bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elevated pulse pressure predicts longitudinal accumulation of tau PET in older adults without dementia
Authors: Weigand Alexandra J. , Nation Daniel A. , Delano‐Wood Lisa , Bangen Katherine J. , Galasko Doug R. , Bondi Mark W. 
Published: December 2020

AbstractBackgroundCardiovascular risk is associated with Alzheimer’s disease (AD) pathology, with possible mechanisms including increased blood‐brain barrier permeability, white matter changes, inflammatory cytokine activation, and neuronal vulnerability due to cerebral hypoperfusion. Prior research has linked pulse pressure (PP), an index of arterial stiffening, to abnormal cerebrospinal fluid measures of tau. However, to our knowledge, no research has examined PP in relation to tau PET imaging.MethodData were analyzed for 139 older adults without dementia from the Alzheimer’s Disease Neuroimaging Initiative who had at least two tau PET scans. Baseline PP was measured as systolic ‐ diastolic blood pressure (with higher values denoting increased arterial stiffening). Tau PET was measured with the AV‐1451 tracer, intensity normalized, partial‐volume corrected, and parcellated into cortical regions using FreeSurfer. A priori regions of interest (ROIs) included AD‐vulnerable cortical areas across Braak stages I‐V including the entorhinal cortex (EC), the inferior temporal gyrus (ITG), and the inferior parietal lobule (IPL). Iterated re‐weighted least squares regression, robust to the influence of outliers, modeled the association between baseline PP and tau PET accumulation across 12 months within each ROI adjusting for age, sex, cognitive diagnosis (i.e., normal or mild cognitive impairment), APOE status, and baseline tau PET signal.ResultHigher PP predicted higher baseline tau PET levels only in the ITG (t = 2.09, p = .04), although it was strongly predictive of increased tau PET accumulation over 12 months for all three ROIs (EC t = 3.15, p = .002; ITG t = 2.98, p = .003; IPL t =2.62, p = .01) over and above the effects of covariates.ConclusionResults indicate that higher PP is strongly predictive of tau PET accumulation across multiple AD vulnerable regions, whereas it is less predictive of baseline tau PET levels. Further, associations were stronger within earlier Braak regions. Findings confirm prior CSF studies and further suggest that arterial stiffening may be especially associated with a trajectory of increasing tau burden. Although the nature of the relationship between vascular risk and tau PET may be bidirectional, our results highlight the importance of cardiovascular intervention in the context of encroaching AD pathology.
Loss of progranulin leads to dysregulation of innate and adaptive immune cell populations, increased susceptibility to experimental colitis, and brain infiltration of peripheral immune cells
Authors: Keating Cody E. , Houser Madelyn C. , MacPherson Kathryn P. , Herrick Mary K. , Coomes Alexandra , Joers Valerie L. , Oliver Danielle , Johnson Ashlyn G. , Chang Jianjun , McEachin Zachary , Varvel Nicholas H. , Prokop Stefan , Tansey Malu Gamez 
Published: December 2020

