bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mass spectrometry measures of plasma Aβ, tau and P‐tau isoforms’ relationship to amyloid PET, tau PET, and clinical stage of Alzheimer’s disease
Authors: Bateman Randall J. , Barthelemy Nicolas R. , Benzinger Tammie L.S. , Bollinger James G. , Fagan Anne M. , Gordon Brian A. , Hansson Oskar , Holtzman David M. , Horie Kanta , Li Melody , Li Yan , Masters Colin L. , Mawuenyega Kwasi G. , McDade Eric , Morris John C. , Ovod Vitaliy , Sato Chihiro , Schindler Suzanne E. , Weiner Michael W. , Xiong Chengjie 
Published: December 2020

AbstractBackgroundRecent advances in understanding the links between amyloid‐beta (Aβ) and specific tau isoforms in brain, cerebrospinal fluid (CSF), and blood indicate that a cascade of events of Alzheimer’s disease (AD) pathophysiology begin with detection of altered CSF and blood Aβ 42/40 ratio, followed by increases in amyloid plaques by Positron Emission Tomography (PET) scan, associated with increased phosphorylation of specific CSF tau isoforms (e.g. p‐tau217 and p‐tau181), before increases in p‐tau205, hypometabolism, and atrophy. Finally, CSF total tau increases before tau aggregation by tau PET and onset of clinical symptoms. The longitudinal tau and Aβ changes which occur in brain and CSF are now being understood in blood, enabling interpretation and understanding of AD progression in much larger and more robust populations.MethodWe compared plasma Aβ 42/40 ratios measured by mass spectrometry to measures of amyloid, tau, and clinical and cognitive status in ADNI, AIBL, Biofinder and the Knight ADRC. In order to improve racial, ethnic, educational, socioeconomic, and comorbid disease diversity, we launched the Study to Evaluate Amyloid in Blood and Imaging Related to Dementia (SEABIRD), a community‐ and clinic‐based study (goal n=1120) to mirror the demographics of the Saint Louis metropolitan area. We mapped the entire blood plasma tau protein with 15 specific regions and analyzed several plasma p‐tau isoforms (e.g. p‐tau217 and p‐tau181) by mass spectrometry and compared with CSF and PET results across two sporadic AD studies.ResultSEABIRD participants had an initial blood collection and 25% underwent confirmatory amyloid PET. Consistent with ADNI, AIBL, Biofinder and ADRC, we found plasma Aβ 42/40 ratios had high concordance with amyloid PET. In blood plasma tau, we found that some, but not all, plasma p‐tau isoforms had a strong concordance with CSF and PET measures and that p‐tau217 was more concordant for amyloid status compared to p‐tau181. Further, plasma Aβ 42/40 and p‐tau measures identify the stage of disease as measured by PET and CSF measures, Figure 1.ConclusionThese findings indicate that blood plasma Aβ and p‐tau measures are highly precise biomarkers of brain amyloidosis, tauopathy, and can identify stages of clinical and preclinical AD.
Cleaved Annexin A1 is elevated in neurodegenerative dementia and is associated with pathological burden of amyloid and inflammatory cytokines
Authors: Chua Xin Ying , Chong Joyce R. , Lee Jasinda , Attems Johannes , Aarsland Dag , Francis Paul T. , Lai Mitchell Kim Peng 
Published: December 2020

AbstractBackgroundInflammation is usually terminated by resolution, mediated by pro‐resolving mediators including Annexin A1 (AnxA1) which is known to be involved in granulocyte trafficking as well as efferocytosis of apoptotic neutrophils. Failure in resolution may lead to chronic inflammation, which has been considered a pathological hallmark of neurodegenerative diseases. We investigated the expression levels of AnxA1 in post‐mortem brain tissues and their correlation with pathological burden in dementia.MethodProtein levels of AnxA1 were measured in post‐mortem parietal cortices (Brodmann area BA40) as well as frontal cortices (BA9) of well characterized Parkinson disease dementia (PDD), dementia with Lewy bodies (DLB), Alzheimer’s disease (AD) patients and healthy controls via immunoblotting. Amyloid and cytokines were quantified via ELISA and Luminex respectively.ResultIn BA40, expression of cleaved (33 kDa) AnxA1 was found to be elevated in DLB and AD as compared to controls. While cleaved AnxA1 (33 kDa) showed an increasing trend in BA9, the increase was not significant. In our cohort of patients with dementia, levels of cleaved AnxA1 was also positively correlated with ratio of soluble amyloid‐β42/40. In addition, as AnxA1 activation has been shown to increase production of anti‐inflammatory markers such as IL10 and IL13. We measured IL10 and IL13 and found positive correlations with AnxA1.ConclusionOur results suggest that elevation of AnxA1 in DLB and AD may be a compensatory response to the increased inflammation in neurodegenerative diseases, in an attempt to resolve inflammation. Previous in vitro and in vivo research also revealed elevated AnxA1 in 5XFAD mice models and in vitro AnxA1 treatment reduced pro‐inflammatory and increased anti‐inflammatory cytokines. Our results demonstrate that similar associations are observed in post‐mortem samples and suggest that AnxA1 may play a similar role in humans.
Speech and language disorders as core diagnostic tools for differentiation of neurodegenerative diseases
Authors: Vasenina Elena , Levin Oleg 
Published: December 2020

