Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

The underlying impairment of mental functioning and motor planning in Parkinson's disease (PD) stems from the dopaminergic signal loss within the striatum and prefrontal cortex. Neurons within these brain regions contain two dopamine D2 receptor isoforms-D2 long (D2L) and D2 short (D2S). The degree of expression for these receptor isoforms are affected by the genotype within two single nucleotide polymorphisms (SNPs), rs2283265 and rs1076560 (both are in high linkage disequilibrium; C>A), found in the DRD2 gene. The importance of these SNPs are heightened clinically as PD patients with the CC genotype showed the most clinical improvement in motor and mental functioning to an anti-parkinsonian medication known as rasagiline compared to minor A allele carriers (AC/AA) (Masellis et al., 2016). However, it is fundamentally unclear how these SNPs affect the distribution of D2 receptors in vivo within the nigrostriatal dopaminergic system and its relevance to behavioral and movement impairment in patients with PD. Therefore, we propose to image PD patients and age-matching controls grouped by their genotype using a high-affinity PET radiotracer biomarker-[11C]-(+)-PHNO (PHNO). This agonist probe has properties allowing high sensitivity and specificity in detecting D2 receptors in certain regions of the brain. Through PHNO PET imaging of PD patients and controls, our objectives are: (1) examine genotype group effects on D2 receptor distribution and correlate it with behaviour and movement functioning; and (2) elucidate how the genotype modulates the dopaminergic system in PD patients. Achieving these objectives will (1) reveal a deeper understanding of the genetic impact on the dopaminergic pathophysiology of PD in vivo and its role in mental and movement impairment; and (2) help pave a path towards the improvement and advancement of personalized medicine for PD patients.