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.

Details

Title
Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort
Author
Simuni, Tanya 1   VIAFID ORCID Logo  ; Merchant, Kalpana 1 ; Brumm, Michael C. 2 ; Cho, Hyunkeun 2 ; Caspell-Garcia, Chelsea 2 ; Coffey, Christopher S. 2 ; Chahine, Lana M. 3 ; Alcalay, Roy N. 4 ; Nudelman, Kelly 5   VIAFID ORCID Logo  ; Foroud, Tatiana 5 ; Mollenhauer, Brit 6 ; Siderowf, Andrew 7 ; Tanner, Caroline 8   VIAFID ORCID Logo  ; Iwaki, Hirotaka 9 ; Sherer, Todd 10 ; Marek, Kenneth 11 ; Seibyl, John 3 ; Coffey, Christopher 12 ; Tosun-Turgut, Duygu 8 ; Shaw, Leslie M. 12 ; Trojanowski, John Q. 12 ; Singleton, Andrew 9 ; Kieburtz, Karl 13 ; Toga, Arthur 14 ; Galasko, Douglas 15 ; Poewe, Werner 16 ; Poston, Kathleen 17 ; Bressman, Susan 18 ; Reimer, Alyssa 10 ; Arnedo, Vanessa 10 ; Clark, Adrienne 10 ; Frasier, Mark 10 ; Kopil, Catherine 10 ; Chowdhury, Sohini 10 ; Casaceli, Cynthia 19 ; Dorsey, Ray 19 ; Wilson, Renee 19 ; Mahes, Sugi 19 ; Salerno, Christina 20 ; Ahrens, Monica 2 ; Brumm, Michael 2 ; Cho, Hyunkeun Ryan 2 ; Fedler, Janel 2 ; LaFontant, David-Erick 3 ; Kurth, Ryan 2 ; Crawford, Karen 14 ; Casalin, Paola 21 ; Malferrari, Giulia 22 ; Weisz, Mali Gani 22 ; Orr-Urtreger, Avi 22 ; Trojanowski, John 12 ; Shaw, Leslie 12 ; Montine, Thomas 17 ; Baglieri, Chris 23 ; Christini, Amanda 23 ; Russell, David 24 ; Dahodwala, Nabila 12 ; Giladi, Nir 22 ; Factor, Stewart 25 ; Hogarth, Penelope 26 ; Standaert, David 27 ; Hauser, Robert 28 ; Jankovic, Joseph 29 ; Saint-Hilaire, Marie 30 ; Richard, Irene 13 ; Shprecher, David 31 ; Fernandez, Hubert 32 ; Brockmann, Katrina 33 ; Rosenthal, Liana 34 ; Barone, Paolo 35 ; Espayc, Alberto 36 ; Rowe, Dominic 37 ; Marder, Karen 38 ; Santiago, Anthony 39 ; Hu, Shu-Ching 40 ; Isaacson, Stuart 41 ; Corvol, Jean-Christophe 42 ; Martinez, Javiar Ruiz 43 ; Tolosa, Eduardo 44 ; Tai, Yen 45 ; Politis, Marios 46 ; Smejdir, Debra 47 ; Rees, Linda 47 ; Williams, Karen 2 ; Kausar, Farah 8 ; Richardson, Whitney 12 ; Willeke, Diana 48 ; Peacock, Shawnees 15 ; Sommerfeld, Barbara 25 ; Freed, Alison 26 ; Wakeman, Katrina 27 ; Blair, Courtney 28 ; Guthrie, Stephanie 29 ; Harrell, Leigh 28 ; Hunter, Christine 29 ; Thomas, Cathi-Ann 30 ; James, Raymond 30 ; Zimmerman, Grace 13 ; Brown, Victoria 31 ; Mule, Jennifer 32 ; Hilt, Ella 33 ; Ribb, Kori 34 ; Ainscough, Susan 35 ; Wethington, Misty 36 ; Ranola, Madelaine 37 ; Santana, Helen Mejia 38 ; Moreno, Juliana 39 ; Raymond, Deborah 49 ; Speketer, Krista 40 ; Carvajal, Lisbeth 41 ; Carvalo, Stephanie 42 ; Croitoru, Ioana 43 ; Garrido, Alicia 44 ; Payne, Laura Marie 45 ; Viswanth, Veena 50 ; Severt, Lawrence 50 ; Facheris, Maurizio 51 ; Soares, Holly 51 ; Mintun, Mark A. 52 ; Cedarbaum, Jesse 53 ; Taylor, Peggy 54 ; Biglan, Kevin 55 ; Vandenbroucke, Emily 56 ; Sheikh, Zulfiqar Haider 56 ; Bingol, Baris 57 ; Fischer, Tanya 58 ; Sardi, Pablo 58 ; Forrat, Remi 58 ; Reith, Alastair 59 ; Egebjerg, Jan 60 ; Hillert, Gabrielle Ahlberg 60 ; Saba, Barbara 61 ; Min, Chris 62 ; Umek, Robert 63 ; Mather, Joe 64 ; De Santi, Susan 65 ; Post, Anke 66 ; Boess, Frank 66 ; Taylor, Kirsten 66 ; Grachev, Igor 67 ; Avbersek, Andreja 68 ; Muglia, Pierandrea 68 ; Merchant, Kaplana 69 ; Tauscher, Johannes 70 

1  Northwestern University Feinberg School of Medicine, Chicago, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507) 
