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