Dissociation of Metabolic and Neurovascular Responses to Levodopa in the Treatment of Parkinson's Disease

Abstract

We compared the metabolic and neurovascular effects of levodopa (LD) therapy for Parkinson's disease (PD). Eleven PD patients were scanned with both [ O]-H 2 O and [18 F]-fluorodeoxyglucose positron emission tomography in the unmedicated state and during intravenous LD infusion. Images were used to quantify LD-mediated changes in the expression of motor-and cognition-related PD covariance patterns in scans of cerebral blood flow (CBF) and cerebral metabolic rate for glucose (CMR). These changes in network activity were compared with those occurring during subthalamic nucleus (STN) deep brain stimulation (DBS), and those observed in a test-retest PD control group. Separate voxel-based searches were conducted to identify individual regions with dissociated treatment-mediated changes in local cerebral blood flow and metabolism. We found a significant dissociation between CBF and CMR in the modulation of the PD motor-related network by LD treatment ( p Ͻ 0.001). This dissociation was characterized by reductions in network activity in the CMR scans ( p Ͻ 0.003) occurring concurrently with increases in the CBF scans ( p Ͻ 0.01). Flow-metabolism dissociation was also evident at the regional level, with LD-mediated reductions in CMR and increases in CBF in the putamen/globus pallidus, dorsal midbrain/pons, STN, and ventral thalamus. CBF responses to LD in the putamen and pons were relatively greater in patients exhibiting drug-induced dyskinesia. In contrast, flow-metabolism dissociation was not present in the STN DBS treatment group or in the PD control group. These findings suggest that flow-metabolism dissociation is a distinctive feature of LD treatment. This phenomenon may be especially pronounced in patients with LD-induced dyskinesia.

Therapeutic High-Frequency Stimulation of the Subthalamic Nucleus in Parkinson's Disease Produces Global Increases in Cerebral Blood Flow

“…The administration of clinically effective doses of levodopa to PD patients and normal controls has been shown to produce diffuse increases in CBF without changes in oxygen utilization, suggesting cerebrovascular dilation (Leenders et al, 1985). A similar dissociation between CBF and glucose metabolism has been found on a regional basis after levodopa administration in PD subjects (Hirano et al, 2008). In general, stimulation of the dopamine system increases CBF (Leenders et al, 1985).…”

Structural and physiological neurovascular changes in idiopathic Parkinson’s disease and its clinical phenotypes

“…The region of hyperperfusion in the globus pallidus in patients is in keeping with previous findings of elevated glucose metabolism in this region. 43 However, it may also be related to L-DOPA medication which has been shown to increase CBF in this region, 44,45 particularly as the hyperperfusion is greatest in the PIGD group of whom a greater proportion were on L-DOPA medication (table 1).…”

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

“…Using positron emission tomography (PET), Hirano et al, 2008 have found that the administration of L-DOPA causes a much larger increase in putaminal and pontine regional cerebral blood flow (rCBF) in PD patients experiencing dyskinesia compared with non-dyskinetic subjects. No difference in cerebral metabolic rate (CMR) for glucose was found on L-DOPA, pointing to a large dissociation between blood flow and glucose metabolism in dyskinetic patients (Hirano et al, 2008). The relationship between changes in rCBF and the angiogenesis induced by L-DOPA is presently unclear, but these phenomena are likely to share some common molecular and chemical determinants.…”