bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large‐scale plasma proteomic analysis identifies proteins and biological pathways associated with incident dementia
Authors: Walker Keenan A , Chen Jingsha , Wu Aozhou , Tin Adrienne , Mosley Thomas H , Fornage Myriam , Ballantyne Christie M , Boerwinkle Eric , Sullivan Kevin J , Zeger Scott L , Ganz Peter , Gottesman Rebecca F , Coresh Josef 
Published: December 2020

AbstractBackgroundWhile plasma levels of several etiologically relevant molecules have been associated with Alzheimer’s disease and dementia more broadly, information about the full range of changes in the plasma proteome that precede dementia is lacking. Accordingly, this study used modified aptamer technology (SOMAscan) to examine the relationship between the plasma levels of 4,877 proteins and risk for incident dementia in a large community‐based sample.MethodsPlasma levels of 4,877 proteins were measured in non‐demented participants who attended visit 5 of the Atherosclerosis Risk in Communities (ARIC) study (2011‐2013; Figure 1A). We examined the association of log2 protein levels with incident dementia risk over 5 years using Cox proportional hazard models adjusted for demographic and cardiovascular risk factors. Dementia‐associated proteins were then measured from plasma samples collected 18 years earlier (visit 3; 1993‐1995) and related to dementia risk between visits 3 and 5 (Figure 1B). Candidate proteins were related to measures of brain structure (by MRI) and amyloid burden (by PET). Ingenuity Pathway Analyses and Mendelian randomization were used to inform biological pathways and causal relationships.ResultsAmong 4,144 participants seen at visit 5 (age: 75 (SD 5)), there were 444 incident dementia cases over the next 5 years. In a proteome‐wide analysis, 50 proteins were significantly associated with incident dementia at a Bonferroni‐corrected threshold (P<1.03e‐05; Figure 2A). When these dementia‐associated proteins were measured in plasma collected almost 20 years earlier (n=11,069; 1,131 dementia cases), 21 of the 50 proteins continued to show a significant association with incident dementia (P<0.001; Figure 2B). We found causal associations with Alzheimer’s disease for two of the top five dementia‐associated proteins using Mendelian randomization, and we demonstrated a relationship between protein levels and neuroimaging measures of atrophy, white matter disease, and cerebral amyloid. A systems‐level analysis of dementia‐associated proteins implicated biological mechanisms involved in metabolic and inflammatory signaling, coagulation and prothrombin activation, and innate immune function, among others (Figure 3).ConclusionsThese findings provide insight into the plasma proteomic patterns that precede the onset of dementia in old age and middle age and highlight novel molecules and mechanistic pathways for further study.
Risk factors for dementia in Cuban older adults
Authors: Peeters Geeske , Almirall‐Sanchez Arianna , Llibre‐Guerra Jorge J , Lawlor Brian , Anne Kenny Rose , Yaffe Kristine , Llibre Juan 
Published: December 2020

AbstractBackgroundLittle is known about risk factors of dementia in Latin American countries. Findings from western countries cannot be readily translated to Latin American countries. To inform risk stratification and targeted preventive strategies, we aimed to identify risk factors of incident dementia in Cuban older adults and explores how these change with age.MethodData were from 1846 participants in the Cuban cohort of the 10/66 Dementia Research Group. Participants completed questionnaires, health examination and cognitive tests at baseline (2003‐06) and on average 4.5 years later (2007‐10). Univariable and multivariable associations between risk factors at baseline and incident dementia at follow‐up were examined using logistic regression for the total sample and for younger (65‐74 yrs) and older (75+ yrs) subgroups.Result9.2% of participants developed dementia. In the total sample, significant univariable associations with dementia were found for age, education, marital status, obesity, stroke, depression, physical activity, fish consumption and family history. In the multivariable model, associations with age (≥75 vs. 65‐74 yrs: OR=2.65, 95%CI=1.86‐3.76), marital status (widowed/divorced/separated vs. married/cohabiting: OR=1.65, 95%CI=1.12‐2.43), physical activity (inactive vs. highly active: OR=2.63, 95%CI=1.58‐4.37), and fish consumption (regular vs. rarely: OR=1.74, 95%CI=1.04‐2.91) remained statistically significant. In the younger age group, significant multivariable associations were found for stroke (OR=2.90, 95%CI=1.22‐7.90), ischaemic heart problems (OR=0.22, 95%CI=0.05‐0.95), depression (OR=1.87, 95%CI=1.05‐3.31), and physical activity (inactive vs. highly active: OR=3.09, 95%CI=1.26‐7.58). In the older age group, significant multivariable associations were found for smoking status (current vs. never/ex‐smoker: OR=2.19, 95%CI=1.17‐4.11), physical activity (inactive vs. highly active: OR=2.05, 95%CI=1.07‐3.92) and fish consumption (regular vs. rarely: OR=2.35, 95%CI=1.24‐4.45).ConclusionThis is the first study in Cuba and one of few in Latin America to identify risk factors for incident dementia. The risk profiles were dominated by chronic conditions in 65‐74 year olds and by lifestyle factors in 75+ year olds. The important role for modifiable risk factors holds promise for future preventive strategies.
Investigating neural correlates of mild cognitive impairment using estimated clinical status from neuropsychological test battery: LASI‐DAD
Authors: Keller Brenton James , Lee Jinkook , Toga Arthur W , Jovicich Jorge ,   LASI‐DAD
Published: December 2020

