bluuebunny/crossref_metadata_2025_split huggingface dataset:
WMH and biomarker heterogeneity of individuals on the amyloid pathway
Authors: Prosser Lloyd , Oxtoby Neil P , Cash David M , Malone Ian B , Carrasco Ferran Prados , Sudre Carole H , Barnes Jo 
Published: June 2023

AbstractBackgroundResearch studies of Alzheimer’s disease (AD) are increasingly using biomarker‐based criteria to define disease. One useful definition is amyloid positivity since it identifies those on a pathological pathway that likely results in AD. However, within amyloid positive individuals, there is substantial heterogeneity in terms of when biomarkers that measure different aspects of the disease become abnormal. Here we examine this heterogeneity amongst biomarkers that reflect various aspects of the disease process.MethodCSF Amyloid positive individuals’ data from Alzheimer’s Disease Neuroimaging Initiative (ADNIGO/2/3) were used (n = 376). Demographics were compared across diagnostic group using linear regression and Fisher’s exact tests where appropriate, table 1. CSF phosphorylated tau (ptau), whole‐brain and hippocampal volume, Logical memory (LM) and Trails A and B, and white matter hyperintensity (WMH) volumes were used to derive data‐driven subtypes using the z‐score version of the SuStaIn algorithm. The algorithm produced subtypes with differing patterns of biomarker orderings. SuStaIn calculated z‐scores using 86 CSF amyloid negative, APOE e4 non‐carrier healthy controls, selected from ADNIGO/2/3. Proportions of APOE e4 carriers, and clinical diagnosis were compared between subtypes using Fisher’s exact test.Result359 individuals were grouped into three subtypes (figure 1); determined using cross‐validation. Subtype one (n = 136) had an initial event of WMH, followed by LM, trails A and B, and whole‐brain volume (hippocampal sparing). Subtype two (n = 115) had initial events of ptau, followed by LM and hippocampal volume (tau‐led). Subtype three (n = 108) had initial events of LM total, followed by ptau and hippocampal volume (tau‐late). 17 individuals were not subtyped, as their biomarker data showed no significant abnormalities and would suggest that they are not on an AD pathway.There was a trend towards a higher proportion APOE e4 carriers in subtype one and three (p = .06). There was a significant difference in clinical diagnosis between subtypes (p < .001), with subtype one having a lower proportion of CNs and a higher proportion of MCIs than subtypes two and three (figure 1).ConclusionWe found considerable heterogeneity in biomarker progression sequences in individuals with elevated amyloid.
Fat and the brain: its connection and implication in AD pathogenesis
Authors: Bettinetti‐Luque Miriam , Trujillo‐Estrada Laura , Andreo‐Lopez Juana , Cantero‐Molina Francisco , Da Cunha Celia , Sanchez‐Mejias Elisabeth , LaFerla Frank , Gutierrez Antonia , Baglietto‐Vargas David 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is a complex disorder and multiple cellular and molecular mechanisms are involved in AD onset and progression. Recent evidences has suggested that metabolic alterations are an important pathological feature in disease progression in AD. Likewise, diabetes and obesity, two mayor metabolic illnesses, are risk factors for AD. These two overwhelming diseases are associated with a significant expansion of white adipose tissue. Here, we hypothesize that the white adipose tissue may serve as a key communicator organ between the brain and peripheral metabolic illnesses and affecting both types of disorders.MethodWe used histological stains, immunohistochemistry and biochemical means to determine changes in the white adipose tissue from WT and db/db mice. Moreover, similar techniques were used in the brain of 3xTg‐AD mice that received white fat pads from WT and db/db donors to determine any changes in amyloid and tau pathology.ResultOur study shows that recipient 3xTg‐AD mice from db/db fat pads mice develop profound changes in tau pathology due to increased CDK5 expression compared to 3xTg‐AD mice that received fad pads from WT mice. This increment in tau level was associated with elevated levels in IL‐1β and profound microglia activation. Moreover, we found the opposite effect on amyloid pathology, in which insoluble Aβ levels and Thioflavin positive plaques were reduced in recipient 3xTg‐AD mice from db/db fat pads compared to 3xTg‐AD mice that received fad pads from WT mice. These reduction in Aβ levels were correlated with an increment in microglia phagocytic capacity.ConclusionOverall, our study demonstrate a novel important crosstalk between Alzheimer´s disease and diabetes type II through white adipose cells and a differential effect on tau and Aβ pathology mediated by an activated immune response.
