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Table of Contents    
Year : 2018  |  Volume : 66  |  Issue : 7  |  Page : 68-78

Neuroimaging in Parkinsonian Disorders

1 Department of Nuclear Medicine, All Institute of Medical Sciences, New Delhi, India
2 Department of Radiology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication1-Mar-2018

Correspondence Address:
Dr. Madhavi Tripathi
Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.226460

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 » Abstract 

Neuroimaging (NI) in Parkinson's disease (PD) includes functional techniques like positron emission tomography (PET) and single photon emission computed tomography (SPECT), and morphological imaging using magnetic resonance imaging (MRI) and transcranial sonography to probe different aspects of the neurobiology of PD. Changes in neurotransmitters in various regions of the brain and their influence on brain networks is the basis for the motor symptoms of PD which are interrogated by NI. The recent Movement Disorders Society Clinical Diagnostic Criteria for PD (MDS-PD) have included the results of a few of these neuroimaging techniques to serve as single supportive criteria or absolute exclusion criteria for the diagnosis of PD. While dopaminergic imaging is useful in the early stages of disease to differentiate the neurodegenerative versus non-degenerative causes of parkinsonism like essential tremors, it has also been used for the differential diagnosis of dementia with Lewy bodies (DLB) from Alzheimer's disease (AD), for inclusion of PD patients into clinical trials and for evaluating response to cell–replacement therapies in PD. Metabolic patterns on F-18 fluorodeoxyglucose positron emission tomography have been used effectively for the classification and differential diagnosis of the parkinsonian syndromes using visual and quantitative approaches. Disease related network-patterns have been used for a completely automated approach to differential diagnosis of parkinsonian syndromes on a single case basis. Structural MRI and advanced MR techniques have been used for the classification of PD and the atypical parkinsonian syndromes. Thus, multimodal imaging in PD may aid in an early, accurate and objective diagnostic classification by highlighting the underlying neurochemical and neuroanatomical changes that underlie this spectrum of disorders. The present challenge in PD is to develop radioligands which could bind selectively to alphasynuclein in-vivo.

Keywords: Parkinson's disease, functional, dopaminergic, F-18 fluorodeoxyglucose, Tc-99m dopamine transporter imaging, 99mTc- TRODAT-1 SPECT imaging

How to cite this article:
Tripathi M, Kumar A, Bal C. Neuroimaging in Parkinsonian Disorders. Neurol India 2018;66, Suppl S1:68-78

How to cite this URL:
Tripathi M, Kumar A, Bal C. Neuroimaging in Parkinsonian Disorders. Neurol India [serial online] 2018 [cited 2023 Dec 10];66, Suppl S1:68-78. Available from:

Key Message:
Functional and structural neuroimaging provide useful tools for the evaluation of parkinsonian syndromes. Dopaminergic imaging is useful for the diagnosis of neurodegenerative parkinsonism in its early stages. Dopaminergic imaging, however, has not been proven to be useful for the differential diagnosis of PD resulting from atypical parkinsonian syndromes. Therefore, metabolic and perfusion imaging and structural MRI can be used for the classification of parkinsonian syndromes while dopaminergic and metabolism imaging is useful for the differential diagnosis of dementia with Lewy bodies (DLB) from Alzheimer disease (AD). Molecular tools for imaging pathology, like in vivo amyloid and tau, have also provided useful insights especially in the evaluation of cognitive impairment associated with this group of disorders.

Parkinson's disease (PD) is the best studied of all movement disorders. PD is a progressive neurodegenerative disorder which is characterized by the loss of dopaminergic neurons in the substantia nigra-pars compacta [1] resulting in a striatal dopaminergic deficit [2] which underlies the motor manifestations that characterise this disease. The demonstration of intracytoplasmic Lewy bodies is the pathological hallmark of PD and is necessary for a definitive diagnosis of PD.[1],[2] In fact, PD and the secondary or atypical parkinsonian syndromes (APS) of multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS) are proteinopathies which are characterized by aggregation of misfolded proteins like alpha synuclein seen in PD and MSA or Tau (seen in PSP and CBS).