AbstractBackgroundMutations in the progranulin gene (GRN) reduce levels of progranulin (PGRN) and granulins (GRNs) causing frontotemporal dementia (FTD), the most common form of early‐onset dementia. PGRN loss in neurons is associated with lysosome dysfunction resulting in diminished cathepsin protease activity. PGRN is also highly expressed in brain‐resident microglia and peripheral immune cells. Therefore, we asked if PGRN loss impacts immune cell profiles and communication in the gut‐brain axis during chronic systemic inflammation.MethodsWe measured lysosomal‐associated proteases in microglia and peripheral immune cells using probes for cathepsin D and pan‐cysteine cathepsins; performed multiplexed RNA & digital spatial protein profiling analyses, immunohistochemistry, and deep‐immunophenotyping by flow cytometry on brain, spleen, and peripheral blood of Grn KO and Grn‐suffficient mice aged 3‐30 months. Furthermore, we exposed mice to experimental colitis to interrogate alterations in the gut‐brain axis.ResultsHighest cathepsin D activity was found amongst Ly6C+, CD11b+ blood monocytes while pan‐cathepsin activity was highest in neutrophils and monocytes. In the spleen of aged Grn KO mice, T cell counts were reduced while Ly6C‐, CD68+ macrophages were increased compared to age‐matched Grn‐sufficient mice. In blood, aberrant T cell and monocyte activation markers in Grn KO mice were evident with minimal increases in inflammatory cytokines in plasma. Aged Grn KO mice exhibited decreased microglia (CD45int, CD11bhi) in the brain relative to Grn‐sufficient mice, with altered MHCII and CD68 expression. Additionally, CD4+ and CD8+ T cells were impacted in the brain of Grn KO mice compared to age‐matched Grn‐sufficient mice. PGRN loss was also associated with increased brain infiltration of activated peripheral monocytes and, interestingly, increased vulnerability to experimental colitis that was mitigated by loss of CCR2 function.ConclusionsThese novel findings suggest that PGRN plays key regulatory functions in innate and adaptive immune cell populations, in central‐peripheral immune cell crosstalk and traffic to the CNS, and in regulating susceptibility to immune challenges that disrupt the gut‐brain signaling axis. Analysis of peripheral immune cells and colonic tissue from patients with Grn mutations or SNPs is ongoing and may shed light on the mechanisms by which GRN haploinsufficiency causes FTD.
Genetic associations with brain amyloidosis
Authors: Raghavan Neha S. , Dumitrescu Logan , Mormino Elizabeth C. , Mahoney Emily R. , Lee Annie , Gao Yizhe , Bilgel Murat , Goldstein David B. , Harrison Theresa M. , Engelman Corinne D. , Saykin Andrew J. , Whelan Christopher , Liu Jimmy , Jagust William J. , Albert Marilyn S. , Johnson Sterling C. , Yang Hyun‐Sik , Johnson Keith A. , Aisen Paul S. , Resnick Susan M. , Sperling Reisa A. , De Jager Philip L. ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI), Schneider Julie A. , Bennett David A. , Schrag Matthew , Vardarajan Badri N. , Hohman Timothy J. , Mayeux Richard 
Published: December 2020

AbstractBackgroundGenetic studies of Alzheimer’s disease (AD) have focused on the clinical or pathological diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease. Our goal was to identify the underlying genetic bases for brain amyloidosis during the preclinical phase of AD.MethodWe performed genome‐wide association studies of positron emission tomography (PET) amyloid levels and meta‐analyzed the results. Genetic and imaging data were acquired from ten cohorts of primarily non‐demented individuals. The largest cohort, the A4 study (n = 3,154) was a secondary prevention trial designed to slow cognitive decline associated with brain amyloidosis. The other, smaller longitudinal cohort studies, similar in design, provided additional amyloid PET data with existing genetic data (n = 1,160 analyzed and n = 550 currently being analyzed).ResultWe identified a locus for amyloidosis within RBFOX1 in addition to APOE along with several loci nearing significance.ConclusionMultiple genetic loci may be associated with brain amyloidosis. Further research into these specific loci and genes will help in our understanding of the molecular bases of amyloid buildup in the brain.
Impact of APOE e4 on cognitive trajectory in early‐onset vs late‐onset Alzheimer’s disease
Authors: Kim Jaeho , Kang Sung Hoon , Kim Ji Sun , Kim Jun Pyo , Woo Sook‐Young , Kim Seonwoo , Na Duk L , Seo Sang Won , Kim Hee Jin 
Published: December 2020

AbstractBackgroundAging and the apolipoprotein E e4 (APOE4) are the two major risk factors for Alzheimer’s disease (AD). Previous reports suggest that the impact of APOE4 on increasing risk for AD differs according to age. However, whether the impact of APOE4 on cognitive trajectories in AD differ according to age is not well established. Thus, we evaluated the impact of APOE4 on cognitive trajectories in early‐onset AD (EOAD) and late‐onset AD (LOAD).MethodIn this retrospective longitudinal study, we collected 807 AD patients who underwent two or more neuropsychological tests after they were diagnosed with AD. We categorized the patients into two groups according to their age at symptom onset: 222 patients with EOAD (age at onset <65 years) and 585 patients with LOAD (age at onset ≥ 65 years). Linear mixed‐effects model analyses were performed to evaluate the effects of APOE4 on cognitive changes after controlling for age, sex, and education in each group.ResultIn LOAD, APOE4 carriers showed more rapid cognitive decline compared to APOE4 noncarriers in language and visuospatial functions. However, in EOAD, APOE4 noncarriers showed more rapid cognitive decline compared to APOE4 carriers in general cognitive function and in all cognitive domains including language, visuospatial, memory, and frontal executive function.ConclusionOur data showed that APOE4 is associated with accelerated cognitive decline in LOAD whereas the association is reversed in EOAD. We suggest that in EOAD, there might be other genetic or environmental factors that overshadow the detrimental effects of APOE4.
Visual atrophy scales are not a useful tool to help the clinician in diagnosing clinical or preclinical AD
Authors: Socher Karen LR , Lopes Deborah , Nunes Douglas Mendes , Busatto Geraldo , Nitrini Ricardo , Brucki Sonia MD 
Published: December 2020

