Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort
Authors: Simuni Tanya , Merchant Kalpana , Brumm Michael C. , Cho Hyunkeun , Caspell-Garcia Chelsea , Coffey Christopher S. , Chahine Lana M. , Alcalay Roy N. , Nudelman Kelly , Foroud Tatiana , Mollenhauer Brit , Siderowf Andrew , Tanner Caroline , Iwaki Hirotaka , Sherer Todd , Marek Kenneth ,   Parkinson’s Progression Marker Initiative Authors,   Steering Committee, Siderowf Andrew , Seibyl John , Coffey Christopher , Tosun-Turgut Duygu , Shaw Leslie M. , Trojanowski John Q. , Singleton Andrew , Kieburtz Karl , Toga Arthur , Mollenhauer Brit , Galasko Douglas , Poewe Werner , Foroud Tatiana , Poston Kathleen , Bressman Susan , Reimer Alyssa , Arnedo Vanessa , Clark Adrienne , Frasier Mark , Kopil Catherine , Chowdhury Sohini ,   Study Cores, Casaceli Cynthia , Dorsey Ray , Wilson Renee , Mahes Sugi , Seibyl John , Salerno Christina , Ahrens Monica , Brumm Michael , Cho Hyunkeun Ryan , Fedler Janel , LaFontant David-Erick , Kurth Ryan , Crawford Karen , Casalin Paola , Malferrari Giulia , Weisz Mali Gani , Orr-Urtreger Avi , Trojanowski John , Shaw Leslie , Montine Thomas , Baglieri Chris , Christini Amanda ,   Site Investigators, Russell David , Dahodwala Nabila , Giladi Nir , Factor Stewart , Hogarth Penelope , Standaert David , Hauser Robert , Jankovic Joseph , Saint-Hilaire Marie , Richard Irene , Shprecher David , Fernandez Hubert , Brockmann Katrina , Rosenthal Liana , Barone Paolo , Espayc Alberto , Rowe Dominic , Marder Karen , Santiago Anthony , Bressman Susan , Hu Shu-Ching , Isaacson Stuart , Corvol Jean-Christophe , Martinez Javiar Ruiz , Tolosa Eduardo , Tai Yen , Politis Marios ,   Coordinators, Smejdir Debra , Rees Linda , Williams Karen , Kausar Farah , Williams Karen , Richardson Whitney , Willeke Diana , Peacock Shawnees , Sommerfeld Barbara , Freed Alison , Wakeman Katrina , Blair Courtney , Guthrie Stephanie , Harrell Leigh , Hunter Christine , Thomas Cathi-Ann , James Raymond , Zimmerman Grace , Brown Victoria , Mule Jennifer , Hilt Ella , Ribb Kori , Ainscough Susan , Wethington Misty , Ranola Madelaine , Santana Helen Mejia , Moreno Juliana , Raymond Deborah , Speketer Krista , Carvajal Lisbeth , Carvalo Stephanie , Croitoru Ioana , Garrido Alicia , Payne Laura Marie ,   Industry and Scientific Advisory Board (Acknowledgment), Viswanth Veena , Severt Lawrence , Facheris Maurizio , Soares Holly , Mintun Mark A. , Cedarbaum Jesse , Taylor Peggy , Biglan Kevin , Vandenbroucke Emily , Sheikh Zulfiqar Haider , Bingol Baris , Fischer Tanya , Sardi Pablo , Forrat Remi , Reith Alastair , Egebjerg Jan , Hillert Gabrielle Ahlberg , Saba Barbara , Min Chris , Umek Robert , Mather Joe , De Santi Susan , Post Anke , Boess Frank , Taylor Kirsten , Grachev Igor , Avbersek Andreja , Muglia Pierandrea , Merchant Kaplana , Tauscher Johannes 
Published: October 2022

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.