Assistant Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Sarva reports no financial relationships relevant to this field of study.

SYNOPSIS: A meta-analysis of 142 studies demonstrated that functional imaging studies in Parkinson’s disease using tracers for aromatic acid decarboxylase showed smaller defects compared to those using tracers targeting dopamine transport and VMAT2. Symptom severity correlated linearly with dopamine neuron loss as determined by these imaging studies.

SOURCE: Kaasinen V, Vahlberg T. Striatal dopamine in Parkinson disease: A meta-analysis of imaging studies. Ann Neurol 2017;82:873-882.

Kaasinen et al assessed 1,520 papers obtained through a PubMed search using various search terms, including dopamine, Parkinson’s disease (PD), parkinsonism, PET, and SPECT. Out of these 1,520 papers, 142 studies were included in this analysis if they met the following inclusion criteria: human PET or SPECT study; aromatic l-amino decarboxylase (AADC), vesicular monoamine transporter 2 (VMAT2), or dopamine transporter (DAT) tracer was used; idiopathic Parkinson’s disease patients were compared with healthy controls; and binding was reported as a mean for both PD and healthy controls in at least one striatal region. Twelve studies were excluded because of repetition of subjects. There were 157 separate PD samples in these 142 studies. The total number of PD patients was 3,605 and the total number of healthy controls was 2,352. Of these 142 studies, 67 were AADC studies, 64 were DAT studies, and 11 were VMAT2 studies. All of the studies demonstrated a 13.2% to 77% lower binding of AADC, DAT, and VMAT2 in PD patients compared with controls. In order of effect size from most to least, the posterior putamen showed the most effect size, then the entire putamen, followed by the anterior putamen, and lastly the caudate nucleus. The defect in AADC was consistently smaller than the defects in VMAT2 or DAT. The correlation between disease severity and dopamine loss was linear and this correlation was strongest in the caudate compared to the putamen. The longitudinal studies (total of 18; 3 AADC studies, and 15 DAT studies) had inconsistent results but suggested a negative exponential progression of dopamine loss.

COMMENTARY

Dopaminergic functional imaging has been used in research for nearly 30 years. This study confirms the relationship between dopamine loss and disease severity. The strengths of this meta-analysis include the large number of studies and subjects. Publication bias was not found to be significant. However, important considerations need to be noted. Different methods and machines can provide varying results that can contribute to the stark contrast between neuropathology showing a lack of dopamine fibers and imaging, which shows a reduction in fibers by 50%. In addition, PD has varying subtypes that also may contribute to the large range in reduction in binding of AADC, VMAT2, and DAT. Along these lines, the search terms included atypical parkinsonisms, and these imaging modalities cannot accurately distinguish between PD and the atypical Parkinson patients. Thus, the inclusion of atypicals in these studies can lead to varying binding reduction. Although the imaging modalities can help correlate disease severity and neuronal loss at a single time point, longitudinal analysis was found to be inconsistent. Thus, these functional imaging studies still are not reliable biomarkers of PD. Further research into the type of tracer and target is required to establish functional imaging as a reliable biomarker.