bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurophysiologic Correlates of Preclinical Alzheimer's Disease
Authors: Manning Daniel , Morse Christie , Northrop Andrew , Zeng Victor , Bolo Nicolas , Shaughnessy Lynn , Baratono Sheena , Buss Stephanie S. , Ozdemir Recep , Shafi Mouhsin , Fried Peter J. 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is associated with neurophysiologic changes, including cortical hyperexcitability and reduced long‐term potentiation (LTP)‐like plasticity, that can be investigated using transcranial magnetic stimulation (TMS). AD is preceded by a preclinical phase of beta‐amyloid accumulation without clinical or cognitive symptoms. Our goal is to test the relationship of TMS‐based neurophysiologic markers against established cognitive and MRI‐based measures of preclinical AD. If neurophysiologic changes precede the clinical manifestation of AD, they could serve as prognostic markers and targets for therapeutic interventions to slow its progression.MethodData was acquired from eight cognitively unimpaired older adults (three females, ages 65‐78 years) as part of an ongoing study (BrightFocus™ Foundation‐A2021288S, IRB#‐2020P000889). Cognition was evaluated with the 5‐item Preclinical Alzheimer’s Cognitive Composite (PACC5), which is sensitive to early AD‐associated decline. Global cortical atrophy was assessed from MRI as the mean thickness across the AD Cortical Signature Network (ACSN)—regions showing morphologic changes that precede the clinical manifestation of AD. Cortical excitability was assessed as the average amplitude of TMS‐evoked EEG potentials (TEPs) elicited from TMS to motor cortex, while LTP‐like cortical plasticity was assessed as the change in TEPs following intermittent theta‐burst stimulation (iTBS). The strength of associations between the neurophysiologic, imaging, and cognitive measures were performed using non‐parametric Spearman Rho coefficients.ResultSpearman coefficients revealed a large association between reduced cortical thickness (more atrophy) and worse cognition (Rho=0.71), as expected. Higher excitability (larger TEPs) showed a large association with worse cognition (Rho=‐0.54) and a small association with reduced cortical thickness (Rho=‐0.29). Lower cortical plasticity (smaller change in TEPs post‐iTBS) showed a medium association with worse cognition (Rho=0.46) and a large association with reduced cortical thickness (Rho=0.86).ConclusionIn cognitively unimpaired older adults, TMS‐EEG measures of cortical excitability and LTP‐like plasticity are strongly correlated, respectively, with cognitive and MRI‐based markers of Preclinical AD. These finding suggest cortical hyperexcitability and reduced LTP‐like plasticity, which are present in AD, may occur before its clinical manifestation. If these results are confirmed in a larger cohort with biomarker testing, these markers could help prognosticate the development of AD symptoms and serve as targets for therapeutic intervention.
Early accumulation of Aβ and Tau is associated with increase in cortical thickness
Authors: Hojjati Seyed Hani , Habeck Christian , Butler Tracy A , RoyChoudhury Arindam H , Luchsinger Jose A , Devanand Davangere P. , Stern Yaakov , Razlighi Qolamreza 
Published: December 2022

AbstractBackgroundThere is no consensus in the field regarding the relationship between AD pathologies (Aβ, and Tau) and neurodegeneration. One reason that may contribute to this disagreement is the definition of cut‐point to categorize participants with or without significant pathologies. This approach overlooks an important early stage of pathological accumulation. In this study, we take advantage of Florbetaben/MK6240 PET scans from 61/21 young (<40) and healthy participants to redefined the cut‐point of Aβ/Tau uptake and investigate their association with cortical thickness as a measurement of neurodegeneration.MethodTo capture the early effect of pathologies, we quantify global pathologies by averaging AD‐related regions uptake; global Aβ: frontal, parietal, temporal, anterior and posterior cingulate, and precuneus, global Tau: fusiform, amygdala, parahippocampal, entorhinal, inferior temporal, middle temporal, and medial temporal lobe (MTL) Tau: entorhinal and parahippocampal. We redefied the cut‐point of AD pathologies using 95% percentile of the fitted normal distribution to the young subject's uptakes. Using newly defined cut‐points (1.01<global Aβ<1.25, 0.72<global Tau<1.15, and 0.66<MTL Tau<1.11), we identified 232 older participant (64.79±3.55, 94 males, 229 HC) from 394 healthy control (HC) and 52 with mild cognitive impairment (MCI). To assess the relationship between AD pathologies and neurodegeneration, we run a multiple regression to model cortical thickness at each vertex in the identified elders with global Aβ, and global Tau controlling for age, gender, and Intracranial volume (ICV).ResultEarly and low accumulation of Aβ and Tau were associated with higher cortical thickness in many regions throughout the cerebral cortex. More interestingly, MTL (where the early Tau deposition occurs) was among the regions showing a positive association with Aβ deposition and cortical thickness.ConclusionThese results, provide preliminary evidence that early and low accumulations of AD pathologies are associated with higher cortical thickness. Our results may shed some light on the discrepancies between the existing studies investigating the same relationship. As it has been recently hypothesized, it suggests that the cascade of events in AD may start much earlier than what had been considered in the field and this early accumulation of Aβ and Tau has completely different consequences on brain structure/function.