The gold-standard diagnostic technique in PD is expert clinical opinion. The sensitivity for establishment of a clinical diagnosis of PD by a movement disorder specialist has been reported to be as high as 91.1% in clinicopathological studies.[3] A recent study has, however, clearly demonstrated a difference in diagnostic accuracies between early and advanced disease.[4] Early in the course of the disease, the hallmarks of the disease pathology may not manifest, and it progression and treatment response may be undefined, making clinical diagnosis uncertain (clinically uncertain Parkinsonian syndrome; CUP). Neuroimaging (NI) in these early stages can help to distinguish PD from PD-mimics. It can also aid in the differential diagnosis of parkinsonian syndromes, monitor disease progression, and measure the effects and complications of various therapies.

In this article, we will briefly be reviewing the role of magnetic resonance imaging (MRI), and functional imaging modalities- single photon emission tomography (SPECT) and positron emission tomography (PET)- in the evaluation of the Parkinsonian syndromes of PD, MSA, PSP, and CBS.

MRI in parkinsonian syndromes

MRI has been extensively used in the imaging of parkinsonian syndromes. Besides the conventional MRI sequences, recent advanced techniques including diffusion weighted imaging with tensor imaging, MR morphometry, magnetisation transfer imaging and MR spectroscopy have also been used in the diagnosis of these group of disorders. Imaging is helpful to confirm the diagnosis of parkinsonian syndromes, classify them into various subtypes, rule out the alternative differential diagnosis and determine the severity of brain changes.

Conventional MRI

The various subtypes of disorders constituting the spectrum of parkinsonian syndrome may show a wide range of imaging findings depending upon the severity of the disease and the subtype. The imaging findings may vary from a completely normal scan to the classical diagnostic features. Overall, the imaging is highly specific to differentiate between PD and APS like PSP, multisystem atrophy – parkinson variant (MSA-P) and CBS.

Parkinson's disease

The conventional T1 and T2 weighted MR images, especially at 1.5 Tesla strength, are often normal in Parkinson's disease. The MRI is more often used to rule out other conditions like demyelination, vascular insults and normal pressure hydrocephalus. The advanced cases may show hyperintense signal changes on T2 weighted images in bilateral substantia nigra [Figure 1] as the only finding.[5]
Figure 1: Axial T2 weighted MR image at the level of midbrain shows hyperintense signal changes (arrows) involving bilateral substantia nigra in this patient of Parkinson's disease

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Progressive supranuclear palsy

The characteristic imaging findings in PSP include atrophy of the midbrain with signal changes on T2 weighted images. The tegmentum, inferior olives and superior cerebellar peduncles show atrophy resulting in prominent cerebrospinal fluid (CSF) spaces around the midbrain. On a sagittal view, the shape of the midbrain tegmentum and the pons in these patients is described as a 'hummingbird' sign.[6]

Multisystem atrophy – Parkinson variant (MSA-P)

Patients suffering from MSA-P show changes in both the supra and infra-tentorial brain tissue. The characteristic infra-tentorial findings include atrophy of the pons with signal changes on T2 weighted images giving rise to the classical 'hot cross bun' sign [Figure 2], cerebellar atrophy and hyperintensity of middle cerebellar peduncles. The supratentorial findings include atrophy of the putamen with slightly hypointense signal changes on T2 weighted images with a hyperintense putaminal rim. These findings are not very sensitive but are highly specific, and thus, can be used to differentiate between MSA-P and PD.[7],[8]
Figure 2: Axial (a) and sagittal (b) T2 weighted images of a patient of MSA-P shows the classical 'hot cross bun' sign in the midbrain (arrows in A). Note the marked atrophy of the pons (arrow in B) and the cerebellum

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Cortico-basal degeneration

The imaging findings are non-specific in CBD and include cortical atrophy with signal changes in the cortex and subcortical white matter. The putamen may also show hypointensity on T2 weighted images, as seen in MSA-P.[7]

Advanced MR techniques

Diffusion weighted and diffusion tensor imaging

Patients of PD have shown decreased fractional anisotropy (FA) values in the region of substantia nigra as compared to healthy controls in various studies published in literature. This can help to diagnose PD even when no changes are seen on conventional MR images. Similarly, measurement of increased diffusivity values in the putamen, middle cerebellar peduncles and superior cerebellar peduncles have been tried by various researchers to differentiate atypical Parkinson's syndromes from PD and also from each other.[9]

