Parkinson's disease tremor-related metabolic network: Characterization, progression, and treatment effects

Abstract

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 during 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 four 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.

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…Finally, the cerebellar outflow pathways also seem to be involved in aspects of the pathophysiology of PD, specifically tremor [95,175,176], as suggested by imaging studies [177], and by the finding that, unlike other signs of the disease, parkinsonian tremor is effectively treated with surgical interventions targeting the cerebellar-receiving portions of the thalamus [178,179]. While dopamine loss is, in some way, related to the expression of tremor, this parkinsonian sign is often less sensitive to dopamine replacement therapy than the other parkinsonian signs, and not strongly related to beta-band power in LFP signals recorded in the basal ganglia [163].…”

Identification of Disease-related Spatial Covariance Patterns using Neuroimaging Data

“…Thus, covariance topographies designed for accurate differential diagnosis of clinically similar "look-alike" conditions ("diagnostic biomarkers") may be composites of complex physio-chemical processes, not necessarily corresponding to easily interpretable physical networks 13 . By contrast, other patterns may be optimal for capturing the topographical hallmarks of specific disease manifestations such as parkinsonian tremor or cognitive dysfunction 15,51,52 , or for monitoring disease progression 7,16 . The specific objective of the biomarker's function should be considered in making a final selection.…”

“…This approach can be vitally important given the high rate of clinical misdiagnosis in individuals with early disease, and the varying prognosis and treatment outcome associated with the different underlying pathologies. As a final point, SSM pattern-based group score evaluation can be a valuable tool in clinical trials of experimental therapies for brain disorders 15,53,54 .…”

Nuclear Medicine Applications in Movement Disorders

“…Parkinsonizm sendromlarında beyin FDG PET görüntüleme saptanan anormal bulguların yaygınlığı ve derecesi klinik bulgular ile genellikle korelasyon gösterir (1,3,19,23,24,30,34,35,39,49,50,51,52). PH için klinik belirtiler ile ilişkili özgül metabolik tutulum biçimleri bulunur: Örneğin; tremor ile ilişkili serebellotalamo-kortikal yolakların etkilendiği (23,31,53); motor belirtiler ile ilişkili olarak putamen ve premotor korteksi içine alan (19,50,52,53); bilişsel bozukluklar ile ilişkili olarak da frontal ve parietal asosiyasyon alanlarında hipometabolizma ve serebellumda hipermetabolizma ile karakterize özgül metabolik ağ yapıları tanımlanmıştır (53,54).…”