2  The University of Iowa, Iowa, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) 
3  University of Pittsburgh, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
4  Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (GRID:grid.413449.f) (ISNI:0000 0001 0518 6922); Columbia University, Department of Neurology, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
5  Indiana University School of Medicine, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919) 
6  University Medical Center Goettingen Göttingen, Göttingen, Germany (GRID:grid.411984.1) (ISNI:0000 0001 0482 5331) 
7  The University of Pennsylvania, Pennsylvania, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
8  University of California San Francisco, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
9  National Institute on Aging, Bethesda, USA (GRID:grid.419475.a) (ISNI:0000 0000 9372 4913) 
10  The Michael J. Fox Foundation for Parkinson’s Research, New York, USA (GRID:grid.430781.9) (ISNI:0000 0004 5907 0388) 
11  Institute for Neurodegenerative Disorders New York, New York, USA (GRID:grid.430781.9) 
12  University of Pennsylvania, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
13  University of Rochester, Rochester, USA (GRID:grid.16416.34) (ISNI:0000 0004 1936 9174) 
14  University of Southern California, Laboratory of Neuroimaging (LONI), Los Angeles, USA (GRID:grid.42505.36) (ISNI:0000 0001 2156 6853) 
15  University of California, San Diego, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
16  Innsbruck Medical University, Innsbruck, Austria (GRID:grid.5361.1) (ISNI:0000 0000 8853 2677) 
17  Stanford University, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
18  Mount Sinai, New York, USA (GRID:grid.416167.3) (ISNI:0000 0004 0442 1996) 
19  Clinical Trials Coordination Center, University of Rochester, Rochester, USA (GRID:grid.16416.34) (ISNI:0000 0004 1936 9174) 
20  Institute for Neurodegenerative Disorders New York, New York, USA (GRID:grid.16416.34) 
21  BioRep, Milan, Italy (GRID:grid.42505.36) 
22  Tel Aviv Medical Center, Tel Aviv, Israel (GRID:grid.413449.f) (ISNI:0000 0001 0518 6922) 
23  Blackfynn, Philadelphia, USA (GRID:grid.504248.f) (ISNI:0000 0004 6107 7482) 
24  Institute for Neurodegenerative Disorders New York, New York, USA (GRID:grid.504248.f) 
25  Emory University of Medicine, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
26  Oregon Health and Science University, Portland, USA (GRID:grid.5288.7) (ISNI:0000 0000 9758 5690) 
27  University of Alabama at Birmingham, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000000106344187) 
28  University of South Florida, Tampa, USA (GRID:grid.170693.a) (ISNI:0000 0001 2353 285X) 
29  Baylor College of Medicine, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X) 
30  Boston University, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558) 
31  Banner Research Institute, Sun City, USA (GRID:grid.414208.b) (ISNI:0000 0004 0619 8759) 
32  Cleveland Clinic, Cleveland, USA (GRID:grid.239578.2) (ISNI:0000 0001 0675 4725) 
33  University of Tuebingen, Tuebingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447) 
34  Johns Hopkins University, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
