bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unique cognitive trajectories associated with inflammatory markers of blood‐brain barrier permeability in atrial fibrillation: An analysis of the Cardiovascular Health Study Cohort
Authors: Marion Danielle , Li Zhe , Roseborough Austyn D , Whitehead Shawn N , Freeman Ellen , Birnie David , Elahi Fanny M , Hachinski Vladimir , Elkind Mitchell S.V. , Lopez Oscar L. , Longstreth W.T. , Edwards Jodi D. 
Published: December 2023

AbstractBackgroundAtrial fibrillation (AF) increases risk of cognitive decline independent of stroke, but mechanisms remain unclear. Elevated levels of peripheral inflammatory markers common in AF are associated with increased blood‐brain barrier (BBB) permeability and may contribute to neuroinflammation and degeneration. To examine the role of these markers in dementia risk, we estimated associations of plasma C‐reactive protein (CRP), interleukin‐6 (IL‐6), and fibrinogen with dementia and cognitive decline in aging adults with and without AF.MethodDementia free adults aged ≥ 65 years were identified from the Cardiovascular Health Cognition Study. Exposures were plasma CRP, IL‐6, and fibrinogen at baseline and follow‐up and primary outcomes were dementia and cognitive function, measured and adjudicated annually with the Modified Mini‐Mental State Examination (3MS). Competing risks Cox proportional hazards regression was used to estimate associations between time‐varying exposures and dementia. Latent class growth models were used to identify cognitive trajectories adjusted binomial logistic regression to test associations between these trajectories and baseline markers. All models were stratified by AF status, with interaction terms for sex and apolipoprotein E (APOE) ε4 status.ResultAmong 3,375 adults (505 with AF and 2,870 without), 480 developed dementia over a median follow‐up of 9.3 years. No associations between inflammatory markers and dementia hazard were observed, but latent class analyses identified two unique cognitive trajectories, with 82% showing a stable trajectory and 18% showing rapidly progressing decline. Among those with AF, elevated CRP and IL‐6 increased the odds of cognitive decline by 10% (95% CI 1.05 – 1.15) and 32% (95% CI 1.22 – 1.44), respectively. Sex‐specific models indicated that a 1g/L increase in fibrinogen increased the odds of cognitive decline by 57% among females with AF only (95% CI 1.36‐1.81). Among those with AF, inflammatory markers were more positively associated with cognitive decline in the presence of the APOE ε4 allele.ConclusionElevated IL‐6 was associated with cognitive decline in aging adults both with and without AF and elevated CRP and fibrinogen were associated with cognitive decline in those with AF only. Critically, sex and APOE genotype significantly modified these associations. Future work using more sensitive markers of central inflammation is needed.
Racial disparities in Alzheimer’s Disease and Related Dementias (ADRD): The association between early life adversity and ADRD
Authors: Rose Deborah 
Published: December 2023

AbstractBackgroundAdverse childhood experiences (ACEs) are an important public health concern that predict neuroanatomical changes in development such as decreased prefrontal cortex and hippocampal volumes, and can lead to poor health outcomes in adulthood, including cognitive impairment. Alzheimer’s disease (AD) is the most common cause of dementia, and it disproportionately affects racial and ethnic minoritized (REM) individuals. Research demonstrates that some of the mechanisms underlying these racial disparities may include differences in exposure to specific types of ACEs (i.e. parental remarriage and/or death). A significant ACE burden can lead to disruption of the hypothalamic‐pituitary adrenal (HPA) axis, our fight‐or‐flight response system to environmental threats and stressors. Growing evidence has shown an association between ACEs and the development of cognitive impairment in older adulthood, including AD and related dementias (ADRD). We do not know, however, how biomarkers related to HPA axis dysregulation in association with ACEs are correlated to ADRD biomarkers (pathology) in a nationally representative, diverse cohort of individuals.MethodsA preliminary study is being conducted to evaluate the associations between early life adversity (measured retrospectively through surveys) and ADRD in several cohorts, including the Minority Aging in Research Study (MARS) from the Rush University Alzheimer’s Disease Research Center, the Stress and Resilience in Dementia (STRIDE) cohort from the University of Wisconsin, and the Duke University Medical Center clinics using DEDUCE, an on‐line query system in MaestroCare, Duke University Hospital’s electronic medical record system. Statistical analyses will be performed using R software.ResultsPending statistical analyses.ConclusionValidation of ACEs as independent risk factors for AD and contributors to the racial disparities seen in this condition will offer new potential therapeutic targets at the molecular level, new clinical screening modalities for specific ACEs instigating cognitive decline, and public policy insights to address a history of childhood trauma in patients with a clinical diagnosis of ADRD. This is especially for those REM individuals who have historically had a delayed or missed diagnosis and have been disproportionately impacted by ADRD.The research project described is supported by the National Institute On Aging of the National Institutes of Health under Award Number P30AG072958.
Roadway Weather Challenges Illuminate Real‐World Driving Biomarkers of Dementia Risk
Authors: Hasan Md Zahid , Basulto‐Elias Guillermo , Tan Russell Kai Liang , Chang Jun Ha , Sarkar Soumik , Sharma Anuj , Hallmark Shauna , Rizzo Matthew , Merickel Jennifer 
Published: December 2023