Cognitive resilience and severe Alzheimer’s disease neuropathology: role of smoking
Authors: Ahangari Narges , Fischer Corinne E. , Schweizer Tom A. , Munoz David G. 
Published: June 2023

AbstractBackgroundWhy some individuals with significant Alzheimer’s disease(AD) lesions in their brain retain their cognitive abilities while others with the same level of pathology manifest symptoms of dementia remains incompletely understood. The term cognitive resilience refers to this phenomenon. With limited success in pharmacological interventions that prevent the onset of AD pathology, more efforts are aiming toward developing strategies to delay the clinical expression of AD; acetylcholinesterase inhibitors serve as an example, and compounds with similar pharmacodynamics such as nicotine may play a similar role. Here we sought to identify demographic, clinical, genetic, and neuropathological features associated with cognitive resilience in participants with severe AD neuropathology.MethodData for this retrospective cohort was collected from the datasets developed by the National Alzheimer’s Coordinating Centre (NACC). Individuals with severe AD pathology and no other primary neuropathology diagnoses who had their last visit within 2 years of their time of death were included. Severe AD pathology definition was based on National Institute on Aging–Reagan (NIA‐Reagan) criteria pathology, i.e., frequent neuritic plaques and Braak & Braak stage V/VI pathology. Cognition was assessed using the Mini‐Mental Status Examination (MMSE) score at their last visit and cases with scores ≥24 were defined as being cognitively intact, and thus resilient. Following bivariate analysis to compare resilient with non‐resilient groups, significantly different variables were adjusted for demographics using logistic regression analysis. Subsequently, statistically significant characteristics were entered in a multivariable model.ResultsWe classified 59(9%) individuals as resilient and 595(91%) as non‐resilient. The binary logistic regression model showed that resilient subjects were older (odds ratio[OR] = 1.03;95% confidence interval[CI] = 1–1.07), had more years of education (OR = 1.16;95%CI = 1.04‐1.29), had lower BMI (OR = 0.91;95%CI = 0.85‐0.99), were more likely to be a smoker (OR = 2.78;95% CI = 1.45‐5.34), and were more likely to use an anticoagulant/antiplatelet at last visit compared with subjects with impaired cognition (OR = 1.87;95%CI = 1.01‐3.48).ConclusionsOur results corroborated previous findings that lower BMI and higher education are associated with AD cognitive resilience, and additionally demonstrated that the level of smoking and usage of anticoagulant/antiplatelet medication have a direct relationship with cognitive resilience to AD severe pathology. Nicotine mimetics could be explored as a potential option for preventing AD clinical expression.
Reconfigured metabolism brain network in asymptomatic microtubule‐associated protein tau mutation carriers: A graph‐theoretical analysis
Authors: Liu Li , Chu Min , Xie Kexin , Cui Yue , Rosa‐Neto Pedro , Chen Kewei 
Published: June 2023

AbstractBackgroundStudies exploring topologic properties of the metabolic network in the presymptomatic stage of genetic frontotemporal dementia (FTD) are scarce, which may be important for understanding brain function and disease pathogenesis. This study aimed to explore FTD‐specific patterns of metabolism topology reconfiguration in asymptomatic microtubule‐associated protein tau (MAPT) mutation carriers.MethodSix asymptomatic carriers of MAPT P301L mutation were compared with 12 non‐carriers who were all from the same large family of FTD. For comparison, we included 32 behavioral‐variant FTD (bvFTD) patients and 33 unrelated healthy controls. Each participant underwent neuropsychological assessments, genetic testing, and hybrid PET/MRI scan. Voxel‐wise gray matter volume and standardized uptake value ratio were calculated and compared for structural MRI and FDG‐PET, separately. The sparse inverse covariance estimation (SICE) method was applied to topologic properties and metabolic connectomes of brain functional networks derived from 18F‐fluorodeoxyglucose PET/MRI data. Independent component analysis was used to explore metabolic connectivity in the salience (SN) and default mode networks (DMN).ResultThe mean estimated years from symptom onset was 8.33 ± 1.875 years in the mutation carrier group. The asymptomatic MAPT carriers show no significant differences in cognitive tests, gray matter volume and FDG uptake compared to non‐carriers. They also retained normal global parameters of metabolism network, but not for bvFTD patients. However, we revealed lost hubs in the ventromedial prefrontal, orbitofrontal, and anterior cingulate cortices and reconfigured hubs in the anterior insula, precuneus, and posterior cingulate cortex in asymptomatic carriers, which is consistent with the findings in bvFTD patients. Similarly, significant differences in local parameters of these nodes were observed in asymptomatic carriers. The reduction in connectivity was marked in lost hub regions during the asymptomatic stage. Functional connectivity within the SN and DMN was enhanced in asymptomatic carriers, while reduced in bvFTD patients.ConclusionOur findings showed that asymptomatic MAPT carriers were initially involved in medial prefrontal areas and actively compensated in task‐related regions. Topologic properties of the metabolic network may contribute to further investigations and monitoring of the earliest stages of FTD in individuals with genetic backgrounds.