AbstractBackgroundA patient suffering from a neurodegenerative disease may demonstrate various combinations of dysarthria, aphasia, and apraxia. Besides, a speech disorder can be a primary and dominant sign (primary progressive aphasia or apraxia), or can develop secondarily as part of general clinical picture. No unified approach to classification and diagnostics of various speech disorder forms has been developed to date. Aim: to study speech disorders in various forms of neurodegenerative diseases, to assess common structure, clinical‐neuroimaging heterogeneity, and to develop a unified algorithm for differential diagnosis.Method1008 patients with neurodegenerative diseases were included in the study by continuous sampling of consultant practice specializing in neurodegenerations: 234 AD, 118 DLB, 62 FTD (behavior and language variants), 366 PD, 22 PSP, 14 CBS, and 292 patients with unspecified and other forms of neurodegenerative pathology. All patients were screened for cortical speech disorders (pure dysarthria was not considered). Patients demonstrating speech and language disorders were tested using the speech disorder assessment test battery we have developed. Structural MRI was performed for all the patients with speech and language disorders to assess ROI.Resultspeech and language disorders were identified in 41% of patients in aggregate group, 78% of AD, 48% of DLB, 31% of PD, 82% of FTD, 64% of PSP, and 96% of CBS patients. Based on the detailed speech assessment battery in aggregate group of all the neurodegenerative diseases 7 subtypes of speech and language disorders were highlighted by means of cluster analysis (Figure 1), principal component method allowed to identify the most significant tests for differentiation of these forms. Aphasia forms and neurodegenerative diseases forms were matched using multinomial logistic regression (Figure 2). We identified the main ROI for all subtypes (Figure 3)Conclusionspeech disorders in patients with neurodegenerative diseases have a specific structure with clinical‐neuroimaging heterogeneity, which allowed to develop a unified algorithm for differential diagnosis.
Shared genetic etiology underlying Alzheimer’s disease and major depressive disorder
Authors: Chiba‐Falek Ornit , Lutz Michael W , Sprague Daniel , Barrera Julio 
Published: December 2020

AbstractBackgroundPatients with late‐onset Alzheimer’s disease (LOAD) frequently manifest comorbid neuropsychiatric symptoms with depression and anxiety being most frequent, and individuals with Major depressive disorder (MDD) have an increased prevalence of LOAD. This suggests shared etiologies and intersecting pathways between LOAD and MDD. Nonetheless, the genetic pleiotropic between LOAD and neuropsychiatric disorders, including MDD, has been understudied.MethodsWe performed pleiotropy analyses by applying a robust new statistical strategy that integrates GWAS summary statistics results for two traits, LOAD and MDD. We used LOAD and MDD GWAS datasets from the International Genomics of Alzheimer’s Project (IGAP) and the Psychiatric Genomics Consortium (PGC), respectively. We complement the study with functional genomic and bioinformatic analyses including, pathway, gene expression and eQTL analyses.ResultsWe found a moderate enrichment for SNPs associated with LOAD across increasingly stringent levels of significance with the MDD GWAS association (LOAD|MDD), of maximum 4 and 8‐folds including and excluding the APOE‐region, respectively. Association analysis excluding the APOE‐region identified numerous SNPs corresponding to 40 genes, 9 of which are known LOAD‐risk loci primarily on chromosome 11 regions that contain the SPI1 gene and MS4A genes‐cluster, and others were novel pleiotropic risk‐loci for LOAD conditional with MDD. The most significant associated‐SNPs on chromosome11 overlapped with eQTLs found in whole‐blood and monocytes, suggesting functional role in gene regulation. The reverse conditional association analysis (MDD|LOAD) showed a moderate level, ∼7‐fold, of polygenic overlap, however, no SNP showed significant association. Pathway analyses replicated previously reported LOAD biological pathways related to immune response and regulation of endocytosis.ConclusionHere we provide insights into the overlapping genetic signatures underpinning the common phenotypic manifestations and inter‐relationship between LOAD and MDD. The outcomes of this study have several important implications to LOAD genetic architecture including, demonstration of genetic pleiotropy effects between LOAD and MDD, identification of new LOAD loci, validation of LOAD pathways. Furthermore, our data proposes genetic interpretation for the heterogeneity of depression in LOAD. These findings are impactful for the development of actionable targets for novel therapies to treat depression preceding dementia in an effort to delay or ultimately prevent the onset of LOAD.
Hippocampal atrophy is independent of amyloid status 3 years after ischemic stroke
Authors: Brodtmann Amy , Khlif Mohamed Salah , Bird Laura J. , Churilov Leonid , Cumming Toby , Werden Emilio 
Published: December 2020