AbstractBackgroundCognitive decline is a leading early predictor of dementia risk and may be evident in real‐world (RW) digital data even before patients ever present to clinic. This study examined the feasibility of using video and digital sensor profiles of real world (RW) driving in adverse weather as a marker of dementia risk.Method70 older drivers (mean age = 75.6 years) without dementia participated in a RW driving study for 2, 3‐month periods, one year apart (Wang, et al. 2021) . Self‐reported demographics and neuropsychological tests relevant to dementia and driving were collected at study start. Drivers were classed as cognitively neurotypical (N = 33) or impaired (N = 44) based on normed neuropsychological scores. Sensors installed in each driver’s vehicle collected video, speed, and GPS data across 405,104 miles driven. GIS data categorized roadway type (residential, commercial, interstate). A computer vision model (99% accuracy) we developed classed roads as clear or poor (rain, snow). Bayesian mixed‐effect logistic regressions assessed driver speed limit compliance (vehicle speed‐posted speed limit) across driver class, roadway, and weather.ResultDrivers were 8.01 times more likely to speed on interstates (95% CI: 7.61‐8.61) than residential roads (15‐25 mph). Impaired drivers were 15% more likely to drive slower than neurotypical drivers on clear roadways (95% C: 1.0413‐1.2829). This pattern reversed in poor weather with impaired drivers driving faster than neurotypical (b = 0.74, 95% CI: 0.57‐0.94)ConclusionDigital biomarkers from RW data show promise to screen for early dementia risk, advancing research and innovative clinical trials to prevent dementia. Driving challenges, like poor weather, discriminate cognitive decline before dementia. Impaired drivers showed self‐restriction by driving slower on clear roads and reduced self‐restriction by driving faster in poor weather despite risk. Big data strategies, like computer vision, complement driver performance data to identify RW environmental risk, paving the road for the car as a medical diagnostic device.
Klotho protein concentrations as a function of sex, APOE, family history or Alzheimer’s disease biomarker status in an at‐risk cohort
Authors: Driscoll Ira , Betthauser Tobey J , Gallagher Catherine L. , Hermann Bruce P , Sager Mark A. , Carlsson Cynthia M. , Kollmorgen Gwendlyn , Carboni Margherita , Wang Dan , Blennow Kaj , Zetterberg Henrik , Johnson Sterling C , Asthana Sanjay , Dubal Dena B. , Okonkwo Ozioma 
Published: December 2023

