Paradoxical Effect of Dopamine Medication on Cognition in Parkinson’s Disease: Relationship to Side of Motor Onset

Abstract

Parkinson's disease (PD) is characterized by asymmetric motor symptom onset attributed to greater degeneration of dopamine neurons contralateral to the affected side. However, whether motor asymmetries predict cognitive profiles in PD, and to what extent dopamine influences cognition remains controversial. This study evaluated cognitive variability in PD by measuring differential response to dopamine replacement therapy (DRT) based on hemispheric asymmetries. The influence of DRT on cognition was evaluated in mild PD patients (n = 36) with left or right motor onset symptoms. All subjects were evaluated on neuropsychological measures on and off DRT and compared to controls (n = 42). PD patients were impaired in executive, memory and motor domains irrespective of side of motor onset, although patients with left hemisphere deficit displayed greater cognitive impairment. Patients with right hemisphere deficit responded to DRT with significant improvement in sensorimotor deficits, and with corresponding improvement in attention and verbal memory functions. Conversely, patients with greater left hemisphere dopamine deficiency did not improve in attentional functions and declined in verbal memory recall following DRT. These findings support the presence of extensive mild cognitive deficits in early PD not fully explained by dopamine depletion alone. The paradoxical effects of levodopa on verbal memory were predicted by extent of fine motor impairment and sensorimotor response to levodopa, which reflects extent of dopamine depletion. The findings are discussed with respect to factors influencing variable cognitive profiles in early PD, including hemispheric asymmetries and differential response to levodopa based on dopamine levels predicting amelioration or overdosing.

Tablet-Based Application for Objective Measurement of Motor Fluctuations in Parkinson Disease

“…The lower tapping accuracy in the ON (hyperdopaminergic) state may be due to the hypothesis of Vaillancourt et al [24]: a dopamine overdose effect in the ventral and anterior striatum could negatively affect the cognitive challenge of tapping both quickly and accurately. In fact, multiple cognitive domains may be adversely affected by dopamine flooding [25]. The blinded video analysis suggested dyskinesia did not affect accuracy, regardless of the presence of dyskinesia in the upper or lower extremity.…”

Dopaminergic Therapy Increases Go Timeouts in the Go/No-Go Task in Patients with Parkinson’s Disease

“…Addressing bradykinesia and increasing the speed and fluency of movements and motor responses is the chief beneficial effect of dopaminergic therapy in PD (Espay et al, 2011 ; Macerollo et al, 2016 ). There is little evidence to suggest that dopaminergic therapy generally slows cognitive processes and in fact there is support that it hastens them (Cools et al, 2001 ; Shook et al, 2005 ; Hood et al, 2007 ; Righi et al, 2007 ; MacDonald and Monchi, 2011 ; MacDonald et al, 2011 ; Hanna-Pladdy et al, 2015 ). In contrast, as we review in sections below, dopaminergic therapy has been shown to increase response inhibition as well as to promote adopting a more conservative response criterion, consistent with our explanation for increased Go Timeouts in the ON-state for PD patients in our study.…”

The Effect of Dopaminergic Medication on Beat-Based Auditory Timing in Parkinson’s Disease

“…Besides deficient dopamine, other factors also contribute to cognitive deficits in the disease, including structural changes to the brain ( 18 , 19 ), and accumulation of amyloid plaques and tau protein ( 20 , 21 ). Moreover, the role of dopamine, and influence of dopaminergic medication, in cognition is variable, as previous studies show both improvement and worsening of different cognitive functions by medication, depending on task demands and individual differences in baseline dopamine levels ( 22 , 23 ), as well as side of motor symptom onset ( 24 ).…”