Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies.
People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes.



We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinson's disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage (18F-6-fluoro-L-dopa;18F-FDOPA). We compared findings with those in people with sporadic Parkinson's disease and age-matched healthy controls. In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parkinson's disease, and age-matched healthy controls seen from November, 2012, to May, 2016, were studied with tracers for the serotonin transporter and vesicular monoamine transporter 2 (VMAT2). Striatal dopamine transporter binding, VMAT2 binding,18F-FDOPA uptake, and serotonin transporter binding in multiple brain regions were compared by ANCOVA, adjusted for age.



Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinson's disease, and 35 healthy controls. We identified significant group differences in striatal dopamine transporter binding (all age ranges in caudate and putamen, p<0·0001) and18F-FDOPA uptake (in caudate: age ≤50 years, p=0·0002; all other age ranges, p<0·0001; in putamen: all age ranges, p<0·0001). LRRK2 mutation carriers with manifest Parkinson's disease (n=15) had reduced striatal dopamine transporter binding and18F-FDOPA uptake, comparable with amounts seen in individuals with sporadic Parkinson's disease of similar duration. LRRK2 mutation carriers without manifest Parkinson's disease (n=25) had greater18F-FDOPA uptake and dopamine transporter binding than did individuals with sporadic Parkinson's disease, with18F-FDOPA uptake comparable with controls and dopamine transporter binding lower than in controls. Between November, 2012, and May, 2016, we obtained data for our second study from 16 LRRK2 mutation carriers, 13 individuals with sporadic Parkinson's disease, and nine healthy controls. Nine LRRK2 mutation carriers without manifest Parkinson's disease had significantly elevated serotonin transporter binding in the hypothalamus (compared with controls, individuals with LRRK2 Parkinson's disease, and people with sporadic Parkinson's disease, p<0·0001), striatum (compared with people with sporadic Parkinson's disease, p=0·02), and brainstem (compared with LRRK2 mutation carriers with manifest Parkinson's disease, p=0·01), after adjustment for age. Serotonin transporter binding in the cortex did not differ significantly between groups after age adjustment. Striatal VMAT2 binding was reduced in all individuals with manifest Parkinson's disease and reduced asymmetrically in one LRRK2 mutation carrier without manifest disease.



Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinson's disease and individuals with sporadic Parkinson's disease, but LRRK2 mutation carriers without manifest Parkinson's disease show increased serotonin transporter binding in the striatum, brainstem, and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of Parkinson's disease. Increased serotonergic innervation might contribute to clinical differences in LRRK2 Parkinson's disease, including the emergence of non-motor symptoms and, potentially, differences in the long-term response to levodopa.



Canada Research Chairs, Michael J Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinson's Research Institute, National Research Council of Canada.
University of British Columbia, Department of Medicine, Vancouver, BC, Canada. Electronic address: dwile@mail.ubc.ca.
Daryl J
DJ
Wile
Global Hospitals, Mumbai, India.
Pankaj A
PA
Agarwal
Department of Statistics, Vancouver, BC, Canada.
Michael
M
Schulzer
Pacific Parkinson's Research Centre, Vancouver, BC, Canada.
Edwin
E
Mak
Department of Physics and Astronomy, Vancouver, BC, Canada.
Katherine
K
Dinelle
Department of Physics and Astronomy, Vancouver, BC, Canada.
Elham
E
Shahinfard
Department of Physics and Astronomy, Vancouver, BC, Canada.
Nasim
N
Vafai
Sagamihara National Hospital, Sagamihara, Japan.
Kazuko
K
Hasegawa
Veterans Affairs Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, WA, USA.
Jing
J
Zhang
Pacific Parkinson's Research Centre, Vancouver, BC, Canada.
Jessamyn
J
McKenzie
Pacific Parkinson's Research Centre, Vancouver, BC, Canada.
Nicole
N
Neilson
Mayo Clinic, Jacksonville, FL, USA.
Audrey
A
Strongosky
Mayo Clinic, Jacksonville, FL, USA.
Ryan J
RJ
Uitti
Centre for Movement Disorders, Toronto, ON, Canada.
Mark
M
Guttman
Veterans Affairs Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, WA, USA.
Cyrus P
CP
Zabetian
New York University School of Medicine, New York, NY, USA.
Yu-Shin
YS
Ding
TRIUMF, Vancouver, BC, Canada.
Mike
M
Adam
Norwegian University of Science and Technology, Trondheim, Norway.
Jan
J
Aasly
Mayo Clinic, Jacksonville, FL, USA.
Zbigniew K
ZK
Wszolek
Department of Medical Genetics, Vancouver, BC, Canada.
Matthew
M
Farrer
Department of Physics and Astronomy, Vancouver, BC, Canada.
Vesna
V
Sossi
University of British Columbia, Department of Medicine, Vancouver, BC, Canada; Pacific Parkinson's Research Centre, Vancouver, BC, Canada.
A Jon
AJ
Stoessl
D000328:Adult; D000368:Aged; D001921:Brain / Q000378:metabolism; D003430:Cross-Sectional Studies; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005260:Female; D006579:Heterozygote; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2