DaT-SPECT assessment depicts dopamine depletion among asymptomatic G2019S LRRK2 mutation carriers

Abstract

Identification of early changes in Dopamine-Transporter (DaT) SPECT imaging expected in the prodromal phase of Parkinson's disease (PD), are usually overlooked. Carriers of the G2019S LRRK2 mutation are known to be at high risk for developing PD, compared to non-carriers. In this work we aimed to study early changes in Dopamine uptake in non-manifesting PD carriers (NMC) of the G2019S LRRK2 mutation using quantitative DaT-SPECT analysis and to examine the potential for early prediction of PD. Eighty Ashkenazi-Jewish subjects were included in this study: eighteen patients with PD; thirty-one NMC and thirty-one non-manifesting non-carriers (NMNC). All subjects underwent a through clinical assessment including evaluation of motor, olfactory, affective and non-motor symptoms and DaT-SPECT imaging. A population based DaT-SPECT template was created based on the NMNC cohort, and data driven volumes-of-interest (VOIs) were defined. Comparisons between groups were performed based on VOIs and voxel-wise analysis. The striatum area of all three cohorts was segmented into four VOIs, corresponding to the right/left dorsal and ventral striatum. Significant differences in clinical measures were found between patients with PD and non-manifesting subjects with no differences between NMC and NMNC. Significantly lower uptake (p<0.001) was detected in the right and left dorsal striatum in the PD group (2.2±0.3, 2.3±0.4) compared to the NMC (4.2±0.6, 4.3±0.5) and NMNC (4.5±0.6, 4.6±0.6), and significantly (p = 0.05) lower uptake in the right dorsal striatum in the NMC group compared to NMNC. Converging results were obtained using voxel-wise analysis. Two NMC participants, who later phenoconverted into PD, demonstrated reduced uptake mainly in the dorsal striatum. No significant correlations were found between the DaT-SPECT uptake in the different VOIs and clinical and behavioral assessments in the non-manifesting groups. This study shows the clinical value of quantitative assessment of DaT-SPECT imaging and the potential for predicting PD by detection of dopamine depletion, already at the pre-symptomatic stage. Clinical registration numbers: NCT01089270 and NCT01089283.

Fig 1. Population based template.

(A) Population based template obtained from non-manifesting non carriers of the LRRK2 mutations (n = 31) group. (B) The defined striatum area. (C) The four defined VOIs: ventral and dorsal striatum in the right and left hemispheres, following k-means segmentation of the DaT-SPECT images of the three groups.

Fig 2. Differences in DaT-SPECT uptake between groups within VOIs.

Mean standardized DaT-SPECT values obtained in the striatum VOIs in the three groups. NMNC = non-manifesting non-carriers of LRRK2 mutations, NMC = non-manifesting LRRK2 mutations carriers; (*significant group differences, p<0.05, corrected for age and for multiple comparisons).

Fig 3. Differences in DaT-SPECT uptake between groups -voxel-wise analysis.

NMNC> NMC (A), NMNC>PD (B), NMC>PD (C); NMNC = non-carriers of LRRK2 mutations, NMC = non-manifesting LRRK2 mutations carriers.

Fig 4. Scatter plots of DaT-SPECT uptake.

Scatter plot of the striatum VOI's; Mean standardized values of DaT-SPECT uptake versus age. NMNC = non-manifesting LRRK2 mutation carriers (blue triangle); NMC = non manifesting non-carriers of LRRK2 mutation (green triangle); PD = Parkinson patients (black square). NMC who converted to PD patients are marked with red triangles.