and cerebrospinal fluid markers of amyloid, tau, and neurodegenerative biomarkers: implications for understanding the biology of the disease
Authors: Gordon Brian A. , Wisch Julie K. , Hobbs Diana A. , McKay Nicole S. , Schultz Stephanie A. , Flores Shaney , Keefe Sarah J. , Dincer Aylin , Ances Beau M , Morris John C. , Schindler Suzanne E. , Fagan Anne M. , Benzinger Tammie L.S. 
Published: December 2022

AbstractBackgroundAlzheimer disease (AD) is a complex disorder characterized by changes in amyloid, tau, as well as neurodegeneration. Neuroimaging and cerebrospinal fluid (CSF) assays provide complimentary measures of these pathologies although the Correspondence between such biomarkers is not well elucidated.MethodsData from 313 cognitively unimpaired and 59 impaired individuals aged 45 to 91 was drawn from the Charles F. and Joanne Knight Alzheimer Disease Research Center. Participants had neuroimaging, CSF, and clinical data acquired within one year. Neuroimaging variables included summary measures of amyloid (Centiloids from either PiB or Florebetapir), tau (Flortaucipir), and atrophy (MRI cortical signature). CSF variables were the Aβ42/40 ratio, ptau181, and neurofilament light chain (NfL). Biomarker cutoffs were determined using Gaussian‐Mixture modeling as well as a Youden Index to maximally separate cognitively unimpaired individuals from those with a clinical AD diagnosis. Rank order congruence between biomarkers was determined using Kendall correlations (t).ResultsGaussian Mixture Modeling (dashed lines) and Youden Index (solid lines) approaches produced disparate cutoffs, particularly for neurodegenerative markers (NfL/atrophy) indicating the challenges inherent to binarizing continuous variables (Figure 1). Kendall’s t provide an estimate of pairwise congruence between biomarkers in cognitively unimpaired (CN, CDR=0, upper left diagonal) and impaired individuals (CI, CDR >0, lower right diagonal) (Figure 2). Measures of amyloid had generally high concordance (t ‐0.45 and ‐0.43 for CN and CI respectively ) than those of non‐specific neurodegeneration, which were quite low (t ‐0.16 and ‐0.23). Although ptau181 and tau were moderately related (t 0.21 and 0.23), ptau181 had higher Correspondence with both PET and CSF measures of amyloid. A sequential timing of biomarkers could be clearly seen when plotting z‐scored biomarkers as a function of amyloid PET (Figure 3).ConclusionsNeuroimaging and CSF markers provide complimentary information and help to deeply phenotype the AD biological cascade. While measures of amyloid are highly congruent, non‐specific markers of neurodegeneration have poor agreement., CSF measures of phosphorylated tau likely index a response to amyloidosis rather than being a marker of tau aggregation.
A More Efficient Outcome for Alzheimer Disease Research: the Item Response Theory Based Score for the Clinical Dementia Rating (CDR®)
Authors: Li Yan , Wang Guoqiao , Xiong Chengjie , Moulder Krista L. , McDade Eric , Hassenstab Jason J. , Aschenbrenner Andrew J. , Benzinger Tammie L.S. , Gordon Brian A. , Fagan Anne M. , Chatterjee Saptarshi , Cheng Yun‐Ju , Bateman Randall J. , Morris John C. 
Published: December 2022

AbstractBackgroundCDR sum of boxes (CDR‐SB) is widely used as a primary outcome in Alzheimer disease (AD) research due to its reliability and accuracy. However, it is an ordinal rank measure instead of a continuous measure and therefore may not be able to capture subtle changes in cognition. Additionally, it weights each domain equally, without accounting for the patterns of the responses scores across CDR items. To generate a more optimal score, we developed a bi‐factor model based on the item response theory (IRT) which can account for different response pattern, item difficulty and discrimination level to provide an improved estimate of the dementia severity. We demonstrated the superiority of the IRT score in two independent cohorts.MethodBaseline item level CDR data from 2949 participants enrolled in the WashU Knight ADRC study were used to develop the IRT model. The best fitting IRT model was then applied to the longitudinal item level CDR data in both the Knight ADRC and DIAN‐TU‐001 (142 participants) studies to generate the IRT scores (a continuous measure) for each participant at each visit.ResultCorrelations between the CDR IRT score and SB were consistent at different visits (0.89 ∼ 0.92 for DIAN‐TU cohort, 0.92 ∼ 0.94 for Knight ADRC cohort). The IRT score had a much larger effect size (> 60% for the DIAN‐TU cohort and > 40% for the Knight ADRC cohort) than that of CDR‐SB when comparing converter to stable cognitively normal participants. For CDR‐SB of 0 group, the IRT score was significantly associated with some of the clinical/cognitive outcomes and biomarkers. For CDR‐SB > 0 group, the IRT score had slightly higher correlations with other outcomes than CDR‐SB. The IRT score correlated better with the estimated age from dementia onset in the DIAN cohort. Using IRT score as the primary outcome in clinical trials could save 10% ∼ 30% of the sample size compared to that of using CDR‐SB.ConclusionThe CDR IRT score could potentially be used as a more efficient outcome in AD research to gain precision in detecting cognitive decline and improve power (or reduce sample size).