Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort
Tanya Simuni, Kalpana Merchant, Michael C. Brumm, Hyunkeun Cho, Chelsea Caspell‐Garcia, Christopher S. Coffey, Lana M. Chahine, Roy N. Alcalay, Kelly Nudelman, Tatiana Foroud, Brit Mollenhauer, Andrew Siderowf, Caroline M. Tanner, Hirotaka Iwaki, Todd Sherer, Kenneth Marek, Parkinson’s Progression Marker Initiative Authors, Andrew Siderowf, John Seibyl, Christopher S. Coffey, Duygu Tosun, Leslie M. Shaw, John Q. Trojanowski, Andrew Singleton, Karl Kieburtz, Arthur W. Toga, Brit Mollenhauer, Douglas Galasko, Werner Poewe, Tatiana Foroud, Kathleen L. Poston, Susan Bressman, Alyssa Reimer, Vanessa Arnedo, Adrienne Clark, Mark Frasier, Catherine Kopil, Sohini Chowdhury, Study Cores, Cynthia Casaceli, Ray Dorsey, Renée Wilson, Sugi Mahes, John Seibyl, Christina M. Salerno, Monica Ahrens, Michael C. Brumm, Hyunkeun Ryan Cho, Janel Fedler, David-Erick Lafontant, Ryan Kurth, Karen Crawford, Paola Casalin, Giulia Malferrari, Mali Gani Weisz, Avi Orr‐Urtreger, John Q. Trojanowski, Leslie M. Shaw, Thomas J. Montine, Chris Baglieri, Amanda Christini, Site Investigators, David Russell, Nabila Dahodwala, Nir Giladi, Stewart A. Factor, Penelope Hogarth, David G. Standaert, Robert A. Hauser, Joseph Jankovic, Marie Saint‐Hilaire, Irene Hegeman Richard, David Shprecher, Hubert Fernandez, Katrina Brockmann, Liana S. Rosenthal, Paolo Barone, Alberto Espayc, Dominic B. Rowe, Karen Marder, A. Parra Santiago, Susan Bressman, Shu‐Ching Hu, Stuart Isaacson, Jean‐Christophe Corvol, Javiar Ruiz Martinez, Eduardo Tolosa, Yen Tai, Marios Politis, Coordinators, Debra Smejdir, Linda Rees, Karen Williams, Farah Kausar, Karen Williams, Whitney Richardson, Diana Willeke, Shawnees Peacock, Barbara Sommerfeld, Alison Freed
Abstract
We examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson's Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive motor and non-motor scales, dopamine transporter (DAT) imaging, and biofluid biomarkers. The latter included cerebrospinal fluid (CSF) Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). At baseline, LRRK2 G2019S NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 13% had DAT deficit (defined as <65% of age/sex-expected lowest putamen SBR) and 11% had hyposmia (defined as ≤15th percentile for age and sex). Only 5 of 176 LRRK2 NMCs developed PD during follow-up. Although NMCs scored significantly worse on numerous clinical scales at baseline than HCs, there was no longitudinal change in any clinical measures over 2 years or in DAT binding. There were no longitudinal differences in CSF and serum biomarkers between NMCs and HCs. Urinary BMP was significantly elevated in NMCs at all time points but did not change longitudinally. Neither baseline biofluid biomarkers nor the presence of DAT deficit correlated with 2-year change in clinical outcomes. We observed no significant 2-year longitudinal change in clinical or biomarker measures in LRRK2 G2019S NMCs in this large, well-characterized cohort even in the participants with baseline DAT deficit. These findings highlight the essential need for further enrichment biomarker discovery in addition to DAT deficit and longer follow-up to enable the selection of NMCs at the highest risk for conversion to enable future prevention clinical trials.