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 - Sorbonne Université Access content directly
Journal Articles The Lancet Neurology Year : 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

Tanya Simuni (1) , Liz Uribe , Hyunkeun Ryan Cho , Chelsea Caspell-Garcia (2) , Christopher Coffey (2) , Andrew Siderowf (3) , John Trojanowski (4) , Leslie Shaw (3) , John Seibyl , Andrew Singleton (5) , Arthur Toga , Doug Galasko , Tatiana Foroud , Duygu Tosun (6, 7) , Kathleen Poston , Daniel Weintraub , Brit Mollenhauer (8) , Caroline Tanner (6, 7) , Karl Kieburtz (9) , Lana Chahine , Alyssa Reimer , Samantha Hutten , Susan Bressman , Kenneth Marek , 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 , David Russell , 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 (10) , Javiar Ruiz Martinez , Eduardo Tolosa , Yen Tai , Marios Politis , Debra Smejdir , Linda Rees , Karen Williams , Farah Kausar , Karen Williams , 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 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
Liz Uribe
  • Function : Author
Hyunkeun Ryan Cho
  • Function : Author
John Seibyl
  • Function : Author
Arthur Toga
  • Function : Author
Doug Galasko
  • Function : Author
Tatiana Foroud
  • Function : Author
Kathleen Poston
  • Function : Author
Daniel Weintraub
  • Function : Author
Lana Chahine
  • Function : Author
Alyssa Reimer
  • Function : Author
Samantha Hutten
  • Function : Author
Susan Bressman
  • Function : Author
Kenneth Marek
  • Function : Author
Vanessa Arnedo
  • Function : Author
Adrienne Clark
  • Function : Author
Mark Fraiser
  • Function : Author
Catherine Kopil
  • Function : Author
Sohini Chowdhury
  • Function : Author
Todd Sherer
  • Function : Author
Nichole Daegele
  • Function : Author
Cynthia Casaceli
  • Function : Author
Ray Dorsey
  • Function : Author
Renee Wilson
  • Function : Author
Sugi Mahes
  • Function : Author
Christina Salerno
  • Function : Author
Karen Crawford
  • Function : Author
Paola Casalin
  • Function : Author
Giulia Malferrari
  • Function : Author
Mali Gani Weisz
  • Function : Author
Avi Orr-Urtreger
  • Function : Author
Thomas Montine
  • Function : Author
Chris Baglieri
  • Function : Author
Amanda Christini
  • Function : Author
David Russell
  • Function : Author
Nabila Dahodwala
  • Function : Author
Nir Giladi
  • Function : Author
Stewart Factor
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Penelope Hogarth
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David Standaert
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Robert Hauser
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Joseph Jankovic
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Marie Saint-Hilaire
  • Function : Author
Irene Richard
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David Shprecher
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Hubert Fernandez
  • Function : Author
Katrina Brockmann
  • Function : Author
Liana Rosenthal
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Paolo Barone
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Alberto Espay
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Dominic Rowe
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Karen Marder
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Anthony Santiago
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Shu-Ching Hu
  • Function : Author
Stuart Isaacson
  • Function : Author
Javiar Ruiz Martinez
  • Function : Author
Eduardo Tolosa
  • Function : Author
Yen Tai
  • Function : Author
Marios Politis
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Debra Smejdir
  • Function : Author
Linda Rees
  • Function : Author
Karen Williams
  • Function : Author
Farah Kausar
  • Function : Author
Karen Williams
  • Function : Author
Whitney Richardson
  • Function : Author
Diana Willeke
  • Function : Author
Shawnees Peacock
  • Function : Author
Barbara Sommerfeld
  • Function : Author
Alison Freed
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Katrina Wakeman
  • Function : Author
Courtney Blair
  • Function : Author
Stephanie Guthrie
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Leigh Harrell
  • Function : Author
Christine Hunter
  • Function : Author
Cathi-Ann Thomas
  • Function : Author
Raymond James
  • Function : Author
Grace Zimmerman
  • Function : Author
Victoria Brown
  • Function : Author
Jennifer Mule
  • Function : Author
Ella Hilt
  • Function : Author
Kori Ribb
  • Function : Author
Susan Ainscough
  • Function : Author
Misty Wethington
  • Function : Author
Madelaine Ranola
  • Function : Author
Helen Mejia Santana
  • Function : Author
Juliana Moreno
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Deborah Raymond
  • Function : Author
Krista Speketer
  • Function : Author
Lisbeth Carvajal
  • Function : Author
Stephanie Carvalo
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Ioana Croitoru
  • Function : Author
Alicia Garrido
  • Function : Author
Laura Marie Payne
  • Function : Author
Veena Viswanth
  • Function : Author
Lawrence Severt
  • Function : Author
Maurizio Facheris
  • Function : Author
Holly Soares
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Mark Mintun
  • Function : Author
Jesse Cedarbaum
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Peggy Taylor
  • Function : Author
Kevin Biglan
  • Function : Author
Emily Vandenbroucke
  • Function : Author
Zulfiqar Haider Sheikh
  • Function : Author
Baris Bingol
  • Function : Author
Tanya Fischer
  • Function : Author
Pablo Sardi
  • Function : Author
Remi Forrat
  • Function : Author
Alastair Reith
  • Function : Author
Jan Egebjerg
  • Function : Author
Gabrielle Ahlberg Hillert
  • Function : Author
Barbara Saba
  • Function : Author
Chris Min
  • Function : Author
Robert Umek
  • Function : Author
Joe Mather
  • Function : Author
Susan de Santi
  • Function : Author
Anke Post
  • Function : Author
Frank Boess
  • Function : Author
Kirsten Taylor
  • Function : Author
Igor Grachev
  • Function : Author
Andreja Avbersek
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Pierandrea Muglia
  • Function : Author
Kaplana Merchant
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Johannes Tauscher
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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.

Dates and versions

hal-04578696 , version 1 (17-05-2024)

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Tanya Simuni, Liz Uribe, Hyunkeun Ryan Cho, Chelsea Caspell-Garcia, Christopher Coffey, et al.. 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, 2020, 19 (1), pp.71-80. ⟨10.1016/S1474-4422(19)30319-9⟩. ⟨hal-04578696⟩
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