AbstractBackgroundHaving ways to quickly assess cognitive impairment is critical for developing nations. Here we examine how different combinations of neuropsychiatric tests identify cognitive impairment using the Longitudinal Aging Study in India ‐ Diagnostic Assessment of Dementia (LASI‐DAD). We then investigate for brain regions that show structural morphological differences between cognitive impairment and cognitive normal groups.MethodsA total of 103 subjects (female = 46, age = 68 ± 6 years) were studied from three clinical 3T MRI centers using the ADNI 3 MRI protocol (NIMHANS, Bangalore, N=52, NM Medical, Mumbai, N=23, and Institute of Kolkata N=28). Cognitive impairment clinical status was missing for 62 of the subjects. Cognitive impairment status was investigated using the LASI‐DAD main dataset (clinical status n = 1486). We examined different combinations of factors from the LASI‐DAD neuropsychological assays to predict clinical impairment status. After estimating cognitive impairment status, brain morphometry data was studied with Freesurfer using volumetric ROI‐analysis and vertex‐based cluster‐corrected structural analysis.ResultsWe found a combination of JORM IQCODE, Cognitive Activity Score, years of education, HMSE, and the interaction between HMSE and general cognition to best predict clinical status (AUC=0.90). Clinical status was calculated for the MRI subjects lacking a clinical diagnosis (CN=38, CI=24). Cognitive impairment was found to be associated with thickness and volumetric decline, especially the right hemisphere transverse temporal gyrus (10‐15%) and medial orbitofrontal cortex (6‐9%), and bilateral volumetric decline of the hippocampus (presubiculum and molecular layer, 5‐8%). Furthermore, age was not found to affect hippocampal volume, yet there was a significant negative effect on hippocampal volume with the interaction of cognitive impairment and age (6‐8%). A significant interaction between cognitive impairment and age was also found to reduce the curvature of the left hemisphere fusiform.ConclusionsWe investigated combinations of neurophysiological tests to predict cognitive impairment status. Using the predicted cognitive impairment status, we found significant morphological changes in the brain between groups. This demonstrates how quick neurocognitive exams can be used in areas lacking clinicians who can diagnosis dementia.
Correcting the MIR‐124/PTPN1 signal abnormality rescues tauopathy in Alzheimer’s disease
Authors: Zhou Yang 
Published: December 2020

AbstractBackgroundMicroRNAs have been implicated in diverse physiological and pathological processes.MethodCell Culture and Treatment, RNA Isolation and Quantitative Real‐Time PCR (qRT‐PCR), Preparation of Soluble and Insoluble Fraction.ResultWe demonstrated that disturbance of the miR‐124/PTPN1 signal induced animbalance of the phosphatase/kinase system by enhancing the tyrosine phosphorylation of GSK‐3β and PP2A, which then caused the activation of GSK‐3β and inactivation of PP2A and ultimately led to AD‐like tauopathy.ConclusionWe first replicated the alteration in the miR‐124/PTPN1 signal in AD by artificially upregulating miR‐124 or silencing PTPN1 in the hippocampus of C57 mice and found that disturbance of miR‐124/PTPN1 signal resulted in AD‐like tauopathy, including hyperphosphorylation, aggregation and missorting, as well as learning and memory deficits.
Implication of healthy lifestyles and the taking of Fortasyn Connect© in the cognitive impairment evolution
Authors: Zea‐Sevilla María Ascensión , Palomo María Sagrario Manzano 
Published: December 2020

