bluuebunny/crossref_metadata_2025_split huggingface dataset:
Motoric Cognitive Risk Syndrome and Cognition: The Influence of Depression
Authors: Aliberti João Paulo Quessada , Serraglio Ana Beatriz dos S , Suemoto Claudia Kimie , Aliberti Marlon Juliano Romero 
Published: December 2022

AbstractBackgroundMotoric Cognitive Risk (MCR) syndrome is a practical tool used to identify independent people at risk of developing dementia. Although mood disorders and MCR relates, whether depression changes the association of MCR with cognition remains uncertain. We estimated the associations of MCR with cognitive performance and impairment in people aged ≥50 years and examined whether depression modifies the relationship between these conditions.MethodCross‐sectional analysis comprising participants without dementia or physical disability of the Brazilian Longitudinal Study of Aging (ELSI‐Brazil), a nationally representative sample. MCR syndrome was defined as presence of memory complaints and slow gait (one standard deviation below age‐ and sex‐specific gait speed means). Depression was assessed through the 8‐item Center for Epidemiologic Studies Depression Scale (CES‐D). We estimated the associations of MCR with global cognition, orientation, memory, and verbal fluency z‐scores, using linear regressions adjusted for sociodemographic, clinical, and lifestyle factors. The relationship of MCR with cognitive impairment was examined using logistic regressions. We explored interactions between MCR and depression for cognition.ResultWe evaluated 7,131 participants (mean age 62±9 years; 53% women). Individuals with MCR (7% of the sample) had poorer scores for global cognitive performance than those without the syndrome (β = ‐0.29; 95%CI = ‐0.42 to ‐0.17). Participants with MCR were also associated with 2‐fold odds of cognitive impairment compared to those without the syndrome (39% vs. 19%; aOR = 1.93; 95%CI = 1.44 to 2.71). However, depression modified the relationship between MCR and cognitive impairment in people aged 50 to 64 years, with a p‐value for interaction = 0.02 (Figure 1). In middle‐aged adults without depression, MCR was not associated with cognitive impairment. In contrast, in middle‐aged adults with depression, MCR was associated with almost 3‐fold odds of cognitive impairment (aOR = 2.70; 95%CI = 1.60 to 4.40).ConclusionMCR syndrome was associated with worse cognitive performance. Among middle‐aged adults, MCR was related to cognitive impairment only in those with depression. Depression evaluation alongside MCR may help clinicians identify individuals who are more likely to experience cognitive impairment. Future studies should test the impact of treating depression on those with MCR.
Comparative characterization of 5XFAD and hAbetaSAA mouse models of familial AD
Authors: Elk Kevin J , Garceau Dylan , Oblak Adrian L , Pandey Ravi S , Carter Gregory W , Ferron Gianna , Linehan Stefan T , Ragan Tim , Little Gabriela , Williams Sean‐Paul , Rizzo Stacey J Sukoff , Lin Sherry , Datta Sandeep Robert , Sasner Michael 
Published: December 2022

AbstractBackgroundThe failure of most clinical Alzheimer’s disease (AD) trials has been partially attributed to the lack of translatability of current AD mouse models to human patients. A recently developed model of familial AD (fAD), expressing Swedish, Arctic and Austrian mutations in App (hAbetaSAA), has been shown to be a useful amyloidogenic model which recapitulates many aspects of human AD, including plaque distribution and microglial transcriptional changes. Our aim is to further characterize the hAbetaSAA model and compare it to the widely used 5xFAD transgenic model.MethodMotion Sequencing (MoSeq) software was used to model the underlying structure of spontaneous behaviors recorded in an open field in hAbetaSAA and 5xFAD mice longitudinally from 10 to 18 months of age. Aged hAbetaSAA and 5xFAD brain tissue was used for spatial transcriptomic/proteomic profiling, performed by Nanostring’s GeoMx®, which allowed for quantification of gene and protein expression in plaque‐associated and non‐plaque‐associated regions of interest. A fluorophore‐conjugated amyloid antibody (Methoxy‐X04) was administered to cohorts of hAbetaSAA and 5xFAD prior to harvest at various ages. An additional fluorophore‐conjugated antibody (lectin Dylight®594) was administered to 19‐month‐old cohorts permitting visualization of cerebral amyloid angiopathy (CAA). Whole brains were sectioned/imaged using Serial Two‐Photon Tomography on the TissueCyte (TissueVision), creating indexed tissue sections and high‐resolution 3D models of each brain. Subsequent rounds of staining permitted characterization of disease‐associated microglia (DAM) and dystrophic neurites. An independent cohort was evaluated for EEG telemetry.ResultMoSeq revealed divergent behaviors of 5xFAD and hAbetaSAA mice suggesting differences in behavioral phenotypes of these two models. Preliminary GeoMx data shows upregulation of DAM genes localized to plaques in hAbetaSAA homozygotes as identified by RNA‐seq; correlating 5xFAD data is in progress. Further assessments of bulk RNA‐Seq, amyloid distribution, CAA burden and cortical EEG spectral analysis are underway.ConclusionComparison of hAbetaSAA and 5xFAD using innovative modes of assessment showcase hAbetaSAA as an amyloidogenic mouse model of fAD that aligns more closely with human than 5xFAD. This model is available for preclinical research with no licensing restrictions and is devoid of artifacts related to transgenic overexpression, positioning it as an improved mouse model for studying fAD mutations.