Association of Delirium with Long‐term Cognitive Decline: An Update
Authors: Goldberg Terry E. , Wang Yuanjia , Hua May , Garcia Paul , Whittington Robert A , Moitra Vivek 
Published: December 2022

AbstractBackgroundDelirium has been associated with a variety of unfavorable outcomes, including increasing length of stay in the hospital, poor functioning, and death. We compiled the literature and conducted a meta‐analysis (Goldberg et al, JAMA Neurol, 2021) in order to determine if delirium was also associated with long term cognitive decline. Twenty‐three studies that included over 3500 delirium and 6900 control patients were included in the meta‐analysis. Cognitive assessments were conducted on average at 2.3 years after the episode of delirium. We found that the overall effect size G was .45 (P<.001) indicating that patients who experienced delirium performed significantly worse than controls who did not experience delirium.MethodWe will search the literature on cognitive changes after delirium from Jan 1, 2019 onward. We will include all relevant studies with the same inclusion criteria as our prior study (namely an episode of delirium, cognitive assessment 3 or more months after the episode, and a control group). We will then compute the effect size G for each individual study in order to determine if the values are consistent with our previous findings. We will also examine if delirium meets Bradford Hill criteria for playing a causal role in cognitive decline in association studies.Second, we will review the literature on cognitive changes after delirium in individuals experiencing SARS‐CoV‐2 infection, given the many reports of patients experiencing delirium in the ICU while ventilated. We will derive G for these studies, so long as they incorporate a control group that adjusts for disease severity and virus positivity.ResultWe will present results of this new review in terms of G for individual studies, overall G when these are added to the original meta‐analysis, and a Bradford Hill criteria checklist. For delirium after SARS‐Cov‐2 infection we will rely on a narrative description.ConclusionFirst, we will examine trends in reports of the magnitude cognitive changes after delirium over the past three years, as well as examine if newer or more comprehensive methodologies are being deployed. Second, we will examine the extent of cognitive changes after delirium in the context of severe COVID‐19.
