PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation

Abstract

Parkinson's disease may arise from multiple aetiologies, including genetic mutations that are for the most part uncommon. We describe here the positron emission tomography (PET) findings in clinically affected and asymptomatic, high-risk members of two autosomal dominantly inherited Parkinson's disease kindreds with recently described mutations at the PARK8 locus, in a novel gene encoding a leucine-rich repeat kinase (LRRK2). Affected family members have L-dopa-responsive parkinsonism with loss of dopaminergic nigral neurons and pleomorphic subcellular pathology. Fifteen family members underwent PET using: 18F-6-fluoro-L-dopa (18F-dopa) to assess dopamine (DA) synthesis and storage, 11C-(+/-)-dihydrotetrabenazine (11C-DTBZ) for the vesicular monoamine transporter, and 11C-d-threo-methylphenidate (11C-MP) for the membrane dopamine transporter (DAT). Measurements were compared with normal (n = 33) and sporadic Parkinson's disease (sPD) (n = 67) control groups. Four clinically affected members had findings similar to sPD, with impaired presynaptic DA function affecting the putamen more than the caudate. In two affected members, D2 dopamine receptor binding was intact. Two asymptomatic mutation carriers had abnormal DAT binding with another two developing such abnormalities over 4 years of follow-up. In these individuals, 18F-dopa uptake remained normal, although two of them also displayed abnormal 11C-DTBZ binding. Our study demonstrates that the in vivo neurochemical phenotype of LRRK2 mutations is indistinguishable from that of sPD, despite the pathological heterogeneity of the condition. Furthermore, we suggest that compensatory changes including downregulation of the DAT and upregulation of decarboxylase activity may delay the onset of parkinsonian symptoms.

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

“…Although most monogenic mutations account for only a very small proportion of the PD population, the mutation of specific genes like LRRK2 may be associated with as much as 30% of PD patients in some populations like Ashkenazi Jews (Ozelius et al, 2006;Saunders-Pullman et al, 2006;Cookson, 2010;Dachsel and Farrer, 2010). Some imaging studies have demonstrated abnormal dopaminergic function in the striatum in small groups of patients with LRRK2 or other Park gene mutations (Khan et al, 2002;Adams et al, 2005). Various large-scale consortium efforts are currently underway to characterize the status of striatal dopamine imaging in larger cohorts of LRRK2 family relatives (Healy et al, 2008;Cookson, 2010;Dachsel and Farrer, 2010).…”

Neuroimaging in Parkinson's Disease

“…FD PET has also demonstrated abnormalities in asymptomatic twins [95]. In the case of dominantly inherited PD, PET abnormalities have been identified in asymptomatic family members and, by reassigning phenotype, can assist in the identification of the mutation [96,97].…”

Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity

“…Most PARK8-linked families described to date exhibit a clinical and in vivo neurochemical phenotype indistinguishable from that of sporadic PD (9). In contrast, pathological heterogeneity in affected individuals examined so far ranges from pure nigral degeneration without Lewy bodies to nigral degeneration associated with Lewy bodies typical of PD, widespread Lewy bodies consistent with diffuse Lewy body disease, or neurofibrillary -positive tangles (2,10).…”