From Mouse Models to Patients: Development of a Novel 18f-Dtbz Pet Imaging as a Biomarker to Monitor Neurodegeneration of Park6 and Park8 Parkinsonism

Background Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the elderly population. Current therapies of PD are symptomatic and based on a dopamine replacement strategy. A disease-modifying therapy in PD is the most important unmet issue in the management of PD. To conduct a successful study of disease-modifying therapy in PD has several requirements: An ideal animal model of PD that can recapitulate most features of sporadic PD with relentlessly progressive course and a preferential loss of dopamine (DA) neurons within the substantia nigra (SN); Recruitment of patients that have identical underlying genetic or environmental causes of PD. The clinical progression rate of PD is highly variable and unpredictable. The different etiology of patients and unsatisfactory diagnostic accuracy may contribute to the heterogeneity of patients. Thus, an objective biomarker is critical for improving the diagnostic accuracy of PD, as well as for monitoring neurodegeneration of disease. Functional imaging is a useful tool to detect dopaminergic denervation. Vesicular monoamine transporter 2 (VMAT2), located on the vesicular membrane, allows the packaging of terminal dopamine into synaptic vesicles. The VMAT2 density is linearly related to the integrity of SN dopamine neurons. The VMAT2 availability is not subject to 18 drug- or lesion-compensatory regulation. F-9-fluoropropyl-(+)- dihydrotetrabenzazine (18F-DTBZ) is a novel VMAT2 ligand. Our preliminary data showed that the binding potential of 18F-DTBZ significantly correlated with the clinical severity of PD. 18F-DTBZ PET is a potential tool to monitor degeneration of dopaminergic afferents. Mutation in the leucine-rich repeat kinase-2 (LRRK2) gene is the most frequent identified genetic cause in both sporadic and familial type 8 of PD (PARK8). (G2019S) is the most frequent identified pathogenic mutation of LRRK2 in Caucasian population, whereas polymorphic (G2385R) LRRK2 mutation is a genetic risk factor for sporadic PD patients of Chinese ethnicity. PINK1 mutation might be the second most common causative gene worldwide in autosomal recessive juvenile parkinsonism. Our previous imaging studies suggested that PARK6 and PARK8 patients may have distinct rate of neurodegeneration from idiopathic PD patients. Therefore, longitudinal studies to analyze the rate of DA degeneration of PARK6 and PARK8 patients by 18F-DTBZ PET is quite important for further neuro-modifying therapy. Prof. Wang have generated two successful mouse models of PARK8: transgenic mouse expressing (G2019S) LRRK2, and chronic MPTP intoxication in transgenic mouse expression (G2385R) LRRK2 (combination of genetic risk factor and environmental factor). G2019S/+ The better and clinically more relevant animal models, humanized LRRK2 or t ddyoY1699C/+u + 彳 彳• • 1 T G308D/G308D i L346P/L346P LRRK2 heterozygous knockin mice and PINK1 or PINK1 homozygous mice, will be generated (subproject 1 and 2). The data and experiences from animal studies will be helpful to interpret the results of human study. Objectives To access the utility of 18F-DTBZ PET imaging as an in vi^vo biomarker to monitor neurodegeneration of both PD mouse models PD patients, and to analyze progression rate of genetic-proving PARK8 and PARK6 patients who have homogeneous phenotype and genotype by 18F-DTBZ PET imaging. Materials and Methods: Study duration is expected to be completed in a period of 3 year. Animal study: 18F-DTBZ microPET scan will be performed at age of 8-, 12-, and 16-month in the (G2019S) LRRK2 transgenic mice, LRRK2G2019S/+or LRRK2Y1699C/+ heterozygous knockin mice, PINK 1G308D/G308D or PINK1L346P/L346P homozygous mice, and wild-type control mice. In (G2385R) LRRK2 transgenic mice and wild-type FVB/N mice, the microPET imaging will be done before after complete of MPTP treatment. The brain uptake and distribution of 18F-DTBZ will be analyzed and compared with the dopaminergic neuron counts by immunohistochemical staining. Human study: A total of 60 patients, 20 LRRK2 G2385R, 20 PARK6, and 20 idiopathic PD, 18 will be recruited. Subjects will be evaluated sequentially with F-DTBZ during a 36 month period. 18F-DTBZ PET scans will be performed twice, at baseline, and 24 (21〜27) months following the start of their participation in the study. Subjects will receive a single i.v. 18 administration of approximately 10 mCi F-DTBZ immediately prior to imaging. Whitney test will be used to compare the mean standard uptake value ratio (SUVR) values between groups. The decline rate of VMAT2 density will be calculated by comparing the SUVRs of age-matched healthy subjects from our previous studies.

Project ID:PC10009-0046
External Project ID:NSC100-2321-B182-012