Genome‐Wide Association Study for CSF Aβ42, Tau, and pTau in a Large Multi‐cohort Study to Identify Novel AD Genetic Variants
Authors: Gomez‐Fonseca Duber 
Published: June 2023

AbstractBackgroundPrevious studies have identified more than 20 genetic loci to be associated with AD risk. These reported loci do not account for all the estimated heritability nor report enough information on the undelaying biological mechanism. Genome‐wide association studies of endophenotypes have identified new loci associated with Alzheimer’s disease. To better understand AD pathology and identify new variants implicated in AD much larger samples size is needed. We conducted a GWAS of Amyloid‐beta (Aβ42) tau, and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) to detect novel variants associated with AD.MethodsAD CSF biomarkers were measured in 7282 individuals from 24 different cohorts. Samples were genotyped using different array technology with stringent quality control standards to each dataset before combining datasets. Minimum call rate for single nucleotide polymorphism (SNP) and individuals was 99.85%. SNPs not in Hardy–Weinberg equilibrium were excluded. X‐chromosome SNPs were analyzed to verify sex identification. Duplicates and cryptic relatedness among samples were tested by pairwise genome‐wide estimates of proportion identity‐by‐descent. PLINK was used to calculate principal component analysis. CSF biomarker levels were log10‐transformed to approximate a normal distribution with the mean standardized to zero for each dataset to account for the variability on the different platforms used to measure proteins levels. One‐stage joint‐GWAS to maximize the power in our analysis. Post‐GWAS analyses Colocalization, Madelian Randomization, LD Score Regression, were implemented to detect colocalization of two potential related signals to detect common causal variant and to evaluate the overlap in genetic architecture of CSF Biomarkers and risk factor for ADResultsThis study represents one of the largest multi‐cohort GWAS analyses on CSF AD biomarkers. Several genome‐wide significant hits were found including APOE. Additional analyses are underway.ConclusionsCSF Aβ42, tau, and ptau are well established AD endophenotypes with a clear genetic association with APOE genotype and AD risk. Genetic studies on endophenotypes provide enough power to detect association with a smaller sample size than case‐control studies helping us to better understand the biological mechanism of the disease. With this study we aim to identify novel variants implicated in AD.