AbstractBackgroundThere is increasing evidence that beyond modifiable risk factors there are modifiable factors associated with Alzheimer's disease, including those related to cardiovascular risk ‐ high blood pressure, hypercholesterolemia, diabetes, smoking and overweight. And with a diet lifestyle, physical exercise and cognitive and social activity. Based on this premise, we analyze on a series of patients treated with Fortasyn connect (Souvenaid®) their “healthy life” habits.MethodOn 39 patients with mild cognitive impairment or mild Alzheimer's disease in treatment with Souvenaid®, life habits questionnaires were completed in daily and leisure activities, in social and food participation.ResultWe studied 39 subjects around the age of 81.1 years (± 4.5), in treatment with Souvenaid ® (53.8% associated with IAch and 10.3% with memantine). Compliance with Souvenaid ® treatment was 79.5% (due to intolerance dropped 7.7%). The mean treatment follow‐up of patients who finished the study was 12.9 months (± 8.0). The adherence to the Mediterranean diet was moderate. 37.8% of the subjects maintained or improved the MMSE score at the time of follow‐up. The loss of the monthly MMSE score tended to be greater in the elderly (p = 0.082) and was significantly lower in those who regularly drove (p = 0.009), read (p = 0.036) or engaged in light physical activity (p = 0.018). In the multivariate study, driving and light physical activity was associated with a lower monthly loss of MMSE.ConclusionThe study of healthy lifestyles could help elucidate the best combination of pharmacological and non‐pharmacological treatments, in order to develop a "precision medicine" approach and an individual and multimodal strategies, in order to prevent, diagnose and develop therapies more precise and effective against AD.
An integrative, hypothesis‐free, multi‐omics approach uncovers biological pathway alterations in Alzheimer’s disease
Authors: Clark Christopher , Dayon Loic , Masoodi Mojgan , Popp Julius 
Published: December 2020

AbstractBackgroundIn recent years, different ‘omics approaches have identified multiple pathway alterations in Alzheimer’s disease (AD). However, the pathogenic mechanisms are still not fully understood. Here, we test an integrative approach combining multiple ‘omics results to identify and explore in depth central nervous system (CNS) pathway alterations in AD.MethodsMulti‐omics data were obtained from a well‐characterised cohort of community‐dwelling elder subjects including healthy volunteers with normal cognition and memory clinic patients with either mild cognitive impairment or mild AD dementia. Inflammatory biomarkers were quantified by sandwich immunoassays in cerebrospinal fluid (CSF) samples; metabonomics (covering amino acids, carboxylic acids, and central energy metabolism), ionomics, proteomics, and lipidomics were performed using nuclear magnetic resonance or mass spectrometry coupled to liquid, supercritical fluid or gas chromatography. Alterations associated with AD were identified using Elastic‐Net regression at single ‘omics level and Multi‐Omics Factor Analysis, a hypothesis‐free Bayesian approach, for multi‐omics integration. Pathway enrichment analysis was performed in the Reactome database for selected analytes.ResultsWe identified five major dimensions of heterogenicity (latent factors, LFs) within the cohort. We evaluated the performance of this model by separating participants in the cohort with low vs. high CSF expression levels of amyloid, tau and phosphorylated tau (P‐tau). Best performance was obtained for tau and P‐tau with 93 and 96% sensitivity, respectively. Using these LFs we could furthermore identify analytes associated with either amyloid pathology (21) or neurodegeneration (37). We also identified specific patterns of expression of these analytes across LFs, revealing interactions between multiple ‘omics modalities. Pathway enrichment analysis also revealed an over representation of the hemostasis, immune response and extracellular matrix signalling pathways.ConclusionsIn this proof‐of‐principle work, we demonstrate that integrating expression from multiple ‘omics levels allows for a more comprehensive exploration of alterations related to AD pathology at CNS level. We identify novel metabolic alterations at molecular and pathway levels, and describe their relationships with amyloid pathology, neuronal injury, and tau hyperphosphorylation.
Single cell RNA sequencing of human microglia uncovers a subset that is associated with Alzheimer’s disease
Authors: Olah Marta , Menon Vilas , Habib Naomi , Taga Mariko , Ma Yiyi , Khairallah Anthony , Yung Christina J. , Coronas‐Samano Guillermo , Vonsattel Jean P , Teich Andrew F. , Schneider Julie A. , Bennett David A. , Regev Aviv , De Jager Philip L. 
Published: December 2020

