Striatal dopamine in Parkinson disease: A meta‐analysis of imaging studies

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At the neurotransmitter level, Parkinson disease (PD) is characterized by a dopamine deficiency in the striatum. The loss of striatal dopamine can be visualized and quantified in vivo using functional neuroimaging with positron emission tomography (PET) or single photon emission computed tomography (SPECT), and these methods have been widely used in PD research since the first human study was published in 1983.1 However, the interpretation of individual studies has not always been straightforward. Small sample sizes, in combination with differences in patient clinical characteristics, scanners, tracers, analysis methods, and reporting, have made it difficult to estimate precise levels of dopaminergic degeneration over the course of PD and the clinical correlates of such degeneration. Another important issue is the pattern of the progressive dopaminergic decline in PD. A linear decline of dopamine function has been suggested by some imaging studies,2 whereas an alternative model, also supported by neuropathological work,6 assumes exponential neuronal decay in which a relatively short‐term event leads to a rapid destruction that later decelerates.
Dopaminergic neurotransmission is, in itself, a complex sequence of events. Dopamine is synthesized in the cytosol of catecholaminergic neurons in a 2‐step process. First, L‐tyrosine is hydroxylated to L‐dopa by tyrosine hydroxylase, followed by the decarboxylation of L‐dopa to dopamine.7 6‐[18F]fluoro‐L‐dopa, a commonly used tracer for PET, enters in the second phase of the biosynthesis when it is converted to [18F]fluorodopamine by aromatic L‐amino‐acid decarboxylase (AADC; also known as dopa decarboxylase). Similar to endogenous dopamine, [18F]fluorodopamine is then transported to intraneuronal storage vesicles by vesicular monoamine transporter 2 (VMAT2).8 As a result of the excitation of dopaminergic neurons, the vesicles are finally emptied into the synaptic cleft, and the synaptic dopamine then interacts with postsynaptic dopamine receptors. Both AADC and VMAT2 are important targets in dopaminergic neuroimaging reflecting two different aspects of the process (dopamine synthesis or AADC activity vs dopamine storage). The third important synaptic mechanism comes into play after dopamine has been released to the synaptic cleft. For signaling to stop, extracellular dopamine has to be removed from the synapse; dopamine transporter (DAT) is the most important component in terminating dopamine neurotransmission.9 There are a number of DAT tracers for PET and SPECT, but the most commonly used tracers are the 123I‐, 18F‐, or 11C‐linked tropane derivatives 2β‐carbomethoxy‐3β(4‐iodophenyl)tropane (β‐CIT) and N‐ω‐fluoropropyl‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)nortropane (FP‐CIT).
Although dopaminergic striatal presynaptic PET and SPECT with AADC, DAT, and VMAT2 tracers have been popular in PD clinical research for more than three decades, no previous comprehensive meta‐analyses have been performed. The objective of this meta‐analysis was to estimate the degree of the dopaminergic loss in PD as measured with tracers for AADC, DAT, and VMAT2. An additional aim was to study whether the decline of presynaptic dopaminergic function in PD is linear or nonlinear.

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