AbstractBackgroundThe KLOTHO gene encodes for a longevity and neuroprotective klotho hormone. The non‐human animal literature suggests that higher levels of klotho promote resilience against Alzheimer’s disease (AD)‐related neuropathology. Human carriers of the functionally advantageous KLOTHO KL‐VS variant have higher serum klotho levels and show attenuation of proteins involved in AD‐related neuropathology (β‐amyloid (Aβ) and tau). How klotho protein relates to AD neuropathology or risk factors (APOE gene, family history, sex) is less well understood.MethodThe sample consists of 318 middle‐aged and older, cognitively normal adults (MeanAge(SD) = 63.8(6.66); range = 44‐80; 65% female) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center studies. Stratifications of the sample into positive vs. negative AD biomarker status were made using local reference cutpoints measured via cerebrospinal fluid (CSF: Aβ40, Aβ42, total tau, phosphorylated tau, and their respective ratios to Aβ42) or positron emission tomography (PET; β‐amyloid: 11C‐Pittsburgh compound B(PiB); tau: 18F‐MK‐6240). We examined whether baseline serum klotho protein concentrations differed based on AD biomarker status (whether positive (i.e., abnormal) for β‐amyloid or tau) or characteristics related to AD risk.ResultThere were no significant differences in baseline serum klotho concentrations between those considered positive vs. negative for β‐amyloid or tau whether by CSF or PET (P’s>0.19). Females (844 pg/mL) compared to males (765 pg/mL) had significantly higher serum klotho concentrations (F
(1,317) = 7.37; P = 0.007). No differences were observed based on APOE4 status or parental AD history (P’s>0.31).ConclusionWe confirm sex‐dependent difference in serum klotho favoring females. No significant differences in serum klotho protein concentrations were observed based on APOE4, AD family history or AD biomarker status (+/‐) in our cohort of middle‐aged and older, cognitively normal adults, albeit enriched for AD risk. While this may seem in contrast to a recent case‐control study (Grøntvedt, 2022) suggesting that klotho protein is associated with β‐amyloid and tau burden and clinical stages of AD, that study measured circulating klotho in plasma and included participants with MCI and AD diagnoses. Our results add to the growing KLOTHO literature and highlight the need for better understanding of the underlying mechanisms for its effects.
Selective RNA‐targeting of mTORC1 and 2 to ameliorate Alzheimer’s Disease pathogenesis
Authors: Stahl Jack , Joji Aswathy , Khorkova Olga , Volmar Claude‐Henry , Wahlestedt Claes 
Published: December 2023

AbstractBackgroundIt has been well described that inhibition of the kinase, mechanistic target of rapamycin (mTOR), improves age‐related pathologies including Alzheimer’s Disease (AD). However, mTOR exists as a complex and exerts differential functions depending on its binding partners. Suppression of mTORC1 has yielded positive outcomes for AD‐related measures (decreased amyloid beta/tau pathologies and improved cognition)1. In contrast, increased mTORC2 activity also resulted in positive outcomes in AD models (improved brain insulin sensitivity and neuronal survival)2, suggesting that a therapeutic which inhibits mTORC1 while upregulating mTORC2 may be desirable for AD. However, no such therapeutic exists.MethodTo inhibit mTORC1, we used a raptor siRNA which has been chemically modified to be stable for in vivo purposes. To upregulate mTORC2, we bioinformatically identified natural antisense transcripts (NATs) of rictor and designed custom siRNAs to target the various transcripts. Following an in vitro screen of the custom siRNAs, we determined which NATs yield upregulation of rictor when targeted and designed more siRNAs targeting the same transcript to optimize our mTORC2‐upregulating siRNA. Cellular RNA and protein were quantified using RT‐qPCR and western blot, respectively.ResultWe demonstrate efficient knockdown of raptor in all transfected cell lines, as well as in mouse brain. Raptor knockdown has been confirmed at both the RNA and protein level. Furthermore, we successfully upregulated expression of rictor using rictor NAT‐targeting siRNAs (AntagoNATs) in multiple cell lines. Downstream analyses suggest a therapeutic effect for both raptor knockdown and rictor upregulation in the context of AD.ConclusionNucleic acid‐based therapeutics which target RNA have been outcompeting and replacing small molecule protein‐targeting drugs in recent years. However, RNA‐targeted therapeutics have been largely unexplored for AD. Chemical linkage of raptor siRNA to rictor AntagoNAT siRNA yields the first therapeutic to selectively inhibit mTORC1 and upregulate mTORC2, providing a modern RNA‐targeting therapeutic for AD.References1. Querfurth, H., Lee, HK. Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration. Mol Neurodegeneration 16, 44 (2021).2. Lee, H.‐K. et al. mTORC2 (Rictor) in Alzheimer’s Disease and Reversal of Amyloid‐β Expression‐Induced Insulin Resistance and Toxicity in Rat Primary Cortical Neurons. J Alzheimers Dis 56, 1015‐1036 (2017).
Associations of subcortical shapes with age‐related neuropathologies in community‐based older adults
Authors: Saifullah Khalid , Makkinejad Nazanin , Evia Arnold M , Bennett David A. A , Schneider Julie A , Arfanakis Konstantinos 
Published: December 2023

