Imaging Dopaminergic Neurotransmission in Neurodegenerative Disorders

Abstract

Imaging of dopaminergic transmission in neurodegenerative disorders such as Parkinson disease (PD) or dementia with Lewy bodies plays a major role in clinical practice and in clinical research. We here review the role of imaging of the nigrostriatal pathway, as well as of striatal receptors and dopamine release, in common neurodegenerative disorders in clinical practice and research. Imaging of the nigrostriatal pathway has a high diagnostic accuracy to detect nigrostriatal degeneration in disorders characterized by nigrostriatal degeneration, such as PD and dementia with Lewy bodies, and disorders of more clinical importance, namely in patients with clinically uncertain parkinsonism. Imaging of striatal dopamine D_2/3 receptors is not recommended for the differential diagnosis of parkinsonian disorders in clinical practice anymore. Regarding research, recently the European Medicines Agency has qualified dopamine transporter imaging as an enrichment biomarker for clinical trials in early PD, which underlines the high diagnostic accuracy of this imaging tool and will be implemented in future trials. Also, imaging of the presynaptic dopaminergic system plays a major role in, for example, examining the extent of nigrostriatal degeneration in preclinical and premotor phases of neurodegenerative disorders and to examine subtypes of PD. Also, imaging of postsynaptic dopamine D_2/3 receptors plays a role in studying, for example, the neuronal substrate of impulse control disorders in PD, as well as in measuring endogenous dopamine release to examine, for example, motor complications in the treatment of PD. Finally, novel MRI sequences as neuromelanin-sensitive MRI are promising new tools to study nigrostriatal degeneration in vivo.

Keywords: PET; Parkinson; SPECT; dopamine; neurodegeneration.

FIGURE 1.

Simplified diagram of striatal dopaminergic synapse. On presynaptic side, markers for imaging of integrity of dopaminergic neurons in humans are shown. ¹⁸F-FDOPA and ¹⁸F-FMT PET provide measures of structural and biochemical integrity of dopaminergic neurons. ¹¹C-DTBZ and ¹⁸F-DTBZ are radiopharmaceuticals for vesicular monoaminergic transporter. Substituted (nor)phenyltropanes (¹¹C-PE2I, ¹⁸F-FE-PE2I, ¹²³I-FP-CIT, and ^99mTc-TRODAT) are frequently used PET and SPECT radioligands for imaging of DAT. On postsynaptic side, ¹¹C-NNC112 and ¹¹C-SCH23390 radiopharmaceuticals for dopamine D₁ receptor are shown. Dopamine D₂ receptors are expressed predominantly on postsynaptic side as compared with presynaptic side of dopaminergic synapse. ¹¹C-NPA and ¹¹C-PHNO are agonist radioligands for dopamine D_2/3 receptors. Commonly used antagonist radioligands for D_2/3 receptors are substituted benzamides (¹¹C-raclopride, ¹¹C-FLB 457, ¹⁸F-fallypride, and ¹²³I-IBZM). (Reprinted from (6).)

FIGURE 2.

Transversal ¹²³I-FP-CIT SPECT images obtained in patient with CUPS without striatal DAT loss (top) and in CUPS patient with striatal DAT loss (bottom). Asymmetric striatal binding can be seen, as well as severe loss of DAT binding, especially in putamen, in subject with dopaminergic deficit. This study was acquired on brain-dedicated SPECT system (InSPira; NeuroLogica).

FIGURE 3.

Transversal planes of ¹⁸F-FDOPA PET images obtained in patient with CUPS without nigrostriatal cell loss (top) and in CUPS patient with nigrostriatal degeneration (bottom). Asymmetric striatal uptake can be seen, as well as severe loss of ¹⁸F-FDOPA uptake, especially in putamen, of subject with nigrostriatal degeneration.

FIGURE 4.

Transversal images of neuromelanin-sensitive MRI scans of mesencephalon. Substantia nigra is visible as hyperintense area next to cerebral peduncles. Left panel shows example of neuromelanin-sensitive MRI in healthy control, and right panel shows example of patient with PD. Loss of signal can be seen in substantia nigra in PD patient. Arrows point to substantia nigra. (Reprinted from (74).)