bluuebunny/crossref_metadata_2025_split huggingface dataset:
TNF‐β inhibitors in preventing mild cognitive impairment (MCI), dementia, and Alzheimer's disease (AD): An updated retrospective review using both EMR and claims data
Authors: Stacey Jennifer L. 
Published: December 2020

AbstractBackgroundIt is widely believed that inflammation contributes to the pathogenesis of AD. TNF‐α has been implicated in both AD and neurological inflammation. Previous research found anti‐TNF‐α therapies to be of potential benefit for preventing AD, and here updated analyses further contribute to this research while incorporating preceding diagnoses as potential outcomes.MethodPatients were identified as either receiving an anti‐TNF‐α drug (etanercept, adalimumab, certolizumab, infliximab, or golimumab) or patients who were anti‐TNF‐α naïve receiving methotrexate (MTX). Patient cohorts were generated in both an electronic medical records (EMR) research network of 59M patient lives and a 201M patient network of linked primary care data with medical and pharmacy claims. Neither cohort had MCI (ICD‐9 331.83 or ICD‐10 G31.84), dementia (ICD‐9 290 or 294.1 or 294.2 or ICD‐10 F02 or F03), or AD (ICD‐9 331.0 or ICD‐10 G30) prior to the outcome window. The risk of MCI, dementia, and AD from 1 year after first exposure to either anti‐TNF‐α or MTX were analyzed using measures of association and survival analysis conducted via Kaplan‐Meier estimator. Cohort comparisons were run with propensity score matching (PSM) to control for demographic, comorbidity, medication, and diagnostic procedure confounders.ResultThere was significant MCI, dementia, and AD prevention with anti‐TNF‐α treatment compared to MTX found in both EMR and claims data networks without and with PSM. Only exception was EMR outcomes of AD with PSM (Risk Difference 0.04%; 95% CI (‐0.003%,0.079%); p=0.0679). [See Table 1]. Time to outcomes were measured up to 7,000 days in the EMR cohort up to 6,000 days post index in the claims cohorts.ConclusionThis study provides further RWD based evidence that points to anti‐TNF‐α therapies as a beneficial therapy in the prevention of MCI, dementia, and AD. Further research is warranted to investigate these findings in larger cohorts and for outcomes to be monitored in a longer observation window.
Accuracy of test battery harmonization: Simulation results using the HRS and MHAS studies
Authors: Koscik Rebecca L , Gavett Brandon E , Ma Yue , Ilango Sindana , Eng Chloe W , Helfand Benjamin KI , Trittschuh Emily H , Mungas Dan M 
Published: December 2020

AbstractBackgroundStandardized measures of cognitive function are often used in research to understand predictors of heterogeneity in cognitive aging. Increasingly, researchers seek to pool data across studies. When assessment protocols contain overlapping items, item response theory and associated analytical techniques can be used to combine test items across studies into harmonized cognitive outcome(s). To better understand how characteristics of test item overlap impact a harmonized outcome, this study uses psychometric data from two cognitive aging studies to simulate and compare the accuracy of harmonization across six total items/overlapping items scenarios.MethodItem‐level cognitive data from 19 unique items across the Health and Retirement Study (HRS; 12 items) and the Mexican Health and Aging Study (MHAS; 10 items) were used (Table 1). Item response theory (IRT) calibration of a unidimensional model using data from the combined sample yielded item parameter and ability (theta) estimates that were then used to simulate six scenarios exploring item count and overlap combinations (19/19, 12/12, 10/10, 19/4, 19/3, and 19/1 for total/overlapping (akak “linking”) items, respectively). Briefly, simulation methods were: generate 500 simulated item‐level data sets with two groups (n = 500/group), each group having mean(sd) true ability set equal to HRS and MHAS estimates, respectively; apply IRT calibration to each simulated dataset, generating factor scores (using expected a posteriori (EAP) method); accuracy of harmonization was quantified by the difference between the IRT‐estimated factor scores and thetas for each simulated dataset using root mean square error (RMSE).ResultRMSE generally improved (decreased error) with increasing numbers of overlapping tests and linking items (Fig1). Differences between group means were poorly reproduced with <4 linking items (Fig2). The scenario representing the true overlap of three items between MHAS and HRS items (19/3) did not reproduce means(sd) well (suggesting that, without at least one additional linking item with desirable measurement properties (scenario 5), these tests may not be harmonized accurately.ConclusionFuture simulations should attempt to disentangle the effects of linking item quantity and characteristics (e.g. range of difficulty) from the effects of differences in group means and standard deviations on RMSE.
Genome wide association study of chronic traumatic encephalopathy
Authors: Atherton Kathryn , Khan Mohammed Muzamil , Shea Conor , Chung Jaeyoon , Nair Evan , Baucom Zachary H. , Abdolmohammadi Bobak , Uretsky Madeline , Martin Brett M. , Palmisano Joseph , Farrell Kurt W. , Cherry Jonathan D. , Alvarez Victor E. , Huber Bertrand R. , Alosco Michael L. , Lunetta Kathryn L. , Tripodis Yorghos , Stein Thor D. , Farrer Lindsay A. , Crary John F. , McKee Ann C. , Mez Jesse 
Published: December 2020

