scholarly journals Blood-Based ATN Biomarkers of Alzheimer’s Disease: A Meta-Analysis

2021 ◽  
Vol 79 (1) ◽  
pp. 177-195
Author(s):  
Ivan Koychev ◽  
Katrin Jansen ◽  
Alina Dette ◽  
Liu Shi ◽  
Heinz Holling
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Molecule ◽  
Meta Analysis ◽  
Random Effect ◽  
Neurofilament Light ◽  
Meta Analyses ◽  
And Control ◽  
T Tau ◽  
Biological State

Background: The Amyloid Tau Neurodegeneration (ATN) framework was proposed to define the biological state underpinning Alzheimer’s disease (AD). Blood-based biomarkers offer a scalable alternative to the costly and invasive currently available biomarkers. Objective: In this meta-analysis we sought to assess the diagnostic performance of plasma amyloid (Aβ40, Aβ42, Aβ42/40 ratio), tangle (p-tau181), and neurodegeneration (total tau [t-tau], neurofilament light [NfL]) biomarkers. Methods: Electronic databases were screened for studies reporting biomarker concentrations for AD and control cohorts. Biomarker performance was examined by random-effect meta-analyses based on the ratio between biomarker concentrations in patients and controls. Results: 83 studies published between 1996 and 2020 were included in the analyses. Aβ42/40 ratio as well as Aβ42 discriminated AD patients from controls when using novel platforms such as immunomagnetic reduction (IMR). We found significant differences in ptau-181 concentration for studies based on single molecule array (Simoa), but not for studies based on IMR or ELISA. T-tau was significantly different between AD patients and control in IMR and Simoa but not in ELISA-based studies. In contrast, NfL differentiated between groups across platforms. Exosome studies showed strong separation between patients and controls for Aβ42, t-tau, and p-tau181. Conclusion: Currently available assays for sampling plasma ATN biomarkers appear to differentiate between AD patients and controls. Novel assay methodologies have given the field a significant boost for testing these biomarkers, such as IMR for Aβ, Simoa for p-tau181. Enriching samples through extracellular vesicles shows promise but requires further validation.

scholarly journals Plasma Proteomic Biomarkers Relating to Alzheimer’s Disease: A Meta-Analysis Based on Our Own Studies

2021 ◽  
Vol 13 ◽  
Author(s):  
Liu Shi ◽  
Noel J. Buckley ◽  
Isabelle Bos ◽  
Sebastiaan Engelborghs ◽  
Kristel Sleegers ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Meta Analysis ◽  
Random Effect ◽  
Blood Biomarkers ◽  
Gamma Chain ◽  
Significant Difference ◽  
The Mean ◽  
Meta Analyses ◽  
Complement Component 4

Background and Objective: Plasma biomarkers for the diagnosis and stratification of Alzheimer’s disease (AD) are intensively sought. However, no plasma markers are well established so far for AD diagnosis. Our group has identified and validated various blood-based proteomic biomarkers relating to AD pathology in multiple cohorts. The study aims to conduct a meta-analysis based on our own studies to systematically assess the diagnostic performance of our previously identified blood biomarkers.Methods: To do this, we included seven studies that our group has conducted during the last decade. These studies used either Luminex xMAP or ELISA to measure proteomic biomarkers. As proteins measured in these studies differed, we selected protein based on the criteria that it must be measured in at least four studies. We then examined biomarker performance using random-effect meta-analyses based on the mean difference between biomarker concentrations in AD and controls (CTL), AD and mild cognitive impairment (MCI), MCI, and CTL as well as MCI converted to dementia (MCIc) and non-converted (MCInc) individuals.Results: An overall of 2,879 subjects were retrieved for meta-analysis including 1,053 CTL, 895 MCI, 882 AD, and 49 frontotemporal dementia (FTD) patients. Six proteins were measured in at least four studies and were chosen for meta-analyses for AD diagnosis. Of them, three proteins had significant difference between AD and controls, among which alpha-2-macroglobulin (A2M) and ficolin-2 (FCN2) increased in AD while fibrinogen gamma chain (FGG) decreased in AD compared to CTL. Furthermore, FGG significantly increased in FTD compared to AD. None of the proteins passed the significance between AD and MCI, or MCI and CTL, or MCIc and MCInc, although complement component 4 (CC4) tended to increase in MCIc individuals compared to MCInc.Conclusions: The results suggest that A2M, FCN2, and FGG are promising biomarkers to discriminate AD patients from controls, which are worthy of further validation.