AbstractBackgroundVisual atrophy scales are useful as auxiliary methods in Alzheimer's disease (AD) diagnosis. Atrophy of temporal medial region is an established risk factor for conversion from mild cognitive impairment (MCI) to AD dementia. Our aims were to compare two visual magnetic resonance imaging (MRI) scales and establish accuracy of these scales in classifying patients in relation to clinical diagnosis and amyloid statusMethodA Brazilian multi ethnic group was analyzed using two visual MRI scale (ERICA for quantification of atrophy in the entorhinal cortex) and MTA scale (medial temporal atrophy). 113 MRI were classified by 2 neurologists trained by a radiologist; all patients had amyloid PET (PIB) and clinical diagnosis as: 31 AD dementia, 52 MCI, and 30 normal cognition.ResultIn this sample, 51(45%) had PIB‐PET positive for amyloid deposition. Visual scales had great to excellent inter‐rater reliability (0.8‐1) by Cohen k analysis. AD patients have higher ERICA scores (mean: 1.92) and MTA score (mean: 1.7) for both hemispheres comparing to subgroups without dementia (p<0.01). MTA has greater specificity and ERICA has greater sensitivity in the DA and MCI groups (above 70%). The accuracy for ERICA and MTA scores were 56.6% and 70% in controls, 53.8% and 59.6% in MCI, 67% and 41% in AD, respectively. The PVV was 84%, for DA group in both scores and NPV were above 68% in non dementia group.ConclusionOn clinical practice of a neurologist who has no availability of amyloid status tests and would like to monitor visual scales of atrophy as a prognostic biomarker, they have a moderate sensitivity for the MCI and AD subgroup, moderate specificity for controls and MCI, and poor accuracy. These findings could be explained by the fact that atrophy is present in advanced stages of the disease, not allowing an early diagnosis.
The use of second generation RT‐QuIC assay for the diagnosis of Creutzfeldt Jakob disease patients in Brazil
Authors: Barbosa Breno José Alencar Pires , Vieira Tuane C. R. G. , Castrillo Bruno , Alvim Ricardo Pires , Nitrini Ricardo , Smid Jerusa 
Published: December 2020

AbstractBackgroundThe recent development of IQ‐CSF, the second generation of Real Time Quaking‐Induced Conversion (RT‐QuIC) using cerebrospinal fluid (CSF), for the diagnosis of Creutzfeldt Jakob Disease (CJD) represents a major diagnostic advance in the field. High accuracy results have been reported with encouraging reproducibility among different centers. The aim of this research is to report the pilot use of IQ‐CSF in a small cohort of Brazilian patients with possible or probable CJD, implementing a reference center in the country.MethodWe stored CSF samples from patients with possible, probable or genetic CJD (one case) during the timeframe of December 2016 through June 2018. All CSF samples were processed according to standardized protocols without access to the clinical data. Eight patients presented to our team with a rapidly progressive dementia and typical neurological signs of CJD. We used CSF samples from 8 patients with other neurological conditions as controls.Result7 out of 9 suspected cases had positive tests; among controls, there was 1 false‐positive (a CSF sample from a 4‐year‐old child with leukemia under treatment). The occurrence of a false positive in one of the negative control samples raises the possibility of the presence of interfering components in the CSF sample from patients with non‐neurodegenerative pathologies.ConclusionOur pilot results illustrate the feasibility of having CJD CSF samples tested in Brazilian centers and highlight the importance of inter‐institutional collaboration to pursue a higher diagnostic accuracy in CJD in Brazil and Latin American.
Endothelial APP expression exacerbates cerebral amyloid angiopathy in AD model mice
Authors: Tachida Yuriko , Ogasawara Naomi , Saito Takashi , Shindo Akihiro , Kawaguchi Yasushi , Tomimoto Hidekazu , Saido Takaomi C. , Kitazume Shinobu 
Published: December 2020

