Vol 6 n° 3 - Parkinson's disease
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3 1 2 Posters & images in neuroscience Imaging dopamine neurotransmission in Parkinson’s disease: biomarker versus surrogate end point Imaging   of   dopamine   (DA)   neurotransmission   in Parkinson’s disease (PD) began with positron emission tomography (PET) measurements of dopamine synthe- sis using [ 18F]fluorodopa (FDOPA). This precursor is converted within DA neurons to the ionically charged [ 18F]fluorodopamine, and this radioactive metabolite is trapped within the cell. The rate of trapping is propor- tional  to  the  amount  of  converting  enzyme  (DOPA decarboxylase), which itself is correlated with the num- ber of DA terminals in the striatum. Two other targets were subsequently imaged as bio- markers for DA neurotransmission: dopamine trans- mitter (DAT) and vesicular monoamine transporter, type 2 (VMAT2). DAT is located on the terminals of DA neurons in the striatum and functions to remove DA from the synapse to the intracellular space for recycling or metabolism. VMAT2 is located on the vesicle mem- branes of DA and noradrenergic neurons, and transports intracellular DA (or norepinephrine) into the vesicle, which is subsequently released by exocytosis on electri- cal stimulation. DA synthesis and VMAT2 are measured with PET, whereas DAT levels have been measured with both PET and single photon emission computed tomog- raphy (SPECT). All three targets (DOPA decarboxy- lase, DAT, and VMAT2) are clearly biomarkers for DA neurotransmission (Table I). Representative images in PD patients and healthy subjects are shown in Figure 1. Because they are biomarkers of DA neurotransmission, the imaging of these targets has clear utility in the study of the pathophysiology of PD. For example, imaging has demonstrated the following: • The known loss of DA innervation in PD. • A  negative  correlation  between  the  brain  imaging measurement  and  symptom  severity  in  groups  of patients. • The increasing progression of symptoms over time within inspanidual subjects. At least two of these targets (DA synthesis and DAT) have been shown to have modest diagnostic specificity. That is, imaging of these two targets can clearly distin- guish PD from benign senile tremor, but has marginal, if any,  utility  to  distinguish  idiopathic  PD  from  other “parkinsonisms,” such as multisystem atrophy and stria- tonigral degeneration. All three targets have demon- strated significant “reserve function” in brain, such that >50% loss of the target is required for the onset of clin- ical symptoms. Serial studies of DA synthesis and DAT levels in inspanidual patients have shown about 10% loss per annum in the early stages of the disease. As a rough back-extrapolation, these results suggest that the pre- clinical phase of the disease is ~5 years before the pres- ence of symptoms adequate to make the diagnosis of PD (ie, 50%/10% per annum = 5 years). Taken as a whole, these results suggest imaging of DA neurotransmission in PD may have at least two important clinical applica- tions: • Diagnosis in both clinical and preclinical phases. • A biomarker for the efficacy of agents designed to slow progression of the disease, ie, neuroprotective agents. Significant controversy surrounds the utility of imaging to provide a “biomarker for efficacy” (ie, a surrogate end point) for a potential neuroprotective agent. On first consideration, it seems obvious that DA imaging is a Copyright © 2004 LLS SAS. All rights reserved Table I. Three targets for imaging dopamine (DA) neurotransmission in Parkinson’s disease. DOPA, dihydroxyphenylalanine. DOPA decarboxylase   DOPA converting enzyme DAT Dopamine transmitter VMAT2 Vesicular monoamine transporter, type 2