scholarly journals Brain-Derived Exosomal Proteins as Effective Biomarkers for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 980
Author(s):  
Ka-Young Kim ◽  
Ki-Young Shin ◽  
Keun-A. Chang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Web Of Science ◽  
Meta Analysis ◽  
Cochrane Library ◽  
Blood Biomarkers ◽  
Cell Lineages ◽  
The Central Nervous System ◽  
New Biomarkers ◽  
T Tau

Alzheimer’s disease (AD), a progressive neurodegenerative disease, affects approximately 50 million people worldwide, which warrants the search for reliable new biomarkers for early diagnosis of AD. Brain-derived exosomal (BDE) proteins, which are extracellular nanovesicles released by all cell lineages of the central nervous system, have been focused as biomarkers for diagnosis, screening, prognosis prediction, and monitoring in AD. This review focused on the possibility of BDE proteins as AD biomarkers. The articles published prior to 26 January 2021 were searched in PubMed, EMBASE, Web of Science, and Cochrane Library to identify all relevant studies that reported exosome biomarkers in blood samples of patients with AD. From 342 articles, 20 studies were selected for analysis. We conducted a meta-analysis of six BDE proteins and found that levels of amyloid-β42 (standardized mean difference (SMD) = 1.534, 95% confidence interval [CI]: 0.595–2.474), total-tau (SMD = 1.224, 95% CI: 0.534–1.915), tau phosphorylated at threonine 181 (SMD = 4.038, 95% CI: 2.312-5.764), and tau phosphorylated at serine 396 (SMD = 2.511, 95% CI: 0.795–4.227) were significantly different in patients with AD compared to those in control. Whereas, those of p-tyrosine-insulin receptor substrate-1 and heat shock protein 70 did not show significant differences. This review suggested that Aβ42, t-tau, p-T181-tau, and p-S396-tau could be effective in diagnosing AD as blood biomarkers, despite the limitation in the meta-analysis based on the availability of data. Therefore, certain BDE proteins could be used as effective biomarkers for AD.

scholarly journals Traumatic Brain Injury and Risk of Dementia and Alzheimer’s Disease: A Systematic Review and Meta-Analysis

2021 ◽  
Author(s):  
Dongqing Gu ◽  
Shan Ou ◽  
Guodong Liu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Meta Analysis ◽  
Random Effect ◽  
Random Effect Model ◽  
Subsequent Development ◽  
Medical Monitoring ◽  
Increased Risk

Introduction: Previous studies have investigated the potential role of traumatic brain injury (TBI) in subsequent development of dementia and Alzheimer’s disease (AD) but reported inconsistent results. We aim to determine the association between TBI and subsequent occurrence of dementia and AD. Methods: We performed a systematic search in PubMed and Web of Science for studies that quantitatively investigated the association between TBI and risk of dementia and AD and were published on or before September 21, 2021. A random-effect model was used to combine the estimates. Results: Twenty-five eligible articles were included in this meta-analysis. The results suggested that TBI was associated with an increased risk of dementia (pooled odds ratio [OR] = 1.81, 95% confidence interval [CI] = 1.53 - 2.14). However, no association was observed between TBI and Alzheimer’s disease (pooled OR = 1.02, 95% CI = 0.91 - 1.15). In the subgroup analysis, TBI with loss of consciousness was not associated with risk of dementia (pooled OR = 0.96, 95% CI = 0.84 - 1.09). Besides, Asian ethnicity, male gender, and mean age of the participants less than 65 were associated with a higher risk of dementia. Conclusion: Our study suggests an increased risk of dementia among individuals with TBI, highlighting the need for more intensive medical monitoring and health education in individuals with TBI. Biological mechanisms linking TBI and the development of dementia are needed in future studies.

scholarly journals Occupational Exposures and Neurodegenerative Diseases—A Systematic Literature Review and Meta-Analyses

2019 ◽  
Vol 16 (3) ◽  
pp. 337 ◽  
Author(s):  
Lars-Gunnar Gunnarsson ◽  
Lennart Bodin
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Occupational Exposure ◽  
Neurodegenerative Diseases ◽  
Meta Analysis ◽  
Occupational Exposures ◽  
Increased Risk ◽  
Meta Analyses