MicroRNA‐502‐3p regulates the GABAergic synapse function in Alzheimer’s disease
Authors: Kumar Subodh 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is most common dementia in the aged individuals. Synapse dysfunction is the early event in the brain that initiate AD progression. Studies found the reduced inhibitory GABAergic synapse function in AD subjects.MethodsGlobal microRNA (miRNA) affymetrix analysis was performed on synaptosomal fractions from AD subjects and cognitively normal individuals. In silico analysis and luciferase assays were performed to confirm the miR‐502‐3p binding at the GABRA1 mRNA. MiR‐502‐3p agomiRs (overexpression) and antagomiRs (suppression) studies were performed on mouse primary hippocampal (HT22) neurons. The GABA receptor functions were accessed by electrophysiology studies using patch clamp analysis.ResultsOur global microRNA (miRNA) affymetrix study of synaptosomal fraction identified miR‐501‐3p/miR‐502‐3p as potential miRNAs. Data analysis showed the higher expression of miR‐502‐3p in the AD synapse relative to cognitively healthy synapse. On the other hand, Gamma‐Aminobutyric Acid Type A Receptor Subunit Alpha1 (GABRA1) levels were found to be reduced in AD synapse. In silico analysis and luciferase assay confirmed that miR‐502‐3p binds to multiple sites at the GABRA1 mRNA and suppresses its translation. In vitro studies using mouse primary hippocampal (HT22) neurons unveiled that miR‐502‐3p agomiRs (overexpression) decreased HT22 cell survival and antagomiRs (suppression) treated cells showed improved cell survival. qRT‐PCR, immunoblotting and immunostaining analysis conformed the reduced levels of GABRA1 by miR‐502‐3p overexpression, while suppression of miR‐502‐3p increases the GABRA1 protein levels. Further, electrophysiology studies using patch clamp analysis showed reduced GABA receptor functions and impaired chloride ion (Cl−) channel by over expression of miR‐502‐3p. On the other hand, reduced expression of miR‐502‐3p showed increased GABA receptor functions and Cl− influx into the cells.ConclusionOur initial observations confirmed that miR‐502‐3p modulate GABRA1 receptor functions. Therefore, miR‐502‐3p could be a therapeutic target to improve the GABAergic synapse function in AD.
Cognitive decline in Autosomal Dominant Alzheimer’s Disease and its relation to TauPET and fMRI Complexity in the Hippocampus
Authors: Jann Kay , Cen Steven Y , Ringman John M , Wang Danny JJ 
Published: December 2022

AbstractBackgroundIn recent years the neurofibrillary tangle pathology detected with tauPET imaging has been found to be closely related to cognitive decline in Alzheimer’s Disease. However, PET scans are expensive and involve radioactive tracers. We and others have proposed the complexity of rs‐fMRI using MultiScaleEntropy (MSE) as an index for neuronal function. Reduced entropy values have been associated with aging, APOEɛ4 genotype and cognitive function in AD. Here we hypothesize that the BOLD signal complexity is sensitive to tau‐related neuronal injury and cognitive decline in AD.MethodData (N=44, Table1) was obtained from the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) study, which examines persons at‐risk for autosomal‐dominant AD. All subjects had T1, tauPET (18F‐AV1451) and two resting‐state fMRI scans. FMRI data underwent standard preprocessing before computing MSE. SUVR images were calculated with inferior cerebellum as reference region. Correlations between SUVR tauPET and MSE were calculated voxel‐wise including age, gender and gray ‐matter volume as covariates. Mediation effects in hippocampal clusters between MSE, tauPET and cognitive function (MMSE) were tested in SAS (95% confidence‐interval was estimated with 1000 bootstrapping samples).ResultWe observed gradually decreasing entropy and gradually increasing tauPET from NC to MCI and AD (Fig1). This inverse relationship was significant (p<0.05,corrected) in hippocampus, lateral temporal lobe and anterior cingulate cortex (Fig2). Mediator analysis revealed significant indirect (mediation) effects of PET to the association between MSE and MMSE (log‐transformed) in both hippocampi: Left: total 1.37 95%CI (0.6,2.14) indirect 0.86(0.27,1.85) and Right: total 1.49(0.66,2.31) indirect 1.04(0.48,1.84).ConclusionOur findings show that there is a statistically significant total effect between MSE and cognitive decline that is largely mediated by tauPET, with 63% and 70% of total effect for right and left hippocampus respectively. These results support the relevance of hippocampal tauopathy on cognitive decline. Moreover, complexity of rs‐fMRI is associated with both regional tau protein accumulation and cognitive decline, and thus could provide a safe and cost‐effective alternative marker for regional neuropathology and prediction of cognitive decline in AD.
Short‐term cognitive practice effects and their relation to amyloid and tau in preclinical Alzheimer’s disease
Authors: Young Christina B , Mormino Elizabeth C. , Papp Kathryn V. 
