Flow-metabolism dissociation in the pathogenesis of levodopa-induced dyskinesia

Abstract

Levodopa-induced dyskinesia (LID) is the most common, disruptive complication of Parkinson's disease (PD) pharmacotherapy, yet despite decades of research, the changes in regional brain function underlying LID remain largely unknown. We previously found that the cerebral vasomotor and metabolic responses to levodopa are dissociated in PD subjects. Nonetheless, it is unclear whether levodopa-mediated dissociation is exaggerated in LID or distinguishes LID from non-LID subjects. To explore this possibility, we used dual-tracer positron emission tomography to quantify regional cerebral blood flow and metabolic activity in 28 PD subjects (14 LID, 14 non-LID), scanned before and during intravenous levodopa infusion. Levodopa-mediated dissociation was most prominent in the posterior putamen ( < 0.0001) and greater in LID than in non-LID and test-retest subjects. Strikingly, LID subjects also showed increased sensorimotor cortex (SMC) activity in the baseline, unmedicated state. Imaging data from an independent PD sample (106 subjects) linked these differences to loss of mesocortical dopamine terminals in advanced patients. In aggregate, the data suggest that LID results from an overactive vasomotor response to levodopa in the putamen on a background of disease-related increases in SMC activity. LID may thus be amenable to treatment that modulates the function of these 2 regions.

Increased putamen hypercapnic vasoreactivity in levodopa-induced dyskinesia

“…Globally normalized CBF increased with HC when measured off medication in the areas of levodopa-mediated dissociation that were previously reported in the putamen ( Figure 1A), internal globus pallidus (Figure 2A), and pons ( Figure 2B) (3,4). In each of these regions, significant HC CBF responses were observed in LID, nondyskinetic (NLID), and healthy control subjects (P < 0.05; paired Student's t tests).…”

“…Dissociation of vasomotor and metabolic responses to levodopa has been noted as a consistent feature of acute drug administration in human PD (3,4) and in the 6-OHDA rat model (5,6). This phenomenon is closely linked to levodopa-mediated increases in local CBF, likely related to engagement of D 1 receptors on blood vessels apposed to dopamine terminals in the mammalian striatum (8,9,19).…”

“…While the mechanism of LID is not precisely known, experimental evidence from the 6-hydroxydopamine (6-OHDA) rat model has implicated neurovascular dysregulation in dopaminergically denervated brain regions as a major factor underlying the development of levodopa-mediated involuntary movements (2). Evidence for this hypothesis has been provided by recent dual-tracer PET studies conducted in human PD subjects (3,4) and in the rodent model (5,6). In brief, levodopa administration is associated with increases in local cerebral blood flow (CBF) and with simultaneous reductions in cerebral glucose metabolic rate (CMR) in the same brain regions.…”

“…In brief, levodopa administration is associated with increases in local cerebral blood flow (CBF) and with simultaneous reductions in cerebral glucose metabolic rate (CMR) in the same brain regions. Dissociation of local vasomotor and metabolic drug responses (referred to as "regional dissociation") has been observed as a stereotyped feature of levodopa treatment in PD subjects, involving areas of monoaminergic terminal loss in the posterior putamen, globus pallidus, ventral thalamus, and dorsal pons (3,4). Levodopa-mediated CBF increases in these regions have been attributed to drug effects on the local microvasculature, mediated by dopamine terminals apposed to the vessel wall (see, e.g., refs.…”

“…In addition to human PD, levodopa-mediated dissociation has been observed in the 6-hydroxydopamine rat model (6). In both species, levodopa-mediated dissociation is most prominent in the basal ganglia, with notably greater effects in human subjects and experimental animals with druginduced dyskinesia (4,5).…”