35  University of Salerno, Salerno, Italy (GRID:grid.11780.3f) (ISNI:0000 0004 1937 0335) 
36  University of Cincinnati, Cincinnati, USA (GRID:grid.24827.3b) (ISNI:0000 0001 2179 9593) 
37  Macquarie University, Sydney, Australia (GRID:grid.1004.5) (ISNI:0000 0001 2158 5405) 
38  Columbia University, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
39  The Parkinson’s Institute, Sunnyvale, USA (GRID:grid.420053.0) (ISNI:0000 0004 0422 9144) 
40  University of Washington, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657) 
41  Parkinson’s Disease and Movement Disorders Center of Boca Raton, Boca Raton, USA (GRID:grid.477790.a) 
42  Hospital Pitie-Salpetriere, Paris, France (GRID:grid.411439.a) (ISNI:0000 0001 2150 9058) 
43  Hospital Donostia, San Sebastian, Spain (GRID:grid.414651.3) (ISNI:0000 0000 9920 5292) 
44  Hospital Clinic de Barcelona, Barcelona, Spain (GRID:grid.410458.c) (ISNI:0000 0000 9635 9413) 
45  Imperial College London, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
46  King’s College London, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
47  Institute for Neurodegenerative Disorders New York, New York, USA (GRID:grid.13097.3c) 
48  Paracelsus-Elena Klinik, Kassel, Germany (GRID:grid.440220.0) 
49  Beth Israel Medical Center, New York, USA (GRID:grid.471368.f) (ISNI:0000 0004 1937 0423) 
50  Allergan, Dublin, Ireland (GRID:grid.472734.1) (ISNI:0000 0004 0568 4122) 
51  Abbvie, North Chicago, USA (GRID:grid.431072.3) (ISNI:0000 0004 0572 4227) 
52  Avid Radiopharmaceuticals, Inc, Philadelphia, USA (GRID:grid.417540.3) (ISNI:0000 0000 2220 2544) 
53  Biogen Idec, Cambridge, USA (GRID:grid.417832.b) (ISNI:0000 0004 0384 8146) 
54  BioLegend, Dedham, USA (GRID:grid.422444.0) (ISNI:0000 0004 0619 8660) 
55  Eli Lilly and Company, Indianapolis, USA (GRID:grid.417540.3) (ISNI:0000 0000 2220 2544) 
56  GE Healthcare, Princeton, USA (GRID:grid.418143.b) (ISNI:0000 0001 0943 0267) 
57  Genentech, San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718) 
58  Genzyme Sanofi, Cambridge, USA (GRID:grid.418158.1) 
59  GlaxoSmithKline, Brentford, UK (GRID:grid.418236.a) (ISNI:0000 0001 2162 0389) 
60  H. Lundbeck A/S, Copenhagen, Denmark (GRID:grid.424580.f) (ISNI:0000 0004 0476 7612) 
61  Institut de Recherches Internationales Servier, Neuilly-sur-Seine, France (GRID:grid.418301.f) (ISNI:0000 0001 2163 3905) 
62  Merck and Co, Kenilworth, USA (GRID:grid.417993.1) (ISNI:0000 0001 2260 0793) 
63  Meso Scale Diagnostics, Rockville, USA (GRID:grid.417791.d) (ISNI:0000 0004 0630 083X) 
64  Pfizer Inc, Cambridge, USA (GRID:grid.410513.2) (ISNI:0000 0000 8800 7493) 
65  Piramal Group, Mumbai, India (GRID:grid.410513.2) 
66  F. Hoffmann-La Roche Limited, Basel, Switzerland (GRID:grid.417570.0) (ISNI:0000 0004 0374 1269) 
67  Teva Pharmaceutical Industries, Petah Tikva, Israel (GRID:grid.452797.a) (ISNI:0000 0001 2189 710X) 
68  UCB Pharma, Brussel Belgium, Belgium (GRID:grid.421932.f) (ISNI:0000 0004 0605 7243) 
69  TransThera Consulting, Portland, USA (GRID:grid.421932.f) 
70  Takeda, Osaka, Japan (GRID:grid.419841.1) (ISNI:0000 0001 0673 6017) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
23738057
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41531-022-00404-w
ProQuest document ID
2727283389
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.