Invited Symposium: Assessing DA Function using PET Techniques
Materials and Methods
All scans have been performed on a Siemens/ECAT 953B tomograph in 3D mode, with an in-plan resolution of 5.6 mm. Following reconstruction, there are 31 axial planes with a separation of 3.37 mm. Attenuation correction is achieved using rotating 68Ge rod sources. The patient is positioned in the scanner using a gantry-mounted laser to obtain axial planes parallel to the inferior orbitomeatal line. A molded thermoplastic mask is fitted to reduce head movement. Tracers are administered via an indwelling intravenous cannula by intravenous bolus over 60 s using a Harvard pump. Images summed over the last 30 minutes of data acquisition are used to aid in the placement of circular regions of interest (ROIs; 8.8 mm diameter) over the head of the caudate nucleus (1 region per side) and along the axis of the putamen (3 regions per side), which are then copied onto each of the time frames to allow for graphical analysis of FD uptake (Ki [5,6]) or estimation of binding potential, using a tissue input function . For presynaptic tracers, occipital cortex was used as the reference region. For D1 and D2 binding, cerebellum was used.
Presynaptic dopaminergic function in patients with asymmetric PD
More than 40 patients with idiopathic PD have been studied. The majority of these individuals have had relatively mild and highly asymmetric disease. Antiparkinson medication is withheld for at least 12 hours (18 hours for controlled release levodopa and 18-24 hours for dopamine agonists) and patients take a low-protein breakfast prior to scanning. Presynaptic dopaminergic function is assessed by sequential scans with [11C]dihydrotetrabenazine (DTBZ; VMAT2 ligand; 5 mCi), [11C]d-threo-methylphenidate (MP; DAT ligand; 5 mCi) and FD (5 mCi). All scans are performed on the same day or over 2 days, with an interval of at least 2.5 h between scans to allow for radioactive decay. Acquisition times are 60 minutes for DTBZ and MP, 90 minutes for FD. Results have been normalized to data obtained from 7 age-matched controls scanned in an identical fashion.
In order to assess the susceptibility of FD uptake to pharmacological intervention, we have scanned 7 individuals with and without bromocriptine treatment. Six of these were scanned before starting bromocriptine as an adjunct to levodopa; the 7th was initially scanned while on bromocriptine, which was later stopped due to side effects, following which the second scan was performed.
Pathophysiology of fluctuations and motor complications in PD
In order to assess the hypothesis that fluctuations in motor function might reflect reduced "buffering capacity" secondary to loss of dopaminergic nerve terminals, FD uptake was assessed in 36 patients, 11 with a stable response to levodopa and 25 with fluctuations. The patients were matched for age but not for disease duration (longer in the fluctuators). Scans for this study were acquired in 2D mode.
As a further test of the presynaptic system, we have been assessing the time course of dopamine release following oral administration of levodopa (250 mg). In order to do this, we exploit the ability of endogenous dopamine to compete for [11C]raclopride (RAC) binding [8,9]. RAC scans are performed at baseline, 1 hour following oral levodopa (at a time of expected peak clinical effect) and 4 hours after levodopa (at which point the effect should be wearing off in patients with fluctuations). The binding potential (or distribution volume ratio) for raclopride is determined at each time point. A decline in binding potential corresponds to an increase in synaptic levels of dopamine.
We have also examined the status of dopamine D1 and D2 receptors in patients at various stages of PD using [11C]SCH 23390 (SCH) and RAC, respectively. A total of 32 patients were studied, 4 untreated, 7 treated and stable, 5 with wearing off alone, 8 with mild dyskinesia alone and 8 with severe fluctuations and dyskinesias. Finally, we are beginning studies to assess the affinity of dopamine receptors for a dopamine agonist, by determining the ability of apomorphine to displace SCH or RAC binding.
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|Stoessl, AJ; Lee, CS; Sossi, V; Calne, DB; Ruth, TJ; (1998). Imaging Studies of the Dopamine System in Parkinson's Disease. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/nahmiaspet/stoessl0717/index.html|
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