Hutten, S. J. | Search bioRxiv

bioRxiv2019

Cross-Sectional and Longitudinal Validation of Serum Neurofilament Light Chain (NfL) as a Biomarker of Parkinson’s Disease Progression

ObjectiveTo assess neurofilament light chain (NfL), as a biomarker for Parkinsons disease (PD). MethodsWe quantified NfL in (1) longitudinal CSF samples from PD, other cognate/neurodegenerative disorders (OND), and healthy controls (HC); (2) a cross-sectional cohort with paired CSF and serum samples from participants with PD, OND, and HC, and (3) a large longitudinal validation cohort with serum samples from PD, OND, HC, prodromal conditions, and mutation carriers. ResultsIn the longitudinal discovery cohort (1) NfL in CSF was highest in OND and higher in PD vs. HC across all visits (p<0.05) but did not change longitudinally. In the cross-sectional cohort (2) paired CSF and serum NfL samples were highly correlated (Spearmans rank [Formula]; p<10^-6). In the large validation cohort (3) mean baseline serum NfL was higher in PD (13{+/-}7.2pg/ml) vs. HC (12{+/-}6.7pg/ml; p=0.0336) and was highest in OND (18{+/-}7pg/ml; p=0.0351). Serum NfL increased longitudinally in PD vs. HC (p<0.01). Longitudinal motor scores were positively longitudinally associated with NfL, whereas some cognitive scores showed a negative longitudinal association with NfL. ConclusionsNfL levels in serum samples are increased in PD vs. HC, increase significantly over time, and correlate with clinical measures of PD severity. Although the specificity of NfL in PD is low and more specific biomarkers are needed, serum NfL is the first blood-based biomarker candidate that could support disease stratification (PD vs. OND), track clinical progression, and possibly assess responsiveness to neuroprotective treatments. NfL as a biomarker of response to neuroprotective interventions remains to be determined. Funding sources for studyPPMI is sponsored by the Michael J. Fox Foundation for Parkinsons Research (MJFF) and is co-funded by MJFF, Abbvie, Avid Radiopharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Covance, Eli Lilly & Co., F. Hoffman-La Roche, Ltd., GE Healthcare, Genentech, GlaxoSmithKline, Lundbeck, Merck, MesoScale, Piramal, Pfizer and UCB. The funders had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, in the preparation, review, or approval of the manuscript or in the decision to submit the manuscript for publication. Financial Disclosure/Conflict of Interest concerning the research related to the manuscriptBrit Mollenhauer, Douglas Galasko, Tatiana Foroud, Lana M. Chahine, Christopher S. Coffey, Andrew B. Singleton, Tanya Simuni, Daniel Weintraub, John Seibyl, Arthur W. Toga, and Caroline M. Tanner received funding from The Michael J. Fox Foundation for Parkinsons Research. Mohammed Dakna, Tzu-Ying Liu, Henrik Zetterberg, Sebastian Schade, Roland G. Gera, Wenting Wang, Feng Gao, Niels Kruse, Mark Frasier, Jesse M. Cedarbaum, Samantha J. Hutten, Claudia Trenkwalder, and Danielle Graham report no disclosures.

neuroscience↗

bioRxiv2019

An assessment of LRRK2 serine 935 phosphorylation in human peripheral blood mononuclear cells in idiopathic Parkinson’s disease and G2019S LRRK2 cohorts

The phosphorylated form of LRRK2, pS935 LRRK2, has been proposed as a target modulation biomarker for LRRK2 inhibitors. To qualify the biomarker for therapeutic trials, we assessed pS935 LRRK2 levels in Peripheral Blood Mononuclear Cells (PBMCs). Analyses of PBMCs from healthy controls, idiopathic Parkinsons disease (iPD), and G2019S carriers with and without PD showed significant reductions in pS935 LRRK2 levels normalized to total LRRK2 levels in G2019S carriers with PD compared to those without PD or iPD. Neither analyte correlated with age, gender, or disease severity. Thus, pS935 LRRK2 in PBMCs may reflect a state marker for G2019S LRRK2-driven PD.

neuroscience↗

bioRxiv2019

Genome-wide association study of Parkinson's disease progression biomarkers in 12 longitudinal patients' cohorts

BackgroundSeveral reports have identified different patterns of Parkinsons disease progression in individuals carrying missense variants in the GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinsons disease, however, has not been well studied. ObjectivesTo test the association between genetic variants and the clinical features and progression of Parkinsons disease on a genome-wide scale. MethodsWe accumulated individual data from 12 longitudinal cohorts in a total of 4,093 patients with 25,254 observations over a median of 3.81 years. Genome-wide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently-identified disease risk variants, were also investigated for the associations with these phenotypes. ResultsTwo variants were genome-wide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (HR 2.04 [1.58, 2.62], P-value = 3.46E-8). Rs61863020(G>A), an intergenic variant and eQTL for ADRA2A, was associated with a lower prevalence of insomnia at baseline (OR 0.63 [0,52, 0.75], P-value = 4.74E-8). In the targeted analysis, we found nine associations between known Parkinsons risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K, rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. ConclusionsWe identified novel genetic factors associated with heterogeneity of progression in Parkinsons disease. The results provide new insights into the pathogenesis of Parkinsons disease as well as patient stratification for clinical trials.

genetics↗