Volumetry and morphometry

Advanced MR software allows quantitative measurement of volumes of various regions of the brain. Quantitative assessment of volume of the regions involved in the Parkinson's disorders like the putamen, cerebellar peduncles, midbrain, pons and cerebral cortex is helpful to objectively determine the volume loss which is an integral feature of the disorders. Selective volume loss of one region compared to the other is helpful in differentiating the various disorders.[10]

MR spectroscopy

MR spectroscopy helps to determine the levels of various metabolites in the brain parenchyma. Spectroscopy done in the affected region shows a decreased N-acetylaspartate to creatine (NAA/Cr) ratio. Evaluation of the pons, midbrain and putamen can be done for differentiating the various subtypes.[11]

Magnetisation transfer imaging

Various studies in literature have shown that magnetization transfer (MT) ratios are decreased in the involved regions of the brain. Hence measurement of MT ratios in the substantia nigra, putamen and brainstem can be helpful in the diagnosis of PD and also to differentiate one from the other subtype.[11],[12]

Hybrid imaging

Integrated PET/MRI has made it possible to obtain structural (MRI) and functional (PET) information simultaneously on the same platform.[13] The advantage of PET/MRI as a single-investigation for the comprehensive evaluation of neurodegenerative disorders like PD is foreseeable. The role of PET/MRI, utilizing the F-18 florbetaben labelled stilbene derivative, a radiopharmaceutical developed to visualize beta-amyloid plaques in the brain in diagnosing Alzheimer's disease (AD) and in differentiating it from dementia associated with Lewy body (LBD) has been reported.[14]

Echogenic Imaging

Transcranial sonography is a noninvasive imaging technique in Parkinsonism. A hyperechogenic substantia nigra in patients with PD [15] and a hyperechogenic lentiform nucleus in patients with PSP, MSA or CBS have been used for establishing the imaging diagnosis of the disease.[16],[17] The diagnostic accuracy of this modality is establishing the presence of early PD is still under evaluation.

 » Functional Imaging-Spect and Pet Top

Dopaminergic imaging


The dopaminergic pathway is the key neurotransmitter system implicated in PD and APS and radiotracers that bind to various targets on the presynaptic and postsynaptic dopaminergic nerve terminal [Figure 3] and [Table 1] can be used to assess the integrity of this pathway.
Figure 3: Dopaminergic nerve terminals and targets for dopaminergic radiotracers in vivo

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Table 1: Dopaminergic imaging targets and SPECT and PET radioligands targeting these sites

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The three major targets on the presynaptic dopaminergic nerve terminal [Figure 3] are A) aromatic acid decarboxylase (AADC) which converts dopa to dopamine (DA) and is assessed using F-18 fluoro-dihydroxyphenylalanine (FDOPA) PET; B) Dopamine transporter (DAT) which can be assessed using technetium-99m (Tc-99m) ([2-[2-[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3, 2, 1]oct-2-yl] methyl](2-mercaptoethyl)- amino] ethyl] amino] ethanethiolato (3-)-N2, N2', S2, S2']oxo-[1R-(exo-exo)]) [TRODAT-1] SPECT; I-123 2-β-carboxymethoxy- 3 β-(4-iodophenyl) tropane (βCIT) and its fluroalky esters; fluorinated N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane (FPCIT) (DAT scan) [SPECT tracer]; and,123 I-FP-CIT (N-ω-fluoropropyl-2β-carboxymethoxy-3β-{4-iodophenyl} tropane) [F-18 FP-CIT] (PET tracers); and, C) Vesicular monoamine transmitter (VMAT), located on the vesicular membrane, that is responsible for transporting dopamine from the cytoplasm into the secretory vesicles, can be assessed using F-18 fluoropropyl-dihydrotetrabenazine (DTBZ) PET.

The imaging pattern of striatal involvement for all tracers [Figure 4] is similar in PD with an asymmetric striatal decrease, which is more marked contralateral to the clinically affected side with a rostro-caudal gradient of uptake in which the posterior putamen is maximaly affected.[18],[19],[20],[21],[22],[23],[24] This posterior putaminal decrease is because neuronal loss in early PD takes place in the ventrolateral part of the substantia nigra which projects to the posterior putamen.[25] The uptake of the dopaminergic tracers declines with disease progression.[20],[26] In animal models, the reduction of the dopaminergic tracer uptake has correlated with striatal dopamine and fibre density upto a limited fibre loss of approximately 50%.[27] Semi-quantitative evaluation of the regional and sub-regional patterns of dopaminergic loss in the striatum using striatum-to-occipital ratios (SOR) can be used alongside visual interpretation. These SOR's have been used to assist in the differential diagnosis of disease entities amongst the Parkinsonian syndromes. The Parkinson plus syndromes of MSA and PSP demonstrate an earlier and a greater reduction of striatal binding in the ventral putamen and anterior caudate respectively, resulting in a lower gradient of uptake between the dorsal and ventral striatum.[28],[29]
Figure 4: Top row-Tc-99m TRODAT SPECT images of a (a) normal control, (b) early PD-showing decreased tracer binding in the left putamen, and (c) advanced PD showing decreased binding in both putamina. Bottom row-FDOPA PET images of a (d) normal control, (e) early PD-showing decreased tracer uptake in the left putamen, and (f) advanced PD showing decreased tracer uptake in both putamina

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In terms of practical clinical utility, dopaminergic imaging can help to distinguish PD from PD-mimics like essential tremor, vascular parkinsonism, drug-induced parkinsonism and psychogenic parkinsonism. However, its utility in differentiating PD from the atypical parkinsonian syndromes is limited.[30],[31],[32] Dopaminergic imaging is also useful in assisting in the differentiation of DLB from AD, wherein it is a indicative biomarker that can be used for the diagnosis of probable or possible DLB.[33] DAT imaging can distinguish DLB from AD with 78-80% sensitivity and 90-92% specificity.[34],[35]

The sensitivity and specificity of DAT tracers for differentiating parkinsonism from non-parkinsonian states, like essential tremors and drug induced parkinsonism, has been in the range of 87-100% and 80-100%, respectively.[36],[37] The reported sensitivities and specificities for FDOPA PET have ranged from 90-100% and 91-100%, respectively.[38],[39] Overall, PET imaging has a superior sensitivity and spatial resolution to the SPECT imaging; however, this is achieved at a higher cost. In the early stages of the disease process, there is a downregulation of DAT, while AADC activity is upregulated in the surviving dopaminergic neurons; thus the reduction in striatal uptake is greatest for the DAT ligands.[40] Interestingly, it has been shown that VMAT2, DAT and FDOPA binding declines in approximately 17 years, 13 years and 6 years, respectively, before the onset of the disease.[41] A good correlation between the DAT SPECT and FDOPA PET imaging has been demonstrated in patients with de novo and advanced Parkinson's disease.[42] Dopaminergic dysfunction has also been shown in recessive Parkin and PINK1 (PTEN-induced putative kinase 1] mutations and in LRRK2 (leucine-rich repeat kinase) and GBA (glucocerebrosidase) mutations, wherein the dopaminergic defect is indistinguishable from that of sporadic PD.[43],[44]

The degree of reduction in the tracer uptake targeting the dopaminergic sites appears to be strongly correlated with bradykinesia and rigidity,[24],[25],[45] while tremor appears linked to the serotonergic dysfunction.[46],[47] A PET scan using serotonin transporters (SERT) and 5 hydroxytryptamine 1 A (5HT1A) receptor binding has revealed that a decline in serotonergic function in raphe nuclei and corpus striatum striatum correlates with increased tremor scores. The SERT PET scanning has also shown that patients with tremor-dominant PD have more globally impaired serotonergic function than do those with akinetic-rigid PD.[48] Further, putaminal uptake appears more closely related to the motor function than the tracer uptake in the caudate nucleus.[49],[50],[51] Cortical and thalamic cholinergic hypofunctioning rather than dopaminergic dysfunctioning is associated with the risk of fall that occurs in patients with in PD, perhaps relating to the thalamic innervations from the pedunculopontine nucleus.[52]

Patients with PD have been shown to have a mean annual decline in dopamine capacity ranging from 8-12% in the putamen, and 4-6% in the caudate nucleus, while the decline with age is approximately 0.5% in the putamen and 0.7% in the caudate nucleus.[30],[32] At the time of symptom onset, evidence has indicated that approximately six years of dopaminergic decline have elapsed with a 30-55% loss of putaminal uptake persisting.[53]