AbstractBackgroundHippocampal atrophy, long thought to be an imaging signature of Alzheimer’s disease, is seen in a range of neurodegenerative disorders, and in association with vascular risk factors in people without dementia. We examined hippocampal volume (HV) in a group of ischemic stroke patients who participated in an amyloid PET imaging study 3 years after their stroke. Given the complex interactions between normal brain aging, vascular risk factors and brain histopathology, we hypothesized that there would be no association between HV and amyloid status.MethodThe Cognition And Neocortical Volume After Stroke (CANVAS) study is an observational cohort study of 135 patients with ischemic stroke examining brain volume and cognition over 3 years compared to healthy controls. Amyloid 18F‐NAV4694 PET imaging was offered at 3 years as a sub‐study. Only participants with usable MRI scans at 3 years were included. We report centiloids (CLs) not SUVRs for comparison of our results with others using different amyloid PET tracers. CL amyloid status was classified as: CL<15 NEGATIVE; CL 15‐25 UNCERTAIN; CL>25 POSITIVE. In addition, Brain Banking was offered to all CANVAS participants: participants are classified amyloid‐positive with Braak staging>3. We compared HVs between the amyloid‐positive and ‐negative groups and associations between co‐morbidities and vascular risk factors (VRFs) by comparing Charlson Co‐morbidity Indices (CCI) and number of VRF using Multiway ANOVA (anovan, MATLAB 2019b).ResultOne participant was Brain Banked; 34 (27 men) participated in the PET imaging sub‐study. There were no differences in years of education, VRF and CCI between PET and non‐PET participants, although PET participants had larger heads (Fig1). CCI was significantly associated with HV (p<0.0001) but CCI variability was explained by age (collinear). VRFs were not significantly associated with HV. PET participants were significantly older than the 61 (42 men) non‐PET participants (69.6+/‐8.6 vs 64.2+/‐13.5 years; p=0.037). Five participants were amyloid‐positive: Brain Bank participant (Braak Stage 5), 4 PET participants (Fig2). There was no association between amyloid CLs and HV, but amyloid positivity was associated with greater CCI.ConclusionIn this small study of stroke patients, hippocampal atrophy occurred independently of amyloid pathology and was more associated with age and co‐morbidity.
Identification of subtypes for the behavioral variant of frontotemporal dementia based on the assessment of disinhibition and compulsion
Authors: Godefroy Valérie , Tanguy Delphine , Sezer Idil , Ber Isabelle Le , Bouzigues Arabella , Rametti‐Lacroux Armelle , Carle Guilhem , Azuar Carole , Bendetowicz David , Levy Richard , Batrancourt Bénédicte , Migliaccio Raffaella 
Published: December 2020

