Cognitive Stress Reduces Levodopa Effect on Parkinson’s Tremor

Cognitive co-activation is associated with a significantly smaller levodopa effect on resting tremor in Parkinson's disease.

Cognitive stress significantly reduces the levodopa effect on resting tremor in Parkinson’s disease, according to a study in CNS Neuroscience & Therapeutics.1

Researchers from the Radboud University Medical Center in Nijmegen, the Netherlands, and colleagues examined whether cognitive stress modulates the levodopa effect on resting tremor in 69 tremulous patients with PD, all of whom were examined by 2 independent movement disorders specialists. The patients without current dopaminergic medications had to meet at least 3 of the “supportive UK Brain bank criteria” (unilateral onset, rest tremor, and progressive disorder). Only patients with a resting tremor score of ≥1 point in at least 1 arm on item 17 of the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale were included.2,3

The researchers measured the patients in 2 treatment conditions (off vs on levodopa) and in 2 behavioral contexts (rest vs cognitive co-activation). They assessed the patients twice on 1 day: after overnight fasting, both before (off medication) and after (on medication) a levodopa challenge. They defined the “off” state as being more than 12 hours after intake of their most recent dose of levodopa, more than 30 hours after dopaminergic agonists, and more than 24 hours after anticholinergics or beta blockers.4 Patients had to forgo caffeine for more than 12 hours to avoid potential influence on tremor.

For the “on” assessment, patients first received 10 mg domperidone to reduce potential adverse effects and improve gastrointestinal absorption. Then, 1 hour later, they received a standard dose of 250 mg dispersible levodopa-benserazide (about 75% higher than the patients’ own morning dose, on average).

The researchers found that levodopa significantly reduced tremor intensity across behavioral contexts, whereas tremor intensity was increased by cognitive co-activation across treatment conditions. Compared with during rest, during cognitive co-activation the levodopa effect was significantly smaller. There was an increase in resting tremor variability after levodopa, whereas a decrease was seen during cognitive co-activation.

Levodopa significantly reduced maximal tremor intensity [main effect of treatment, F(1,68) = 42.9; P <.001], whereas cognitive co-activation significantly increased tremor intensity [main effect of context, F(1,68) = 128.9; P <.001). The effect of levodopa was significantly smaller during cognitive co-activation than during rest [treatment × context interaction, F(1,68) = 5.6; P =.02]. This means that the positive effect of levodopa was counteracted by a negative effect of cognitive stress such that maximal tremor intensity during cognitive co-activation in the on state was similar to maximal tremor intensity during rest in the off state [t(68) = 1.4; P =.2].

“Cognitive stress reduces the levodopa effect on Parkinson’s tremor,” the researchers confirmed. “This effect may be explained by a stress-related depletion of dopamine in the basal ganglia motor circuit, by stress-related involvement of nondopaminergic mechanisms in tremor (e.g., noradrenaline), or both. Targeting these mechanisms may open new windows for treatment.”

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  1. Heidemarie Zach H, Dirkx MF, Pasman JW, Bloem BR, et al. Cognitive stress reduces the effect of levodopa on Parkinson’s resting tremor [published online January 10, 2017]. CNS Neurosci Ther. doi: 10.1111/cns.12670
  2. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinicianJ Psychiatr Res. 1975;12:189-198.
  3. Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: A Frontal Assessment Battery at bedsideNeurology. 2000;55:1621-1626.
  4. Albanese A, Bonuccelli U, Brefel C, et al. Consensus statement on the role of acute dopaminergic challenge in Parkinson’s diseaseMov Disord. 2001;16:197-201.