AbstractBackgroundThe extent of microglial heterogeneity in the aging human brain remains a central, yet poorly explored question in light of the development of therapies targeting this cell type in age related neurodegenerative diseases, such as Alzheimer’s disease.MethodsUsing single cell RNA sequencing, we investigated the population structure of microglia purified from human cerebral cortex of aged donors with and without Alzheimer’s disease.ResultsWe describe the population structure of microglia in the aged human brain and establish the divergent association of the different microglia subsets to age related neuropathologies and measures of cognitive decline. We confirm the presence of the identified microglial subpopulations histologically and explore their topological relationship to histopathological hallmarks of aging and AD in situ. Based on our data we prioritize one microglial cluster, cluster 7, which is enriched for genes involved in endosomal/vacuolar pathway. Interestingly we find that the signature gene set of cluster 7 is depleted in the cortical transcriptomic profile of individuals with AD. Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data.ConclusionsThus, single cell transcriptomic profiling of live human microglia identifies a range of microglia subtypes in the aged human brain, and we prioritize one of these as being altered in AD.
A common risk variant in the MTHFR gene contributes to age‐related cerebrovascular dysfunction in VCID
Authors: Reagan Alaina M. , Christensen Karen , Haber Annat , Rozen Rima , Carter Gregory W. , Sasner Michael , Howell Gareth 
Published: December 2020

AbstractBackgroundCerebrovascular damage occurs during aging, Alzheimer’s disease and Vascular Dementia, commonly referred to as Vascular Contributions to Cognitive Impairment and Dementia (VCID). However, few mouse models currently recapitulate human cerebrovascular deficiencies in disease. The C677T variant in methylenetetrahydrofolate reductase (MTHFRC677T
) is commonly associated with VCID. MTHFR codes for an enzyme involved in production of folate, homocysteine, and methionine metabolism. The MTHFRC677T
polymorphism is predicted to result in hyperhomocysteinemia, a condition that causes vascular inflammation and vascular damage. Additionally, methionine deficiency can result in DNA hypomethylation and has been confirmed in MTHFRC677T
carriers. Despite the fact that, in some populations, MTHFRC677T
is more common than APOE
E4, mechanisms by which MTHFR
C677T increases risk for VCID are not known.MethodsCRISPR technology was employed to engineer the Mthfr
C677T allele into C57BL/6J (B6) mice. Vascular health is being assessed in 6, 12, 18 and 24 months‐old mice using leakage assays (FITC‐dextran and presence of extravascular fibrin) and immunofluorescence (IF) to examine blood brain barrier integrity in the cerebrovascular unit: endothelium (CD31) smooth muscle (aSMA) pericytes (PDGRFb) basement membrane (ColIV) and tight junctions (Claudin‐5, Occludin, ZO‐1). Functional MRI is used to determine in vivo vascular reactivity. Bulk RNA sequencing and Reduced Representation Bisulfite Sequencing (RRBS) were performed on half brains to assess differential gene expression and DNA methylation, respectively.ResultsMice with the Mthfr
C677T risk variant have significantly reduced liver enzymatic activity, significantly increased plasma homocysteine levels and decreased methionine levels, recapitulating the human phenotype. Transcriptional profiling of brain tissue revealed genes regulating circadian rhythm, neurogenesis, ER stress and GABA signaling are differentially expressed (DE) in B6.Mthfr
C677T compared to B6 samples. RRBS data demonstrated significant genome‐wide DNA hypomethylation in these mice. Hypomethylated and DE genes are expressed in astrocytes, microglia and endothelial cells and are predicted to regulate apoptosis/proliferation, inflammation and glucose transport across the blood brain barrier. Validation by IF is underway.ConclusionWe have created a novel mouse strain to determine the precise mechanisms by which MTHFR
C677T increases risk for VCID. This work aims to identify novel therapeutic approaches that preserve cerebrovascular health throughout aging to prevent VCID.
Natural history of apathy in Alzheimer’s disease
Authors: Zhu Carolyn W. , Grossman Hillel , Sano Mary 
Published: December 2020