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). CTE has distinct neuropathology defined by perivascular hyperphosphorylated tau (ptau) deposition. The presence and severity of CTE pathology varies among those with similar RHI exposure, suggesting a role for non‐RHI risk factors, including genetics. Here we conducted the first genome‐wide association study (GWAS) of neuropathologically‐confirmed CTE.Method175 brain donors from the Veterans Affairs‐Boston University‐Concussion Legacy Foundation Brain Bank with known exposure to RHI in the form of contact sports and/or military service were assessed for CTE pathology. CTE pathology was staged on a semiquantitative scale from 0 to 4 (0 = absent; 4 = most severe). Ptau burden was also assessed across 11 brain regions commonly affected in CTE on a semiquantitative scale from 0 to 3 (0 = absent; 3 = most severe). We tested the association of genome‐wide genotyped and imputed single nucleotide polymorphisms (SNPs) with CTE stage in a linear regression model adjusted for 10 principal components of population substructure. We tested the association of top hits with ptau burden in each of the 11 brain regions.ResultTwo loci achieved genome‐wide significance: top SNP rs63565460 [minor allele frequency (MAF) = 0.08; beta = ‐1.64; p = 2.4 × 10−8] is an intronic SNP in PIP5K1B on chromosome 9; and top SNP rs12447028 (MAF = 0.07; beta = ‐1.84, p = 2.6 × 10−8) is an intronic SNP in ABAT on chromosome 16. The PIP5K1B locus had the largest effects in cortical regions. PIP5K1B is expressed in brain and has been associated with intelligence in GWAS. The ABAT locus had the largest effects in the inferior orbital gyrus and the locus coeruleus. ABAT is expressed in brain and has been associated in GWAS with anger proclivity, a symptom of CTE. The ABAT protein functions in GABA catabolism.ConclusionIn the first GWAS of CTE, two promising loci in PIP5K1B and ABAT achieved genome‐wide significance. Both loci had the largest effects in brain regions affected early in CTE. Efforts to enlarge the sample size, incorporate measures of RHI exposure and test additional endophenotypes are underway. Identified loci may implicate disease mechanisms, provide targets for therapies, and guide counseling of athletes regarding risk of play.
Association between depressive symptoms and cognitive function in older adults with type 1 and type 2 diabetes compared to those without diabetes
Authors: Lacy Mary E. , Gilsanz Paola , Eng Chloe W. , Beeri Michal Schnaider , Karter Andrew , Whitmer Rachel A. 
Published: December 2020

AbstractBackgroundDepression is a major risk factor for cognitive impairment among people with type 2 diabetes (T2D) and the general population. Depression is 3 times more prevalent among people with type 1 diabetes (T1D) than in the general population and interferes with self‐management. Understanding the association between depression and cognitive function in older adults with T1D is crucial.MethodUsing baseline data from the Study of Longevity in Diabetes (SOLID), we examined the association between depressive symptoms and cognition in older adults with T1D (n=799), T2D (n=240), and without diabetes (n=256 matched on age, sex, race/ethnicity, and education). Based on recommended guidelines, a score of >5 on the 15‐item Geriatric Depression Scale indicated presence of depressive symptoms. Cognitive function was evaluated at baseline. Factor analyses identified the following cognitive domains: executive function (Trail Making A and B, Digit Symbol Substitution, and Stroop Interference Test), language (List sorting, MINT, Phonemic and Category fluency), simple attention (Diamond and TMX cancellation), verbal episodic memory (Word List Learning), and visual episodic memory (Benson). All cognitive scores were standardized (mean=0; SD=1). Linear regression models evaluated the association between depressive symptomatology and cognitive function adjusting for age at interview, sex, race/ethnicity, and education.ResultSubjects (mean age of 67.9 years and 50.9% were female) with diabetes had a greater prevalence of depressive symptoms than those without diabetes (T1D: 9.8%; T2D: 9.2%; no diabetes: 2.7%; chi‐square p‐value=0.002). In T1D, depression was associated with poorer performance on the language, executive function, and verbal episodic memory domains (Table 1). In T2D, depression was associated with poorer performance on the executive function domain. There was no observed association between depression and cognitive function among those without diabetes.ConclusionAmong older individuals with T1D, depressive symptoms were associated with lower scores on a range of cognitive domains. By contrast, depressive symptoms were only associated with executive function in T2D and were not associated with any cognitive domains in those without diabetes. Our findings underscore the importance of mental health as a key component of healthy aging in older adults with T1D and T2D.
Is statin related to conversion of mild cognitive impairment to dementia?
Authors: Cintra Marco Túlio , Ávila Rafaela , Lage Ariane Flávia , de Oliveira Hansen Erika , Costa Mônica Vieira , Rocha Divino Pedro Alves , Bicalho Maria Aparecida 
Published: December 2020

