Functional Imaging in Movement Disorders: Diagnostic Advantages

Parkinson disease (PD) affects an estimated 10 million people worldwide, surpassed only by Alzheimer disease.¹ Despite its prevalence, clinical diagnosis is rarely clear. Fortunately, functional imaging can help neurologists navigate diagnosis and inform treatment and patient outcomes.

When to Use Functional Imaging

The neurologists’ goal is to diagnose Parkinson’s before the appearance of motor symptoms, as interventions can be too little, too late once motor symptoms occur. It is during these stages of the disease that functional imaging can be used to diagnose Parkinson’s earlier and with the confidence to offer interventions.²

Molecular imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), in particular, are gaining widespread use in the diagnosis and differentiation of PD from Parkinson’s “plus” or atypical parkinsonism (AP).

AP includes progressive diseases that present with some of the symptoms present in PD and include:

• progressive supranuclear palsy
• multiple system atrophy
• corticobasal degeneration
• dementia with Lewy bodies

Functional imaging is also helpful to differentiate AP from conditions with similar pathologies such as essential tremor, dopa-responsive dystonia, Alzheimer disease, and postneuroleptic, psychogenic, and vascular parkinsonism.³

Functional Imaging in Practice

PET and SPECT can be used on an individual basis to confirm diagnosis or correct misdiagnosis. Such molecular techniques will not render the clinical symptom-based diagnosis obsolete, but can be used alongside traditional diagnosis for better accuracy and to reduce false positives or false negatives.

The widely used SPECT technique relies on presynaptic dopaminergic innervation, using the radiotracer/radiolabel [¹²³I]-Ioflupane (SPECT) to visualize brain regions for the presence or absence of dopaminergic degeneration; which is a function of dopamine transporter availability or deficiency. PET techniques, in contrast, rely on [¹⁸F]-Dopa radiolabel that visualizes possible dopaminergic degeneration by analyzing dopa-decarboxylase activity.⁴

These 2 types of functional imaging are primarily used for preclinical diagnosis or differential diagnosis.

Diagnosis Using [¹⁸F]-Dopa PET and/or [¹²³I]-Ioflupane SPECT

Using these functional imaging tools, early diagnosis of PD has been possible with patients exhibiting LRRK2 gene mutations, hyposmia, and rapid eye movement sleep behavior disorder. In patients with this disorder, SPECT and PET allow for diagnosis of PD and AP in up to 40% of cases.²

Difficulties with preclinical diagnosis result from lower sensitivities caused by smaller dopaminergic uptake deficiencies in patients with rapid eye movement sleep behavior disorder than in those exhibiting motor symptoms. Although promising and better than symptom-based diagnosis, more longitudinal studies are needed to assess the efficacy of functional imaging for preclinical diagnosis.

In patients diagnosed with PD, functional imaging allows differentiation of PD and AP from essential tremor and different forms of parkinsonism. Indeed, the value of these functional imaging techniques for differential diagnosis has been demonstrated in several studies:

• Patients with essential tremor will have normal dopamine transporter uptake in SPECT and will not proceed to PD in 65% to 100% of cases, whereas those with reduced dopaminergic uptake could progress to PD in 65% of the cases. Specificity of SPECT for detecting PD and AP is as high as 100%.^3,5,6
• Those exhibiting psychogenic parkinsonism and postneuroleptic parkinsonism will have normal dopamine transporter uptake in SPECT and PET scans.^3,7 Drug-induced parkinsonism, however, will have reduced dopamine uptake in SPECT scans.³
• Vascular parkinsonism (via leucoaraiosis) exhibits normal or mild reduction in radiolabel uptake in striatal SPECT and PET scans. Parkinsonism based on striatal and substantia nigral stroke will exhibit major ipsilateral reduction in SPECT radiotracer uptake.³
• Studies have shown normal SPECT and PET scans in patients with dopa-responsive dystonia. Early-onset PD also shows a normal scan, with disease progression being the sole differentiator.³
• SPECT and PET scans are normal for patients with Alzheimer’s, but show degeneration in patients with dementia with Lewy bodies. Sensitivity and specificity of [¹²³I]-Ioflupane SPECT for differentiating dementia with Lewy bodies over Alzheimer’s are about 80% and 92%, respectively, in clinically diagnosed and autopsy diagnosed cases.^8.9

