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. 2018 Aug;14(8):1052-1062.
doi: 10.1016/j.jalz.2018.02.015. Epub 2018 Mar 28.

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

Min Shi  1 , Lu Tang  2 , Jon B Toledo  3 , Carmen Ginghina  1 , Hua Wang  4 , Patrick Aro  1 , Poul H Jensen  5 , Daniel Weintraub  3 , Alice S Chen-Plotkin  3 , David J Irwin  3 , Murray Grossman  3 , Leo McCluskey  3 , Lauren B Elman  3 , David A Wolk  3 , Edward B Lee  3 , Leslie M Shaw  3 , John Q Trojanowski  3 , Jing Zhang  6
Affiliations

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

Min Shi et al. Alzheimers Dement. 2018 Aug.

Abstract

Introduction: 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.

Methods: CSF total α-syn, phosphorylated α-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 α-syn, when combined with amyloid β 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.

Keywords: Alzheimer's disease; Biomarkers; Cerebrospinal fluid; Differential diagnosis; α-synuclein.

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Conflict of interest statement

Conflicts of Interest: Nothing to report.

Figures

Figure 1
Figure 1. Association of CSF analytes
(A and B) Associations of CSF α-synuclein (α-syn; A) and α-syn phosphorylated at Ser129 (pS129; B) with CSF hemoglobin values in all subjects (n=642); vertical dashed red line represents the 500 ng/mL cut-off selected to exclude CSF α-syn values due to blood contamination. (C, D, and E) Associations of CSF α-syn with CSF amyloid beta peptide 1–42 (Aβ42; C), total tau (t-tau; D), and phosphorylated p-tau at Thr181 (p-tau; E), after excluding subjects with >500 ng/mL of CSF hemoglobin (n=441 after exclusion). (F) Association of CSF α-syn and pS129 in subjects with ≤500 ng/mL hemoglobin.
Figure 2
Figure 2. CSF α-syn, pS129, and the pS129/α-syn ratio stratified by clinical diagnosis in the clinical cohort
CSF total α-syn (A) and pS129 (B) concentrations were measured in the clinical cohort that includes patients with the diagnoses indicated below panel C. The ratio of pS129/α-syn is also shown (C). The boxes extend from the 25th to 75th percentiles. The middle dark lines indicate the medians. The whiskers extend to 1.5 times the height of the box or, if no case has a value in that range, to the minimum or maximum values. Values not included between the whiskers are plotted as outliers with corresponding symbols. No outliers were excluded from the analyses in this study.
Figure 3
Figure 3. ROC analysis of CSF biomarkers in the clinical cohort
(A) Alzheimer disease (AD) vs healthy controls (HC); (B) AD vs frontotemporal degeneration (FTD)/corticobasal syndrome (CBS); (C) AD vs dementia with Lewy bodies (DLB)/Parkinson disease (PD); (D) AD vs amyotrophic lateral sclerosis (ALS). Blue dashed line indicates CSF α-syn alone, orange dot-dashed line indicates CSF Aβ42, black dotted line indicates CSF t-tau or p-tau, and red solid line indicates a combined model of CSF α-syn, Aβ42, and t-tau or p-tau.
Figure 4
Figure 4. CSF α-syn and pS129 stratified by autopsy diagnosis and the differential diagnosis performance of CSF biomarkers in the validation (autopsy) cohort
See this image and copyright information in PMC

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