AbstractBackgroundThe behavioral variant of frontotemporal dementia (bvFTD) is characterized by cognitive and behavioral decline due to the progressive brain damage of frontal and temporal regions. We aimed to: 1. identify bvFTD subtypes through the behavioral assessment of social disinhibition and perseveration/compulsion; 2. disentangle the underlying functional and anatomical correlates.MethodWe assessed occurrences of 19 behaviors (derived from current clinical criteria of bvFTD) linked to disinhibition and perseveration/compulsion in a quasi‐ecological setting in 17 bvFTD patients and 16 healthy controls (HC). Subjects also underwent neurocognitive tests and a structural MRI examination. Dimensions extracted through Principal Component Analysis from the behavior variables were compared between patients and HC. A clustering approach applied to behavioral scores allowed to isolate subgroups within the patients. Voxel based morphometry (VBM) was performed to identify specific grey matter atrophy patterns in each subgroup.ResultWe identified two principal behavioral dimensions significantly different between bvFTD and HC. Using scores on these two components (labelled as Compulsion and Disinhibition), we identified two different subgroups of bvFTD patients (bvFTD‐G1 and bvFTD‐G2). BvFTD‐G1, characterized by high Disinhibition, had a small pattern of atrophy, centered on left medial anterior and posterior temporal cortices. BvFTD‐G2, characterized by high Compulsion and cognitive impulsivity, presented a more diffuse and bilateral atrophy pattern largely involving frontotemporal and subcortical regions.ConclusionThe behavioral assessment of disinhibition and compulsion symptoms allowed the clinical stratification of bvFTD patients into more or less severe stages or forms, and the identification of specific brain circuits associated with disinhibition and compulsion.
Analysis of the relationship between MCI and metabolic syndrome‐related factors in community residents over 50 years old
Authors: Yang Yanrong , LI Zheng , Wang Yan , Pan Gaofeng , Wang Jianghong , FU Liangxiu , Hu Tingting , Gao Jing 
Published: December 2020

AbstractBackgroundCurrent studies had shown that cognitive impairment related to metabolic syndrome, but the relationship between the two has not determined absolutely. Mild Cognitive impairment (MCI) has a high incidence in cognitive impairment and is the early stage of dementia. The analysis of the correlation between MCI and metabolic syndrome related factors can help prevent and cure mild cognitive impairment in the early stag, and reduce the occurrence of dementia and reduce the social burden.MethodWe enrolled 235 cases in community over the age of 50 years. We used the Montreal Cognitive Assessment (MoCA) to assess cognitive function, screening the patients with mild cognitive impairment, and Analyzed the cognitive function and factors associated with metabolic syndrome, such as creatinine (CREA), urea(UA), blood glucose (GLU), low density lipoprotein cholesterol (LDL), very low density lipoprotein cholesterol (VLDL), body mass index (BMI), waist hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure(DBP).ResultThe prevalence of mild cognitive impairment was about 79.2%)n=187( among community residents over 50 years old. Comparing to normal cognitive function group and mild cognitive impairment group, the blood glucose and systolic blood pressure showed significant differences( (P<0.05)),and no significant differences in CREA,UA,LDL,VLDL,BMI,WHR,DBP. Compared to normal blood glucose group, the score of executive, calculation and naming in high blood glucose were decreased, and the differences were significant (P<0.05). Compared to normal systolic blood pressure group, the Score of letter fluency in high systolic blood pressure was decreased, and the differences was significant (P<0.05).ConclusionThe incidence of MCI in community residents over the age of 50 was high, which was closed related to blood glucose and systolic blood pressure. High blood glucose can reduce the patient’s ability of executive, calculation and language, and high systolic blood pressure can reduce letter fluency. Control the metabolic syndrome related factors, can reduce the incidence of mild cognitive impairment, benefit to the life quality of community residents.
Doing more with less: Women’s higher brain metabolic rate compensates for early Alzheimer’s pathological changes
Authors: Sundermann Erin E , Maki Pauline M , Reddy Sarah , Bondi Mark W , Biegon Anat ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundCognitively normal women have consistently shown higher brain glucose metabolism than men across the adult life span in key Alzheimer’s disease (AD) related regions. The goal of our work was to examine whether these sex differences provide resilience to the effect of AD pathologies on cognition.Method1259 participants (44% women; aged 55‐90) from the Alzheimer’s Disease Neuroimaging Initiative completed the Mini Mental Status Exam (MMSE), the Clinical Dementia Rating‐Sum of Boxes (CDR‐SOB) and neuroimaging assessments of glucose metabolism (FDG‐PET) in regions of interest (posterior cingulate, angular gyrus, inferior/middle temporal gyrus), brain volumes (T1 MRI) and cortical amyloid‐β burden (AV45‐PET). First, we examined whether sex moderates the relationship between brain glucose metabolism in the grey matter and whole brain gray matter volume (WBV) in the overall sample and within cognitively normal (CN), amnestic mild cognitive impairment (aMCI) and AD diagnostic groups. Second, we divided the AD pathological markers of cortical amyloid‐β burden and hippocampal volume (HV) into quartiles and examined sex differences in MMSE and CDR‐SOB scores within biomarker quartiles before and after adjusting for brain metabolism and the covariates of age, education, APOE4 and WBV.ResultIn the overall sample and within aMCI, metabolism was higher in women versus men per unit of WBV when WBV was moderate/large but showed a steeper decrease as WBV diminished. Women showed better MMSE and CDR‐SOB scores than men (ps<.05) at mild/moderate levels of AD brain pathology (quartiles 1‐3), particularly after adjustment for sex differences in brain volume. In contrast, men and women showed similarly poor MMSE and CDR‐SOB scores within the highest quartile of severe AD brain pathology (ps>.05). The female cognitive advantage at mild/moderate quartiles of AD pathological markers was eliminated or markedly attenuated (41‐94%) after adjusting for brain metabolismConclusionMore efficient neural function in women versus men may provide women greater resilience against the effects of early AD pathological changes and serve as a mechanism underlying better clinical profiles in women in early disease process and faster decline thereafter. These sex‐based mechanistic differences will have important implications for disease identification and treatment.
Validity of a new brief assessment of apathy: Caregiver version of the apathy motivation index
Authors: Klar Verena S. , Ang Yuen‐Siang , Lockwood Patricia L. , Attaallah Bahaaeddin , Dickson Shannon , Drew Daniel , Kienast Annika , Maio Maria R. , Plant Olivia , Slavkova Elitsa , Toniolo Sofia , Zambellas Rhea , Irani Sarosh , Husain Masud 
Published: December 2020

