Effect of Pridopidine in Huntington Disease (HD) Patients and Healthy Volunteers (HVs) – A Simultaneous Sigma-1 Receptor PET/Multimodality MRI Study

Ziel/Aim Pridopidine is under development as a drug to treat HD. Its effect is mainly mediated via sigma-1 receptor (S1 R) interaction. Little is known so far about how this interaction affects other brain processes in vivo. It was, thus, the aim of this study to investigate this feature by hybrid PET/MRI.

Methodik/Methods 3 HD patients (age 43 ± 13 yrs) and 7 HVs (age 29 ± 3 yrs) were investigated. All subjects underwent simultaneous brain PET/multimodality MRI under baseline conditions and after 90 mg pridopidine. S1 R occupancy was determined by (-)-[¹⁸ F]Fluspidine PET and VOI analysis, 1-tissue compartment modelling (metabolite-corrected arterial input), and Lassen plot analysis. MRI included arterial spin labelling (ASL, pulsed sequence, VOI and SPM analysis, global normalisation), resting-state fMRI (BOLD sequence, seed-based: basal ganglia, sensory-motor and default mode networks [DMN]), and proton MR spectroscopy (MRS, axial slice through striatum, 10 ROIs, Cr, Cho, Ins, and Glx peaks, reference: NAA peak).

Ergebnisse/Results In HVs, 90 mg pridopidine (i) occupied 91 ± 4  % of the S1Rs (n = 4), (ii) decreased rCBF in temporal cortical (p = 0.009) and cerebellar (p = 0.007) areas, (iii) decreased Ins/NAA in white matter (p = 0.037) and (iv) increased connectivity within the basal ganglia network (4/7 subjects) and DMN (6/7 subjects). In HD, the drug effect was not different with regard to S1R occupancy. While no drug effects on rCBF were observed in HD, pridopidine increased Cr/NAA (p = 0.050) and Cho/NAA (p = 0.018) in the putamina as well as functional connectivity within the DMN (3/3 patients).

Schlussfolgerungen/Conclusions Pridopidine intensively acts on S1Rs with multiple effects on brain perfusion, metabolism and functional connectivity. Especially the positive effect on the DMN network connectivity provides further support for pridopidine improving functional impairment in HD. However, pharmacological PET/MRI is a useful tool to improve understanding of drug effects in the brain on a multi-modality level.