Microvascular changes in Parkinson´s Disease: Correlations to levodopa induced dyskinesia and grip froce control

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Levodopa is the most effective medication for the treatment of Parkinson´s disease (PD), but long term treatment causes disruptive motor side effects in the vast majority of patients, i.e. levodopa induced dyskinesias (LID). The mechanisms underlying LID are complex and not fully understood. Recent studies suggest that large, transient increases in striatal levels of dopamine following levodopa (LD) administration may be a key promoter in the pathogenesis of LID. Moreover, LD has opposing effects on cerebral blood flow and metabolism (flow-metabolism-dissociation) that appear to be significantly more pronounced in LID-patients. It is therefore hypothesized that the observed alterations of striatal dopamine levels, at least in part, depend on functional and structural alterations of the brain microvasculature. Impaired hand function is a common symptom in PD. PD patients show a distinct pattern of alterations of the prehensile forces. In particular, PD patients exhibit excessive grip forces (GF). This phenomenon seems to be significantly more pronounced in LID patients. Whether this increase is an intrinsic feature of PD, is caused by dopaminergic treatment, or shares pathophysiological mechanisms with LID, is unknown. We will employ a longitudinal PET-imaging approach to determine whether the hemodynamic and metabolic effects of dopamine are relevant to the pathophysiology of LID. We will investigate whether the overshoot of GF is a reproducible feature of PD or exclusively occurs in LID patients. Lastly, we will determine whether abnormalities in GF control correlate to alterations of the cerebral microvasculature. For this purpose we will assess PET-data as well as GF data in drug naïve patients at baseline and after one year of dopaminergic treatment. The proposed project shall provide a deeper insight into the pathophysiology of LID and should open new avenues for treating this troubling side effect.