Dopamine-responsive and dopamine-resistant resting tremor in Parkinson disease

Abstract

<jats:sec><jats:title>Objective:</jats:title><jats:p>We tested the hypothesis that there are two distinct phenotypes of Parkinson’s tremor, based on inter-individual differences in the response of resting tremor to dopaminergic medication. We also investigated whether this pattern is specific to tremor, by comparing inter-individual differences in the dopamine response of tremor to that of bradykinesia.</jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p>In this exploratory study, we performed a levodopa challenge in 76 tremulous Parkinson patients. Clinical scores (MDS-UPDRS part-III) were collected OFF and ON a standardized dopaminergic challenge (200/50mg dispersible levodopa-benserazide). In both sessions, resting tremor intensity was quantified using accelerometry, both during rest and during cognitive co-activation. Bradykinesia was quantified using a speeded keyboard test. We calculated the distribution of dopamine-responsiveness for resting tremor and bradykinesia. In 41 patients, a double-blinded, placebo-controlled dopaminergic challenge was repeated after approximately six months.</jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p>The dopamine response of resting tremor, but not bradykinesia, significantly departed from a normal distribution. A cluster-analysis on three clinical and electrophysiological markers of tremor dopamine-responsiveness revealed three clusters: dopamine-responsive, intermediate, and dopamine-resistant tremor. A repeated levodopa challenge after six months confirmed this classification. Patients with dopamine-responsive tremor had greater disease severity and tended to have a higher prevalence of dyskinesia.</jats:p></jats:sec><jats:sec><jats:title>Conclusion:</jats:title><jats:p>Parkinson’s resting tremor can be divided into three partially overlapping phenotypes, based on the dopamine-response. These tremor phenotypes may be associated with different underlying pathophysiological mechanisms, requiring a different therapeutic approach.</jats:p></jats:sec>

Preoperative Levodopa Response and Deep Brain Stimulation Effects on Motor Outcomes in Parkinson's Disease: A Systematic Review

“…Not surprisingly, the magnitude of the levodopa responsiveness predicts the short‐term STN DBS responsiveness for bradykinesia and rigidity, which is concordant with the clinical observation and pathophysiological evidence in levodopa replacement therapy; 22,23 the severity of bradykinesia and rigidity are associated with the degree of nigrostriatal dopamine depletion 24,25 . However, for tremor, which is usually characterized by a combination of dopamine‐responsiveness and ‐resistance, 26 the magnitude of the short‐term STN DBS responsiveness was independent of the levodopa responsiveness. Indeed, STN DBS can effectively control levodopa‐responsive and ‐resistant tremors by modulating both dopaminergic and non‐dopaminergic neural circuits (e.g., the dentate‐rubrothalamic tract) 6 .…”

Increasing Serotonin to Reduce Parkinsonian Tremor

“…However, while these approaches seem to produce amelioration for most PD motor dysfunctions, they generate variable responsiveness for resting tremor (Helmich et al, 2012 ; Wu and Hallett, 2013 ; Connolly and Lang, 2014 ). The lack of dopamine-based therapies consistency with tremor could be explained by considering that based on the dopamine response, PD resting tremor can be divided into various partially overlapping phenotypes that may be associated with different pathophysiological mechanisms (Zach et al, 2020 ). These mechanisms might be produced by a cortical-subcortical network involving areas traditionally not directly related to PD.…”

“…One mainly due to a direct dopaminergic system deficiency and for which dopamine-based actions work. Others involving the dopaminergic system and other brain areas, for which dopamine-based treatments are less effective (Pasquini et al, 2018 ; Zach et al, 2020 ).…”

The Role of the Cerebellum in Tremor – Evidence from Neuroimaging

“…Clinically, PD resting tremor has a variable response to dopaminergic medication. In 30 of 76 tremor-dominant PD patients (39%), resting tremor did not respond at all to a levodopa challenge, while the remaining 46 patients (61%) showed an excellent response (64–81% reduction in tremor amplitude) [ 64 ]. A combined EMG-fMRI study showed that dopaminergic medication reduced tremor-related activity in the VIM and globus pallidus, but not in the cerebellum or M1 [ 65 ].…”