bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trajectories in Depressive Symptoms and Midlife Brain Health
Authors: Dintica Christina S. , Habes Mohamad , Erus Guray , Schreiner Pamela J. , Yaffe Kristine 
Published: December 2023

AbstractBackgroundEvidence in older adults suggests that depressive symptoms may be part of prodromal mood changes in dementia, rather than a risk factor. However, it is unclear whether variations in depressive symptoms in adulthood exhibit distinct characteristics in brain structure and cognitive function in midlife.MethodsFrom the Coronary Artery Risk Development in Young Adults study, we identified 662 Black and White participants (age 23‐36 at baseline) who completed the Center for Epidemiological Studies Depression scale (CES‐D) at six time points over 20 years. 20 years after baseline, the participants underwent magnetic resonance imaging to characterize gray matter (GM) structures (total GM, temporal cortex, hippocampus, and entorhinal cortex) and white matter hyperintensities (WMHs). Participants also completed neuropsychological tests including the Digit Symbol Substitution Test (DSST), Rey‐Auditory Verbal Learning Test (RAVLT), Stroop Test, Montreal Cognitive Assessment (MoCA), and category and letter fluency tests, analyzed as z‐scores.ResultsUsing growth mixture modeling, we identified four trajectories of depressive symptoms (Figure 1): consistently low scorers (“steady low”; n = 509, 76.9%), a class with an early peak and decline in symptoms (“declining”; n = 63, 9.5%), a class with late increases in symptoms (“increasing”; n = 49, 7.4%), and consistently high scorers (“steady high”; n = 41, 6.2%). Compared to the steady low class, the steady high class had lower entorhinal cortex volume (β: ‐180.80, 95% CI: ‐336.69 to ‐24.91). The increasing class, had more WMHs (β: 0.55, 95% CI: 0.22 to 0.89) and less total brain volume (β: ‐9269.25, 95% CI: ‐17104.67 to ‐1444.82). Both the steady high and the increasing classes had poorer performance on the Stroop task (β: ‐0.40, 95% CI: ‐0.70 to ‐0.10; β: ‐0.39, 95% CI: ‐0.64 to ‐0.14, respectively), however the steady high also had poorer DSST performance (β: ‐0.40, 95% CI: ‐0.67 to ‐0.13), while the increasing class had poorer performance on the MoCA (β: ‐1.20, 95% CI: ‐2.04 to ‐0.37). The declining group was not significantly different from the steady low group on any brain or cognitive measures.ConclusionsOur findings suggest that trajectories in depressive symptoms in young to mid‐adulthood show different cognitive and brain phenotypes in midlife.
Prophylactic effect of passive immunotherapy with tau antibody 43D in 3xTg‐AD mice
Authors: Dai Chunling , Gong Cheng‐Xin , Iqbal Khalid 
Published: December 2023

AbstractBackgroundAccumulation of abnormally hyperphosphorylated tau protein is a histopathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Immunotherapy targeting tau represents a promising disease‐modifying therapeutic strategy for treating AD. We have found that immunization with monoclonal 43D antibody against tau 6‐18 weekly for 6 weeks can inhibit the seeding and spread of tau pathology templated by AD hyperphosphorylated tau, reduce both tau and Aβ pathologies and rescue cognitive impairment in 3xTg‐AD mice at mild to moderate stage of the disease. In this study, we investigated whether tau immunization with 43D prior to the onset of AD‐like pathologies can reduce AD‐like pathologies and improve cognitive function in 3xTg‐AD mice.MethodsWe immunized 3‐ to 4‐month‐old female 3×Tg‐AD mice with nine monthly doses of 15 µg of mouse monoclonal antibody 43D or, as a control, of mouse immunoglobulin G (IgG) intravenously. Age‐matched wild‐type mice treated with mouse IgG were also used as controls. The effect of immunization on cognition was analyzed by using one‐trial novel object recognition test and Morris water maze test, and the effect on tau pathology was assessed by Western blot.ResultsWe found that 3xTg‐AD mice exhibited cognitive impairment as compared to the WT mice, as determined by novel object recognition test and Morris water maze test, and that immunization with 43D antibody improved the cognitive function seen in both tests. Immunization with 43D also decreased tau pathologies in the 3xTg‐AD mice. Additionally, long‐term treatment with 43D antibody did not display side events in 3xTg‐AD mice.ConclusionsThese findings suggest that passive immunization with 43D antibody targeting proximal N‐terminal domain tau 6‐18 may be as both prophylactic and therapeutic approaches for treating AD and related tauopathies.
Development of a web application for cognitive and functional assessment for dementia screening for Thai population
Authors: Senanarong Vorapun , Piyaamornpan Nattaporn , Srisuwannanukorn Suwat , Tangthamrongthanawat Kosit , Mekhasingharak Pornsawan , Rattanabannakit Chatchawan , Wongkom Natthamon , Hunnangkul Saowalak 
Published: December 2023