AbstractBackgroundAlthough randomized controlled trials have not confirmed cognitive impairing effects of statins, continuing evidence suggests statins have the ability to cause reversible cognitive impairment in some patients. Paradoxically, statins have also been shown to decrease risk of dementia, Alzheimer’s disease, and to improve cognitive impairment in some cases. However, randomized controlled trials have similarly failed to find the beneficial effect. We conducted evaluate the effect of statin on the conversion of mild cognitive impairment (MCI) to dementia in a Cohort of elderly individuals without functional and cognitive impaiment (NC) and with MCI patients.MethodCohort was reassessed annually by geriatricians and neuropsychologists for an average period of 3.01 ± 1.43 years. The effect of statin on cognition was evaluated when it was in use throughout the follow‐up period and, it was in use at any time during the follow‐up. Chi‐square and Fisher tests (categorical variables) and student t tests, ANOVA, Mann Whiney (continuous variables) were used.Results176 individuals were selected (53 CG, 111 with amnestic MCI ‐ aMCI‐ and 12 with non‐amnestic MCI ‐naMCI), aged 76.52 ± 7.27 years, 69% female and 3.61 ± 3.23 years of schooling. We observed conversion of aMCI to dementia in 27 participants (92.6% Alzheimer dementia), corresponding to a conversion rate of 24.3%. In the aMCI group, the remission rate was 13.5%. 51.1% of the sample received statin at some point during the follow‐up and 30.7% used it throughout the study. 98.8% of prescribed statins had moderate potency. Comparing stable MCI group throughout the study with the group which progressed to dementia, the group that used it any time during the follow‐up analysis showed a p‐value of 0.104, whereas the group that used it during the entire follow‐up showed a p‐value of 0.166. Comparing remission and conversion groups, the one that used statin any time during the follow‐up showed a p‐value of 0.542, patients who received statin during the entire follow‐up had a p‐value of 0.746.ConclusionStatins were not associated with conversion from aMCI to dementia, even when used throughout the entire follow‐up.
Association of cerebral white matter disease with cardiovascular risk factors, amyloid accumulation, and cognition
Authors: Cody Karly Alex , Berman Sara E , Koscik Rebecca L. , Rivera‐Rivera Leonardo A , Hoffman Carson A , Erickson Claire M , Mueller Kimberly D , Clark Lindsay R , Chin Nathaniel A. , Christian Bradley T , Rowley Howard A. , Wieben Oliver , Johnson Kevin M , Betthauser Tobey J , Johnson Sterling C. , Eisenmenger Laura 
Published: December 2020

