Molecular imaging and the neuropathologies of Parkinson's disease.

The main motor symptoms of Parkinson's disease (PD) are linked to degeneration of the nigrostriatal dopamine (DA) fibers, especially those innervating the putamen. This degeneration can be assessed in molecular imaging studies with presynaptic tracers such as [(18)F]-fluoro-L-DOPA (FDOPA) and ligands for DA transporter ligands. However, the pathologies of PD are by no means limited to nigrostriatal loss. Results of post mortem and molecular imaging studies reveal parallel degenerations of cortical noradrenaline (NA) and serotonin (5-HT) innervations, which may contribute to affective and cognitive changes of PD. Especially in advanced PD, cognitive impairment can come to resemble that seen in Alzheimer's dementia, as can the degeneration of acetylcholine innervations arising in the basal forebrain. The density of striatal DA D(2) receptors increases in early untreated PD, consistent with denervation upregulation, but there is an accelerated rate of DA receptor loss as the disease advances. Animal studies and post mortem investigations reveal changes in brain opioid peptide systems, but these are poorly documented in imaging studies of PD. Relatively minor changes in the binding sites for GABA are reported in cortex and striatum of PD patients. There remains some controversy about the expression of the 18 kDa translocator protein (TSPO) in activated microglia as an indicator of an active inflammatory component of neurodegeneration in PD. A wide variety of autonomic disturbances contribute to the clinical syndrome of PD; the degeneration of myocardial sympathetic innervation can be revealed in SPECT studies of PD patients with autonomic failure. Considerable emphasis has been placed on investigations of cerebral blood flow and energy metabolism in PD. Due to the high variance of these physiological estimates, researchers have often employed normalization procedures for the sensitive detection of perturbations in relatively small patient groups. However, a widely used normalization to the global mean must be used with caution, as it can result in spurious findings of relative hypermetabolic changes in subcortical structures. A meta-analysis of the quantitative studies to date shows that there is in fact widespread hypometabolism and cerebral blood flow in the cerebral cortex, especially in frontal cortex and parietal association areas. These changes can bias the use of global mean normalization, and probably represent the pathophysiological basis of the cognitive impairment of PD.