Prognostic value of regional tau PET measures in Alzheimer’s Disease
Authors: Tunali Ilke , Svaldi Diana , Kotari Vikas , Collins Emily C. , Shcherbinin Sergey , Initiative Disease Neuroimaging 
Published: December 2022

AbstractBackgroundRecent findings (Ossenkoppele et al, JAMA Neurology, 2021; Pontecorvo et al, Brain, 2019) suggest that tau‐positron emission tomography (PET) may better predict cognitive change in AD compared to amyloid‐PET and MRI‐based cortical thickness. However, the relationship between region‐based standardized uptake value ratio (SUVR) metrics and cognitive change in terms of prognostic value is not clearly understood. In this study, we evaluated the potential utility of region‐based tau‐PET metrics to stratify patients by cognitive decline risk and amyloid status in the brain.MethodsWe analyzed a subgroup of N=100 symptomatic (24 MCI and 76 AD) subjects from the ADNI database that had longitudinal cognitive scores and flortaucipir and florbetapir scans acquired within ±6 months of baseline cognitive scores. We quantified tau burden using global MUBADA SUVR (Devous et al, JNM, 2018) and AAL atlas‐based temporal and parietal regions using a modified cerebellar gray matter reference region (Pontecorvo et al, Brain, 2017). For every global and region‐based tau SUVR, patients were dichotomized into tau groups of high (T+) and low (T‐) by using a series of thresholds (1.15‐1.45). For all identified tau groups, average Mini‐Mental State Exam (MMSE) score, average MUBADA SUVR, percentage of amyloid‐positive individuals and change in 13‐item Alzheimer’s Disease Assessment Scale‐Cognitive subscale (ADAS‐Cog13) scores were assessed. Signal‐to‐noise ratios (SNRs) and mean annual cognitive changes were measured using ADAS‐Cog13 scores that were obtained in a 2‐to‐3‐year period per patient.ResultsFor every global and region‐based flortaucipir measure, an increase in SUVR threshold resulted in lower average MMSE score, larger average global tau burden, higher percentage of amyloid‐positive patients and increased mean cognitive decline for patients in T+ group. SUVR thresholds that identified subgroups with high percentage (≥90%) of amyloid‐positive (Table 1) and high (>1) SNRs (Table 2), were observed to be lower for brain regions identified later in the tau pathologic cascade: inferior temporal (1.45), lateral temporal (1.35), lateral parietal (1.20).ConclusionsRegion‐based tau‐PET analysis showed that utilizing temporal and parietal SUVR values could help stratify patients by risk of cognitive decline and amyloid status. Clinical trial eligibility algorithms based on region‐based tau metrics, might enable enrolling patients into customized AD trials.
The association of the of late‐life onset psychotic symptoms with incident cognitive impairment in a cognitively normal sample.