Advances in Functional Imaging

Routine [¹²³I]-Ioflupane SPECT and [¹⁸F]-dopa PET scans differentiate PD, AP, and dementia with Lewy bodies from nonparkinsonian syndromes, appearing as reduced radiolabel binding in scans of diagnosed patients and as normal for patients with nonparkinsonian disorders. PD and AP, however, are difficult to differentiate with [¹²³I]-Ioflupane SPECT and [¹⁸F]-dopa PET techniques.

Fortunately, several newer techniques that involve postsynaptic dopaminergic radiotracers, brain perfusion, and cerebral glucose metabolism are showing promising results in AP differentiation. Postsynaptic radiolabels such as [¹²³I]-IBZM SPECT or [¹¹C]-Raclopride PET are useful in untreated patients and can differentiate PD from multiple system atrophy and progressive supranuclear palsy, although patients receiving medications will have skewed results as a result of interference of dopaminergic drugs on radiolabel uptake and detection.¹⁰

Cerebral glucose metabolism studies using [¹⁸F]-FDG PET show it also to be a promising method to separate PD from AP. Studies have shown >75% sensitivity and >90% specificity, leading to 90% correct diagnosis.^11,12 AP has characteristic hypometabolism patterns that are distinguishable from each other and from PD:

• Progressive supranuclear palsy presents with bilateral frontal hypometabolism.
• Multiple system atrophy will have bilateral striatal hypometabolism.
• Corticobasal degeneration will have a characteristic asymmetrical frontoparietal hypometabolism.
• DLB can be distinguished by its bilateral occipital hypometabolism.

Another exciting area of advancement in functional imaging involves the use of PET radiotracers with affinity for tau proteins (which have been implicated in Alzheimer’s, PD, and some forms of AP). The radiotracer [¹⁸F]-AV1451, also known as [¹⁸F]-flortaucipir, can allow progressive supranuclear palsy and Alzheimer disease differentiation by means of tau deposit levels of basal ganglia and mesencephalon. Increased deposits of tau proteins are found in progressive supranuclear palsy vs patients with Alzheimer disease and control patients. In the temporal cortex, in contrast, increased deposits of tau protein are found in patients with Alzheimer disease vs progressive supranuclear palsy and control.¹³

By employing functional imagining techniques when patients present with preclinical and prodromal symptoms, PD and AP can be detected before the appearance of motor symptoms. These techniques can also help differentiate AP from related conditions. By employing other radiolabels, such as [¹²³I]-IBZM SPECT or [¹¹C]-Raclopride PET and [¹⁸F]-FDG PET, PD and AP can be more effectively differentiated. With such advances in functional imaging, the future looks to be 1 in which preclinical diagnosis and the accurate identification of different parkinsonian syndromes is in sight, enabling faster diagnosis and intervention.

References

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10. Politis M, Wilson H, Wu K, Brooks DJ, Piccini P. Chronic exposure to dopamine agonists affects the integrity of striatal D receptors in Parkinson’s patients. Neuroimage Clin. 2017;16:455-460.
11. Hellwig S, Amtage F, Kreft A, et al. [¹⁸F]FDG-PET is superior to [¹²³I]IBZM-SPECT for the differential diagnosis of parkinsonism. Neurology. 2012;79(13):1314-1322.
12. Walker Z, Gandolfo F, Orini S, et al. Clinical utility of FDG PET in Parkinson’s disease and atypical parkinsonism associated with dementia. Eur J Nucl Med Mol Imaging. 2018;45(9):1534-1545.
13. Whitwell JL, Lowe VJ, Tosakulwong N, et al. [¹⁸F]AV-1451 tau positron emission tomography in progressive supranuclear palsy. Mov Disord. 2017;32(1):124-133.