Abstract
Parkinson disease (PD) is a progressive disorder characterized by dopaminergic neurodegeneration in the brain. The development of parkinsonism is preceded by a long prodromal phase, and >50% of dopaminergic neurons can be lost from the substantia nigra by the time of the initial diagnosis. Therefore, validation of in vivo imaging biomarkers for early diagnosis and monitoring of disease progression is essential for future therapeutic developments. PET and single-photon emission CT targeting the presynaptic terminals of dopaminergic neurons can be used for early diagnosis by detecting axonal degeneration in the striatum. However, these techniques poorly differentiate atypical parkinsonian syndromes from PD, and their availability is limited in clinical settings. Advanced MRI in which pathological changes in the substantia nigra are visualized with diffusion, iron-sensitive susceptibility and neuromelanin-sensitive sequences potentially represents a more accessible imaging tool. Although these techniques can visualize the classic degenerative changes in PD, they might be insufficient for phenotyping or prognostication of heterogeneous aspects of PD resulting from extranigral pathologies. The retina is an emerging imaging target owing to its pathological involvement early in PD, which correlates with brain pathology. Retinal optical coherence tomography (OCT) is a non-invasive technique to visualize structural changes in the retina. Progressive parafoveal thinning and fovea avascular zone remodelling, as revealed by OCT, provide potential biomarkers for early diagnosis and prognostication in PD. As we discuss in this Review, multimodal imaging of the substantia nigra and retina is a promising tool to aid diagnosis and management of PD.
Key points
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Advanced nigral MRI techniques in Parkinson disease (PD) include diffusion tensor free water measurement, quantitative susceptibility mapping of iron signals, evaluation of nigrosome 1 (N1) loss on iron-sensitive sequences and quantification of neuromelanin loss on neuromelanin-sensitive sequences.
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N1 signal loss and neuromelanin reduction in the substantia nigra pars compacta can be detected in prodromal PD, although longitudinal studies are required to validate this approach.
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Multimodal imaging capturing pathological changes in the substantia nigra should substantially enhance diagnostic accuracy in early PD, and longitudinal multimodal MRI studies could provide essential pathophysiological insights and provide markers to monitor disease progression.
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Visual disturbances observed in patients with PD are linked to retinal dopamine loss, which results in functional derangement of couplings between retinal cells and defective synaptic transmission.
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Parafoveal inner retinal change can be detected from the early stages of PD, extending to the macula and peripapillary nerve fibre layer at advanced stages and showing associations with visual hallucinations and cognitive impairment.
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Retinal imaging could provide a convenient imaging tool for early diagnosis and monitoring progression in PD, and further investigation of the link between retinal and brain pathology could provide further pathophysiological insights into neurodegenerative diseases.
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J.-Y.L., A.M.-B., A.M.-G. and N.C. researched data for the article. J.-Y.L., I.G., P.P. and B.J. contributed substantially to discussion of the content. J.-Y.L., A.M.-B., A.M.-G., I.G. and N.C. wrote the article. All authors reviewed and/or edited the manuscript before submission.
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Glossary
- Lewy bodies
-
Eosinophilic intracytoplasmic neuronal inclusions, composed largely of α-synuclein, that are characteristically found in the brain of individuals with neurodegenerative diseases such as Parkinson disease and dementia with Lewy bodies.
- Nigrosomes
-
Clusters of calbindin-negative dopaminergic cells in the substantia nigra.
- Melanophagia
-
Phagocytosis of melanin.
- Neuronophagia
-
Destruction of neurons by phagocytic cells.
- Marinesco bodies
-
Intranuclear inclusions found in pigmented neurons in the substantia nigra.
- Somatodendrite
-
Region of a neuron that includes the cell body and dendrite.
- Single-shell scans
-
Diffusion signal scans acquired in a single shell.
- Multi-shell scans
-
Diffusion signal scans acquired from a multi-shell scheme.
- Free water fractional volume
-
The volume fraction of free water within the regional volume defined by a voxel.
- Bi-tensor modelling
-
A diffusion tensor imaging analysis model consisting of two tensor compartments; for example, free water and tissue compartments.
- Fractional anisotropy
-
A measure of the degree of anisotropy of water molecules in diffusion tensor imaging analysis, which ranges from 0 (infinite isotropy, no restrictions in all directions) to 1 (anisotropy, movement in only one axis and limited to others).
- Hoehn and Yahr stages
-
Clinical staging system for parkinsonian disorders proposed by M. Hoehn and Y. Yahr in 1967.
- Partial volume
-
The actual volume occupied by a small species of molecules or particles in a solution.
- Region of interest (ROI) analysis
-
Analysis of data extracted from specified ROIs for the study.
- Quantitative susceptibility mapping
-
(QSM). An MRI technique for quantifying the spatial distribution of magnetic susceptibility within the tissue.
- T2* dephasing
-
Immediately after forming transverse magnetization by a radiofrequency pulse, the transverse magnetization starts decreasing in magnitude as protons start going out of phase (dephasing). Dephasing can be altered by magnetic field inhomogeneity, magnetic susceptibility difference of various elements in the tissues, and the gradients applied. T2* relaxation is the decay of transverse magnetization with gradient echo sequences, which is used to visualize haemorrhage, calcification and iron deposition.
- Fast spin-echo
-
An MRI technique that records multiple echoes after a 90° excitation pulse by transmitting a series of 180° inversion pulses at set intervals. By contrast, the conventional spin-echo sequence measures a single echo.
- Magnetization transfer
-
The transfer of nuclear spin polarization and/or coherence from one population of nuclei to another. This technique can suppress background signals to improve contrast on MRI scans.
- Area under the curve
-
(AUC). Area under the receiver operating characteristic curve (integral) ranging from 0 (no discriminative ability) to 1 (the highest-level ability) to evaluate an ability of a classifier under a classification threshold.
- Scotopic and photopic b-waves
-
Short flashes can elicit an electroretinogram consisting of initial negative deflection (a-wave) and a following positive deflection (b-wave). The b-waves in response to scotopic and photopic stimuli reflect rod and cone ON bipolar cell depolarization, respectively.
- Optical interferometry
-
A measurement method using the phenomenon of interference of light waves. Medical imaging using low-coherence interferometry can provide tomographic visualization of internal tissue microstructure.
- Peripapillary retinal nerve fibre layer
-
(pRNFL). Retinal nerve fibre layer bundle that passes through the optic papilla (optic disc).
- Honeymoon phase
-
A period of relative stability with an excellent response to levodopa in patients with Parkinson disease, which usually lasts for a few years following the start of levodopa therapy.
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Lee, JY., Martin-Bastida, A., Murueta-Goyena, A. et al. Multimodal brain and retinal imaging of dopaminergic degeneration in Parkinson disease. Nat Rev Neurol 18, 203–220 (2022). https://doi.org/10.1038/s41582-022-00618-9
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DOI: https://doi.org/10.1038/s41582-022-00618-9
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