Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI): a cross-sectional study

Tanya Simuni, Liz Uribe, Hyunkeun Ryan Cho, Chelsea Caspell-Garcia, Christopher S. Coffey, Andrew Siderowf, John Q. Trojanowski, Leslie M. Shaw, John Seibyl, Andrew Singleton, Arthur W. Toga, Doug Galasko, Tatiana Foroud, Duygu Tosun, Kathleen Poston, Daniel Weintraub, Brit Mollenhauer, Caroline M. Tanner, Karl Kieburtz, Lana M. Chahine & 113 others Alyssa Reimer, Samantha J. Hutten, Susan Bressman, Kenneth Marek, PPMI Investigators, Vanessa Arnedo, Adrienne Clark, Mark Fraiser, Catherine Kopil, Sohini Chowdhury, Todd Sherer, Nichole Daegele, Cynthia Casaceli, Ray Dorsey, Renee Wilson, Sugi Mahes, Christina Salerno, Karen Crawford, Paola Casalin, Giulia Malferrari, Mali Gani Weisz, Avi Orr-Urtreger, Thomas Montine, Chris Baglieri, Amanda Christini, Nabila Dahodwala, Nir Giladi, Stewart Factor, Penelope Hogarth, David Standaert, Robert Hauser, Joseph Jankovic, Marie Saint-Hilaire, Irene Richard, David Shprecher, Hubert Fernandez, Katrina Brockmann, Liana Rosenthal, Paolo Barone, Alberto Espay, Dominic Rowe, Karen Marder, Anthony Santiago, Shu Ching Hu, Stuart Isaacson, Jean Christophe Corvol, Javiar Ruiz Martinez, Eduardo Tolosa, Yen Tai, Marios Politis, Debra Smejdir, Linda Rees, Karen Williams, Farah Kausar, Whitney Richardson, Diana Willeke, Shawnees Peacock, Barbara Sommerfeld, Alison Freed, Katrina Wakeman, Courtney Blair, Stephanie Guthrie, Leigh Harrell, Christine Hunter, Cathi Ann Thomas, Raymond James, Grace Zimmerman, Victoria Brown, Jennifer Mule, Ella Hilt, Kori Ribb, Susan Ainscough, Misty Wethington, Madelaine Ranola, Helen Mejia Santana, Juliana Moreno, Deborah Raymond, Krista Speketer, Lisbeth Carvajal, Stephanie Carvalo, Ioana Croitoru, Alicia Garrido, Laura Marie Payne, Veena Viswanth, Lawrence Severt, Maurizio Facheris, Holly Soares, Mark A. Mintun, Jesse Cedarbaum, Peggy Taylor, Kevin Biglan, Emily Vandenbroucke, Zulfiqar Haider Sheikh, Baris Bingol, Tanya Fischer, Pablo Sardi, Remi Forrat, Alastair Reith, Jan Egebjerg, Gabrielle Ahlberg Hillert, Barbara Saba, Chris Min, Robert Umek, Joe Mather, Susan De Santi, Anke Post, Frank Boess, Kirsten Taylor, Igor Grachev, Andreja Avbersek, Pierandrea Muglia, Kaplana Merchant, Johannes Tauscher

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: The Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding. Methods: This cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, χ2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023. Findings: Between Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p<0·0001 for both comparisons) and the Scale for Outcomes for PD – autonomic function (5·8 [3·7] vs 8·1 [5·9] and 8·4 [6·0], p<0·0001 for both comparisons). There was no difference in daytime sleepiness, anxiety, depression, impulsive–compulsive disorders, blood pressure, urate, and rapid eye movement (REM) behaviour disorder scores. Hyposmia was significantly more common only in LRRK2 non-manifesting carriers (69 [36%] of 194 healthy controls vs 114 [55%] of 208 LRRK2 non-manifesting carriers; p=0·0003). Finally, GBA but not LRRK2 non-manifesting carriers showed increased DAT striatal binding ratios compared with healthy controls in the caudate (healthy controls 2·98 [SD 0·63] vs GBA 3·26 [0·63]; p<0·0001), putamen (2·15 [0·56] vs 2·48 [0·52]; p<0·0001), and striatum (2·56 [0·57] vs 2·87 [0·55]; p<0·0001). Interpretation: Our data show evidence of subtle motor and non-motor signs of Parkinson's disease in non-manifesting carriers compared with healthy controls that can precede DAT deficit. Longitudinal data will be essential to confirm these findings and define the trajectory and predictors for development of Parkinson's disease. Funding: Michael J Fox Foundation for Parkinson's Research.

