Faculty Bibliography

The circuit changes that mediate parkinsonian tremor, while likely differing from those underlying akinesia and rigidity, are not precisely known. In this study, to identify a specific metabolic brain network associated with this disease manifestation, we used FDG PET to scan nine tremor dominant Parkinson's disease (PD) patients at baseline and during ventral intermediate (Vim) thalamic nucleus deep brain stimulation (DBS). Ordinal trends canonical variates analysis (OrT/CVA) was performed on the within-subject scan data to detect a significant spatial covariance pattern with consistent changes in subject expression during stimulation-mediated tremor suppression. The metabolic pattern was characterized by covarying increases in the activity of the cerebellum/dentate nucleus and primary motor cortex, and, to a less degree, the caudate/putamen. Vim stimulation resulted in consistent reductions in pattern expression (p<0.005, permutation test). In the absence of stimulation, pattern expression values (subject scores) correlated significantly (r=0.85, p<0.02) with concurrent accelerometric measurements of tremor amplitude. To validate this spatial covariance pattern as an objective network biomarker of PD tremor, we prospectively quantified its expression on an individual subject basis in independent PD populations. The resulting subject scores for this PD tremor-related pattern (PDTP) were found to exhibit: (1) excellent test-retest reproducibility (p<0.0001); (2) significant correlation with independent clinical ratings of tremor (r=0.54, p<0.001) but not akinesia-rigidity; and (3) significant elevations (p<0.02) in tremor dominant relative to atremulous PD patients. Following validation, we assessed the natural history of PDTP expression in early stage patients scanned longitudinally with FDG PET over a 4-year interval. Significant increases in PDTP expression (p<0.01) were evident in this cohort over time; rate of progression, however, was slower than for the PD-related akinesia/rigidity pattern (PDRP). We also determined whether PDTP expression is modulated by interventions specifically directed at parkinsonian tremor. While Vim DBS was associated with changes in PDTP (p<0.001) but not PDRP expression, subthalamic nucleus (STN) DBS reduced the activity of both networks (p<0.05). PDTP expression was suppressed more by Vim than by STN stimulation (p<0.05). These findings suggest that parkinsonian tremor is mediated by a distinct metabolic network involving primarily cerebello-thalamo-cortical pathways. Indeed, effective treatment of this symptom is associated with significant reduction in PDTP expression. Quantification of treatment-mediated changes in both PDTP and PDRP scores can provide an objective means of evaluating the differential effects of novel antiparkinsonian interventions on the different motor features of the disorder.

We analyzed rest tremor, one of the etiologically most elusive hallmarks of Parkinson disease (PD), in 12 consecutive PD patients during a specific task activating the locus coeruleus (LC) to investigate a putative role of noradrenaline (NA) in tremor generation and suppression. Clinical diagnosis was confirmed in all subjects by reduced dopamine reuptake transporter (DAT) binding values investigated by single photon computed tomography imaging (SPECT) with [(123)I] N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl) tropane (FP-CIT). The intensity of tremor (i.e., the power of Electromyography [EMG] signals), but not its frequency, significantly increased during the task. In six subjects, tremor appeared selectively during the task. In a second part of the study, we retrospectively reviewed SPECT with FP-CIT data and confirmed the lack of correlation between dopaminergic loss and tremor by comparing DAT binding values of 82 PD subjects with bilateral tremor (n = 27), unilateral tremor (n = 22), and no tremor (n = 33). This study suggests a role of the LC in Parkinson tremor.

Transdermal rotigotine was used in six patients with advanced Parkinson's disease and sleep disorders (UPDRS part II item 12 score >/= 2) receiving oral levodopa and diurnal apomorphine infusions. Transdermal rotigotine (2-4 mg/24h) was used at night for four months. Sleep disorders improved, the total Parkinson's Disease Sleep Scale score falling by an average of 45%; significant improvements emerged in the items quality of sleep and difficulty in remaining asleep (p<0.05). No undesirable dopaminergic effects were reported. This preliminary open-label study suggests that transdermal rotigotine may be a well tolerated and effective treatment in patients with advanced Parkinson's disease, reducing nocturnal disability and ameliorating sleep disorders without inducing undesirable dopaminergic effects.

To investigate over time changes in striatal dopamine transporter (DAT), we performed two sequential N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl) tropane single photon computed tomography (SPECT) scans in 20 subjects with essential tremor (ET), in 13 with Parkinson disease (PD) and in 23 healthy controls (HC, one scan only). We also performed an [(99m)Tc]ethyl cysteinate dimer bicisate SPECT exam for regional brain network analysis in 9 ET, in a second group of 18 PD (9 with tremor, tPD and 9 akinetic-rigid dominant, arPD) and in 8 HC. PD subjects had a reduced DAT binding in comparison to ET and HC with an annual decline rate of 7.3% in the contralateral putamen. There were no mean uptake differences between ET and HC at baseline and no uptake loss over time in ET. A discriminant analysis grouped 30% (first scan) and 5% (second scan) of ET as PD and a partition analysis showed overlap between ET and PD for caudate nucleus uptake. Spatial covariance analysis revealed that the expression of the PD-related regional pattern separated both tPD and arPD from ET and HC. In conclusion, PD and ET do not share a common pattern of dopaminergic loss over time. However, mild impairment of dopamine transporter in the caudate nucleus may contribute to tremor onset in ET.