Published: December 2022

AbstractBackgroundIdentification of cognitive paradigms that relate to biomarker evidence of Alzheimer’s disease (AD), such as tau, can greatly enhance patient selection for clinical trials. Computerized cognitive assessments that can be frequently administered may yield multiple unique variables that can improve detection of subtle cognitive decline in preclinical AD. Indeed, practice effects (i.e., improved performance on repeated testing) are diminished in clinically unimpaired older adults with abnormal amyloid, but their relations with tau are unknown. Here, we determine whether baseline performance and practice effects at 3 months re‐testing on the Computerized Cognitive Composite (C3) relate to medial temporal lobe (MTL) tau.MethodWe examined 390 clinically unimpaired older adults from the A4 study with tau PET (flortaucipir) imaging who completed two C3 assessments pre‐study randomization. C3 assessments were completed approximately 90 days apart and included pattern separation [Behavioral Pattern Separation Test – Object (BPS‐O)], associative memory [Face Name Associative Memory Exam (FNAME)], and visual memory [One‐Card Learning (OCL)]. C3 baseline performance and practice effects (change in performance from Assessment 1 to 2) were examined in relation to continuous amyloid and MTL tau burden.ResultGreater amyloid burden was significantly associated with lower baseline C3 scores (B(SE) = ‐0.86 (0.24), p<0.001) but not C3 practice effects (B(SE) = ‐0.09 (0.23), p = 0.702). In contrast, greater tau in the MTL was significantly associated with reduced C3 practice effects (B(SE) = ‐0.49 (0.21), p = 0.023) and marginally associated with baseline C3 performance (B(SE) = ‐0.37 (0.22), p = 0.099) while controlling for continuous amyloid and demographic variables. Further examination of C3 subtests revealed that pattern separation (BPS‐O; B(SE) = ‐0.70 (0.34), p = 0.039) and associative memory (FNAME; B(SE) = ‐1.13 (0.42), p = 0.007) were driving MTL tau associations with C3 practice effects.ConclusionDiminished practice effects on memory‐based measures are associated with elevated MTL tau burden in preclinical AD. Furthermore, diminished practice effects offer a unique signal above and beyond cross‐sectional performance. For clinical trials, examination of practice effects on computerized assessments over a short timescale may be a cost‐effective method to facilitate identification of those with biomarker evidence of AD.
Examining the cognitive performance of older adults in urban and rural regions of India.
Authors: Arora Sonakshi , Wong Christina G. 
Published: December 2022

AbstractBackgroundAging population is rapidly growing in India, with the majority of the older adult population residing in rural regions. Studies globally show a higher prevalence of cognitive impairment in rural regions than urban. With the lack of research on aging in India, there is an urgent need to evaluate the cognitive health of older adults in India to allow for their care needs to be met appropriately and promote healthy aging.MethodThis study used data from Harmonized Longitudinal Aging Study of India, Diagnostic Assessment of Dementia (LASI DAD), which was developed by the Gateway to Global Aging Data. The sample size was nationally representative (n = 4096) of older adults aged 60 years and above in India (urban community = 1561, rural village = 2535). Given the heterogeneity of the population, adapted cognitive instruments were used. This study assessed if geographical residency (urban vs. rural) of older adults influenced their cognitive performance above and beyond demographic factors (i.e., age and gender) and education using a hierarchical regression in SPSS.Result18% of the variance in cognitive performance was accounted for by age and gender. 37% of the variance in cognitive performance was accounted for by the addition of education. Finally, geographic residency accounted for 1.2% of the variance in cognitive performance of older adults. Older adults living in rural villages had statistically significantly lower cognitive performance than older adults living in urban communities (B = ‐.218, p < 0.01). Women’s cognitive performance was lower than men’s (B = ‐.229, p <0.01).ConclusionThe geographic residency only accounted for a small proportion of variance in the cognitive performance of older adults in India. The majority of the disparity was accounted for by education, with older adults with higher education performing better. Despite that, older adults living in rural villages performed worse on cognitive measures than older adults living in urban communities. Older women performed worse than men. The contribution of factors such as depression, socioeconomic status, and cardiovascular health to the cognitive health of older adults in India should be explored further.
