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 - a cross-sectional study
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
C2 - 31678032
AN - SCOPUS:85076005468
VL - 19
SP - 71
EP - 80
JO - Lancet Neurology
JF - Lancet Neurology
SN - 1474-4422
IS - 1
ER -