Clinical Medicine 2016 Vol 16, No 4: 371–5 CME MOVEMENT DISORDERS I m a g i n g i n P a r k i n s o n ’ s d i s e a s e Authors: G e n n a r o P a g a n o , A F l a v i a N i c c o l i n i B a n d M a r i o s P o l i t i s C The clinical presentation of Parkinson’s disease (PD) Abnormal intra-neuronal (Lewy bodies) and intra-neuritic is heterogeneous and overlaps with other conditions, (Lewy neurites) deposits of fibrillary aggregates are currently including the parkinsonian variant of multiple system considered the key neuropathological alterations in PD. atrophy (MSA-P), progressive supranuclear palsy (PSP) and The majority of these aggregates, mainly composed of alpha essential tremor. Imaging of the brain in patients with (α)−synuclein, are located at presynaptic level and impair ABSTRACT parkinsonism has the ability to increase the accuracy of axonal trafficking, resulting in a series of noxious events that differential diagnosis. Magnetic resonance imaging (MRI), cause neuronal damage to the substantia nigra pars compacta single photon emission computed tomography (SPECT) and with a subsequent dopaminergic denervation of the striatum. positron emission tomography (PET) allow brain imaging The cardinal motor features of PD (bradykinesia and rigidity, of structural, functional and molecular changes in vivo in with or without resting tremor) manifest after a substantial patients with PD. Structural MRI is useful to differentiate denervation of substantia nigra, which is associated with about PD from secondary and atypical forms of parkinsonism. 60–80% loss of dopamine terminals in the striatum. 123I-ioflupane (DaTSCAN TM ) SPECT is a valid tool in the The clinical presentation of PD includes a number of non- differential diagnosis between PD and non-degenerative motor symptoms such as hyposmia, constipation, depression tremors, while cardiac 123I-metaiodobenzylguanidine SPECT and sleep problems, among others. 2 Non-motor symptoms and 18F-fluorodeoxyglucose PET are valid in the differential have been associated with the damage induced by α-synuclein diagnosis between PD and atypical parkinsonism (MSA-P, aggregates in non-dopaminergic pathways, and PET PSP). However, despite significant evidence for the utility of molecular imaging has linked, for example, the development neuroimaging in assessing parkinsonian patients, none of the of depression 3 and weight changes 4 with deficits in the neuroimaging techniques are specifically recommended for serotonergic system in patients with PD. routine use in clinical practice. Hopefully, future larger trials will help to demonstrate additional evidence for the clinical utility of neuroimaging and will include an analysis of the Key points financial benefits for the NHS in the longer term management of the patients. No neuroimaging technique is specifically recommended for routine use in clinical practice for Parkinson’s disease (PD). Introduction 123I-FP-CIT (DaTSCAN TM ) SPECT can be used in the differential Since the 1970s, neuroimaging studies, including structural, diagnosis between PD and non-degenerative forms of functional and molecular imaging of the brain with the use of parkinsonism. magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission Brain MRI, cardiac 123I-mIBG SPECT and 18F-FDG PET have the tomography (PET), have aimed to assess the clinical utility of potential to differentiate PD from atypical parkinsonism. neuroimaging in patients with Parkinson’s disease (PD). 1 O n e of the scopes of neuroimaging studies is to identify mechanisms underlying clinical presentation of PD and their link with PET imaging provides the means to discriminate and reveal neuropathological changes. sub-phenotypes of PD and associations with non-dopaminergic deficits. Further larger neuroimaging trials, including NHS-related financial Authors: A clinical research fellow in neurology, Neurodegeneration analyses, are needed to evaluate the longer term benefits of these Imaging Group, King’s College London, London, UK ; B senior clinical techniques in the management of patients with PD. research fellow in neurology, Neurodegeneration Imaging Group, C King’s College London, London, UK ; clinical senior lecturer and KEYWORDS: Imaging, Parkinson’s, MRI, PET, SPECT, DaTSCAN™, consultant neurologist, Neurodegeneration Imaging Group, King’s mIBG, FDG ■ College London, London, UK © Royal College of Physicians 2016. All rights reserved. 371 CMJv16n4-CME_Pagano.indd 371 30/06/16 6:55 PM CME Movement disorders The clinical presentation of PD, therefore, could be heterogeneous because of underlying dopaminergic and non- Table 1. Diagnostic accuracy of MRI modalities. dopaminergic pathophysiology and overlap with other types of Technique Participants Sensitivity Specificity parkinsonism, including the parkinsonian variant of multiple (n) (%) (%) system atrophy (MSA-P), progressive supranuclear palsy (PSP), and essential tremor (ET). Neuroimaging modalities have the Abnormal putaminal MSA-P (24) 87.5 88.89 ability to increase the accuracy of differential diagnosis. 