AbstractBackgroundApathy is a common behavioral symptom of dementia, yet information on its impact dementia is limited. This study examines prevalence, incidence, and persistence of apathy longitudinally.MethodSample was drawn from the National Alzheimer's Coordinating Center Uniform Data Set (NACC‐UDS) including participants enrolled 9/2005‐5/2019 with at least one follow‐up, with baseline diagnosis of MCI or AD. Presence of apathy was defined using clinician judgment within the NACC‐UDS protocol, indicating whether the participant currently manifests meaningful change in behavior in apathy (yes=1/no=0). Incidence of apathy was defined as the proportion of participants who did not have an endorsement of apathy at baseline but had a new endorsement of apathy at that visit. Persistence of apathy was defined as the proportion of participants who had an endorsement of apathy between two consecutive visits.ResultSample included 9,607 participants with baseline CDR=0.5 (n=5,323), 1 (n=3,115), 2/3 (n=1169). Apathy was endorsed in 59.4% of participants at some point during follow‐up (CDR=0.5: 46.6%, CDR=1: 72.9%, CDR=2/3: 81.2%). Participants with apathy differed from those who never had apathy in: being male (49.0% vs. 44.7%), education (14.6±3.7 vs. 14.9±3.6), reporting depression in the past 2 years (42.7% vs. 26.6%), having at least one APOE e4 allele (58.7% vs. 52.9%), follow‐up years (4.1± 2.1 vs 3.8±2.2), MMSE (21.5±6.3 vs. 24.2±5.1), and FAQ (13.8±9.0 vs. 7.6±8.2) (all p<0.01). Differences in baseline age and comorbidities were statistically insignificant. Presence of apathy increased over time in participants with baseline CDR=0.5 (baseline to visit 5: 19.8% to 33.8%) and CDR=1 (43.9% to 59.9%), but fluctuated around 62.4% in CDR=2/3. Incidence of apathy fluctuated around 12.5%, 15.7% and 13.4 % for each baseline CDR group. Persistence of apathy between consecutive visits increased over time in participants with baseline CDR=0.5 (baseline to visit 5: 12.6% to 21.4%) and CDR=1 (33.2% to 44.8%), but fluctuated around 49.2% in CDR=2/3.ConclusionPrevalence and persistence of apathy increased over time and correlated with disease severity. Incident apathy appears to plateau after CDR=1. The increasing impact of apathy over the course of dementia has clinical relevance and should be considered in designing intervention studies.
ACI‐24 vaccine in adults with Down syndrome
Authors: Rafii Michael S , Mobley William C , Skotko Brian G. , Sabbagh Marwan N. , Burke Anna D. , Yuan Shauna , Rissman Robert A. , Chavez Ronelyn , Delpretti Saskia , Sol Olivier , Beth Greg , Gray Julian JG , dos Santos Antonio Melo , Hliva Valerie , Vukicevic Marija , Kosco‐Vilbois Marie , Pfeifer Andrea , Feldman Howard H. 
Published: December 2020

AbstractBackgroundIndividuals with Down syndrome (DS) are at increased risk for developing Alzheimer’s Disease (AD) with 100% exhibiting amyloid pathology by age 40, making approaches targeting beta‐amyloid a rational strategy for the prevention of dementia. ACI‐24 is a liposomal vaccine eliciting polyclonal anti‐Aβ antibodies in a T‐cell independent manner. In this study, the safety, tolerability and immunogenicity of ACI‐24 in adults with DS are being tested.MethodsThis is a sequential, dose‐escalating, placebo‐controlled, phase 1b study testing the safety and efficacy of ACI‐24 in two cohorts with 8 individuals each. Cohort 1 (ACI‐24 300μg or placebo) was followed by cohort 2 (ACI‐24 1000μg or placebo) each comprised of 6 active and 2 placebo‐treated participants. Each participant received 7 subcutaneous injections of ACI‐24 or placebo over 12 months, followed by a 12‐month safety follow‐up period. Participants are non‐demented DS individuals (25 to 45 yrs), able to complete study‐related procedures with a reliable study partner. Primary endpoints assess the safety and tolerability, including adverse events and other safety measures as well as the induction of anti‐Aβ antibody titers in serum. Secondary objectives explore the effect of ACI‐24 on cognition and behavior (Brief Praxis Test, Clinical Global Impression of Change, Vineland II Adaptive Behavior Scale, Neuropsychiatric Inventory and selected measures of the CANTAB), standard AD biomarkers, including Aβ and tau levels in plasma and/or CSF when available; T‐cell activation; and the effect on whole brain, ventricular and hippocampal volumes.ResultsSixteen participants were randomized into two study cohorts: cohort 1 (n=8; mean age 34.1 yrs) and cohort 2, (n=8, mean age 31.1 yrs). The majority of participants are Caucasian. The study population also has a high prevalence of obesity (mean BMI = 39.6). The safety and tolerability have been good to date, with no reported dropouts, serious adverse events or MRI abnormalities.ConclusionThe recruitment of this world’s first clinical study using an anti‐Aβ vaccine (ACI‐24) in a DS population is now complete and has shown a good safety and tolerability to date. It represents a critical advance in developing potential therapies for the prevention of AD dementia in this at‐risk population.