Progression of dopaminergic dysfunction in a LRRK2 kindred: a multitracer PET study.
OBJECTIVE
Little is known about the progression of dopaminergic dysfunction in LRRK2-associated Parkinson disease (PD). We sought to characterize the neurochemical progression with multitracer PET in asymptomatic members of parkinsonian kindred (family D, Western Nebraska) carrying LRRK2 (R1441C) mutation.


METHODS
Thirteen family D subjects underwent PET scans of presynaptic dopaminergic integrity and five subjects were rescanned 2 to 3 years later.


RESULTS
In subjects 8, 9 (mutation carriers), and 13 (genealogically at risk subject), there was a decline in PET markers over the course of the study that was significantly greater than the expected rate of decline in healthy controls. Reduced dopamine transporter binding was the earliest indication of subclinical dopaminergic dysfunction and progression to clinical disease was generally associated with the emergence of abnormal fluorodopa uptake.


CONCLUSIONS
PET study of presymptomatic members of our LRRK2 kindred revealed dopaminergic dysfunction that progressed over time. This represents an ideal group to study the natural history of early disease and the potential effects of neuroprotective interventions.
Nandhagopal
R
R
Pacific Parkinson's Research Centre, Vancouver, BC, Canada V6T2B5.
Mak
E
E
Schulzer
M
M
McKenzie
J
J
McCormick
S
S
Sossi
V
V
Ruth
T J
TJ
Strongosky
A
A
Farrer
M J
MJ
Wszolek
Z K
ZK
Stoessl
A J
AJ
D000328:Adult; D000368:Aged; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D011237:Predictive Value of Tests; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011699:Putamen / Q000378:metabolism; D019275:Radiopharmaceuticals
D050483:Dopamine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine