This study showed that L‐dopa does not compromise the cognitive or behavioural profiles of patients with parkinsonism and dementia either acutely or over 3 months. After acute L‐dopa challenge, most cognitive measures did not change markedly. Subjective alertness and UPDRS III scores improved to a greater degree in patients with Parkinson's disease than in those with PDD. Over the 2 h after treatment with L‐dopa a marked change in level of fluctuating attention was detected, but this was not in any particular direction and most likely reflects fluctuation in CRT performance despite controlling for the mean performance levels in this task. This is a recognised feature in patients with both PDD and DLB, and this study has replicated previous work by suggesting that both conditions are indistinguishable in CRT, CRT SD or COG RT, but are considerably different in patients with Parkinson's disease.4
An interaction between time point and diagnosis for measures of within‐trial variability (CRT and CRT SD) could simply represent increased fluctuation in attention in patients with dementia compared with patients with Parkinson's disease. The alternative explanation, that L‐dopa caused increased fluctuation in patients with dementia, is, however, impossible to exclude. As with the acute data, most cognitive measures did not change considerably with L‐dopa use over 3 months although mean SRT and DVIG RT worsened in patients with PDD, whereas mean RDS scores deteriorated in the Parkinson's disease group (despite an apparent improvement in mean MMSE). However, with sensitivity analysis showing no marked individual patient deterioration in this time, these results are of uncertain significance. Overall, neuropsychiatric function improved in both patients with Parkinson's disease and PDD, but showed no change in those with DLB, as shown by NPI scores. It is, however, conceivable that an improvement in some scores was masked by concomitant deterioration in others on this measure.
Striatal dopaminergic function reduces by 6–10% per decade from early to late adulthood.25
Cognitive decline in patients with Parkinson's disease may be influenced by the degree of motor impairment and hence the response to L‐dopa, whereas motor response may decrease with the development of dementia in patients with Parkinson's disease.26
We did not find any difference in motor response to acute L‐dopa challenge between Parkinson's disease and PDD groups although the PDD group were younger and received a higher mean dose of L‐dopa. Alternatively, dementia may impair UPDRS III performance and the ability to perform manually based cognitive tasks, and severe cognitive impairment may have an alternative dopamine response. Previous studies have suggested a link between bradyphrenia in Parkinson's disease and simultaneous cognitive task performance, as shown by slower CRT tasks.27
The level of cognitive slowing may correspond to the level of independently assessed motor slowing, raising the possibility that cognitive impairment may reflect dysfunction in the striatum or premotor cortex.28
The most profound short‐term and long‐term cognitive deficit in animals with MPTP (1‐methyl‐4‐phenyl‐1,2,5,6‐tetrahydropyridine)‐induced parkinsonism is impaired spatial working memory, representing damage in the frontostriatal system.29
L‐dopa administration to MPTP‐treated monkeys can considerably ameliorate these impairments.30
Similarly, dopamine withdrawal in patients with Parkinson's disease can highlight selective frontal lobe dysfunction, particularly spatial working memory, executive function, and thinking time and accuracy.31
L‐dopa replacement in patients with Parkinson's disease improves aspects of working memory, particularly visuospatial and object tasks, but by contrast, apomorphine can worsen reaction times without affecting the accuracy.32
These results may represent preferential dopaminergic receptor activation and are supported by animal studies, which suggest that D1 dopamine receptor agonist infusion enhances attention in rats, with similar results reported for L‐dopa and D2 receptor antagonists in humans.33
In this study, neither visuospatial tasks (represented by picture recognition) nor numeric working memory changed after 3 months of L‐dopa treatment.
Executive function includes the inhibition of inappropriate responses to external stimuli. Increased dopamine levels have been linked to an increased frequency of premature response and thus decreased accuracy of response by diminishing the ability to suppress the wrong response, reflecting impulsivity.34
Other studies have, however, failed to detect either change in reaction time responses or working memory subsequent to dopamine administration.35,36
Furthermore, CRTs have been reported by others to deteriorate in patients with Parkinson's disease after acute L‐dopa challenge, potentially due to a sedative effect of treatment.37
Therefore, the acute effect of L‐dopa administration on reaction time and accuracy in dopamine‐depleted conditions remains unclear. We found no adverse acute effect of L‐dopa on any aspect of cognitive function in our Parkinson's disease cohort, including reaction times and accuracy. However, the mean acutely administered dose of L‐dopa was less than that recommended in acute motor challenges, possibly accounting for the lack of change in reaction times and also the maintenance of CRT accuracy.
Apparently conflicting data on the role of dopamine on cognition may be reconciled through animal studies which show that insufficient as well as excessive dopaminergic stimulation in the prefrontal cortex impairs working memory.8
Baseline cognitive performance can influence the effect of dopaminergic drugs. Hence, in patients with Parkinson's disease, treatment with L‐dopa can have both beneficial and deleterious effects on cognitive function depending on the task assessed and the underlying basal corticostriatal dopaminergic function.38
Although no adverse acute effect of L‐dopa on cognition was found in the present study, the results were limited by submaximal acute L‐dopa dosing. Future studies may replicate this “inverted U” dose‐related cognitive response curve for patients with parkinsonism and dementia.
Although objective measures remained unchanged in our study, subjectively patients with DLB and PDD felt more alert, despite increased fluctuating cognition. Reduced SRT or CRT did not accompany this acute improvement in subjective alertness in any group. The beneficial effect of L‐dopa on sense of alertness could reflect concomitant motor benefit, but against this is the fact that these values did not temporally correlate. A dissociable motor and cognitive effect on withdrawal of dopaminergic drugs has been suggested previously,39
with support from functional imaging data which has shown that dopamine modulates cognitive and motor function by separate pathways, with direct dopaminergic input to the prefrontal cortex facilitating working memory via the mesocortical circuits.40
Our study has several methodological flaws, including an open‐label design, small sample size, use of modest L‐dopa dosing in acute challenges, particularly to patients with DLB, and the recognised inadequacies of an overnight fast in excluding the long duration response to L‐dopa. Also, most patients with dementia were receiving ChEIs, and the study was therefore unable to deal with the effect of L‐dopa on cognition in parkinsonism with dementia in ChEI‐naive patients, or the potential interactions between ChEIs and L‐dopa. We conclude that L‐dopa does not have any clinically significant adverse cognitive or behavioural effects in patients with PDD. Furthermore, the cautious use of L‐dopa in DLB is not contraindicated when increasing severity of motor impairment warrants treatment.