The role of radiotracer imaging in Parkinson disease

Abstract

Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.

Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy

“…Because nigrostriatal DA deficiency characterizes PD, a variety of means to visualize abnormalities of DA uptake or storage have been developed, such as 6-[ 18 F]fluorodopa positron emission tomographic (PET) scanning [1]. The occipital cortex (OCC) contains scant dopaminergic innervation; one can quantify striatal DA deficiency from the PUT:OCC ratio of 6-[ 18 F]fluorodopa-derived radioactivity [2,3].…”

Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([18F]AV-133)

“…1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that induces parkinsonism in both humans [4] and non-human primates [5] with the cognitive, biochemical, histological and classical behavioral changes that occur in PD [6] . Therefore, Increasing evidence has suggested that single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging can be used to sensitively and objectively evaluate the integrity of the nigrostriatal dopaminergic system and may be useful tools for providing diagnostic information on PD [7][8][9][10] . There are numerous SPECT and PET imaging tracers for monitoring the integrity of dopaminergic neurons.…”

Protection Against Parkinson’s Disease Progression: Clinical Experience

“…One approach has been to rely on a surrogate biomarker specific for degeneration in dopaminergic nigrostriatal projections. 18,[21][22][23]74 With use of these techniques, disease progression can apparently be inferred even when PD patients continue to receive symptomatic therapy. In each instance, the assumption is that caudate and putamen images provide a direct correlate to the number of dopaminergic projections.…”

“…[21][22][23] Clinical ratings conducted after a pramipexole or levodopa washout of at least 12 hours permitted measurements of UPDRS scores in an unmedicated state. These showed no differences between the two groups; however, the short duration of washout for these symptomatic treatments is likely to have been inadequate for valid comparisons to baseline.…”

“…Although these neuroimaging techniques offer scientifically compelling views of dopaminergic function in PD and can also offer near-linear changes over time, their potential susceptibility to artefactual changes continues to be controversial. [21][22][23] Evaluating impairment of the motor network using metabolic maps from [ 18 F]fluoro-2-deoxyglucose PET is a newly developed approach to view worsening in the PD brain. 24,25 Beyond imaged dopaminergic nigrostriatal pathways, the search for other indirect indicators of disease progression has not led to reliable biomarkers in the living PD patient.…”