Authors: Creese Byron , Aarsland Dag , Ballard Clive G , Brooker Helen , Corbett Anne , Ismail Zahinoor 
Published: December 2022

AbstractBackgroundPrevious research suggests around 5–10% of cognitively normal older people report some degree of psychotic experiences as measured in the Mild Behavioral Impairment framework. Such late‐onset symptoms potentially confer a relatively high risk for neurodegenerative disease so there is a need for studies examining their clinical correlates prior to dementia onset. We compared the relationship between psychotic symptoms and progression to cognitive impairment in a large community‐dwelling sample of adults over 50.Method5,085 participants were drawn from the PROTECT study. These individuals had no reported neurological diseases (including MCI), psychotic disorders or cognitive impairment as rated by the Informant Questionnaire of Cognitive Decline in the Elderly (IQCODE). Cognitive impairment was operationalised as a score of >3.3 on the IQCODE. Participants were followed up for a maximum of 5 years. IQCODE scores were taken every. Survival until ‘cognitive impairment’ (i.e. IQCODE >3.3) was the primary outcome. At baseline participants were dichotomised into those scoring >0 on any of the 5 items pertaining to psychosis on the Mild Behavioral Impairment Checklist (‘MBI‐psychosis’ group) and those scoring 0 on all 5 items (‘no symptoms’ group). Survival until IQCODE >3.3 was assessed in a Cox proportional hazards model (adjusting for age, gender, education and mental health diagnoses). The frequency of other medical conditions and Instrumental Activities of Daily Living (IADL) impairment was also compared between the two groups.ResultThere were 429 (8%) participants in the MBI‐psychosis group (72% men) and 4,656 in the no symptom group (72% men). The mean age was 63 (SD: 6.9). MBI‐psychosis was associated with a 3‐fold (95% CI: 2.4‐3.6, p<0.0001) higher risk of cognitive impairment relative to the no symptom group. There were modestly higher proportions of the following conditions in the MBI‐psychosis group compared with the no symptoms group (p<0.05): heart disease (9%, 6%), high blood pressure (33%, 27%), high cholesterol (30%, 25%), hypothyroidism (11%, 7%), arthritis (26%, 21%). There was no difference in IADL impairments.ConclusionRelatively mild psychotic symptoms that emerge in later are associated with an increased risk of cognitive decline, suggesting that these symptoms in the cognitive normal population may be of clinical significance.
Association of apolipoprotein E in peripheral blood and in vivo Alzheimer’s disease pathologies in nondemented older adults
Authors: Byun Min Soo , Yi Dahyun , Ahn Hyejin , Kim Min Jung , Jung Joon Hyung , Jung Gi Jung , Lee Jun‐Young , Kim Yu Kyeong , Lee Yun‐Sang , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young 
Published: December 2022

AbstractBackgroundPrevious studies reported the link between apolipoprotein E (apoE) in peripheral blood and risk of Alzheimer’s disease (AD) dementia. However, underlying mechanism for this link remains unclear. We investigated whether serum apoE concentration is associated with in vivo AD pathologies in nondemented older adults.MethodA total 437 nondemented older adults were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. All participants underwent comprehensive evaluation including clinical assessment, blood sampling, as well as 11C‐PiB PET and MRI. A subset of participants (N=130) also underwent 18F‐AV1451 PET for measurement of brain tau pathologies. All participants were divided into low, middle, and high apoE concentration tertile groups (i.e., T1, T2, and T3).ResultThere were no significant differences in demographic and clinical variables except the frequency of female and rate of apoE ε4 allele (APOE4) positivity; the lower serum apoE was associated with fewer female (40.1%, 61.6%, and 67.8% for T1, T2, and T3, respectively) and higher APOE4 positivity rate (34.3%, 25.2%, and 16.8%). In terms of AD biomarker, Aβ positivity rate showed significant negative association with serum apoE (40.1%, 31.8%, and 24.8%), which remained significant after adjustment of covariates including age, sex, and diagnosis. In addition, reduced AD‐signature region volume, a neurodegeneration biomarker of AD, was significantly associated with lower serum apoE after controlling the same covariates. With regard to tau biomarker, positivity rate of global tau deposition showed significant negative association with serum apoE level (56.8%, 50%, and 20%) after adjustment of covariates. When we additively controlled the effect of APOE4 positivity, the associations between low serum apoE and greater neurodegeneration and tau positivity remained significant, whereas the association between apoE and Aβ positivity did not reach statistical significance.ConclusionIn the present study, low serum apoE was associated with greater burden of in vivo AD pathologies and such association appears even independent of APOE4 carrier status in regard of tau deposition and neurodegeneration. The finding suggests a potential role of serum apoE as a surrogate marker for in vivo AD pathologies in nondemented older adults.
