Effects of daily L-dopa administration on learning and brain structure in older adults undergoing four weeks of cognitive training: a randomised, parallel-group, double-blind, placebo-controlled trial.
BackgroundCognitive aging creates major individual and societal burden, motivating search for treatment and preventive care strategies. Behavioural interventions can improve cognitive performance in older age, but effects are small. Basic research has implicated dopaminergic signaling in plasticity. We investigated whether transient enhancement of dopaminergic neurotransmission via administration of L-dopa improves effects of cognitive training on performance. MethodsParticipants for this randomised, parallel-group, double-blind, placebo-controlled trial were recruited via newspaper advertisements. Inclusion criteria were: age of 65-75 years, Mini-Mental State Examination score >25, absence of serious medical conditions. Eligible subjects were randomly allocated to either receive 100/25mg L-dopa/benserazide or placebo prior to each of twenty cognitive training sessions administered during a four-week period. Participants and staff were masked to group assignment. Primary outcomes were latent variables of spatial and verbal fluid intelligence. This trial was preregistered at the European Clinical Trial Registry, EudraCT#2016-000891-54. FindingsBetween January 1st and October 10th 2017, we screened 235 people from the population in Stockholm, Sweden and randomly assigned 63 eligible subjects to receive L-dopa (n=32) or placebo (n=31) during cognitive training. Compared to the placebo group, subjects receiving L-dopa improved less in spatial intelligence (-0{middle dot}267 SDs; 95% CI [-0{middle dot}498, -0{middle dot}036]; p=0{middle dot}024). Change in verbal intelligence did not significantly differ between the groups (-0{middle dot}081 SDs, 95% CI [-0{middle dot}242, 0{middle dot}080]; p=0{middle dot}323). Adverse events occurred for 10 subjects (31%) in the active and for 7 participants (23%) in the control groups. InterpretationThe results speak against early pharmacological interventions in older healthy adults to improve cognitive functions by targeting the dopaminergic system and provide no support for learning-enhancing properties of L-dopa supplements. The findings warrant closer investigation about the cognitive effects of early dopamine-replacement therapy in neurological disorders. FundingEuropean Research Council (ERC Grant agreement #617280-REBOOT), Wallenberg Clinical Scholars, and Stiftelse Stockholms Sjukhem. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWhilst pharmacological treatments have so far been largely unsuccessful in making an impact on age-related cognitive decline, recent findings have suggested small improvements of cognitive performance in older people by combining cognitive training with a healthy diet and aerobic exercises. Both exercise and dietary factors may exhibit plasticity-enhancing properties, and therefore increase effectiveness of cognitive training. In related basic research, dopaminergic signaling has been implicated in brain plasticity. An extensive PubMed search was conducted during the preparatory stage of the study (September 2014-July 2016) to investigate the role of dopamine signaling in neural plasticity and learning, as well as the effects of its deterioration on these characteristics in aging and neurodegenerative disorders. As a result, we found a substantial number of studies reporting acute improvements in cognitive performance and learning by administration of exogenous dopamine precursor L-dopa. A similar search was conducted specifically for this drug to evaluate its pharmacological and safety profile. We found a large body of basic research on both animal models and humans that supported the role of dopamine signaling in learning and plasticity. In addition, two smaller studies reported promising effects of repeated L-dopa administration on learning in the healthy younger population. In all studies, standard small-dose (100mg) L-dopa interventions were safe and well-tolerated. Added value of this studyOur study is the first of its kind to evaluate effects of repeated pro-dopaminergic medication on learning during cognitive training and cognitive performance in healthy older adults. Our results do not support the hypothesis of plasticity- and learning-promoting effects of enhanced dopaminergic neurotransmission by administration of exogenous dopamine precursor L-dopa in the healthy older population. The findings indicate that L-dopa treatment may in fact be detrimental to learning and cognitive performance and lead to structural brain changes within the dopaminergic circuit. Implications of all the available evidenceThe results put constraints on the hypothesis of a key role of the deteriorated dopaminergic system in age-related decline of learning abilities, and speak against early pharmacological interventions in older healthy adults to improve cognitive functions by targeting the dopaminergic system. Our findings also raise concerns about usefulness of novel L-dopa-containing supplements that claim to have neuroprotective and learning-enhancing properties, and present an urgent need to carefully investigate the cognitive outcomes of early pro-dopaminergic interventions in clinical populations often receiving substantially larger doses of L-dopa.