Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort

Tanya Simuni; Kalpana Merchant; Michael C. Brumm; Hyunkeun Ryan Cho; Chelsea Caspell-Garcia; Christopher S. Coffey; Lana M. Chahine; Roy N. Alcalay; Kelly Nudelman; Tatiana Foroud; Brit Mollenhauer; Andrew Siderowf; Caroline Tanner; Hirotaka Iwaki; Todd Sherer; Kenneth Marek; Parkinson’s Progression Marker Initiative Authors

doi:10.1038/s41531-022-00404-w

Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort

Tanya Simuni^*, Kalpana Merchant, Michael C. Brumm, Hyunkeun Ryan Cho, Chelsea Caspell-Garcia, Christopher S. Coffey, Lana M. Chahine, Roy N. Alcalay, Kelly Nudelman, Tatiana Foroud, Brit Mollenhauer, Andrew Siderowf, Caroline Tanner, Hirotaka Iwaki, Todd Sherer, Kenneth Marek, Parkinson’s Progression Marker Initiative Authors

^*Corresponding author for this work

Macquarie Medical School

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	140
Pages (from-to)	1-10
Number of pages	10
Journal	npj Parkinson's Disease
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41531-022-00404-w
Publication status	Published - 22 Oct 2022

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Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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Simuni, T., Merchant, K., Brumm, M. C., Cho, H. R., Caspell-Garcia, C., Coffey, C. S., Chahine, L. M., Alcalay, R. N., Nudelman, K., Foroud, T., Mollenhauer, B., Siderowf, A., Tanner, C., Iwaki, H., Sherer, T., Marek, K., & Parkinson’s Progression Marker Initiative Authors (2022). Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort. npj Parkinson's Disease, 8(1), 1-10. [140]. https://doi.org/10.1038/s41531-022-00404-w

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title = "Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort",

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{\textquoteright}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.",

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note = "Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2022",

month = oct,

day = "22",

doi = "10.1038/s41531-022-00404-w",

language = "English",

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Simuni, T, Merchant, K, Brumm, MC, Cho, HR, Caspell-Garcia, C, Coffey, CS, Chahine, LM, Alcalay, RN, Nudelman, K, Foroud, T, Mollenhauer, B, Siderowf, A, Tanner, C, Iwaki, H, Sherer, T, Marek, K & Parkinson’s Progression Marker Initiative Authors 2022, 'Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort', npj Parkinson's Disease, vol. 8, no. 1, 140, pp. 1-10. https://doi.org/10.1038/s41531-022-00404-w

TY - JOUR

T1 - Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort

AU - Simuni, Tanya

AU - Merchant, Kalpana

AU - Brumm, Michael C.

AU - Cho, Hyunkeun Ryan

AU - Caspell-Garcia, Chelsea

AU - Coffey, Christopher S.

AU - Chahine, Lana M.

AU - Alcalay, Roy N.

AU - Nudelman, Kelly

AU - Foroud, Tatiana

AU - Mollenhauer, Brit

AU - Siderowf, Andrew

AU - Tanner, Caroline

AU - Iwaki, Hirotaka

AU - Sherer, Todd

AU - Marek, Kenneth

AU - Parkinson’s Progression Marker Initiative Authors

AU - Seibyl, John

AU - Tosun-Turgut, Duygu

AU - Shaw, Leslie M.

AU - Trojanowski, John Q.

AU - Singleton, Andrew

AU - Kieburtz, Karl

AU - Toga, Arthur

AU - Galasko, Douglas

AU - Poewe, Werner

AU - Poston, Kathleen

AU - Bressman, Susan

AU - Reimer, Alyssa

AU - Arnedo, Vanessa

AU - Clark, Adrienne

AU - Frasier, Mark

AU - Kopil, Catherine

AU - Chowdhury, Sohini

AU - Casaceli, Cynthia

AU - Dorsey, Ray

AU - Wilson, Renee

AU - Mahes, Sugi

AU - Salerno, Christina

AU - Ahrens, Monica

AU - Fedler, Janel

AU - LaFontant, David Erick

AU - Kurth, Ryan

AU - Crawford, Karen

AU - Casalin, Paola

AU - Malferrari, Giulia

AU - Weisz, Mali Gani

AU - Orr-Urtreger, Avi

AU - Montine, Thomas

AU - Baglieri, Chris

AU - Christini, Amanda

AU - Russell, David

AU - Dahodwala, Nabila

AU - Giladi, Nir

AU - Factor, Stewart

AU - Hogarth, Penelope

AU - Standaert, David

AU - Hauser, Robert

AU - Jankovic, Joseph

AU - Saint-Hilaire, Marie

AU - Richard, Irene

AU - Shprecher, David

AU - Fernandez, Hubert

AU - Brockmann, Katrina

AU - Rosenthal, Liana

AU - Barone, Paolo

AU - Espayc, Alberto

AU - Rowe, Dominic

AU - Marder, Karen

AU - Santiago, Anthony

AU - Hu, Shu-Ching

AU - Isaacson, Stuart

AU - Corvol, Jean Christophe

AU - Martinez, Javiar Ruiz

AU - Tolosa, Eduardo

AU - Tai, Yen

AU - Politis, Marios

AU - Smejdir, Debra

AU - Rees, Linda

AU - Williams, Karen

AU - Kausar, Farah

AU - Williams, Karen

AU - Richardson, Whitney

AU - Willeke, Diana

AU - Peacock, Shawnees

AU - Sommerfeld, Barbara

AU - Freed, Alison

AU - Wakeman, Katrina

AU - Blair, Courtney

AU - Guthrie, Stephanie

AU - Harrell, Leigh

AU - Hunter, Christine

AU - Thomas, Cathi-Ann

AU - James, Raymond

AU - Zimmerman, Grace

AU - Brown, Victoria

AU - Mule, Jennifer

AU - Hilt, Ella

AU - Ribb, Kori

AU - Ainscough, Susan

AU - Wethington, Misty

AU - Ranola, Madelaine

AU - Santana, Helen Mejia

AU - Moreno, Juliana

AU - Raymond, Deborah

AU - Speketer, Krista

AU - Carvajal, Lisbeth

AU - Carvalo, Stephanie

AU - Croitoru, Ioana

AU - Garrido, Alicia

AU - Payne, Laura Marie

AU - Viswanth, Veena

AU - Severt, Lawrence

AU - Facheris, Maurizio

AU - Soares, Holly

AU - Mintun, Mark A.

AU - Cedarbaum, Jesse

AU - Taylor, Peggy

AU - Biglan, Kevin

AU - Vandenbroucke, Emily

AU - Sheikh, Zulfiqar Haider

AU - Bingol, Baris

AU - Fischer, Tanya

AU - Sardi, Pablo

AU - Forrat, Remi

AU - Reith, Alastair

AU - Egebjerg, Jan

AU - Hillert, Gabrielle Ahlberg

AU - Saba, Barbara

AU - Min, Chris

AU - Umek, Robert

AU - Mather, Joe

AU - De Santi, Susan

AU - Post, Anke

AU - Boess, Frank

AU - Taylor, Kirsten

AU - Grachev, Igor

AU - Avbersek, Andreja

AU - Muglia, Pierandrea

AU - Tauscher, Johannes

N1 - Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2022/10/22

Y1 - 2022/10/22

N2 - 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.

AB - 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.

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DO - 10.1038/s41531-022-00404-w

M3 - Article

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JO - npj Parkinson's Disease

JF - npj Parkinson's Disease

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M1 - 140

ER -

Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort

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