Objectives: To carry out an integrated and stratified meta-analysis on occupational exposure to electromagnetic fields (EMFs), metals and pesticides and its effects on amyotrophic lateral sclerosis (ALS) and Parkinson’s and Alzheimer’s disease, and investigate the possibility of publication bias. Methods: In the current study, we updated our recently published meta-analyses on occupational exposures in relation to ALS, Alzheimer’s and Parkinson’s disease. Based on 66 original publications of good scientific epidemiological standard, according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines, we analysed subgroups by carrying out stratified meta-analyses on publication year, statistical precision of the relative risk (RR) estimates, inspection of the funnel plots and test of bias. Results: Based on 19 studies the weighted RR for occupational exposure to EMFs was 1.26 (95% confidence interval (CI) 1.07–1.50) for ALS, 1.33 (95% CI 1.07–1.64) for Alzheimer’s disease and 1.02 (95% CI 0.83–1.26) for Parkinson’s disease. Thirty-one studies concerned occupational exposure to pesticides and the weighted RR was 1.35 (95% CI 1.02–1.79) for ALS, 1.50 (95% CI 0.98–2.29) for Alzheimer’s disease and 1.66 (95% CI 1.42–1.94) for Parkinson’s disease. Finally, 14 studies concerned occupational exposure to metals and only exposure to lead (five studies) involved an elevated risk for ALS or Parkinson’s disease and the weighted RR was 1.57 (95% CI 1.11–2.20). The weighted RR for all the non-lead exposures was 0.97 (95% CI 0.88–1.06). Conclusions: Exposure to pesticides increased the risk of getting the mentioned neurodegenerative diseases by at least 50%. Exposure to lead was only studied for ALS and Parkinson’s disease and involved 50% increased risk. Occupational exposure to EMFs seemed to involve some 10% increase in risk for ALS and Alzheimer’s disease only.

scholarly journals Associations of Fully Automated CSF and Novel Plasma Biomarkers With Alzheimer Disease Neuropathology at Autopsy

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012513
Author(s):  
Michel J. Grothe ◽  
Alexis Moscoso ◽  
Nicholas J. Ashton ◽  
Thomas K. Karikari ◽  
Juan Lantero-Rodriguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Braak Stage ◽  
Neuritic Plaques ◽  
Neurofilament Light ◽  
T Tau

Objective:To study cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) analyzed by fully automated Elecsys immunoassays in comparison to neuropathologic gold standards, and compare their accuracy to plasma phosphorylated tau (p-tau181) measured using a novel Simoa method.Methods:We studied ante-mortem Elecsys-derived CSF biomarkers in 45 individuals who underwent standardized post-mortem assessments of AD and non-AD neuropathologic changes at autopsy. In a subset of 26 participants, we also analysed ante-mortem levels of plasma p-tau181 and neurofilament light (NfL). Reference biomarker values were obtained from 146 amyloid-PET-negative healthy controls (HC).Results:All CSF biomarkers clearly distinguished pathology-confirmed AD dementia (N=27) from HC (AUCs=0.86-1.00). CSF total-tau (t-tau), p-tau181, and their ratios with Aβ1-42, also accurately distinguished pathology-confirmed AD from non-AD dementia (N=8; AUCs=0.94-0.97). In pathology-specific analyses, intermediate-to-high Thal amyloid phases were best detected by CSF Aβ1-42 (AUC[95% CI]=0.91[0.81-1]), while intermediate-to-high CERAD neuritic plaques and Braak tau stages were best detected by CSF p-tau181 (AUC=0.89[0.79-0.99] and 0.88[0.77-0.99], respectively). Optimal Elecsys biomarker cut-offs were derived at 1097/229/19 pg/ml for Aβ1-42, t-tau, and p-tau181. In the plasma subsample, both plasma p-tau181 (AUC=0.91[0.86-0.96]) and NfL (AUC=0.93[0.87-0.99]) accurately distinguished pathology-confirmed AD (N=14) from HC. However, only p-tau181 distinguished AD from non-AD dementia cases (N=4; AUC=0.96[0.88-1.00]), and showed a similar, though weaker, pathologic specificity for neuritic plaques (AUC=0.75[0.52-0.98]) and Braak stage (AUC=0.71[0.44-0.98]) as CSF p-tau181.Conclusions:Elecsys-derived CSF biomarkers detect AD neuropathologic changes with very high discriminative accuracy in-vivo. Preliminary findings support the use of plasma p-tau181 as an easily accessible and scalable biomarker of AD pathology.Classification of Evidence:This study provides Class II evidence that fully-automated CSF t-tau and p-tau181measurements discriminate between autopsy-confirmed Alzheimer's disease and other dementias.