AbstractBackgroundAge‐related neuropathologies lead to substantial atrophy of subcortical brain regions. However, the effects of age‐related neuropathologies on the shape of subcortical brain structures are not well understood because a) definitive diagnosis of most neuropathologies is only possible at autopsy and b) multiple neuropathologies often coexist in the brain of older adults. The purpose of this work was to integrate ex‐vivo MRI and detailed neuropathologic examination in a large number of community‐based older adults.Method
Participants and Data
Cerebral hemispheres from 842 older adults participating in four longitudinal, clinical‐pathologic cohort studies of aging: the Rush Memory and Aging Project (MAP), the Religious Orders Study (ROS), the Minority Aging Research Study (MARS) and the Clinical Core (CC) of the Rush Alzheimer’s Disease Research Center (ADRC)1,2 (Fig.1) were included in this work. All hemispheres were imaged at room temperature while immersed in 4% formaldehyde solution using clinical 3T MRI scanners approximately 30 days postmortem. After ex‐vivo MRI, each hemisphere underwent detailed neuropathologic examination by a board‐certified neuropathologist (Fig.1).
Ex‐vivo MRI and Shape Estimation
The subcortical structures were segmented in ex‐vivo T2‐weighted MR images from all participants. Shape analysis was performed using SPHARM‐PDM3. For each subcortical structure, signed shape differences were computed from the average mesh for all vertices and all participants.
Statistical Analysis
Vertex‐wise linear regression was performed for each subcortical structure, modeling the signed shape difference at each vertex (dependent variable) as a function of neuropathologies (specifically amyloid‐β plaques, neurofibrillary tangles, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC), Lewy bodies, arteriolosclerosis, atherosclerosis, gross and microscopic infarcts, and cerebral amyloid angiopathy), and controlling for age at death, sex, years of education, postmortem interval to fixation, postmortem interval to imaging, and scanner. The statistical analysis was conducted using PALM4 with family‐wise error rate correction.ResultThe results are shown in Figure 2. These findings for tangles and LATE‐NC were in good agreement with our previous work5,6. Finally, although MRI was conducted ex‐vivo, we expect the results to translate well to in‐vivo7.ConclusionThe differences in spatial patterns of the effects of various neuropathologies may contribute towards the development of tools for in‐vivo prediction of these neuropathologies.
Resilience to Alzheimer’s Disease: Unraveling the Molecular Mechanisms From Post‐Mortem Tissue
Authors: de Vries Luuk E , Carulli Daniela , Jongejan Aldo , Moerland Perry D , Rozemuller Annemieke J.M. , Huitinga Inge , Swaab Dick F , Verhaagen Joost 
Published: December 2023

AbstractBackgroundApproximately one‐third of elderly individuals remain cognitively intact, despite substantial Alzheimer’s Disease (AD) neuropathological changes. The exact, molecular underpinnings towards resilience in AD remain to be elucidated. Here, we set out to investigate changes in gene expression in the prefrontal cortex of cognitively intact donors with AD pathology, referred to as resilient, and compare them to AD and control subjects.MethodPost‐mortem tissue of individuals with an intermediate or high AD neuropathological score according to the NIA‐AA, but with intact cognition, AD patients with high pathology and low cognition, and age‐matched controls (i.e. cognitively intact subjects without a neurological or psychological disorders) was obtained from the Netherlands Brain Bank. Bulk RNA sequencing was performed on RNA isolated from the prefrontal cortex. Several molecular mechanisms of interest were further immunohistochemically confirmed in post‐mortem tissue.ResultAnalysis revealed transcriptional changes between resilient and AD donors including mitochondrial functioning, metallothionein signaling and the Tyrobp network. Additionally, we found profound changes in the extracellular matrix, including changes in perineuronal nets (PNNs) between resilient, AD and control donors. Using immunohistochemistry, we demonstrated altered morphology and a reduction of PNNs in AD while PNNs were more preserved in resilient donors compared to control donors.ConclusionOur data indicates that changes in mitochondria, altered signaling in astrocytes and microglia via metallothionein and Tyrobp, respectively, and preservation of PNNs were associated with intact cognition despite the presence of AD pathology and could ultimately point to novel targets for therapeutic development.
Cognitive resilience at 3 years after stroke depends on pre‐ and post‐stroke factors
Authors: Khlif Mohamed Salah , Werden Emilio , Bird Laura J. , Brodtmann Amy 
Published: December 2023