AbstractBackgroundApathy is a common, disabling syndrome observed across neurodegenerative diseases. Self‐report of apathy from patients can be misleading so caregiver report is valuable. However, a compact instrument that does not require clinician interview, is brief but adequately detailed is lacking.MethodWe developed a caregiver version of the Apathy Motivation Index (AMI CG) which requires a short 5 minute questionnaire to be completed by an informant. Scores were validated against a more extensive caregiver interview rating (Lille Apathy Rating, LARS CG), and compared to measures of depression, anhedonia, cognitive abilities, activities of daily living and caregiver burden. 124 patients (21 Alzheimer’s; 45 Parkinson’s; 30 limbic encephalitis; and 28 with subjective cognitive impairment) were tested.ResultThe AMI CG showed good internal reliability with a significant three‐factor structure, mapping to domains of Behavioural Activation, Emotional Sensitivity and Social Motivation. It had good external validity, correlating well with other measures of apathy, but not with depression or anhedonia. A cut‐off criterion based on the LARS CG correctly classified patients as apathetic or non‐apathetic in 82% and 72% percent of cases respectively (AUC = 0.85). 20 cases identified as apathetic by the AMI CG but not the LARS CG had loss of social motivation, a dimension of apathy overlooked by traditional instruments. Patients who under‐rated their apathy compared to informants were more likely to be a greater burden to caregivers.ConclusionThe AMI CG successfully detects clinical apathy, including cases of social apathy.
Safety and target engagement profile of two oxaloacetate doses in Alzheimer’s patients
Authors: Swerdlow Russell H 
Published: December 2020

AbstractBackgroundBrain bioenergetics are defective in Alzheimer’s disease (AD). Preclinical studies find oxaloacetate (OAA) enhances bioenergetics, but human safety and target engagement data are lacking.MethodWe orally administered 500 or 1000 mg OAA, twice daily for 1 month, to AD participants (n=15 each group) and monitored safety and tolerability. To assess brain metabolism engagement, we performed fluorodeoxyglucose positron emission tomography (FDG PET) and magnetic resonance spectroscopy (MRS) prior to and after the intervention. We also screened pharmacokinetics and cognitive performance.ResultBoth doses were well‐tolerated. Compared to the 500 mg dose, the 1000 mg dose benefited default mode network glucose utilization on FDG PET (p<0.05), and the 1000 mg dose increased frontoparietal glutathione (p<0.05). We did not demonstrate consistent changes in blood levels, and cognitive scores did not improve.Conclusion1000 mg OAA, taken twice daily for 1 month, is safe in AD patients and engages brain energy metabolism.