AbstractBackgroundUnderstanding cerebrovascular health in Alzheimer’s disease (AD) is vital, as the majority of individuals with dementia due to AD are also found to have vascular disease at autopsy. We examined the relationships between centrally and peripherally measured vascular health markers and amyloid accumulation across the AD clinical spectrum.MethodCerebral white matter (WM) disease was determined by a neuroradiologist using the Cardiovascular Health Study (CHS) score in 236 individuals (75% cognitively healthy, 25% cognitively impaired; Table 1) from the Wisconsin ADRC and WRAP cohorts. A subset (n = 73) of individuals completed [C‐11]PiB PET imaging. Metrics of internal carotid arterial (ICA) health assessed by 4D‐flow MRI as well as WM hyperintensity lesion volume (WMH‐LV), amyloid accumulation, vascular risk factors, and cognitive status were examined across individuals with high (≥3) and low (<3) CHS scores (Table 2, Figures 1 & 2). A threshold for vascular positivity (V+/‐) was identified as 1.5SD>the mean %WMH‐LV of total intracranial volume in individuals with CHS<3. Participants were classified according to their amyloid and vascular positivity status.ResultIn the larger dataset (n = 236), individuals with CHS≥3 were significantly older, more likely to be cognitively impaired, and demonstrated higher pulse pressure, lower cholesterol, and greater %WMH‐LV (Table 1, Figure 1). There was no difference between CHS groups in average ICA blood flow, ICA pulse wave velocity, or global PiB accumulation (Table 2). Neither CHS rating nor %WMH‐LV were associated with amyloid (Spearman’s rho = ‐.128, p = .280; Spearman’s rho = .078, p = .511, respectively). When using %WMH‐LV as a biomarker for cerebrovascular health, the vascular positivity threshold was 0.409%. In individuals with amyloid imaging, 54.8%(38/73) were V‐/A‐, 8.2%(8/73) were V+/A‐, 34.2%(24/73) were V‐/A+, and (2/73)0.8% were V+/A+. CHS rating and vascular positivity were not related to cognitive diagnosis in the amyloid imaging subset (Figure 2).ConclusionElevated cerebral WM disease (CHS≥3) was related to greater WMH lesion burden, but not blood flow or pulse wave velocity of the ICAs. Thus far, in this sample spanning the continuum of AD, neuroimaging measures of vascular health were not related to amyloid, suggesting independence of these pathologies. Investigations into the associations between amyloid, cerebrovascular health, and cognition are ongoing as more data become available.
Lower neocortical tau burden distinguishes Alzheimer’s pathology occurring with vs. without primary non‐Alzheimer’s pathology
Authors: Phillips Jeffrey S , Cousins Katheryn Alexandra Quilico , Irwin David J , Wolk David A , Lee Eddie B , Gibbons Garrett S , McMillan Corey T , Trojanowski John Q , Grossman Murray 
Published: December 2020

AbstractBackgroundThe NIA/AA research framework proposes a biological definition of Alzheimer’s disease (AD) based on the presence of both amyloid and tau. However, AD frequently co‐occurs with other non‐AD pathologies, and it is unclear how these pathologies affect the progression of AD‐associated amyloid‐β and tau. We investigated regional heterogeneity in AD pathology in a postmortem sample of either pure AD or co‐occurring non‐AD and AD pathology. We hypothesized that amyloid‐β and tau would be more likely to co‐localize in pure AD than in the mixed‐pathology group.MethodWe retrospectively identified two groups with intermediate or high levels of AD pathologic change by ABC criteria: 1) cases with a pathologic diagnosis of AD (AD‐pure; n=92) and minimal co‐pathology; and 2) those with a primary non‐AD pathology (frontotemporal lobar degeneration due to tau or TDP‐43; dementia with Lewy bodies; Parkinson’s disease; or amyotrophic lateral sclerosis) coupled with AD co‐pathology (AD co‐path; n=68). Primary outcomes were ordinal ratings (0‐3) of postmortem amyloid‐β and tau burden in the amygdala, entorhinal cortex, CA1/subiculum, superior/middle temporal gyrus, middle frontal gyrus, and angular gyrus; positivity was assessed by ratings of 2‐3.ResultThe AD‐pure group was younger at death (M=74.3, SD=12.2) than AD co‐path (M=78.6, SD=7.9) and was more likely to have high AD pathologic change (OR=18.0, p<0.0001). The AD co‐path group had fewer regions positive for both amyloid‐β and tau (M=0.50, SD=0.27) than the AD‐pure group (M=0.87, SD=0.23), independent of age and Braak stage. AD‐singular patients were more likely than AD co‐path patients to be tau‐positive in middle frontal (84% vs. 21%), angular (84% vs. 29%), and superior/middle temporal cortex (88% vs. 41%). A logistic regression model based on tau ratings in these three neocortical regions distinguished AD‐pure and AD co‐path with 82.4% accuracy. When the analysis was stratified by Braak stage, differences in neocortical tau were limited to Braak V/VI cases.ConclusionAutopsy data indicate AD co‐path cases may have lower neocortical tau burden than AD‐singular cases at end of life. These postmortem findings suggest that AD co‐path cases may be identifiable during life by assessing neocortical tau distribution using tau‐binding PET ligands.
Sex‐associated differences in pathology burden in early‐onset Alzheimer’s disease
Authors: Groh Jenna Rae , Stage Eddie , Logan Paige E. , Iaccarino Leonardo , Joie Renaud , Aisen Paul S , Eloyan Ani , Fagan Anne M. , Foroud Tatiana M. , Gatsonis Constantine , Jack Clifford R. , kramer Joel H. , Koeppe Robert A. , Saykin Andrew J. , Toga Arthur W. , Vemuri Prashanthi , Day Gregory S. , Graff‐Radford Neill R. , Honig Lawrence S. , Jones David T. , Masdeu Joseph C. , Mendez Mario F. , Onyike Chiadi U. , Rogalski Emily J. , Carrillo Maria C. , Dickerson Brad C. , Apostolova Liana G. 
Published: December 2020