AbstractBackgroundTools for web‐based testing to detect cognitive impairment are still underdeveloped in Thailand. Our aim was to generate a web‐based instrument to assess cognitive and functional abilities and to explore its ability for diagnosis of dementia and MCI.MethodWe have developed a web application for cognitive and functional assessment to detect cognitive impairment. We hoped that subjects or family members could use this web‐based tests at home as self‐screening. These web‐based tests included an electronic version of the Thai Mental State Examination (e‐TMSE), a clock drawing test, a category verbal fluency test, a short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), and Thai activities of daily living scale (Thai ADL). Correlations, receiver operator curves (ROCs), sensitivity, and specificity were analyzed using SPSS (version 18).ResultA total of 198 participants (69% female, mean age 66.7 ± 10 years). 57.1% had education of more than 6 years. Forty‐four were Major Neurocognitive Disorder, fifty‐eight were Mild Neurocognitive Disorder (MCI), and ninety‐six were normal controls. The e‐TMSE correlated with both paper‐pencil based TMSE(r = 0.80,p<0.001) as well as clock drawing test (r = 0.470 p<0.001). There were also statistically significant high correlations between digital and paper & pencil tests (e.g, category verbal fluency test, A short form of the IQCODE, and ADL). For diagnosis of dementia, e‐TMSE achieved an AUC of 0.84 (95% bootstrapped CI [0.78, 0.90]. The cut‐off score ≤23 offered sensitivity and specificity of 88.6% and 70.1% respectively. For diagnosis of dementia with the combination of 5 e‐tests, the AUC was 0.832 (p<0.001), while for MCI diagnosis, the AUC was 0.615 (p = 0.013). The area under the ROC of the IQCODE combined with ADL scale test was 0.907 (p<0.001).ConclusionWe demonstrated that our web application that included: e‐TMSE, clock drawing test, category verbal fluency test, IQCODE and Thai‐ADL scale showed good correlation between digital vs paper‐pencil tests. Individual e‐test and combination of them can offer self screening for MCI and dementia.
A genome‐wide association study of LATE‐NC (limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change) reveals a distinct genetic architecture
Authors: Yang Hyun‐Sik , Mukherjee Shubhabrata , Latimer Caitlin S , Teng Ling , White Charles C , Yu Lei , Sperling Reisa A. , Larson Eric B , Crane Paul K , Keene C Dirk , Bennett David A. A , Schneider Julie A , De Jager Philip L 
Published: December 2023

