Objective: Functionally disabling, medication-refractory (FDMR) tremor is a key indication for device-aided therapy in Parkinson’s disease (PD), yet baseline predictors remain poorly characterised.

Background: PD tremor is frequently resistant to dopaminergic therapy, implicating cerebellar and non-dopaminergic circuits. Clinical manifestations of serotonergic and noradrenergic degeneration, including REM sleep behaviour disorder (RBD) and anxiety, may predict subsequent medication-refractory tremor, but prospective longitudinal evidence is lacking.

Method: We analysed 943 individuals with sporadic PD from the Parkinson’s Progression Markers Initiative. FDMR tremor was defined as functionally disabling tremor (MDS-UPDRS 2.10 ≥3) with no meaningful levodopa response (limb tremor 3.15/3.16/3.17 ≥3, not improving to ≤2). Predictors were selected a priori on the basis of non-dopaminergic tremor pathophysiology: probable RBD (RBDSQ ≥5), anxiety (STAI-Trait ≥45), motor subtype, and orthostatic hypotension, adjusted for functional motor burden (MDS-UPDRS Part II) and age. Cox proportional hazards models were used with multiple imputation to handle missing data.

Results: 34 individuals (3.6%) developed FDMR tremor over a mean 5.6-year follow-up (median time from diagnosis: 4.2 years). Three predictors were independently associated: anxiety (HR 2.67, 95% CI 1.18–6.05, p=0.018), probable RBD (HR 2.12, 95% CI 1.05–4.30, p=0.037), and tremor-dominant subtype (HR 4.74, 95% CI 1.41–15.87, p=0.012 vs. non-tremor-dominant), despite adjustment for functional motor burden. Model discrimination was moderate (C-index 0.71). Findings were consistent across sensitivity analyses including adjustment for sex and disease duration.

Conclusion: Baseline clinical manifestations of serotonergic and noradrenergic degeneration, anxiety and probable RBD, independently predict FDMR tremor, supporting a non-dopaminergic aetiological basis for medication-refractory tremor in PD. Early clinical phenotyping may identify candidates for device-aided therapy referral at diagnosis.

References: 1. Ledingham D, Sathyanarayana S, Stewart CB, Iredale R, Foster V, Galley D, Baker M, Pavese N. Tracking Motor Progression and Device-Aided Therapy Eligibility in Parkinson’s Disease. Ann Clin Transl Neurol. 2025 Dec 12. doi: 10.1002/acn3.70188. Epub ahead of print. PMID: 41388605.
2. Dirkx MF, Zach H, van Nuland A, Bloem BR, Toni I, Helmich RC. Cerebral differences between dopamine-resistant and dopamine-responsive Parkinson’s tremor. Brain. 2019 Oct 1;142(10):3144-3157. doi: 10.1093/brain/awz261. PMID: 31509182.
3. Ray Chaudhuri K, Leta V, Bannister K, Brooks DJ, Svenningsson P. The noradrenergic subtype of Parkinson disease: from animal models to clinical practice. Nat Rev Neurol. 2023 Jun;19(6):333-345. doi: 10.1038/s41582-023-00802-5. Epub 2023 May 4. PMID: 37142796.
4. Maillet A, Krack P, Lhommée E, Météreau E, Klinger H, Favre E, Le Bars D, Schmitt E, Bichon A, Pelissier P, Fraix V, Castrioto A, Sgambato-Faure V, Broussolle E, Tremblay L, Thobois S. The prominent role of serotonergic degeneration in apathy, anxiety and depression in de novo Parkinson’s disease. Brain. 2016 Sep;139(Pt 9):2486-502. doi: 10.1093/brain/aww162. Epub 2016 Aug 17. PMID: 27538418.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/probable-rbd-and-anxiety-in-early-parkinsons-disease-predict-subsequent-functionally-disabling-medication-refractory-tremor/