Normal functional neuroimaging of the preynaptic dopaminergic system, if it has been performed, is an absolute exclusion criteria for the diagnosis of PD by the Movement Disorders Society Clinical Diagnostic Criteria for PD (MDS-PD).[54] Thus, ideally 'scans without evidence of presynaptic dopaminergic dysfunction' (SWEDDs) relate to patients who, in reality, do not have PD and should not be included in clinical trials for PD.[55] The concept of 'SWEDD' was highlighted when dopaminergic imaging was used for inclusion of patients into clinical trials for the detection of early PD. Approximately, 1-14% of patients who were clinically diagnosed as having PD and underwent FDOPA imaging, did not show evidence of dopaminergic deficit on their imaging.[55]

Dopaminergic imaging has been used as a primary and secondary endpoint in various clinical trials investigating the treatments for PD. It has been useful for following the status of transplanted embryonic dopaminergic tissue for an in vivo assessment of the graft viability. Imaging changes reliably correlate with clinical outcome in the post-transplantation period.[56] Unpublished data from our centre has shown encouraging results regarding the ability of DAT imaging in predicting clinical outcome following the administration of in-vivo cell-replacement therapies [Figure 5].
Figure 5: Tc-99 m TRODAT SPECT images of a 54- year old diagnosed case of PD who underwent cell replacement therapy, upper row-plain SPECT and bottom row-fused SPECT/CT images at three time points (a) before intervention showing presynaptic dopaminergic dysfunction (B/L), (b) one month and (c) three months after therapy showing definite improvement of tracer binding in both basal ganglia

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After its release into the synaptic cleft, dopamine (DA) interacts with the post-synaptic D1 and D2 receptors. D2 receptor imaging has been used to differentiate PD from the atypical parkinsonian syndromes with a good diagnostic accuracy of about 90%.[57],[58] D2 binding is normal in patients with PD and is decreased in those having the Parkinson plus syndromes. A few recent studies have, however, indicated that a normal D2-receptor binding does not exclude a diagnosis of MSA or PSP.[59],[60] Moreover, the D2 imaging cannot be used to classify the various APS subtypes (MSA, PSP and CBS).

Perfusion and metabolism imaging

'Resting-state' measures of regional glucose utilisation in the brain can be evaluated using F-18 Fluorodeoxyglucose (FDG) PET. PD and the APS have characteristic metabolic patterns that have been validated as metabolic signatures of the disease process.[61],[62],[63],[64] The characteristic metabolic pattern have been described in [Table 2], and illustrated in [Figure 6], [Figure 7], [Figure 8]. These metabolic phenotypes have been utilized for differentiating idiopathic PD from APS, and also for differentiating amongst the subtypes of APS using visual and quantitative approaches like statistical parametric mapping (SPM).[65],[66] The sensitivity and specificity for a classification based on F-18 FDG-PET for detecting PD, MSA and PSP is 75% and 100%, 100% and 87% and 86% and 94%, respectively.[67] Similar patterns have also been demonstrated on perfusion imaging using SPECT [68] and PET tracers.
Table 2: Pattern of dopaminergic binding and metabolic patterns in PD and APS

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Figure 6: (a) Tc-99m TRODAT SPECT images of a case of early PD showing presynaptic dopamnergic dysfunction, (b) plain F-18 FDG PET images of the same patient showing the right putaminal hypermetabolism

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Figure 7: Top row (a) Tc-99m TRODAT SPECT images of a case of MSA-P showing bilateral presynaptic dopamnergic dysfunction, (b) F-18 FDG PET/CT showing bilateral putaminal hypometabolism. Bottom row: F-18 FDG fused PET/CT images of a case of MSA (mixed) showing (c) bilateral putaminal hypometbolism and (d) cerebellar hypometabolism

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Figure 8: Top row (a) Tc-99m TRODAT SPECT/CT images of a case of PSP showing presynaptic dopaminergic dysfunction, (b) F-18 FDG fused PET/CT images showing bilateral basal ganglia, and (c) midbrain hypometabolism. Bottom row: F-18 FDG PET images of a case of CBS showing hypometabolism in the right basal ganglia and right fronto-parietal cortex. Clinical symptoms were more marked on the left side