AbstractBackgroundThe incidence of dementia in stroke survivors is greater than in stroke‐free people. However, some stroke survivors show cognitive resilience, withstanding the detrimental effects of stroke. In this study, we explored the differences between cognitively‐impaired (CI) and cognitively‐normal (CN) survivors in comparison with healthy controls (HC).MethodParticipants were sampled from the Cognition And Neocortical Volume After Stroke (CANVAS) study. Sociodemographic, clinical, neuropsychological, cognitive, neuroimaging, sleep, and physical activity data were obtained for 93 stroke participants at 3‐months and 3‐years post‐stroke and for 35 HC at equivalent timepoints. Stroke participants were classified as CN (n = 71) or CI (n = 22) at 3‐years based on mood scores, clinical interviews, and z‐scores of performance in five cognitive domains: attention, memory, language, executive and visuospatial functions. Structural brain volumes were estimated from T1‐weighted MRI using longitudinal FreeSurfer segmentation. Linear random‐intercept mixed‐effects modelling was used to compare between groups and timepoints accounting for differences in age, sex, years‐of‐education, and total‐intracranial volume.ResultThe stroke group overall had higher incidence of atrial fibrillation, scored higher on anxiety and depression, and had lower sleep efficiency compared to HC. Stroke survivors had thinner cortex, less cerebellar grey‐matter (GM), and larger choroid plexuses, and greater enlargement of the ventricles, at both timepoints. The CI survivors had more comorbidities, were older, were less active at both timepoints, and had lower years‐of‐education compared to both CN survivors and HC. They had more vascular risk factors and APOE‐ε4 allele carriage status compared to controls.Only the CI group showed deficits in ipsilesional cortical GM, hippocampal and thalamic volumes, and reduced total brain volume at 3‐months compared to controls. The CI survivors had larger stroke lesions compared to CN survivors and showed a greater increase in white matter hyperintensities between timepoints.At 3 months in CN survivors, cognitive performance in assessed domains was significantly lower, except for language. While performance in the CN survivors improved over time especially in language and visuospatial function, cognitive scores remained lower in the CI survivors, with a decline in memory scores.ConclusionPost‐stroke cognitive resilience appears dependent on clinical, sociodemographic, and neuroimaging factors, which assist in post‐stroke prognostication.
Dementia knowledge in African immigrants with personal experiences of dementia
Authors: Nkimbeng Manka 
Published: December 2023

AbstractBackgroundThere is a dearth of research on dementia knowledge, care and caregiving with African immigrants. This study describes current understanding of dementia and its correlates with first and second generation African immigrants who have personal experiences of dementia. Our data comes from the Immigrant Memory Collaborative; a community‐based participatory research project that explored dementia care needs and resources in the African immigrant community.MethodLinear regression models were used to describe factors associated with dementia knowledge, including causes and characteristics, communication and behavior, care considerations, and risks and health promotion.ResultOf the 193 participants, 64% were male and 81% were caregivers. The mean age of the sample was 36 (±13.8) years, but first‐generation participants were older (44.3 ±17.2 years; compared to 30.6±7.1years). Women had lower dementia knowledge (b: ‐1.39 95% CI [‐2.58, ‐0.202]) compared to men, while people who were single had higher dementia knowledge (b: 1.36, 96% CI [0.28, 2.43]) and those who would seek care at health related organizations and community based networks had higher dementia knowledge compared to those who would turn to community based networks alone (b: 1.53 95% CI [0.499, 2.56]).ConclusionUnderstanding the correlates of dementia knowledge will inform target areas for dementia literacy interventions with the growing African immigrant population. Our results show that individual factors (sex and marital status) and where an individual would seek care are important correlates of dementia knowledge. Informal community based networks are an important target area for dementia and other health literacy interventions.