1 T2 hypointensity vs PD (27) Brain MRI uses different sequences and contrasts to study Proton density MSA-P (24) 83.3 100 brain structure and function while SPECT and PET imaging putaminal hyperintensity vs PD (27) use ionising radioactive ligands to quantitatively measure T1 MRI: midbrain PSP (25) vs 68 88.8 receptors, transporters or enzymes at nanomolecular level with superior profile PD (27) high specificity and power of resolution. This review discusses the role of neuroimaging in PD clinical practice (Box 1 ). T1 MRI: midbrain PSP (25) vs 68 77.7 atrophy PD (27) Structural and functional imaging T2 MRI: tegmental PSP (25) vs 28 100 hyperintensity PD (27) Traditional structural imaging modalities, such as X-ray computed tomography and brain MRI using anatomical T1 Putaminal T2 MSA (28) vs or T2-weighted sequences, are limited to use for identifying hypointensity T2 PD (32) 32 100 the dopaminergic deficits in the brain of patients with PD. hyperintensity PSP (30) 32 93 However, MRI can be useful in the identification of structural combined CBD (26) 32 85 lesions associated with other forms of parkinsonism, such Overall MRI PD (32) vs as those underlined by vascular pathology or neoplasms. abnormalities MSA (28) 71 91 Structural MRI can also be useful for measuring the degree PSP (30) 70 91 and distribution of brain atrophy. With regards to differential CBD (26) 92 91 diagnosis, it has been shown that abnormal T2 MRI hypo- T1 MRI: voxel-based PSP (12) 83 79 intensities in the putamen discriminate MSA-P from PD with 5 morphometry of versus PD 88% sensitivity and 89% specificity. Decreased putaminal cerebral peduncles and (12) signal intensities were higher using T2*-weighted gradient midbrain echo than T2-weighted fast-spin echo sequences and more useful in differentiating PD from MSA-P.6 Atrophy of the Diffusion-weighted MRI MSA-P (10) 100 100 superior cerebellar peduncles 7 and the frontal cortex 8 a l s o Putaminal rADC vs PD (11) aid in discriminating PSP from PD with 74/94% and 95/91% Putaminal hyperintense MSA-P (10) 80 91 specificity/sensitivity, respectively (Table 1 ). rim vs PD (11) Putaminal atrophy MSA-P (10) 60 100 vs PD (11) Box 1. Use of neuroimaging in Parkinson’s disease CBD = corticobasalganglionic degeneration; MRI = magnetic resonance clinical practice. imaging; MSA-P = multiple system atrophy parkinsonian type; PD = Parkinson’s disease; PSP = progressive supranuclear palsy; rADC = regional apparent In clinical practice, no neuroimaging modalities are currently diffusion coefficient. recommended for routine use. Structural MRI Advanced MRI modalities, such as diffusion-weighted Brain MRI is helpful to detect cerebrovascular damages and to imaging (DWI), spectroscopy, arterial spin labelling (ASL) quantify brain atrophy in patients with parkinsonism. MRI is and resting-state functional MRI, are showing promise for needed to identify the presence of a structural lesion (or lesions) detecting and discriminating PD cases from other forms of that may cause or contribute to parkinsonism, gait disorder parkinsonism. 9 DWI is based on effects of diffusion of water and tremor and should be considered in differential diagnosis molecules in MRI images and allows imaging of white matter between PD and other types of parkinsonism. axonal tracts, including the large-scale structural connections SPECT of the brain. Using single tensor DWI modelling, a study DaTSCAN TM SPECT should be considered in differential diagnosis showed that patients with PSP and MSA-P were differentiated 9 between degenerative and nondegenerative parkinsonism in from those with PD with 90–100% sensitivity and specificity. patients with tremor ( Box 2 ). Cardiac 123I-mIBG SPECT and However, this technique does not allow the separation of water 18F-FDG PET scanning should be considered in differential in brain tissue from water in extracellular space. A novel bi- diagnosis between PD and atypical forms of degenerative tensor diffusion analysis model was implemented in 2016 and 10 parkinsonism (MSA-P, PSP). used to discriminate PD from PSP and MSA-P. T h e y f o u n d that all forms of parkinsonism had elevated free-water in the 123 I-mIBG = 123 I-metaiodobenzylguanindine; 18 F-FDG = 18 F-fludeoxyglucose; DaTSCAN TM = 123I-ioflupane; MRI = magnetic resonance imaging; substantia nigra, but only PSP and MSA-P showed a broad MSA-P = multiple system atrophy parkinsonian type; PD = Parkinson’s disease; network of elevated free-water in the basal ganglia, thalamus, PET = positron emission tomography; PSP = progressive supranuclear palsy; and cerebellum. Spectroscopy allows direct imaging of a wide = SPECT single-photon emission computed tomography. range of endogenous compounds, such as dopamine, GABA, 372 © Royal College of Physicians 2016. All rights reserved. CMJv16n4-CME_Pagano.indd 372 30/06/16 6:55 PM CME Movement disorders glutamate, N-acetylaspartate and glutathione. A proton Table 2. Diagnostic accuracy of SPECT imaging: density hyperintensity was found uniquely in patients with MSA-P and was able to differentiate MSA-P from advanced differentiation of tremulous disorders.