Longitudinal measurement of synaptic density to monitor progression of Parkinson's disease and Huntington's disease

Increasing evidence from cell or animal models and postmortem human studies suggests that synaptic pathology is important in the early disease pathophysiology of Parkinson’s (PD) and Huntington’s disease (HD). PET imaging with 11C‑UCB‑J, targeting the presynaptic protein SV2A, provides an in vivo marker for synaptic density in the human brain. This thesis reports two multimodal imaging studies in people with early PD and early HD respectively, both with an age- and gender-matched healthy control group. The aim of these studies was to assess regional synaptic changes in the human brain and its clinical correlates in vivo in early PD patients and early HD mutation carriers respectively and to evaluate the suitability of 11C‑UCB‑J PET as diagnostic and/or prognostic biomarker in these groups.  

For the longitudinal PD study, 30 patients with PD and 20 healthy controls were included at baseline, and 27 PD patients and 18 controls completed all follow-up visits after approximately 2 years. At baseline and follow-up, 11C‑UCB‑J PET was combined with 18F-FE-PE2I PET, a marker for quantification of dopaminergic presynaptic terminals, and MRI. In addition, all participants underwent a comprehensive assessment of clinical motor and non-motor manifestations. Cortical and subcortical volumes of interest (VOIs) were delineated based on individual 3D MRI. VOI- and voxel-based analyses were performed. All PET image data were analyzed without and with correction for partial volume effects, and statistical analyses were corrected for multiple comparisons. At baseline, clinical characterization demonstrated that PD patients had more severe motor signs and symptoms, cognitive impairment, anxiety, sleep problems and autonomic symptoms compared to controls. Over 2 years, only motor impairment significantly worsened in PD. With 11C‑UCB‑J PET, a significant cross-sectional SV2A loss in the PD group was found in the substantia nigra only. No significant regional SV2A loss could be demonstrated over 2 years. By contrast, 18F-FE-PE2I PET confirmed a profoundly decreased striatal and nigral DAT binding in early PD compared to controls, most prominent in putamen. After 2 years, there was a further significant annual decrease in the striatum in PD, which also was significantly greater than in controls. No correlations between regional decrease in 11C‑UCB‑J or 18F-FE-PE2I binding and clinical scores were found at baseline or longitudinally.

The cross-sectional HD study cohort consisted of 18 early HD mutations carriers (7 premanifest, 11 manifest [7 Shoulson & Fahn stage 1 and 4 stage 2]) and 15 healthy controls. The longitudinal study is still ongoing. SV2A PET was combined with 18F‑FDG PET, given the suspected link between synaptic activity and brain glucose metabolism, and MRI. Motor and non-motor functioning was also assessed in all study participants. Similar to the PD study, cortical and subcortical volumes of interest (VOIs) were delineated based on individual 3D MRI. VOI- and voxel-based analyses were performed. All PET image data were analyzed without and with correction for partial volume effects, and statistical analyses were corrected for age, gender and multiple comparisons. Compared to controls, HD mutation carriers had significantly higher motor scores and more cognitive impairment. 18F‑FDG PET showed regional hypometabolism limited to the striatum in the HD group, whilst 11C‑UCB‑J PET imaging demonstrated widespread loss of presynaptic terminals in striatum, cerebral cortex and cerebellum. A subgroup analysis indicated that SV2A loss was limited to the striatum in premanifest HD, but was much more widespread with also cortical involvement in manifest HD. In the HD group, putaminal SV2A loss was correlated with motor signs.

In conclusion, this thesis provides new insights into synaptic alterations in people with early PD and early HD in vivo. In early PD, 18F‑FE‑PE2I PET provides a robust biomarker for cross-sectional and longitudinal nigrostriatal dopaminergic terminal loss in vivo in early PD, but does not provide a quantitative surrogate endpoint for clinical impairment or progression. 11C‑UCB‑J PET showed cross-sectional loss of SV2A in substantia nigra in early PD, but no longitudinal changes nor correlations with clinical symptoms were found. Therefore, 11C‑UCB‑J binding does not seem suitable as a diagnostic or prognostic biomarker in early PD. In early HD, SV2A loss extends from the striatum in premanifest HD to widespread cortical and subcortical loss in the manifest phase, while glucose hypometabolism is limited to the striatum in both premanifest and manifest HD. Furthermore, motor symptoms correlated inversely with putaminal 11C‑UCB‑J binding. Taken together, SV2A availability as measured by PET could be a promising diagnostic or monitoring imaging biomarker in people with early HD. A longitudinal 2-year follow-up study is ongoing.