PET Study of Non-Motor Symptoms of Parkinson Disease

This research plan is focused on neurochemical positron emission tomography (PET) studies of
Parkinson disease (PD). PD is the most common neurodegenerative movement disorder, and
considerable progress has been made in understanding and treating the "typical" movement
abnormalities of resting tremor, bradykinesia and rigidity. These cardinal PD features are
all initially responsive to dopamine replacement therapy, and have been investigated
intensively with respect to their relationships to degeneration of the nigrostriatal
dopamine projection. More recently, increased attention has focused on the "non-motor"
clinical aspects of PD, including cognitive, mood, chronobiological and peripheral autonomic
defects. These clinical features are less reliably affected by dopaminergic therapy, and are
likely to be associated with other, non-dopaminergic neural degenerations. Indeed, detailed
postmortem assessments of PD brain reveal substantial neuronal losses in a variety of
chemically-defined neurons, including brainstem serotonin and norepinephrine neurons and
basal forebrain cholinergic neurons. Projects in the proposal will focus on dementia,
depression, sleep-apnea and dysautonomia in PD patients, employing PET measures of
presynaptic dopaminergic, serotoninergic and cholinergic CNS neurons and of peripheral
sympathetic neurons. Results of the investigations may identify associations of non-motor PD
signs and symptoms with the non-dopaminergic neuronal losses. These findings will establish
additional therapeutic targets for symptomatic, but also for potential neuroprotective PD
therapies. In addition, a majority of patients will be characterized with all 3 CNS PET
measures. The availability of multiple markers of distinct neuronal populations involved in
PD neurodegeneration will permit exploratory analyses to assess whether the degenerations
are correlated (possibly manifestations of a common pathophysiology) or apparently
independent (possibly a manifestation of multiple PD subtypes or pathophysiologies).
Ultimately, better understanding of these non-motor features will be essential to developing
future treatments that address the entire PD patient.