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To overcome the dependency on the expertise of the reader for the interpretation of visual images, data driven, statistically robust techniques like the scaled subprofile model (SSM) have been put forward. SSM is a spatial covariance method based on principal component analysis (PCA) to assess subjects by region-wise effects seen in perfusion and metabolism-functional brain images.[69],[70],[71] SSM-PCA has been used to derive 'network patterns' for PD, PSP, MSA and CBS, which have been validated on various patient populations.[72],[73],[74],[75],[76] The spatial covariance pattern that is specific for PD is called 'Parkinson's disease related pattern'(PDRP), which is characterised by pallido-thalamic and pontine hypermetabolism with hypometabolism in the prefrontal and parieto-occipital cortices.[72] This pattern basically represents the functional alteration in the cortico-striato-pallido-thalamo-cortical loops which results from the underlying dopaminergic deficit in PD.[77] The degree of PDRP expression has been shown to correlate with the clinical severity of the disease, thus providing a potential biomarker of disease progression.[73] PDRP expression has been shown to have excellent test-retest reproducibility and a consistent linear relationship with standardized motor ratings in multiple patient cohorts.[74] PDRP expression is useful for the differential diagnosis of PD from APS. In the absence of dopaminergic medication, perfusion and metabolism are coupled and PDRP expression can be measured in resting cerebral perfusion studies obtained with O-15 H2O PET or with Tc-99m ethylcysteinate dimer (ECD) SPECT.[71],[78],[79]

The network pattern derived for PSP and MSA is called the PSP-related pattern (PSPRP) and MSA-related pattern (MSARP), respectively.[80] Recently, the CBS related network pattern has been derived and validated.[76] PSRP is characterized by anterior cingulate, midbrain and basal ganglia hypometabolism, while MSARP is characterized by posterior putamen (MSA-P) and/or cerebellar hypometabolism (MSA-mixed and MSA-C, respectively). The CBS related pattern is characterized by bilateral asymmetric metabolic reductions involving the frontal and parietal cortex, thalamus and caudate nucleus. The metabolic reductions are much greater in the cerebral hemisphere opposite to the more clinically affected side. These disease related patterns have been used to develop a completely automated software driven approach for the differential diagnosis of PD from APS, and for differentiating various APS subtypes on a single case basis.[81] This algorithm has also been validated in an Indian subset of patients with Parkinsonism.[82] This image-based classification had a 96% positive predictive value (PPV) in differentiating PD from APS, a 85% PPV for differentiating MSA, and 94% PPV for differentiating PSP. Accurate results were also obtained when this completely automated software driven approach was utilized to classify these diseases in the subset of patients with a short symptom duration.

The practical clinical utility of these disease-specific patterns and the automated differential diagnosis algorithm is that these modalities can be applied to make a differential diagnosis of the parkinsonian syndromes on a single-case basis, especially early on in the disease course even in patients with atypical presentations.

Cardiac sympathetic denervation

Cardiac postganglionic sympathetic denervation is an associated autonomic co-morbidity in PD [83]following alpha-synuclein deposition in the autonomic cardiac plexus and distal axons.[84] Iodine-123(I-123) meta-iodobenzylguanidine (MIBG) is a guanethidine analogue and is taken up by the post-ganglionic sympathetic neurons by the uptake -1 mechanism. There is reduction of the myocardial uptake of I-123 MIBG in early PD. Relative preservation of myocardial I-123 MIBG uptake is seen in APS, which is associated with central and preganglionic sympathetic dysfunction. I-123 MIBG myocardial scintigraphy is, therefore, useful to differentiate PD from APS. The other tracers that can be used to evaluate the myocardial postganglionic sympathetic integrity include C-11 hydroxyephedrine (HED) and F-18 fluorodopamine.[85] A combination of DAT SPECT and MIBG scintigraphy has been suggested to improve the specificity of diagnosis of PD.[86]

MIBG scintigraphy documenting cardiac sympathetic denervation has been included in the supportive criteria of the MDS-PD clinical diagnostic criteria for PD.[54] The applicability of MIBG scintigraphy in routine clinical practice is limited by issues related to the availability of tracers.

Parkinson's disease dementia (PDD)