Inflammasome Activation after Traumatic Brain Injury as a Risk Factor for Alzheimer’s Disease
Authors: Johnson Nathan H , Kerr Nadine A , Vaccari Juan Pablo de Rivero , Bramlett Helen M , Keane Robert W , Dietrich W Dalton 
Published: June 2023

AbstractBackgroundTraumatic Brain Injury (TBI) is a major cause of death and disability in the United States and a recognized risk factor for the development of Alzheimer’s disease (AD). Recent studies identified that heightened inflammasome signaling plays a critical role in the pathogenesis of CNS injury and that the release of apoptosis ‐associated speck‐like protein containing a caspase recruitment domain (ASC) specks from neurons and activated microglia contributes significantly to the detrimental innate immune inflammatory response. This study investigated whether inflammasome signaling after TBI augmented AD‐induced biochemical and neuropathological outcomes and loss of cognitive functionality using established AD‐transgenic mouse models.MethodFive‐month‐old, 3xTg mice (with expressed APPswe, PS1M146V and tauP301L genes) and wild type controls were randomized and underwent moderate TBI controlled cortical impact (CCI) injury or served as controls. Animals were allowed to recover for 1 hour, 1 day, or 1 week after TBI (n = 5‐8/group) to assess acute pathology or were allowed to recover for 12 weeks (n = 10/group) in order to assess cognitive functionality and chronic pathology. At the end of the respective recovery periods, mice were sacrificed. The ipsilateral cortex tissue was processed for inflammasome protein expression by immunoblotting analysis. The chronic group was assessed for behavior utilizing open field (3 days), novel object recognition (2 weeks), and Morris water maze (6 weeks) testing after TBI.ResultThere was a statistically significant increase in the expression of inflammasome signaling proteins Caspase‐1, Caspase‐8, ASC, and IL‐1β in controls and TBI in both wild type and transgenic animals. Importantly, at 1 day after TBI, significant increases in ASC, Caspase‐8 and IL‐1β protein expression were observed in AD mice compared to wild type. In the chronic group, behavioral testing showed that injured mice had increased cognitive loss as indicated by decreased time in the center of the open field, and decreased time investigating the novel object.ConclusionThese findings show that the inflammasome is involved in the regulation of the innate immune response after TBI in AD‐transgenic mice and that TBI acts as a potential accelerant of AD pathology.
Prevalence of dementia and cognitive impairment no dementia in a large nationally representative sample: The ELSI‐Brazil study
Authors: Bertola Laiss , Suemoto Claudia Kimie , Aliberti Marlon Juliano Romero , Gonçalves Natalia G , Pinho Pedro José M. R. , Lima‐Costa Maria Fernanda , Ferri Cleusa P 
Published: June 2023

AbstractBackgroundApproximately 77% of older adults in Brazil with dementia have not been diagnosed, indicating a major public health issue. Previous dementia epidemiologic studies from Brazil were based on data from one geopolitical region. We aimed to estimate the general and subgroup‐specific (age, education, and sex) prevalence of dementia diagnosis and cognitive impairment no dementia (CIND) using data from 5,249 participants aged 60 years and older from the Brazilian Longitudinal Study of Aging (ELSI‐Brazil), a large nationally representative sample of older adults.MethodParticipants were classified as either: having normal cognitive function, CIND, or dementia based on a combination of the individuals’ cognitive and functional status. A normative subsample provided adjusted regression‐based norms for the cognitive assessment, and a z‐score of ‐1.5 or lower for global cognition was considered to indicate cognitive impairment. We considered functional impairment if the participant reported one or more difficulties in four gender‐independent daily living activities. Participants were classified as having normal cognitive function if there was no cognitive and functional impairment, as CIND if there was only cognitive impairment, and as dementia if there were both cognitive and functional deficits or if the informant scored above 3.4 points in the Informant Questionnaire on Cognitive Decline in the Elderly.ResultWe found a general prevalence of 6.1% (95% CI = 5.1‐7.3) for dementia and 8.6% (95% CI = 7.1‐10.3) for CIND (Table 1). Dementia prevalence ranged from 3.3% (60‐64 years) to 43.0% (≥ 90 years) by age, and from 2.0% (College level or higher) to 17.5% (illiterates) by educational level. Females had a higher prevalence (7.4%) than males (4.4%). CIND prevalence was similar across the age, sex, and education groups.ConclusionThe estimated dementia prevalence is in line with previous epidemiologic studies. Only 0.8% of the ELSI participants self‐reported having a previous diagnosis of dementia, revealing that underdiagnosis is rampant and a common reality. Based on our results, we expect that nearly 1.7 million of the 2015 population, and 2 million of the 2019 population, might have dementia in Brazil.
