case_images: PMC11191508_01
case_images: DaTscan reveals left-side asymmetry in striatal DAT binding and is not qualitatively different 11 months after initial scan. Study showing reduced striatal DAT binding both at study initiation and ~11 months (10 months and 28 days) afterwards. Despite worsened symptoms and clinical presentation, two scans 11 months apart do not reveal changes in asymmetry.
case_images: jpd-14-jpd240030-g001.jpg
case_images: PMC11191508_01_jpd-14-jpd240030-g001.jpg
case_images: jpd-14-jpd240030-g001
case_images: The series of DaTscans revealed a pattern consistent with parkinsonism (Fig. 1). Supplementary Material: Genetics. Sequencing results in graphical form are provided in SupplementaryFigure 1. In the patient with a TH mutation, the asymmetric reduction in DaTscan (Fig. 1) at the time of PD diagnosis was reflected by an increase in DAT+ PBMCs (Fig. 2) and UPDRS-III scores.
case_images: DAT+ and TH+ PBMCs are increased in idiopathic PD patients at the time of diagnosis and decreased following improved UPDRS-III scores as a consequence of L-DOPA/Carbidopa treatment. By contrast, unlike the DAT+ PBMCs, in a patient carrying a TH mutation, the TH+ PBMCs remains elevated even after successful pharmacotherapy, representing an uncoupled response to L-DOPA/Carbidopa treatment. Single cells, free from debris, were analyzed via flow cytometry for expression of DAT and TH (Supplementary Figure 2). A-B) DAT+ and TH+ PBMCs (grey dots) are increased in drug naive idiopathic PD patients (n = 16) relative to healthy controls (n = 80, green dashed line). These markers are reduced significantly in drug treated idiopathic PD patients (n = 114), though remaining significantly higher than age/sex matched healthy control levels (***p < 0.001; t,df(3.763, 128), **p < 0.01; t,df(3.138, 128), unpaired Student's t-test with Tukey's correction, alpha = 0.05). In the PD patient carrying a single pathogenic TH mutation (red line), A) the pattern of DAT+ PBMCs change follows the pattern we identified in idiopathic PD patients, i.e., increased at the time of PD diagnosis (drug naive condition) and then decreasing following successful L-DOPA/Carbidopa treatment. However, B) TH+ PBMCs of the PD patient carrying pathogenic TH mutation are uncoupled from both DAT+ PBMCs and the predicted reduction following L-DOPA/Carbidopa treatment, for instance, they are elevated in the drug naive condition and continue to increase despite improved UPDRS-III, as a results of L-DOPA/Carbidopa treatment. C) Similar to idiopathic PD patients, the PD patient carrying pathogenic TH mutation, DAT+ PBMCs (red line) are elevated at the first visit (drug naive) and remain elevated as a function of impaired motor function (UPDRS-III, black line). Once L-DOPA/Carbidopa treatment is initiated, both DAT+ PBMCs and UPDRS-III scores decrease, indicating positive response to pharmacotherapy. D) In the PD patient carrying pathogenic TH mutation, the TH+ PBMCs (blue line) are increased following worsening motor symptoms (UPDRS-III, black line), but TH+ PBMCs continue to rise despite positive response to L-DOPA/Carbidopa (indicated by decreasing UPDRS-III motor scores), suggesting in this patient, only changes in the DAT+ PBMCs are coupled to both worsening motor function and positive L-DOPA/Carbidopa treatment response.
case_images: jpd-14-jpd240030-g002.jpg
case_images: PMC11191508_01_jpd-14-jpd240030-g002.jpg
case_images: jpd-14-jpd240030-g002
case_images: TH+ PBMCs (Fig. 2A, B). Consistent with our prior findings, at the time of diagnosis (drug naive), idiopathic PD patients (n = 130) exhibited increased DAT+ and TH+ PBMCs (Fig. 2A, B, grey dots, black line) relative to age/sex matched healthy control levels (green dashed line, n = 80). Idiopathic PD patients show a significant decrease in DAT+ and TH+ PBMCs, and improved UPDRS-III scores following carbidopa/levodopa treatment (Fig. 2A, B, grey dots, black line, Fig. 2A, B, green). Similar to idiopathic PD patients, the patient with TH mutation revealed an increase in DAT+ PBMCs (Fig. 2A, red line). Consistent with our hypothesis, carbidopa/levodopa treatment provided symptom relief marked by reduced UPDRS III scores (Fig. 2C, black line) and was associated with a reduced frequency of DAT+ PBMCs (Fig. 2C, red line). TH+ PBMCs were increased at the time of diagnosis (drug Naive), but contrary to our hypothesis they remained high and continued to rise despite carbidopa/levodopa and the improved UPDRS-III scores (Fig. 2B, red line, blue line, black line respectively). This finding was in contrast to that observed in idiopathic PD, where there was a direct correlation between decreased TH+ PBMC frequencies and improved UPDRS-III scores following carbidopa/levodopa treatment. The detailed methods are provided in the Supplementary Information: PBMC isolation and flow cytometry.