The potential contribution of the adaptive immune system in frontotemporal dementia
Authors: Eid Abdulmunaim M , Pascual Maria B , Masdeu Joseph C. , Appel Stanley H , Faridar Alireza 
Published: December 2022

AbstractBackgroundInflammation is a significant component of neurodegenerative disorders including frontotemporal dementia (FTD). Co‐localization of neuroinflammation and brain protein aggregation with tau and TDP‐43 has been previously documented in the clinical setting of FTD. However, the role of the adaptive immune system particularly regulatory T cells (Tregs) is not clearly defined. We hypothesize that Tregs immunomodulatory mechanisms are compromised and shift the immune system towards a proinflammatory status which might contribute to disease progression.Method24 FTD patients and 11 age‐matched healthy controls were recruited by the Houston Methodist Nantz National Alzheimer’s Center (NNAC). Venous blood was processed for multicolor flow cytometry to assess the phenotype of Tregs. Tregs were also co‐cultured with corresponding responder T cells (Tresps) in various ratios and proliferation of Tresps was determined by 3H‐thymidine incorporation. Plasma assays of 48 cytokines were obtained through Olink® Target 48 Cytokine panel for FTD patients and age‐matched healthy controls and comparisons were made.ResultThe suppressive function of Tregs on corresponding Tresps proliferation was significantly compromised in both 1:1 (P = 0.034) and 1/2:1 (P = 0.024) Tregs:Tresps ratios. In immunophenotypic analyses, no differences were detected between FTD patients and controls regarding percentages of Tregs, Tresps, CD8+ T cells, or natural killer cells (NKC). The Olink® analysis revealed increased plasma levels of pro‐inflammatory cytokines and chemokines in FTD patients including CXCL9, CXCL10, CXCL11, and TNFα.ConclusionRegulatory T cells immunomodulatory function is compromised in patients with FTD, indicating a shift of peripheral immune cells towards an increased pro‐inflammatory state. In addition, there is upregulation of plasma chemokines CXCL9, CXCL10, CXCL11, which promote immune cell recruitment to CNS sites of inflammation. Combining these two key findings, we propose that pro‐inflammatory peripheral immune cells contribute to neuroinflammation and possibly disease progression in FTD.
Sleep disorders and incident dementia: a nationwide observational cohort study
Authors: Damsgaard Line , Janbek Janet , Laursen Thomas Munk , Erlangsen Annette , Spira Adam P. , Waldemar Gunhild 
Published: December 2022

AbstractBackgroundIn recent years, significant research efforts have focused on identifying modifiable risk factors to be leveraged for dementia prevention. Sleep is required for memory consolidation and normal brain functioning, and various mechanisms are proposed between poor sleep quality and cognitive impairment. Several studies have examined the role of sleep disturbances as a risk factor for dementia; however, most of these studies have involved smaller cohorts and short time intervals, and often rely on retrospective surveys and self‐reported exposure data. Our aim was to examine the association between sleep disorders and late‐onset dementia in an entire population.MethodIn a nationwide cohort with a 40‐year follow up, we linked nationwide population data with information on hospital‐based sleep disorder diagnoses and late‐onset dementia from the extensive Danish health registers. Incidence rate ratios (IRR) were calculated using Poisson regression analysis. Analyses were adjusted for age, sex, calendar year, education, and somatic and psychiatric comorbidities.ResultThe cohort consisted of 1,491,276 people. Those with any hospital‐diagnosed sleep disorder had a 17% higher risk of dementia (IRR 1.17, 95% CI 1.11‐1.24) compared to people with no sleep disorder diagnosis. The highest risk was found for men with ‘other specific disorders’ (e.g. insomnia, hypersomnia, non‐organic sleep disorders) with an IRR of 2.00 (95% CI 1.71‐2.32). The risk of dementia was significantly increased 0 to 5 years after sleep disorder diagnosis (IRR 1.35, 95% CI 1.25‐1.47), while the association after 5 years or more was non‐significant (1.05, 95% CI 0.97‐1.13).ConclusionOur findings indicate an increased short‐term risk of dementia following a hospital‐based sleep disorder diagnosis, while we found weaker evidence of a long‐term risk. While this may indicate that sleep disorders could be early symptoms of dementia as well as a risk factor, further research is needed to evaluate sleep disorders as potential early symptoms of dementia, risk factors for dementia, or both, and characterize how this may change at different points along the dementia course. Increased knowledge of the role of sleep disorders in dementia could help inform efforts towards diagnosing dementia in the early stages of the disease or even in dementia prevention.