Candidate inflammatory biomarkers display unique relationships with alpha-synuclein and correlate with measures of disease severity in subjects with Parkinson's disease

• Authors: Lori N. Eidson, Emory University; George T. Kannarkat, Emory University; Christopher J. Barnum, Emory University; Jianjun Chang, Emory University; Jaegwon Chung, Emory University; Chelsea Caspell-Garcia, University of Iowa; Peggy Taylor, BioLegend, Inc.; Brit Mollenhauer, Paracelsus-Elena-Klinik; Michael G. Schlossmacher, University of Ottawa; Larry Ereshefsky, Follow the Molecule; Mark Yen, PAREXEL International; Catherine Kopil, The Michael J. Fox Foundation for Parkinson’s Research; Mark Frasier, The Michael J. Fox Foundation for Parkinson’s Research; Kenneth Marek, Yale-New Haven Hospital; Vicki Hertzberg, Emory University; MariadeLourdes Tansey, Emory University
• Journal Title: Journal of Neuroinflammation
• Volume: Volume 14, Number 1
• Publisher: BioMed Central | 2017-08-18, Pages 164-164
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1186/s12974-017-0935-1
• Subjects: Biology, Physiology; Health Sciences, Nursing; Health Sciences, General
• Keywords: Science & Technology; Life Sciences & Biomedicine; Immunology; Neurosciences; Neurosciences & Neurology; Parkinson's disease; Inflammation; Protein biomarkers; Daily rhythm; CSF; Serum; TUMOR-NECROSIS-FACTOR; GELATINASE-ASSOCIATED LIPOCALIN; LATE-LIFE DEPRESSION; SINGLE INTRANIGRAL INJECTION; GROWTH-FACTOR-ALPHA; TNF-ALPHA; MICROGLIAL ACTIVATION; DOPAMINERGIC SYSTEM; CEREBROSPINAL-FLUID; GLIAL ACTIVATION

Abstract

Background: Efforts to identify fluid biomarkers of Parkinson's disease (PD) have intensified in the last decade. As the role of inflammation in PD pathophysiology becomes increasingly recognized, investigators aim to define inflammatory signatures to help elucidate underlying mechanisms of disease pathogenesis and aid in identification of patients with inflammatory endophenotypes that could benefit from immunomodulatory interventions. However, discordant results in the literature and a lack of information regarding the stability of inflammatory factors over a 24-h period have hampered progress. Methods: Here, we measured inflammatory proteins in serum and CSF of a small cohort of PD (n=12) and age-matched healthy control (HC) subjects (n=6) at 11 time points across 24h to (1) identify potential diurnal variation, (2) reveal differences in PD vs HC, and (3) to correlate with CSF levels of amyloid β (Aβ) and α-synuclein in an effort to generate data-driven hypotheses regarding candidate biomarkers of PD. Results: Despite significant variability in other factors, a repeated measures two-way analysis of variance by time and disease state for each analyte revealed that serum IFNγ, TNF, and neutrophil gelatinase-associated lipocalin (NGAL) were stable across 24h and different between HC and PD. Regression analysis revealed that C-reactive protein (CRP) was the only factor with a strong linear relationship between CSF and serum. PD and HC subjects showed significantly different relationships between CSF Aβ proteins and α-synuclein and specific inflammatory factors, and CSF IFNγ and serum IL-8 positively correlated with clinical measures of PD. Finally, linear discriminant analysis revealed that serum TNF and CSF α-synuclein discriminated between PD and HC with a minimum of 82% sensitivity and 83% specificity. Conclusions: Our findings identify a panel of inflammatory factors in serum and CSF that can be reliably measured, distinguish between PD and HC, and monitor inflammation as disease progresses or in response to interventional therapies. This panel may aid in generating hypotheses and feasible experimental designs towards identifying biomarkers of neurodegenerative disease by focusing on analytes that remain stable regardless of time of sample collection.