| الوصف: |
The overarching aim of this thesis was to investigate four molecular markers of pathology in Parkinson's disease (PD), namely phosphodiesterase 4 (PDE4), synaptic vesicle protein 2A (SV2A), sigma 1 receptor (1R) and mitochondrial complex 1 (MC1), using molecular positron emission tomography (PET) imaging with [11C]Rolipram for PDE4, [11C]UCB-J for SV2A, [11C]SA-4503 for 1R and [18F]BCPP-EF for MC1. A secondary aim was to investigate the relationship between changes in these molecular markers in vivo with clinical markers of Parkinson's disease burden. The main hypothesis was that PDE4, SV2A, 1R and MC1 could be altered in PD patients with relevance to clinical measures of disease burden. Study 1 (Chapter 3) investigates the expression of the intracellular enzyme PDE4, using [11C]Rolipram PET, and its relevance to cognitive impairment and excessive daytime sleepiness (EDS), in 12 levodopa-treated PD patients. This work showed reductions in [11C]Rolipram volume of distribution (VT) in PD compared to healthy controls (n=12) in the caudate, thalamus, prefrontal and temporal thalamic nuclei, hypothalamus, posterior dorsolateral frontal cortex, medial frontal cortex and supplementary motor area. In PD, worse performance in spatial working memory correlated with lower [11C]Rolipram VT in the posterior dorsolateral frontal cortex, medial frontal cortex, supplementary motor area, precentral gyrus, caudate, and prefrontal thalamic nuclei. PD patients with EDS showed increased [11C]Rolipram VT in the caudate, hypothalamus, hippocampus and limbic striatum compared to patients without EDS. Furthermore, higher Epworth sleepiness scale scores correlated with increased [11C]Rolipram VT in the caudate, hypothalamus, hippocampus and limbic subdivisions of the striatum. The findings demonstrate loss of PDE4 expression in the striato-thalamo-cortical circuit, which is associated with deficits of spatial working memory in PD; and translate into humans preclinical data indicating that increased PDE4 could be associated with EDS in PD. Study 2 (Chapter 4) investigates cross-sectional and longitudinal changes in synaptic integrity, using [11C]UCB-J for SV2A, in drug-naïve PD patients. At baseline, [11C]UCB-J VT was reduced in the caudate, putamen, thalamus, brainstem, dorsal raphe, as well as across cortical regions in PD (n=11) compared with healthy controls (n=16). [11C]UCB-J VT was reduced in the locus coeruleus and substantia nigra but not reaching statistical significance. Lower brainstem [11C]UCB-J VT correlated with the Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) Part-III and MDS-UPDRS total scores. No significant longitudinal changes were identified in seven PD patients, at a mean follow-up of 11±1.3 months, compared with baseline. The findings represent the first in vivo evidence of SV2A loss in drug-naïve PD, suggesting that loss of synaptic integrity likely occurs early in disease pathophysiology and has relevance to symptomatology. Studies in larger cohorts, with longer follow-up, will determine the validity of [11C]UCB-J PET as a marker to track disease progression. Study 3 (Chapter 5) investigates cross-sectional and longitudinal molecular pathology of the endoplasmic reticulum and mitochondria, using [11C]SA-4503 for 1R and [18F]BCPP-EF for MC1, respectively, in drug-naïve PD patients. This work showed non-significant lower levels of 1R and MC1, with the greatest effect size in the caudate and dorsal raphe, respectively, in PD (n=12) compared to healthy controls (n=16). Longitudinal analyses in nine PD patients, at a mean follow-up period of 11±1.3 months, showed the highest annualised increases of 1R in the caudate and MC1 in the putamen, but not reaching statistical significance. The results did not reach statistical significance in this cohort, possibly due to small sample size, early disease stage and short follow-up period. MC1 and 1R pathology warrants further in vivo investigations in PD. Exploratory analysis showed preliminary indications for the concurrent and colocalised loss of SV2A, 1R and MC1 in the caudate and brainstem regions in drug-naïve PD. These findings suggest the potential pathophysiological interplay between mitochondrial, endoplasmic reticulum and synaptic pathology in PD. Overall, the findings of this thesis indicate the presence of PDE4 and SV2A pathology, detected using molecular PET imaging, in PD patients. This work highlights the clinical relevance of PDE4 pathology to cognitive and sleep symptomatology, and SV2A pathology to the severity of motor symptoms and PD clinical burden. Future work is required to delineate changes in 1R and MC1 in PD and their relevance to symptomatology. Taken together, the findings from the studies constituting this thesis add to the evolving literature aiming to characterise the pathophysiology of PD. |