O3-01-03: Multiplex quantitative proteomics of human cerebral spinal fluid from patients with neurodegenerative diseases

Abstract

Background & Objective: Biomarkers are needed to assist in the diagnosis and medical management of various neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy body (DLB) diseases. Method: We have employed a multiplex quantitative proteomics method, isobaric Tagging for Relative and Absolute protein Quantification (iTRAQ), in conjunction with multidimensional chromatography, followed by tandem mass spectrometry (MS), to simultaneously measure relative changes in the proteome of human cerebrospinal fluid (CSF) obtained from the lumbar cistern of patients with AD (n 10), PD (n 10), or DLB (n 5) as well as from age-matched controls (n 10). Subsequent pathologic verification was obtained in all cases of AD and DLB. PD patients and age-matched controls had no change in diagnosis with follow-up evaluations for at least 3 years after lumbar tap. Proteomic results demonstrated that among 1,540 identified proteins, quantitative changes in 154, 81, and 113 proteins were associated with AD, PD, and DLB, respectively. Eight unique proteins were validated by Western blot. Using paired combinations of these validated CSF protein biomarkers, comparison among the four groups while holding specificity at 95% gave sensitivity of 100% for AD, 78% for PD, and 50% for DLB. Conclusion: Here, we have presented the most comprehensive characterization of the adult human CSF proteome. Although these results require confirmation in larger patient populations, our quantitative proteomics of CSF allowed us to generate small protein panels that distinguished among AD, DLB, PD, and controls with high specificity and moderate to high sensitivity. This approach may be developed further into even more robust CSF protein biomarker panels for AD, DLB, and PD patients.