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is the third leading cause of late‐life dementia. However, its pathophysiology remains largely unknown, and the relationship of LATE‐NC with Alzheimer’s disease (AD) pathology and frontotemporal lobar degeneration‐TDP (FTLD‐TDP) remains unclear. To address this knowledge gap, we performed a genome‐wide association study (GWAS) of LATE‐NC.MethodDeceased participants of European ancestry from the Religious Orders Study, the Rush Memory and Aging Project (ROSMAP, n = 1,379), and the Adult Changes in Thought study (ACT, n = 459) were included in our study. The primary phenotypes were LATE‐NC burden (a multi‐regional semi‐quantitative TDP‐43 composite, continuous) in ROSMAP, and the presence/absence of LATE‐NC (binary) in ACT, assessed with post‐mortem TDP‐43 immunohistochemistry. Quantitative amyloid‐β (Aβ) and paired helical filament tau (PHFtau) burden were also examined in ROSMAP. GWAS was performed using linear (ROSMAP) or logistic (ACT) additive models. We controlled age, sex, genotyping platforms, and the first three genotype principal components. Sample size‐weighted GWAS meta‐analysis (total n = 1,838) was performed by combining p‐values considering the direction of the association. Confounding and moderating effects of AD pathology on LATE‐NC risk variants were examined in ROSMAP.ResultWe observed two genome‐wide significant risk loci (p<5.0×10−8) in APOE (ε4) and SHANK2 (s146617441G, allele frequency 0.021). In ROSMAP, APOE ε4 was associated with higher LATE‐NC burden after controlling for quantitative Aβ and PHFtau (beta = 0.27, p = 7.3×10−6), and the APOE ε4 – LATE‐NC association was present in the subgroup without detectable Aβ (n = 170, beta = 0.50, p = 0.025). rs146617441G was not directly associated with quantitative Aβ or tau. Instead, rs146617441G×Aβ interaction term was associated with higher LATE‐NC burden (beta = 0.25, p = 0.032), suggesting the synergy between Aβ‐dependent and LATE‐NC‐specific pathways in LATE‐NC pathogenesis. Three additional loci reached a pre‐specified suggestive p‐value threshold (p<1.0×10−6; CMTM7 [rs56284874G], RNF145 [rs111653954T], and CACNA2D3 [rs71303704C]). A previously reported FTLD‐TDP risk locus in TMEM106B (rs1990622A) showed a weaker positive association with LATE‐NC (meta‐analysis p = 9.6×10−4).ConclusionOur GWAS revealed LATE‐NC‐specific risk loci (SHANK2 and other suggestive loci). The unique genetic architecture of LATE‐NC further supports the distinction between LATE‐NC and FTLD‐TDP, and the AD‐independent effect of APOE ε4 on LATE‐NC highlights the pleiotropic role of APOE in neurodegeneration.
“The place where danger waits”: Ten years of the 1994 Crime Bill incarceration on cognitive function in older adults racialized as Black
Authors: Adkins‐Jackson Paris AJ , Gobaud Ariana N , Kim Boeun , Higgins Cesar , Bailey Zinzi D , Hardeman Rachel R , Ford Tiffany N , Matz Meies‐Amor Blagburn , Uzzi Mudia , Gee Gilbert , Szanton Sarah L , Avila Justina F , Manly Jennifer J. 
Published: December 2023

AbstractBackgroundStructural racism may drive the constellation of structural determinants that increase racialized disparities in the risk for Alzheimer’s disease related dementias (ADRD). Structural racism via adverse policing increases exposure to negative police encounters that produce heightened vigilance, anxiety, and depressed mood in persons racialized as Black. Seminal research suggests high‐police contact and disparities in Black‐White incarceration are positively associated with risk for other health conditions. It is feasible that cumulative stress from anticipatory and recurrent police encounters disrupts the body’s homeostasis leading to accelerated cognitive aging.MethodWe used US county‐level incarceration data to compute the Black‐White difference in prison and jail rates for US counties between 1995‐2005 (succeeding the 1994 Crime Bill). We then averaged the decade and linked said data by county to individual‐level health data for participants racialized as Black >50 years in the Health and Retirement Study (N = 2,300) who completed the core interview between 2006‐18 (mean observation of 3.4 per participant). Cognitive function was assessed using a 27‐item global cognitive score from the modified Telephone Interview for Cognitive Status. A mixed effects model was used to estimate the cognitive effect of a one‐unit change in incarceration (1,000 additional persons racialized as Black compared to White) with covariates of age at baseline, gender, education, and living arrangement.ResultGreater Black‐White 10‐year difference in prison population was significantly associated with worse 2006 cognitive function (β ‐1.08, SE .45, 95% CI ‐1.96,‐.22). The adjusted model was significant for Black‐White difference in prison population with cognitive decline starting in 2006 (β .011, SE .006, 95% CI ‐.001, .023). The Black‐White difference in jail population was not significant.ConclusionTen‐year Black‐White disparities in prison population are associated with cognitive decline among people racialized as Black starting one year later. While the 1994 Crime Bill is a decades‐old federal policy, it put into place a fiscal infrastructure which local governments continue to use to fund prisons, increase average prison time, and implement adverse policing quotas. These findings suggest structural racism via adverse policing is meaningful to explore in the context of ADRD.
Associations of objective and subjective neighborhood measures with cognitive change in a repeated measurement burst design
Authors: Hyun Jinshil , Katz Mindy J. , Derby Carol A. , Wang Cuiling , Lovasi Gina S , Sliwinski Martin J. , Lipton Richard B. 
Published: December 2023

