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Progression of dopaminergic dysfunction in a LRRK2 kindred

A multitracer PET study

From the Pacific Parkinson’s Research Centre (R.N., E.M., M.S., J.M., S.M., V.S., A.J.S.), Vancouver; Department of Physics & Astronomy (V.S.), University of British Columbia, Vancouver; TRIUMF (T.J.R.), Vancouver, BC, Canada; and Departments of Neurology and Neuroscience (A.S., M.J.F., Z.K.W.), Mayo Clinic, Jacksonville, FL.

Address correspondence and reprint requests to Dr. A. Jon Stoessl, Pacific Parkinson’s Research Centre, University of British Columbia, Vancouver Hospital and Health Sciences Centre, Purdy Pavilion, 2221 Wesbrook Mall, Vancouver, BC, Canada V6T2B5 jstoessl{at}interchange.ubc.ca

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.

Method: 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.

Conclusion: 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.

GLOSSARY: DAT = dopamine transporter; DTBZ = ¹¹C-(±)--dihydrotetrabenazine; FD = ¹⁸F-6-fluoro-l-dopa; MP = ¹¹C-d-threo-methylphenidate; PD = Parkinson disease; ROI = region of interest; sPD = sporadic PD.

Disclosure: M.J.F. and Z.K.W. have a patent, "Identification of Mutations in PARK8, a Locus for Familial Parkinson’s Disease," Mayo Clinic case #2004-185, that has been licensed to a commercial entity. No royalties have accrued to M.J.F. or Z.K.W.; however, Mayo Clinic has received royalties of greater than $10,000, the federal threshold for significant financial interest, from the licensing of this technology. The other authors report no conflict of interest.

Received April 21, 2008. Accepted in final form August 25, 2008.