LanguageEnglish
Pages71-80
Number of pages10
JournalThe Lancet Neurology
Volume19
Issue number1
DOIs
Publication statusPublished - 1 Jan 2020

Fingerprint

Dopamine Plasma Membrane Transport Proteins
Parkinson Disease
Cross-Sectional Studies
Mutation
Corpus Striatum
Putamen
Ocular Motility Disorders
REM Sleep
Movement Disorders
Uric Acid
Mental Disorders
Longitudinal Studies
Disease Progression
Cohort Studies
Anxiety
Biomarkers
Demography
Depression
Blood Pressure

Cite this

Simuni, Tanya ; Uribe, Liz ; Cho, Hyunkeun Ryan ; Caspell-Garcia, Chelsea ; Coffey, Christopher S. ; Siderowf, Andrew ; Trojanowski, John Q. ; Shaw, Leslie M. ; Seibyl, John ; Singleton, Andrew ; Toga, Arthur W. ; Galasko, Doug ; Foroud, Tatiana ; Tosun, Duygu ; Poston, Kathleen ; Weintraub, Daniel ; Mollenhauer, Brit ; Tanner, Caroline M. ; Kieburtz, Karl ; Chahine, Lana M. ; Reimer, Alyssa ; Hutten, Samantha J. ; Bressman, Susan ; Marek, Kenneth ; PPMI Investigators. / Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI) : a cross-sectional study. In: The Lancet Neurology. 2020 ; Vol. 19, No. 1. pp. 71-80.
@article{f0f2a5a6dab24ebbb3609a3f8104272d,
title = "Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI): a cross-sectional study",
abstract = "Background: The Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding. Methods: This cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65{\%} of putamen striatal binding ratio expected for the individual's age. We used t tests, χ2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023. Findings: Between Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93{\%} G2019S) and 184 GBA (96{\%} N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60{\%} were female. Of the 286 (73{\%}) non-manifesting carriers that had DAT imaging results, 18 (11{\%}) LRRK2 and four (3{\%}) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p<0·0001 for both comparisons) and the Scale for Outcomes for PD – autonomic function (5·8 [3·7] vs 8·1 [5·9] and 8·4 [6·0], p<0·0001 for both comparisons). There was no difference in daytime sleepiness, anxiety, depression, impulsive–compulsive disorders, blood pressure, urate, and rapid eye movement (REM) behaviour disorder scores. Hyposmia was significantly more common only in LRRK2 non-manifesting carriers (69 [36{\%}] of 194 healthy controls vs 114 [55{\%}] of 208 LRRK2 non-manifesting carriers; p=0·0003). Finally, GBA but not LRRK2 non-manifesting carriers showed increased DAT striatal binding ratios compared with healthy controls in the caudate (healthy controls 2·98 [SD 0·63] vs GBA 3·26 [0·63]; p<0·0001), putamen (2·15 [0·56] vs 2·48 [0·52]; p<0·0001), and striatum (2·56 [0·57] vs 2·87 [0·55]; p<0·0001). Interpretation: Our data show evidence of subtle motor and non-motor signs of Parkinson's disease in non-manifesting carriers compared with healthy controls that can precede DAT deficit. Longitudinal data will be essential to confirm these findings and define the trajectory and predictors for development of Parkinson's disease. Funding: Michael J Fox Foundation for Parkinson's Research.",
author = "Tanya Simuni and Liz Uribe and Cho, {Hyunkeun Ryan} and Chelsea Caspell-Garcia and Coffey, {Christopher S.} and Andrew Siderowf and Trojanowski, {John Q.} and Shaw, {Leslie M.} and John Seibyl and Andrew Singleton and Toga, {Arthur W.} and Doug Galasko and Tatiana Foroud and Duygu Tosun and Kathleen Poston and Daniel Weintraub and Brit Mollenhauer and Tanner, {Caroline M.} and Karl Kieburtz and Chahine, {Lana M.} and Alyssa Reimer and Hutten, {Samantha J.} and Susan Bressman and Kenneth Marek and {PPMI Investigators} and Vanessa Arnedo and Adrienne Clark and Mark Fraiser and Catherine Kopil and Sohini Chowdhury and Todd Sherer and Nichole Daegele and Cynthia Casaceli and Ray Dorsey and Renee Wilson and Sugi Mahes and Christina Salerno and Karen Crawford and Paola Casalin and Giulia Malferrari and Weisz, {Mali Gani} and Avi Orr-Urtreger and Thomas Montine and Chris Baglieri and Amanda Christini and Nabila Dahodwala and Nir Giladi and Stewart Factor and Penelope Hogarth and David Standaert and Robert Hauser and Joseph Jankovic and Marie Saint-Hilaire and Irene Richard and David Shprecher and Hubert Fernandez and Katrina Brockmann and Liana Rosenthal and Paolo Barone and Alberto Espay and Dominic Rowe and Karen Marder and Anthony Santiago and Hu, {Shu Ching} and Stuart Isaacson and Corvol, {Jean Christophe} and {Ruiz Martinez}, Javiar and Eduardo Tolosa and Yen Tai and Marios Politis and Debra Smejdir and Linda Rees and Karen Williams and Farah Kausar and Whitney Richardson and Diana Willeke and Shawnees Peacock and Barbara Sommerfeld and Alison Freed and Katrina Wakeman and Courtney Blair and Stephanie Guthrie and Leigh Harrell and Christine Hunter and Thomas, {Cathi Ann} and Raymond James and Grace Zimmerman and Victoria Brown and Jennifer Mule and Ella Hilt and Kori Ribb and Susan Ainscough and Misty Wethington and Madelaine Ranola and {Mejia Santana}, Helen and Juliana Moreno and Deborah Raymond and Krista Speketer and Lisbeth Carvajal and Stephanie Carvalo and Ioana Croitoru and Alicia Garrido and Payne, {Laura Marie} and Veena Viswanth and Lawrence Severt and Maurizio Facheris and Holly Soares and Mintun, {Mark A.} and Jesse Cedarbaum and Peggy Taylor and Kevin Biglan and Emily Vandenbroucke and {Haider Sheikh}, Zulfiqar and Baris Bingol and Tanya Fischer and Pablo Sardi and Remi Forrat and Alastair Reith and Jan Egebjerg and {Ahlberg Hillert}, Gabrielle and Barbara Saba and Chris Min and Robert Umek and Joe Mather and {De Santi}, Susan and Anke Post and Frank Boess and Kirsten Taylor and Igor Grachev and Andreja Avbersek and Pierandrea Muglia and Kaplana Merchant and Johannes Tauscher",
year = "2020",
month = "1",
day = "1",
doi = "10.1016/S1474-4422(19)30319-9",
language = "English",
volume = "19",
pages = "71--80",
journal = "Lancet Neurology",
issn = "1474-4422",
publisher = "Lancet Publishing Group",
number = "1",

