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Cerebrospinal fluid ?-synuclein contributes to the differential diagnosis of Alzheimer's disease.

ABSTRACT: INTRODUCTION:The ability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers (amyloid ? peptide 1-42, total tau, and phosphorylated tau) to discriminate AD from related disorders is limited. Biomarkers for other concomitant pathologies (e.g., CSF ?-synuclein [?-syn] for Lewy body pathology) may be needed to further improve the differential diagnosis. METHODS:CSF total ?-syn, phosphorylated ?-syn at Ser129, and AD CSF biomarkers were evaluated with Luminex immunoassays in 367 participants, followed by validation in 74 different neuropathologically confirmed cases. RESULTS:CSF total ?-syn, when combined with amyloid ? peptide 1-42 and either total tau or phosphorylated tau, improved the differential diagnosis of AD versus frontotemporal dementia, Lewy body disorders, or other neurological disorders. The diagnostic accuracy of the combined models attained clinical relevance (area under curve ?0.9) and was largely validated in neuropathologically confirmed cases. DISCUSSION:Combining CSF biomarkers representing AD and Lewy body pathologies may have clinical value in the differential diagnosis of AD.

SUBMITTER: Shi M

PROVIDER: S-EPMC6097943 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Cerebrospinal fluid α-synuclein contributes to the differential diagnosis of Alzheimer's disease.

Shi Min M Tang Lu L Toledo Jon B JB Ginghina Carmen C Wang Hua H Aro Patrick P Jensen Poul H PH Weintraub Daniel D Chen-Plotkin Alice S AS Irwin David J DJ Grossman Murray M McCluskey Leo L Elman Lauren B LB Wolk David A DA Lee Edward B EB Shaw Leslie M LM Trojanowski John Q JQ Zhang Jing J

Alzheimer's & dementia : the journal of the Alzheimer's Association 20180328 8

<h4>Introduction</h4>The ability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers (amyloid β peptide 1-42, total tau, and phosphorylated tau) to discriminate AD from related disorders is limited. Biomarkers for other concomitant pathologies (e.g., CSF α-synuclein [α-syn] for Lewy body pathology) may be needed to further improve the differential diagnosis.<h4>Methods</h4>CSF total α-syn, phosphorylated α-syn at Ser129, and AD CSF biomarkers were evaluated with Luminex immunoassays ...[more]

PMID: 29604263

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Project description:BackgroundPD diagnosis is based primarily on clinical criteria and can be inaccurate. Biological markers, such as α-synuclein aggregation, that reflect ongoing pathogenic processes may increase diagnosis accuracy and allow disease progression monitoring. Though α-synuclein aggregation assays have been published, reproducibility, standardization, and validation are key challenges for their development as clinical biomarkers.ObjectiveTo cross-validate two α-synuclein seeding aggregation assays developed to detect pathogenic oligomeric α-synuclein species in CSF using samples from the same PD patients and healthy controls from the BioFIND cohort.MethodsCSF samples were tested by two independent laboratories in a blinded fashion. BioFIND features standardized biospecimen collection of clinically typical moderate PD patients and nondisease controls. α-synuclein aggregation was measured by protein misfolding cyclic amplification (Soto lab) and real-time quaking-induced conversion (Green lab). Results were analyzed by an independent statistician.ResultsMeasuring 105 PD and 79 healthy control CSF samples, these assays showed 92% concordance. The areas under the curve from receiver operating characteristic curve analysis for the diagnosis of PD versus healthy controls were 0.93 for protein misfolding cyclic amplification, 0.89 for real-time quaking-induced conversion, and 0.95 when considering only concordant assay results. Clinical characteristics of false-positive and -negative subjects were not different from true-negative and -positive subjects, respectively.ConclusionsThese α-synuclein seeding aggregation assays are reliable and reproducible for PD diagnosis. Assay parameters did not correlate with clinical parameters, including disease severity or duration. This assay is highly accurate for PD diagnosis and may impact clinical practice and clinical trials. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Project description:Introduction:Given the challenges concerning the differential diagnosis of dementia, we investigated the possible added value of monoaminergic compounds to the standard cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. Particularly, regarding the AD versus dementia with Lewy bodies (DLB) comparison, monoamines or their metabolites might have added discriminative value as there is a more severe neuropathological burden in the locus coeruleus of DLB patients, the principal site of noradrenaline synthesis. Methods:We applied enzyme-linked immunosorbent assay (ELISA) to analyze CSF amyloid ? peptide of 42 amino acids, total tau, and tau phosphorylated at threonine 181, in patients with AD, frontotemporal dementia, DLB/Parkinson's disease dementia, and controls. Reversed-phase high-performance liquid chromatography with electrochemical detection was implemented to study monoamine and metabolite levels in CSF and serum. Stepwise forward conditional logistic regression and receiver operating characteristic (ROC) curve analyses were performed to assess the diagnostic accuracy of these newly fitted models containing the most discriminative indicators of disease status. Results:Most significant differences in CSF and serum were confined to the noradrenergic system. More specifically, CSF 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were higher, whereas serum MHPG levels were lower, in DLB patients compared with all other groups. Addition of CSF and serum MHPG levels to the CSF AD biomarker panel significantly increased diagnostic accuracy between DLB/Parkinson's disease dementia and AD. Interestingly, a model only including CSF and serum MHPG without the classic AD biomarker panel reached similar area under the curve values. Discussion:We hypothesize that varying degrees of neuronal loss in the locus coeruleus of DLB/Parkinson's disease dementia versus AD patients result in differentially altered MHPG levels, making this metabolite a valuable biomarker.

Dataset Information

Cerebrospinal fluid ?-synuclein contributes to the differential diagnosis of Alzheimer's disease.

Publications

Cerebrospinal fluid α-synuclein contributes to the differential diagnosis of Alzheimer's disease.

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