Cognitive resilience polygenic risk score sensitive to preclinical disease changes
Authors: Eissman Jaclyn M. , Khan Omair A. , Liu Dandan , Petyuk Vladislav A , Gifford Katherine A. , Dumitrescu Logan , Jefferson Angela L. , Hohman Timothy J. 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) polygenic risk scores (PRS) are often derived from case/control GWAS, which are typically not sensitive to preclinical disease changes, limiting their clinical utility. To overcome this pitfall, we built and evaluated the performance of multiple PRS of AD‐related endophenotypes, including resilience to cognitive impairment in the presence of amyloid.MethodFour PRS were derived from GWAS of baseline memory, memory decline, cognitive resilience (Dumitrescu et al., 2021), and AD (Kunkle et al. 2019). PRS were built in an independent cohort that was free of dementia, the Vanderbilt Memory and Aging Project (N=255). We used linkage disequilibrium clumping on TOPMed‐imputed genotypes, and a threshold of P=0.01. We ran linear models with baseline memory score as the outcome, and baseline age, sex, and PRS as predictors. Linear mixed effects models, with identical predictors, were used when longitudinal memory was the outcome, letting individual slope and intercept vary. Finally, we tested a CSF Aβ42‐by‐PRS interaction term to assess if PRS modified associations between amyloid and cognition. Sensitivity analyses excluded APOE from PRS calculations.ResultAs expected, the baseline memory PRS related to baseline memory (β=0.12, P=0.04), and the memory decline PRS related to longitudinal memory (β=0.04, P=0.001). Without APOE, the baseline memory PRS and the memory decline PRS results attenuated. The AD PRS related to both baseline memory (β=‐0.19, P=0.002) and longitudinal memory (β=‐0.03, P=0.01), but results attenuated without APOE. The resilience PRS did not have a main effect on baseline or longitudinal memory. However, interestingly, the resilience PRS interacted with CSF Aβ42 on baseline memory (β=‐0.001, P=0.02; Figure 1), whereby the resilience PRS related to memory among amyloid‐positive individuals (β=0.44, P=0.01) but not amyloid‐negative individuals (β=0.06, P=0.46). No other PRS was predictive of memory among amyloid‐positive individuals, and resilience PRS results remained consistent without APOE.ConclusionOur results demonstrate that a resilience PRS appears to be predictive of individual cognitive performance downstream of amyloidosis. Future work is needed to replicate this finding, but our preliminary findings highlight the potential utility of resilience PRS for predicting individual risk for AD‐related cognitive impairment during the preclinical stages of disease.
Type 2 diabetes mellitus and obesity impact AD‐related pathology through overlapping and independent pathways
Authors: Yu Yang Yang , Nowell Joseph , Edison Paul 
Published: December 2022

AbstractBackgroundIt is proposed that neuronal damage in diabetes is related to hyperglycaemia and insulin resistance, whilst inflammation and subsequent oxidative stress affects cognitive function in obesity. We investigated whether obesity and diabetes present distinct neuropathological features of neurodegeneration.MethodsTo compare amyloid, tau and cerebral glucose metabolism, we processed 1973 available PET scans for 18F‐AV‐45, 18F‐flortaucipir and 18F‐fludeoxyglucose (FDG) from 971 participants with diabetes (n=194), obesity (n=377) and without diabetes or obesity (n=400) from the Alzheimer’s Disease Neuroimaging Initiative dataset. Independent t‐tests and multivariate analysis were used for regions of interest (ROIs) analysis in participant groups with diabetes vs non‐diabetic/non‐obese and obesity vs non‐diabetic/non‐obese. This was conducted across different cognitive subgroups, namely Alzheimer’s disease, mild cognitive impairment or normal cognition. Amyloid positive and negative subjects were evaluated separately. Voxel‐wise analysis using SPM was also conducted for these groups.ResultsFor diabetes, higher amyloid uptake was found in the medial temporal regions in the cognitively normal diabetic group compared to the cognitively normal (non‐diabetic/non‐obese) group. This was also found in the amyloid positive mild cognitively impaired diabetic groups compared to mild cognitively impaired (non‐diabetic/non‐obese) group. Similarly, higher amyloid deposition was seen in the hippocampus of the cognitively normal obese group compared to the cognitively normal (non‐diabetic/non‐obese) group.Additionally, higher tau uptake was found in the whole brain (global brain value), frontal, parietal and occipital lobes for cognitively normal diabetic and obese groups, compared to cognitively normal (non‐diabetic/non‐obese) groups. Higher tau was further found in the temporal lobe and anterior cingulate of AD obesity participants compared to the AD (non‐diabetic/non‐obese) participants.Discrete cerebral glucose metabolic patterns were found in diabetes and obesity. In the diabetic groups, reduced FDG uptake was found in mild cognitively impaired participants (whole brain, frontal, parietal and occipital lobes) and amyloid positive AD participants (occipital lobe) compared to non‐diabetic/non‐obese participants. In contrast, increased FDG uptake was mainly found in amyloid negative obese participants.ConclusionsGlucose hypometabolism in diabetic participants in contrast to hypermetabolism in obese participants implies that different pathological processes of neurodegeneration occur in these two conditions. This suggests that these two conditions require different therapeutic strategies to prevent neurodegeneration.