AbstractBackgroundPrior studies have reported associations between neighborhood characteristics and late‐life cognition. These studies assessed neighborhood using either objective (e.g., area‐level data from public database) or subjective (individual‐level perception) measures. However, little research has been done to examine effects of objective and subjective measures simultaneously. The present study aims to investigate the independent associations of objective and subjective neighborhood characteristics with cognitive change in older adults.MethodParticipants include 316 individuals in the Einstein Aging Study (mean age = 77; 67% females; 45% non‐Hispanic Whites, 40% non‐Hispanic Blacks). Subjective neighborhood measures included perceived neighborhood safety, aesthetic quality, social cohesion, and availability of healthy foods (range = 1 poor to 5 excellent). Objective neighborhood measures included violent crime, neighborhood deprivation, volunteering rates, percentage of healthy food retailers, and low access to healthy food. Processing speed was assessed using the brief, smartphone‐administered Symbol Search Test, and was completed 6x/day over two weeks; this was repeated annually from 2017 to 2022. To account for non‐linear retest/practice effects, double negative exponential models were used to estimate the relation of neighborhood measures to asymptotic performance (i.e., fastest response time) at baseline and to change in asymptotic performance over time.ResultMost subjective and objective neighborhood measures were significantly correlated with each other (Table 1). In models containing both objective and subjective neighborhood measures, better perceived safety was associated with greater annual improvement in asymptotic performance (40 milliseconds/year for one point increase in safety) while the objective measure of violent crime was not. Perceived availability of healthy foods was independently associated with a faster baseline asymptotic processing speed (estimate = 160 milliseconds) and with greater annual improvement rate (estimate = 54 milliseconds/year) while the objective measures of food environment were not (Table 2).ConclusionSubjective rather than objective neighborhood characteristics were strongly associated with annual rates of change in processing speed over five years in community‐dwelling older adults. Perception of one’s neighborhood may be a more proximal predictor of cognitive health as it may reflect an individual’s lived experiences and determine one’s psychological states and health‐related behaviors. Alternatively, more fine‐grained objective neighborhood measures (e.g., individual‐level) would be necessary to better characterize objective neighborhood environments.
Plasma Alzheimer biomarker correlates of cerebrovascular disease in adults with Down syndrome
Authors: Edwards Natalie C. , Lao Patrick J. , Sedaghat Amirreza , Rizvi Batool , O'Bryant Sid E. , Mapstone Mark , Tudorascu Dana , Handen Benjamin L. , Christian Bradley T. , Wilcock Donna M. , Gutierrez Jose , Head Elizabeth , Brickman Adam M. 
Published: December 2023

AbstractBackgroundBy age 40 over 90% of adults with Down syndrome (DS) develop Alzheimer’s disease (AD) pathology and most progress to dementia. Despite having fewer systemic vascular risk factors than neurotypical adults, recent studies demonstrate evidence of significant cerebrovascular disease in individuals with DS that track with the clinical progression of AD, suggesting a role for cerebrovascular disease that is not attributable solely to exposure to vascular risk factors. In the current study, we examined the codependency between white matter hyperintensity (WMH) volume, a marker of small vessel cerebrovascular disease, and AD pathophysiology, indexed with plasma AD biomarkers, in adults with DS.MethodOne hundred eighty‐seven participants from the Alzheimer Biomarkers Consortium – Down Syndrome (mean[SD] = 45.1[9.4] years) with available MRI and plasma biomarker data were included in the study. Whole‐brain WMH volumes were derived from T2‐weighted FLAIR MRI scans with in‐house software and plasma p‐tau217, Aβ42/Aβ40, and neurofilament light (NfL) concentrations were measured with SIMOA assays. Separate general linear models tested the association of WMH volume with each of the three biomarker concentrations; subsequent models were stratified by age, based on the median (46 years old).ResultHigher WMH volume was associated with increased p‐tau217 and NfL concentrations but not with Aβ. In stratified analyses, the association between WMH and NfL concentration was stronger in younger adults than in older adults whereas the association between WMH and p‐tau217 concentration was stronger in older adults than in younger adults.ConclusionOur findings suggest a co‐dependency of cerebrovascular disease with tau pathology and neurodegeneration in adults with Down syndrome. Cerebrovascular disease may promote neurodegenerative changes in early adulthood and tau changes in later adulthood. The additional or alternative possibility that tau and neurodegeneration promote white matter changes cannot be ruled out in these cross sectional analyses. Future work will address the relative temporal emergence of these markers in adults with DS.
How are early career dementia researchers considered and supported by national dementia plans and dementia‐specific charities and associations? An overview of global policy approaches
Authors: Karamacoska Diana , Heins Pasclae , Branco Rita Maldonado , Wallcook Sarah , Truong Annie , Leung Isabella Hoi Kei , Sawan Mouna J , Page Zara A , Borelli Wyllians Vendramini , Arroyo‐Miranda Mirna L , Demnitz Naiara , Folarin Royhaan , Guo Tengfei , Shaaban C. Elizabeth , Smith Adam , Bartels Sara 
Published: December 2023