AbstractBackgroundPrevious research has suggested that, compared to males, females are at greater risk for and have greater pathology burden in late onset. However, sex differences in early onset AD (EOAD) have not yet been studied.MethodWe included 167 participants [28 cognitively normal (CN, 68% females), 98 early onset AD (EOAD, 55% females), and 41 cognitively impaired amyloid‐negative (EOnonAD, 31% females] subjects from the Longitudinal Early‐Onset AD Study (LEADS) with available Flortaucipir PET, Florbetaben PET, and MRI data. Multiple linear regression (MLR) models including age and MMSE as covariates were used in the pooled sample to examine the effects of sex on hippocampal and white matter hyperintensity volume, mean cortical thickness, mean tau distribution by Braak regions and mean cortical amyloid SUVR. We also ran voxelwise MLR with sex as the predictor and cortical thickness, amyloid SUVR normalized to whole cerebellum, tau SUVR normalized to cerebellar crus, respectively, as the outcome measures while controlling for age, MMSE, and total intracranial volume (MRI only). Results are displayed at a cluster‐level FWE correction of p<0.05.ResultThere were no significant demographic differences between males and females in any diagnostic group. Across the pooled sample females showed significantly greater atrophy of the hippocampus (p=0.0001), greater tau SUVR in Braak regions 3&4 (p=0.05) and 5&6 (p=0.04) and trend for greater global amyloid uptake (p=0.074) (Table 2). The analyses in imaging space confirmed these findings and showed that the effects are driven by the EOAD group. Females showed greater amyloid deposition globally and greater tau deposition in the frontal, inferior parietal and temporal lobes (Figure 3).ConclusionFemale sex is associated with greater pathology burden in EOAD. Longitudinal studies will be needed to establish whether such difference translates in faster rates of progression in women relative to men.
Tau isoforms drive differential transposable element and gene expression
Authors: Grundman Jennifer Ann , Spencer Brian , Rissman Robert A. 
Published: December 2020

AbstractBackgroundTau isoform overexpression differs in several neurodegenerative. For instance, Alzheimer’s disease (AD) is characterized by overexpression of 3R and 4R tau, while progressive supranuclear palsy (PSP) and Pick’s disease (PiD) show overexpression of 4R and 3R tau, respectively. Tau’s role in nuclear processes have only just begun to draw focus, with studies showing it binds protectively to DNA and can contribute to heterochromatin relaxation (Sultan et al., 2011; Frost et al., 2014). Recently, tau has been implicated in activating transposable elements (TEs), which are normally repressed and can trigger immune responses and genomic stress (Guo et al., 2018; Sun et al., 2018). Yet tau isoforms’ role in these phenomena has not been examined and may reveal new details of tau‐driven pathology.MethodSH‐SY5Y cells were differentiated and infected with lentiviral constructs of 0N3R tau, 2N4R tau, a 1:1 split of 0N3R and 2N4R, or a control construct before treatment with DMSO or Aβ‐42 oligomers. DNA damage and tau translocation were assessed using immunofluorescence and immunoblotting. RNA sequencing was performed and differential gene and TE expression measured using DESeq2 and TEtranscripts, respectively. For all cell‐based experiments, N=3. Further analysis was performed on RNA‐sequencing data of AD, PSP, and control patients (N=20 for each group), which is publicly available through AMP‐AD Knowledge Portal (doi:10.1038/sdata.2016.89).ResultResults revealed more significant differences in gene and TE expression in the presence of overexpressed 4R tau than in overexpressed 3R tau alone. The most dysregulated TEs were ERVs, though all samples overexpressing tau showed dysregulation of LINEs. Notably, 4R tau overexpression also showed downregulation of nuclear processes and the ribosome.ConclusionThese results provide novel insights into the effects of different tau isoforms and their interactions with Aβ‐42 and is the first study to show that tau isoforms uniquely affect TE expression. Our study bolsters support for future research into tau isoforms and tau‐driven activation of TEs and potential therapeutics that target them.