Functional segregation in Parkinson's disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder globally, following Alzheimer’s Disease. Numerous proposed mechanisms aim to explain the pathogenesis of this degenerative condition; however, none currently accounts for the selective vulnerability seen in PD. That is, dopaminergic projections to the dorsal and caudal striatum degenerate first and maximally, followed by more rostral and ventral regions. While a caudal to rostral pattern of progression is supported by previous molecular imaging studies, the possibility of an additional dorsal to ventral gradient is less established. If such a gradient exists, one would expect to see initial PD motor symptoms in the lower limbs, based on the somatotopic mapping of the body within the central nervous system, however this is not in keeping with typical clinical observations. Patients often present with initial impairments in the arm or hand, although this could be possibly explained by greater sensitivity to functional deficits involving fine hand dexterity. Furthermore, loss of dopamine may lead to altered signal to noise ratio in striatal projection neurons, reducing somatotopic segregation in the striatum and its connections. Cortico-striatal loops are thought to be segregated according to function (motor, associative, limbic etc.) and body region. Based on studies of repetitive transcranial magnetic stimulation-evoked dopamine release, it has been suggested that cortical stimulation results in an anatomically broader release of dopamine within the striatum in PD, but of lower magnitude than in the healthy state. The aim of the larger research initiative covered in this thesis was to study the altered striatal plasticity in early-stage PD (less than 5 years duration) and delineate the functional reorganization of dopaminergic projections in PD neurodegeneration. To do this, novel hybrid positron emission tomography and magnetic resonance imaging with [¹¹C]raclopride was utilized to simultaneously assess patterns of dopamine release and striatal activation induced by behavioural tasks involving the various corticostriatal loops in PD and healthy control subjects. The primary focus of this thesis was on a subset of these tasks specifically designed to activate the sensorimotor pathway; finger and foot tapping tasks.Medicine, Faculty ofGraduat