AbstractBackgroundEarly career dementia researchers (ECDRs) represent a crucial workforce to drive dementia research. Many charities, research leaders, and pressure groups, along with people living with dementia, continue to advocate for greater investment in dementia research. It remains unclear how ECDRs are being supported in this push for research through top‐down policy approaches. This study aimed to understand how ECDRs are considered and supported by national dementia plans or strategies across countries, and dementia‐specific charities and associations.MethodForty‐six countries from the G20 member states were evaluated. Each country’s dementia plan or strategy was reviewed alongside the policies of one governmental and one non‐governmental funding body. Data were gathered through internet searches and information requests to contacts at relevant organisations in each country. Data targeting support for ECDRs were extracted and subject to content analysis using inductive coding. Findings regarding ECDR support were categorised and narratively synthesised.ResultDespite efforts to contact stakeholders directly, little to no information could be obtained from some countries due to language barriers. While most G20 member states have a national dementia plan or strategy, only China, the U.S. (excluding Puerto Rico), England, Scotland, Greece, and Denmark specifically mentioned ECDR support in their national policy, referring to creating specific ECDR funding and career opportunities. Thirteen countries were identified as providing targeted support for ECDRs via dementia‐specific charities or associations. This ECDR support reflected the following four categories: (1) research funding, such as fellowships and research grants; (2) research dissemination and networking, e.g., grants for printing a doctoral thesis or conference travel grants; (3) training and career development opportunities; and (4) research advice, including mentoring programs and grant writing assistance.ConclusionECDR support varied greatly across the G20 member states, with few formally recognising ECDRs in their national dementia plan or strategy, and mixed support provided by dementia‐specific charities and associations or government bodies. Overall, ECDRs were not considered in dementia plans and strategies in the majority of included countries, and discrepancies between support levels exist across countries. To facilitate equal prospects for ECDRs, top‐down policy approaches are urged to enhance their efforts in the future.
Middle Age Prevention of Future Alzheimer’s Disease and Related Dementias with Intensive Treatment of Hypertension: Middle PATH Clinical Trial Proposal
Authors: Pruzin Jeremy J. 
Published: December 2023

AbstractStrong epidemiological evidence from multiple studies suggests that elevated systolic blood pressure (SBP) in midlife is a risk factor for Alzheimer’s disease and Related Dementias (ADRD) later in life. The most common neuropathology of biomarker‐confirmed AD is combined AD neuropathological changes and cerebrovascular disease. Hypertension is a leading cause of cerebrovascular disease. The SPRINT MIND trial demonstrated that a goal SBP<120 mm Hg reduced risk for combined mild cognitive impairment (MCI) and dementia by 15% in older individuals compared to a goal SBP<140 mm Hg. SBP can be safely treated with inexpensive medications. Despite being potentially safe and cost‐effective, with strong supporting evidence for benefit, intensive SBP lowering in midlife to reduce future ADRD risk has never been studied, likely because clinical outcomes of MCI and dementia are not practical in this age range in a trial that is usually limited to about 5 years. Elevated SBP is a major risk factor for white matter hyperintensity volume (WMHV) accumulation, an MRI marker with extensive evidence demonstrating this to be associated with and predictive of incident ADRD, making WMHV a suitable surrogate outcome for the initial trial period. While we acknowledge the challenges of using a surrogate outcome, there is no suitable alternative when testing interventions to lower future ADRD risk starting in middle age, a strategy that we believe is essential. The Alzheimer’s Prevention Initiative and Wake Forest have formed a collaboration to investigate the effect of goal SBP<120 mm Hg compared to the SBP achieved by enhanced usual care (SBP≥135 mm Hg) on annualized rate of WMHV accumulation in persons ages 45‐65 who have some existing vascular risk at baseline. Secondary outcomes of changes in AD blood biomarkers and relevant cognitive test scores will help elucidate whether and how SBP and AD are interactive or independent deleterious pathophysiological processes. The intention, should the initial phase prove successful, is to continue and expand the trial until a clinical benefit can definitively be assessed.