scholarly journals Plasma tau and neurofilament light in frontotemporal lobar degeneration and Alzheimer's disease

Neurology ◽  
2020 ◽  
pp. 10.1212/WNL.0000000000011226
Author(s):  
Ignacio Illán-Gala ◽  
Alberto Lleo ◽  
Anna Karydas ◽  
Adam M. Staffaroni ◽  
Henrik Zetterberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Severity ◽  
Cortical Thickness ◽  
Frontotemporal Lobar Degeneration ◽  
Amyloid Pet ◽  
Class Iii ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
T Tau

ObjectiveTo test the hypothesis that plasma total tau (t-tau) and neurofilament light chain (NfL) concentrations may have a differential role in the study of frontotemporal lobar degeneration syndromes (FTLD-S) and clinically-diagnosed Alzheimer's disease (AD-S), we determined their diagnostic and prognostic value in FTLD-S and AD-S and their sensitivity to pathologic diagnoses.MethodsWe measured plasma t-tau and NfL with the Simoa platform in 265 participants: 167 FTLD-S, 43 AD-S, and 55 healthy controls (HC), including 82 pathology-proven cases (50 FTLD-Tau, 18 FTLD-TDP, 2 FTLD-FUS, and 12 AD) and 98 participants with amyloid PET. We compared cross-sectional and longitudinal biomarker concentrations between groups, their correlation with clinical measures of disease severity, progression and survival and cortical thickness.ResultsPlasma NfL, but not plasma t-tau discriminated FTLD-S from HC and AD-S from HC. Both plasma NfL and t-tau were poor discriminators between FLTD-S and AD-S. In pathology confirmed cases, plasma NfL was higher in FTLD than AD and in FTLD-TDP compared to FTLD-Tau, after accounting for age and disease severity. Plasma NfL, but not plasma t-tau, predicted clinical decline and survival and correlated with regional cortical thickness in both FTLD-S and AD-S. The combination of plasma NfL with plasma t-tau did not outperform plasma NfL alone.ConclusionsPlasma NfL is superior to plasma t-tau for the diagnosis and prediction of clinical progression of FTLD-S and AD-S.Classification of evidenceThis study provides Class III evidence that plasma NfL has superior diagnostic and prognostic performance than plasma t-tau in FTLD and AD.

A Systematic Review on Natural Medicines for the Prevention and Treatment of Alzheimer's Disease with Meta-Analyses of Intervention Effect of Ginkgo

2014 ◽  
Vol 42 (03) ◽  
pp. 505-521 ◽  
Author(s):  
Mengmeng Yang ◽  
Dan Dan Xu ◽  
Yan Zhang ◽  
Xinyou Liu ◽  
Robin Hoeven ◽  
...  
Keyword(s):  
Systematic Review ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
English Language ◽  
Meta Analysis ◽  
Cochrane Library ◽  
Significant Heterogeneity ◽  
Meta Analyses ◽  
Natural Medicines

We performed a systematic review to evaluate the efficacy of natural medicines for the treatment of Alzheimer's disease (AD) in randomized controlled trials (RCTs). Disease-specific and intervention terms were searched in MEDLINE, EMBASE, the Cochrane Library and PsycINFO to identify RCTs for the AD intervention of natural medicines, and searched for literatures in English language. The RCTs compared natural medicines and either placebo or orthodox medication in AD patients. The quality of literature was evaluated by Jadad's score and the Cochrane assessing tool to reduce the risk of bias. Meta-analysis and the heterogeneity of results across the trials were performed. Out of the literatures, 21 clinical reports were included in this review that satisfied the particular selection criteria. Apart from Ginkgo, other treatments we came across had minimal benefits and/or the methodological quality of the available trials was poor. The meta-analyses showed that Ginkgo had better outcomes than the placebo, with the standardized mean difference (SMD) between Ginkgo and the placebo on cognition being -1.62 (95% CI: -2.69 to -0.56) and on activities of daily living being -1.55 (95% CI: -2.55 to -0.55), with the existence of significant heterogeneity across studies. The meta-analysis for assessing the prevention effect of Ginkgo against AD suggested that risk ratio (RR) is 1.06 (95% CI: 0.92 to 1.22) between Gingko and the placebo, with no significant heterogeneity across studies (test for heterogeneity, p = 0.49). Our results suggest that Ginkgo may help established AD patients with cognitive symptoms but cannot prevent the neurodegenerative progression of the disease.

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