AbstractBackgroundMost AD patients show accumulation of Ab peptides in both brain parenchyma and blood vessels. We recently found that brain vascular endothelial cells specifically express APP770 and produces Ab40/42. We then expect endothelial APP770 could contribute to cerebral amyloid angiopathy (CAA).MethodWe first generated conditional transgenic mice harboring loxP‐neo(R)‐loxP‐APP770NL, (APP770(flox)), then crossed with the mice with Tie2‐Cre mice that specifically express Cre recombinase in their endothelial cells. We then crossed the mice with AD model mice, AppNL‐F.ResultWe found that aged endothelial APP770NL expressing mice exhibit Ab deposition in brain vessels but not the parenchyma. Remarkably, not all but some of the aged transgenic mice show cerebral hemorrhage. By crossing this CAA model mice with AD model mice, massive CAA pathology was observed.ConclusionThese findings highlight the contribution of endothelial APP770 to vascular Ab deposition.
Relation of neuroticism to frontal cortical transcriptome and Alzheimer’s disease
Authors: De Jager Celine H. , Bennett David A. , Ma Yiyi 
Published: December 2020

AbstractBackgroundPrior studies have shown that certain personality traits are associated with differences in aging‐related cognitive decline and incidence of Alzheimer’s disease (AD). Neuroticism, proneness to pscyhological distress, worsens cognitive decline while conscientiousness is protective. However, the molecular composition of these personality traits and the series of molecular events that lead from personality traits to AD in the brain is unknown.MethodWe examined data from 1419 participants in one of two longitudinal studies of cognitive aging with prospectively collected brains at autopsy: the Religious Order Study and the Rush Memory & Aging Project (ROSMAP). We accessed RNA sequence data (>13,000 genes) from the dorsolateral prefrontal cortex (DLPFC); linear regression adjusting for age, sex, and education. We performed a mediation analysis to assess whether certain modules mediate the association of neuroticism to cognitive decline.ResultWe first confirmed that neuroticism contributes to accelerated cognitive decline and AD onset (p=6.75x10‐7) while conscientiousnessis protective (p=4.34x10‐4). We then evaluated the 6 gene modules previously associated with cognitive decline (p<0.001) and found that three of them displayed some association with neuroticism (p<0.05). Mediation modeling suggests that these three modules of co‐expressed genes are altered by in individual’s with greater neuroticism. Neurotic is associated with higher m7 which in turn is related to cognitive decline (p=0.008) than its direct causal effect on cognitive decline which is not mediated through m7 (p=0.042).ConclusionWe demonstrate neuroticism is associated widespread differences in RNA profiles and that these differences contribute to the onset of AD. Although results need further investigation, they identify a new gene signature that could be used to develop new therapies that minimize the risk of AD in individuals with a neurotic personality.
Severe multimorbidity is prevalent in those with cognitive decline, which challenges neurologists and family physicians: A clinical decision‐support software (CDSS) platform provides guidance
Authors: Zelek Mark C , Walker John Q , Sabbagh Marwan N 
Published: December 2020