}

Simuni, T, Uribe, L, Cho, HR, Caspell-Garcia, C, Coffey, CS, Siderowf, A, Trojanowski, JQ, Shaw, LM, Seibyl, J, Singleton, A, Toga, AW, Galasko, D, Foroud, T, Tosun, D, Poston, K, Weintraub, D, Mollenhauer, B, Tanner, CM, Kieburtz, K, Chahine, LM, Reimer, A, Hutten, SJ, Bressman, S, Marek, K & PPMI Investigators 2020, 'Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI): a cross-sectional study', The Lancet Neurology, vol. 19, no. 1, pp. 71-80. https://doi.org/10.1016/S1474-4422(19)30319-9

Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI) : a cross-sectional study. / Simuni, Tanya; Uribe, Liz; Cho, Hyunkeun Ryan; Caspell-Garcia, Chelsea; Coffey, Christopher S.; Siderowf, Andrew; Trojanowski, John Q.; Shaw, Leslie M.; Seibyl, John; Singleton, Andrew; Toga, Arthur W.; Galasko, Doug; Foroud, Tatiana; Tosun, Duygu; Poston, Kathleen; Weintraub, Daniel; Mollenhauer, Brit; Tanner, Caroline M.; Kieburtz, Karl; Chahine, Lana M.; Reimer, Alyssa; Hutten, Samantha J.; Bressman, Susan; Marek, Kenneth; PPMI Investigators.

In: The Lancet Neurology, Vol. 19, No. 1, 01.01.2020, p. 71-80.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI)

T2 - Lancet Neurology

AU - Simuni, Tanya

AU - Uribe, Liz

AU - Cho, Hyunkeun Ryan

AU - Caspell-Garcia, Chelsea

AU - Coffey, Christopher S.

AU - Siderowf, Andrew

AU - Trojanowski, John Q.

AU - Shaw, Leslie M.

AU - Seibyl, John

AU - Singleton, Andrew

AU - Toga, Arthur W.

AU - Galasko, Doug

AU - Foroud, Tatiana

AU - Tosun, Duygu

AU - Poston, Kathleen

AU - Weintraub, Daniel

AU - Mollenhauer, Brit

AU - Tanner, Caroline M.

AU - Kieburtz, Karl

AU - Chahine, Lana M.

AU - Reimer, Alyssa

AU - Hutten, Samantha J.

