The role of neuroimaging in Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of people worldwide. Two hallmarks of PD are the accumulation of alpha-synuclein and the loss of dopaminergic neurons in the brain. There is no cure for PD, and all existing treatments focus on alleviating the symptoms. PD diagnosis is also based on the symptoms, such as abnormalities of movement, mood, and cognition observed in the patients. Molecular imaging methods such as magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET) can detect objective alterations in the neurochemical machinery of the brain and help diagnose and study neurodegenerative diseases. This review addresses the application of functional MRI, PET, and SPECT in PD patients. We provide an overview of the imaging targets, discuss the rationale behind target selection, the agents (tracers) with which the imaging can be performed, and the main findings regarding each target's state in PD. Molecular imaging has proven itself effective in supporting clinical diagnosis of PD and has helped reveal that PD is a heterogeneous disorder, which has important implications for the development of future therapies. However, the application of molecular imaging for early diagnosis of PD or for differentiation between PD and atypical parkinsonisms has remained challenging. The final section of the review is dedicated to new imaging targets with which one can detect the PD-related pathological changes upstream from dopaminergic degeneration. The foremost of those targets is alpha-synuclein. We discuss the progress of tracer development achieved so far and challenges on the path toward alpha-synuclein imaging in humans.

Keywords: PET; Parkinson's disease; SPECT; alpha-synuclein; neurodegeneration; neuroimaging.

FIGURE 1

(a) Simplified scheme of dopamine biosynthesis and degradation. (b) Outline of a dopaminergic synapse. (c) Simplified overview of the known mechanisms leading to neurodegeneration in PD. AADC, aromatic‐L‐amino acid decarboxylase; ALDH, aldehyde dehydrogenase; COMT, catechol‐O‐methyl transferase; DAT, dopamine transporter; DOPAC, 3,4‐dihydroxyphenylacetic acid; HVA, homovanillic acid; L‐DOPA, L‐3,4‐dihydroxyphenylalanine; MAO, monoamine oxidase; VMAT2, vesicular monoamine transporter type 2; 3‐MT, 3‐methoxytyramine; SNCA, α‐synuclein gene; UCHL1, ubiquitin carboxyl‐terminal hydroxylase‐1 gene; PRKN, parkin E3 ubiquitin ligase gene; PINK1, phosphatase and tensin homolog‐induced putative putative kinase 1 gene; LRRK2, leucine‐rich repeat kinase 2 gene; ROS, reactive oxygen species; MPTP, 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine. Figure created with BioRender.com

FIGURE 2

Examples of dopaminergic system imaging in PD research and diagnostics. (a) Decline of striatal [¹⁸F]F‐DOPA uptake in PD patients after 4.5 years of progressing disease. CL, contralateral side, IL, ipsilateral side. The colored scale bar indicates voxel‐level t‐statistic. Reproduced and adapted from (Gallagher, Oakes, et al., 2011) with permission. (b) Comparison of [¹⁸F]FE‐PE2I‐PET and [¹²³I]FP‐β‐CIT‐SPECT images in the same individuals. Reproduced and adapted from (Jakobson Mo et al., 2018) under the terms of the Creative Commons Attribution 4.0 International License

FIGURE 3

Examples of non‐dopaminergic imaging in PD research and diagnosis. (a) Association of SERT availability with fatigue in PD. Brain uptake of the SERT tracer [¹¹C]DASB shown in a healthy control (left), PD patient without (middle) and with fatigue (right). Color bar shows [¹¹C]DASB binding potential. Reproduced and adapted from (Pavese et al., 2010) with permission. (b) PD‐related pattern (PDRP) in brain glucose metabolism identified by network analysis of [¹⁸F]FDG scans in PD patients and healthy controls. Color coding indicates areas with increased (red to yellow) and decreased (blue to purple) metabolism. Reproduced from (Ma et al., 2007) with permission. (c) PD‐related pattern in neural activity identified network analysis of resting state fMRI scans in PD patients and healthy controls. Color coding indicates increased (red) and decreased (blue) neural activity. Reproduced from (Wu et al., 2015) with permission

FIGURE 4

The most promising candidate structures for α‐Syn tracer development