DNA methylation of mitochondrial DNA shows variation in human brain.
Authors: Wheildon Greg , Smith Adam R. , Soanes Darren , Southern Francesca , Devall Mathew , Moore Karen , O'Neill Paul , Troakes Claire , Lunnon Katie 
Published: December 2022

AbstractBackgroundThere is growing evidence for the role of DNA methylation in regulating the transcription of mitochondrial genes, particularly in neurodegenerative disorders characterized by mitochondrial dysfunction including Alzheimer’s disease (AD). However, to date, a cross‐comparative analysis of the mitochondrial DNA methylome in neurodegenerative disorders has yet to be undertaken.MethodHere, we present an interrogation of the mitochondrial DNA methylome at single base resolution, using pyrosequencing, across different types of neurodegenerative disorders. We performed a targeted study design to investigate the D‐Loop methylation of the mtDNA in the entorhinal cortex (EC) for a pilot cohort of 26 AD, 22 Dementia with Lewy bodies (DLB) and 26 control samples, matched as closely as possible for age and sex. This research forms the basis of a larger study which will compare D‐Loop methylation in several brain regions including the EC, superior temporal gyrus and cerebellum in AD, DLB, Vascular dementia, Huntington’s (HD) and Parkinson’s disease (PD) samples. The striatum and substantia nigra, will also be analyzed in the HD and PD samples respectively.ResultWe have identified DNA methylation differences at the D‐Loop in different neurodegenerative diseases. In particular, we have found two statistically significant sites that show a decrease in percentage methylation of approximately 4% and 3% in the EC of the DLB brain samples compared to controls.ConclusionWe have discovered differences in DNA methylation across the mitochondrial genome between different types of neurodegenerative disorders in human brain samples using pyrosequencing. Moving forward we will take this approach and expand into the larger cohort to further investigate the role of mitochondrial epigenetic mechanisms in neurodegenerative disorders.
Bulk and single cell transcriptomic analysis of different dementia types in human hippocampus
Authors: Olayinka Oluwatosin A , Hu Junming , O'Neill Nicholas K , Wong Melissa , Rickner Hannah , Simkin Irene , Stein Thor D. , Wolozin Benjamin , Zhang Xiaoling , Farrer Lindsay A. 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is characterized by cognitive deterioration and extracellular amyloid beta deposits and neurofibrillary tangles in the brain. These may occur in tandem with markers of Lewy body (LB) and vascular dementia (VaD). Studying bulk and single‐cell expression profiles for these disorders may identify factors shared between and unique to AD and other dementias.MethodBulk RNA‐sequencing was performed using 210 human postmortem hippocampal region samples obtained from brains donated to the BU Alzheimer Disease Research Center. After quality checks (QC), 191 samples classified as AD+LB (n=43), AD+VaD (n=54), AD alone (n=73), and controls (n=17) were included in the study. Analysis of expression differences between each of these AD groups and controls was performed using limma software with models including covariates for age, sex, RNA quality, plate, and two surrogate variables to adjust for unknown variation. Weighted gene co‐expression network analysis (WGCNA) was used to identify clusters of co‐expressed genes. Additionally, high quality single‐nuclei RNA sequencing data (snRNA‐seq) was obtained from 8 of the 210 hippocampal samples with an average of 6000 cells detected per sample and 1800 genes per cell after QC. This snRNA‐seq data was integrated with the bulk data using Scissor to identify cell populations positively and negatively associated with AD.Result481 genes were differentially expressed between AD cases and controls. Upregulated genes in AD subjects were enriched for cilia function and morphological development and downregulated genes in AD subjects were enriched for mitochondrial energy production. A WGCNA module strongly associated with ciliary function was found to be overrepresented in AD (and especially AD+VaD) samples compared to controls. Multiple brain cell types were detected from our snRNA‐seq data. Of these, a subpopulation of ependymal cells related to the ciliary WGCNA module was positively associated with AD status.ConclusionOur results suggest that different sets of co‐expressed genes in hippocampus distinguish AD brains with and without pathological hallmarks related to other forms of dementia, and brains without AD pathology. This study also provides preliminary evidence for the involvement of ependymal cell populations in AD