Spatiotemporal patterns of putaminal dopamine processing in Parkinson's disease: A multi-tracer positron emission tomography study

Abstract

Alterations in different aspects of dopamine processing may exhibit different progressive behaviours throughout the course of Parkinson's disease. We used a novel data-driven multivariate approach to quantify and compare spatiotemporal patterns related to different aspects of dopamine processing from cross-sectional Parkinson's subjects obtained with: 1) 69 [¹¹C]±dihydrotetrabenazine (DTBZ) scans, most closely related to dopaminergic denervation; 2) 73 [¹¹C]d-threo-methylphenidate (MP) scans, marker of dopamine transporter density; 3) 50 6-[¹⁸F]fluoro-l-DOPA (FD) scans, marker of dopamine synthesis and storage. The anterior-posterior gradient in the putamen was identified as the most salient feature associated with disease progression, however the temporal progression of the spatial gradient was different for the three tracers. The expression of the anterior-posterior gradient was the highest for FD at disease onset compared to that of DTBZ and MP (P = 0.018 and P = 0.047 respectively), but decreased faster (P = 0.006) compared to that of DTBZ. The gradient expression for MP was initially similar but decreased faster (P = 0.015) compared to that for DTBZ. These results reflected unique temporal behaviours of regulatory mechanisms related to dopamine synthesis (FD) and reuptake (MP). While the relative early disease upregulation of dopamine synthesis in the anterior putamen prevalent likely extends to approximately 10 years after symptom onset, the presumed downregulation of dopamine transporter density may play a compensatory role in the prodromal/earliest disease stages only.

Keywords: Multivariate analysis; PET; Parkinson’s disease; Spatiotemporal patterns; Striatal dopamine processing.

Fig. 1

Schematic diagram of the dynamic mode decomposition (DMD) approach. DTBZ = dihydrotetrabenazine. FD = fluoro-l-DOPA. MP = d-threo-methylphenidate. PET = positron emission tomography.

Fig. 2

Standardized PET values for DTBZ, MP and FD in the less and more affected anterior and posterior putamen in early disease (disease duration less than 5 years). The standardized PET values were derived as the tracer binding values (BP_ND for DTBZ and MP and K_occ for FD) normalized by the age-matched normal values. One-way analysis of variance was used to examine the differences between tracers. * = P-value < 0.05. ** = P-value < 0.01. *** = P-value < 0.001. DTBZ = dihydrotetrabenazine. FD = fluoro-l-DOPA. MP = d-threo-methylphenidate. PET = positron emission tomography.

Fig. 3

Dynamic mode decomposition (DMD) modes/spatial patterns (z-transformed) in the less and more affected putamen for (A) DTBZ, (B) MP and (C) FD. DTBZ = dihydrotetrabenazine. FD = fluoro-l-DOPA. MP = d-threo-methylphenidate. DV = dorsal–ventral. ML = Medial-lateral. AP = anterior-posterior.

Fig. 4

Dynamic mode decomposition (DMD) temporal progression (unitless) curves for DTBZ, MP and FD, associated with the anterior-posterior gradient in the putamen (DMD modes shown in Fig. 3). Error bars of the temporal progression curves were obtained using cross-validation. DTBZ = dihydrotetrabenazine. FD = fluoro-l-DOPA. MP = d-threo-methylphenidate.