AbstractBackgroundMultimorbidity is the concurrent occurrence of two or more chronic diseases, with severe multimorbidity (abbreviated here as SMM) meaning three or more. Patients have chronic diseases that fall into different domains (e.g., cardiovascular or endocrine), and many of these diseases themselves, such as diabetes, contribute to the onset and progression of cognitive decline. Chronic diseases may interact, curtailing compensatory mechanisms and increasing the likelihood of physical and cognitive decline. Physicians often miss diagnoses of cognitive decline when addressing SMM, while cognitive decline, in turn, can reduce a person’s ability to manage SMM. This becomes a vicious cycle.MethoduMETHOD Health has developed a CDSS platform to address cognitive decline (i.e., dementia, MCI, and mild AD) through the creation of personalized, multidomain treatment plans. Across a population of 2,079 individual 65 years or older, the platform evaluated 19 chronic disease conditions (the three most frequent: CKD, hypertension, and dyslipidemia), plus diseases detected in CBC serum analysis (such as macrocytosis and thrombocytopenia) and CMP serum analysis (such as hypercupremia and hypernatremia). Disease status was determined by physicians’ diagnoses or by the software, through analyzing lab reports, vital signs, medications, and medical status.ResultIn this population, 7.2% individuals had no comorbid chronic diseases. 64.5% had three or more chronic diseases (that is, SMM), with two people having 14 concurrently (mean: 3.85 chronic diseases, std: 2.63). 64.3% of the 2,079 had cognitive decline. A symmetry (by coincidence) emerged when considering cognitive decline: 75% of those with SMM had cognitive decline; 75% of those with cognitive decline had SMM. Lastly, the percentage of people with cognitive decline increased as the number of concurrent chronic diseases increased.ConclusionTreatment plans for cognitive decline are already multivariable, and must address multidomain SMM as part of their coverage. Neurologists need processes for developing comprehensive care plans that address cognitive decline and comorbidities in concordance, and coordinating care with other physicians simultaneously caring for a given patient. This CDSS platform generates effective and highly‐usable guidelines for identifying and prioritizing concurrent chronic diseases, and giving guidance on the total picture: what needs to happen, how, and when.
Associated factors with mortality at three‐year follow‐up in a population‐based Mexican elderly cohort study
Authors: Rodríguez Nallely Solano , Santiago Brenda Margarita Carrillo De , Ibarrola Mariana Longoria , Acosta‐Castillo Gilberto Isaac , Sosa‐Ortiz Ana Luisa 
Published: December 2020

AbstractBackgroundThe highest proportion of deaths occurs in people over 65 years. Factors related to mortality differ between clinical and community population. In Mexico there are few population‐based studies that explore sociodemographic factors, comorbidities, cognitive status and disability, associated with mortality in community elders.MethodThis is a secondary analysis of the 10/66 Dementia Research Group cohort study, after three years of follow‐up. The participants were evaluated with the protocols of the Dementia Research Group 10/66 Mexico, in 2006 (baseline) and in 2009. We identified two groups deceased and survivors participants and 1,570 participants were selected. Summary and variability measures were calculated, comparing the distribution of both groups. The association of the sociodemographic and clinical variable of interest, with mortality at three years of follow‐up was estimated using multivariate models’ analyses.ResultThe factors associated with mortality at 3 years of follow‐up were: male gender, being 80 years of age or older, zero education, 3 or less goods or services at home (BSD), presence of dementia, cognitive impairment (CI ), DM ‐2, disability and having suffered 2 or more falls in the last year (table 1). Of the 12 neuropsychiatric symptoms evaluated, only : hallucinations, depression, psychomotor agitation and appetite disturbances, showed significant associations; in the multivariate adjustment the persistent associations were: male gender, dementia, CI and disability (table 2).ConclusionMale gender, the presence of dementia, CI and disability were the factors associated with mortality in Mexican older adults in this analysis. This information contributes to the evidence of relevant factors associated to mortality in Mexican elders. Dementia and CI exceeded the mortality risk of other chronic diseases. In the epidemiological reports , dementia and CI do not appear within the first 10 causes of mortality, probably because they are under‐diagnosed and under‐documented.
Multipredictor risk models for predicting individual risk of Alzheimer’s disease
Authors: Yu Jin‐Tai , Hou Xiao‐He , Suckling John , Shen Xue‐Ning , Liu Yong , Zuo Chuantao , Huang Yu‐Yuan , Wang Hui‐Fu , Tan Chen‐Chen , Cui Mei , Dong Qiang , Tan Lan ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundWe aimed to develop and validate risk models for predicting AD onset at the individual level.MethodParticipants were included from Alzheimer's Disease Neuroimaging Initiative. Least Absolute Shrinkage and Selection Operator Cox regression was applied for candidate predictors selection and model construction.ResultIn the prediction of individual risk of prodromal AD in cognitively normal (CN) individuals, the AUC of the final CN model was 0.81 within five years. The final MCI model predicted individual risk of AD dementia in MCI patients with an AUC of 0.92 within five years. The models were also associated with longitudinal change of Mini‐Mental State Examination (p<0.001). An ATN model was developed which could predict the Alzheimer’s continuum for individuals with normal AD biomarkers within three years with high accuracy (AUC=0.91).ConclusionRisk models were able to provide personalized risk for AD onset at each year after evaluation, which could improve early diagnosis.