Over 80% of patients with PD develop dementia over 20 years into the disease process.[87] PD dementia shares a number of characteristics with dementia with Lewy bodies (DLB).[88] Guidelines have suggested that patients who develop parkinsonism a year or more before the onset of dementia are likely to be having PDD; and, those who develop dementia and parkinsonism concurrently are more likely to be belonging to the DLB category.[89] Several pathological processes have been implicated in PDD, which include degeneration of the dopaminergic neurons, cholinergic dysfunction, Lewy body and amyloid plaque deposition in neocortical regions and also the presence of a vascular pathology.[90] F-18 FDG PET can be used to distinguish between PDD or DLB and Alzheimer's disease related dementia (AD). DLB is characterised by metabolic reductions in the primary visual and medial occipital cortex with preserved uptake in the posterior cingulate cortex (the 'cingulate island sign'). In AD, the visual cortices show a relatively preserved uptake with a decrease in the uptake in the posterior cingulate cortex. Hypometabolism in the visual cortices has been included in the list of supportive features for the diagnosis of probable-DLB.[89] The sensitivity and specificity of metabolic patterns that may be helpful in distinguishing DLB from AD is 90% and 80%, respectively and has been found to be greater than that of the clinical diagnostic criteria applied retrospectively to data from a review of the medical charts.[91],[92] As mentioned earlier, dopaminergic imaging can also be used for differentiating DLB from AD.

PD-related cognitive pattern (PDCP) is the covariance pattern that underlies the cognitive dysfunction (executive functioning) in PD. This pattern is characterized by a metabolic reduction in the frontal and parietal association cortices; and, an increase in this parameter in the cerebellar vermis and dentate nuclei.[93] The PDCP expression increases with worsening cognitive performance [94] but does not correlate with concurrent decline in the dopaminergic function.[95]

Cholinergic denervation is an early phenomenon in PD and is more marked in patients suffering from PDD (post-mortem evidence suggests loss of forebrain cholinergic function is associated with PDD) than in non-demented patients with PD.[96],[97],[98]

Imaging pathological in-vivo targets

Neurodegenerative disorders are characterised by aggregates of misfolded proteins, alpha-synuclein in PD and MSA, and tau proteins in PSP and CBS. Alpha-synuclein is the pathological hallmark of PD and currently efforts are directed to find ligands which could be used to label alpha-synuclein in-vivo. Presently, radiolabelled tracers are available to perform an in vivo imaging of amyloid and tau aggregates [Table 3].
Table 3: Pathological targets and tracers for in vivo imaging

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Amyloid-β (Aβ), which is the pathological hallmark of AD, can contribute to cognitive impairment in PD. While cortical Aβ is infrequent in PDD, patients with DLB show increased cortical retention of Aβ.[99] Amyloid imaging agents like C-11 Pittsburg compound B have been used to demonstrate the cortical retention of amyloid Aβ in DLB and PDD.[100],[101] Aβ retention in patients with PD and mild cognitive impairment places them at an increased risk for further cognitive decline in the future.[102],[103] C-11 labelled tracers need an on-site cyclotron, while the availability of F-18 labelled tracers targeting amyloid in-vivo has overcome this limitation. Cost and availability issues limit the use of these tracers.

Recently, a number of groups have come up with radiolabelled benzimidazole, benzimidazole pyramidine, benzothiazole and quinoline derivatives for tau imaging [Table 3]. Retention of F-18 THK-5351 (a quinoline derivative) has been shown in the globus pallidus and midbrain of patients with PSP.[104] Tau aggregates differ in isoforms and conformations across disorders, and as a result, one radiotracer may not be appropriate for all taupathies. Also, the specificity and selectivity for tau binding poses a major limitation of these agents. C-11 PBB3, a benzothoiazole derivative, was used in PSP patients. These patients showed an increased retention of the tracer in the basal ganglia. However, binding was also seen in a case of MSA, which is not typically associated with pathological tau deposition. This suggests the possibility that C-11 PBB3 binds to alpha-synuclein,[105] thus limiting its specificity.

 » Conclusion Top

Neuroimaging in Parkinsonian disorders in the clinical setting can support an early diagnosis of PD and differentiate PD from APS. The present guidelines have supported SPECT and PET techniques in the clinical diagnostic criteria for PD. PET is an expensive molecular tool; availability issues, therefore, are a major concern for its widespread implementation. Inclusion of patients into clinical trials for PD, as well as the use of dopaminergic imaging for following the effects of interventional therapies has also been suggested to help in unequivocally differentiating between various disease entitites presenting with parkinsonian features. Hybrid PET/MRI protocols are expected to provide a comprehensive evaluation of the parkinsonian syndromes; and, the results of studies investigating the role of radioligands for an in vivo alpha-synuclein imaging are eagerly awaited.


The authors wish to acknowledge Mr Ramchandra B Pokale, senior artist for his help with the figures. The authors would also like to thank the movement disorder specialists associated with them.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]

  [Table 1], [Table 2], [Table 3]

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