BENEFICIAL EFFECTS OF PROTEIN RESTRICTION ON METABOLIC HEALTH, COGNITIVE FUNCTION AND NEUROPATHOLOGY IN A MOUSE MODEL OF ALZHEIMER’S DISEASE
Authors: Lamming Dudley , Babygirija Reji , Calubag Mariah , Sonsella Michelle , Murphy Michaela , Pak Heidi , Yeh Yang , Flores Victoria , Green Cara , Matouska Ryan , Michael John , Tobon Anna , Lab Lamming 
Published: June 2023

AbstractBackgroundAge is the greatest risk factor in developing Alzheimer’s Disease (AD); hence, there is great interest in the possibility of targeting AD through interventions that slow or delay aging. Dietary protein restriction (PR) has been shown to be beneficial in improving overall healthspan in both humans and mice. However, the effect of PR in delaying the symptom progression of AD is largely unknown. In this study, we sought to determine the effects of PR in improving metabolic dysfunction, cognitive deficits and AD pathology along with examining the role of mTORC1 and its downstream targets in the 3xTg mouse model of AD.MethodSix month old male and female 3xTg‐AD mice were placed on either 21% protein (control) or 7% protein (PR) diets starting from 6 months and continued until 15 months to determine their effects on cognition, metabolic health and AD neuropathology. Cognitive functioning was assessed via Novel Object Recognition (NOR) test and Barnes maze test.ResultFemale 3xTg‐AD mice on PR diet showed improved long‐term memory (LTM), and males showed a positive trend in improved cognitive function compared with their age matched controls. Based on latency measurements in Barnes maze, we found that a PR diet substantially improved spatial memory in both male and female 3xTg mice. Female and male mice on low protein diets exhibited improvement in glucose tolerance, however females showed a stronger effect in glycemic control than males following a glucose tolerance test (GTT). Histopathological analysis of the hallmarks of AD showed that mice on PR had decreased tau phosphorylation and Aß plaques. Phosphorylation of the mTORC1 substrate S6K1 was decreased in PR fed 3xTg mice which suggest that reduced mTORC1 signaling may be mediating the beneficial effects of PR on AD pathology. We also found that levels of p62 protein, the major autophagy cargo receptor, is increased in 3xTg AD mice and following PR, decreased p62 expression was observed, suggesting that PR activates autophagy.ConclusionThese results suggests the molecular interplay between mTORC1 and autophagy in PR mediated beneficial effects in diminishing AD pathology.
Endogenous hormones in mid‐life and later‐life subjective memory impairment in women
Authors: Sharma Sneha , Clendenen Tess V , Wu Fen , Afanasyeva Yelena , Koenig Karen L , Zeleniuch‐Jacquotte Anne , Chen Yu 
Published: June 2023

AbstractBackgroundReproductive hormones may impact cognition in women. Recent literature suggests that subjective memory complaints (SMCs) can be an early indicator of cognitive impairment. However, epidemiologic data are mixed, with few prospective studies exploring endogenous sex hormones in relation to later‐life SMCs. Assessing this potential association may elucidate an etiology of risk for cognitive impairment in women.MethodWe included 616 premenopausal and 102 postmenopausal women from the New York University Women’s Health Study (NYUWHS), a prospective cohort study with blood samples collected at enrollment (1985‐91) and over 35 years of follow‐up to collect health and lifestyle information. Women were ineligible for inclusion in the cohort if they used hormone medications or were pregnant 6 months prior to enrollment. Healthy controls from prior NYUWHS case‐control studies were eligible for participation in this study if their baseline blood sample had already been used to measure circulating hormones, and they responded to at least one of two follow‐up questionnaires (2018‐present) featuring 6 questions about SMCs. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of baseline hormones with subsequent SMCs, adjusting for age, race, education, original case‐control study, and body mass index (BMI) in a separate model.ResultAndrostenedione, testosterone, dehydroepiandrosterone sulfate (DHEAS), and sex hormone binding globulin (SHBG) were measured in samples collected at baseline for pre‐ and post‐menopausal women; estradiol and estrone were also measured in postmenopausal women. There were no significant associations between premenopausal circulating hormones or SHBG and SMCs. Postmenopausal hormones were inversely associated with SMCs, including in age and BMI‐adjusted models: ORs (95% CIs) for SMCs associated with doubling in testosterone and estradiol were 0.58 (0.35‐0.95) and 0.39 (0.17‐0.90), respectively.ConclusionHigher postmenopausal concentrations of testosterone and estradiol are inversely associated with risk of later‐life SMCs in women.