AU - Bressman, Susan

AU - Marek, Kenneth

AU - PPMI Investigators

AU - Arnedo, Vanessa

AU - Clark, Adrienne

AU - Fraiser, Mark

AU - Kopil, Catherine

AU - Chowdhury, Sohini

AU - Sherer, Todd

AU - Daegele, Nichole

AU - Casaceli, Cynthia

AU - Dorsey, Ray

AU - Wilson, Renee

AU - Mahes, Sugi

AU - Salerno, Christina

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 - 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 - Espay, Alberto

AU - Rowe, Dominic

AU - Marder, Karen

AU - Santiago, Anthony

AU - Hu, Shu Ching

AU - Isaacson, Stuart

AU - Corvol, Jean Christophe

AU - Ruiz Martinez, Javiar

AU - Tolosa, Eduardo

AU - Tai, Yen

AU - Politis, Marios

AU - Smejdir, Debra

AU - Rees, Linda

AU - Williams, Karen

AU - Kausar, Farah

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 - Mejia Santana, Helen

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 - Haider Sheikh, Zulfiqar

AU - Bingol, Baris

AU - Fischer, Tanya

AU - Sardi, Pablo

AU - Forrat, Remi

AU - Reith, Alastair

AU - Egebjerg, Jan

AU - Ahlberg Hillert, Gabrielle

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 - Merchant, Kaplana

AU - Tauscher, Johannes

PY - 2020/1/1

Y1 - 2020/1/1

N2 - Background: The Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding. Methods: This cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, χ2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023. Findings: Between Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p<0·0001 for both comparisons) and the Scale for Outcomes for PD – autonomic function (5·8 [3·7] vs 8·1 [5·9] and 8·4 [6·0], p<0·0001 for both comparisons). There was no difference in daytime sleepiness, anxiety, depression, impulsive–compulsive disorders, blood pressure, urate, and rapid eye movement (REM) behaviour disorder scores. Hyposmia was significantly more common only in LRRK2 non-manifesting carriers (69 [36%] of 194 healthy controls vs 114 [55%] of 208 LRRK2 non-manifesting carriers; p=0·0003). Finally, GBA but not LRRK2 non-manifesting carriers showed increased DAT striatal binding ratios compared with healthy controls in the caudate (healthy controls 2·98 [SD 0·63] vs GBA 3·26 [0·63]; p<0·0001), putamen (2·15 [0·56] vs 2·48 [0·52]; p<0·0001), and striatum (2·56 [0·57] vs 2·87 [0·55]; p<0·0001). Interpretation: Our data show evidence of subtle motor and non-motor signs of Parkinson's disease in non-manifesting carriers compared with healthy controls that can precede DAT deficit. Longitudinal data will be essential to confirm these findings and define the trajectory and predictors for development of Parkinson's disease. Funding: Michael J Fox Foundation for Parkinson's Research.

AB - Background: The Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding. Methods: This cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, χ2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023. Findings: Between Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p<0·0001 for both comparisons) and the Scale for Outcomes for PD – autonomic function (5·8 [3·7] vs 8·1 [5·9] and 8·4 [6·0], p<0·0001 for both comparisons). There was no difference in daytime sleepiness, anxiety, depression, impulsive–compulsive disorders, blood pressure, urate, and rapid eye movement (REM) behaviour disorder scores. Hyposmia was significantly more common only in LRRK2 non-manifesting carriers (69 [36%] of 194 healthy controls vs 114 [55%] of 208 LRRK2 non-manifesting carriers; p=0·0003). Finally, GBA but not LRRK2 non-manifesting carriers showed increased DAT striatal binding ratios compared with healthy controls in the caudate (healthy controls 2·98 [SD 0·63] vs GBA 3·26 [0·63]; p<0·0001), putamen (2·15 [0·56] vs 2·48 [0·52]; p<0·0001), and striatum (2·56 [0·57] vs 2·87 [0·55]; p<0·0001). Interpretation: Our data show evidence of subtle motor and non-motor signs of Parkinson's disease in non-manifesting carriers compared with healthy controls that can precede DAT deficit. Longitudinal data will be essential to confirm these findings and define the trajectory and predictors for development of Parkinson's disease. Funding: Michael J Fox Foundation for Parkinson's Research.

UR - http://www.scopus.com/inward/record.url?scp=85076005468&partnerID=8YFLogxK

U2 - 10.1016/S1474-4422(19)30319-9

DO - 10.1016/S1474-4422(19)30319-9

M3 - Article

VL - 19

SP - 71

EP - 80

JO - Lancet Neurology

JF - Lancet Neurology

SN - 1474-4422

IS - 1

ER -