Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease.

INTRODUCTION: Both polymorphisms and mutations in glucocerebrosidase (GBA) may influence the development of dementia in patients with Parkinson's disease. METHODS: Four hundred forty-two patients and 419 controls were followed for 7 years. Dementia was diagnosed using established criteria. Participants were analyzed for GBA genetic variants, including E326K, T369M, and L444P. Associations between GBA carrier status and dementia were assessed with Cox survival analysis. RESULTS: A total of 12.0% of patients with Parkinson's disease carried a GBA variant, and nearly half (22/53) of them progressed to dementia during follow-up. Carriers of deleterious GBA mutations (adjusted hazard ratio 3.81, 95% confidence interval 1.35 to 10.72; P = .011) or polymorphisms (adjusted hazard ratio 1.79; 95% confidence interval 1.07 to 3.00; P = .028) progressed to dementia more rapidly than noncarriers. DISCUSSION: GBA variants are of great clinical relevance for the development of dementia in Parkinson's disease, especially due to the relatively higher frequency of these alleles compared with other risk alleles.

Computerized cognitive training in Parkinson's disease: A systematic review and meta-analysis.

Cognitive impairment is a central non-motor symptom of Parkinson's disease (PD), and there are no established treatments. Computerized cognitive training (CCT) is a safe and efficacious strategy but its efficacy in PD is unclear. We aimed to investigate the efficacy of CCT on cognitive, psychosocial and daily function, and assess potential effect moderators in people with PD without dementia. Randomized controlled trials of CCT were included in multivariate meta-analyses and meta-regressions. Seventeen studies (16 trials) encompassing 679 participants were included. The pooled effect of CCT relative to control was small and statistically significant for overall cognitive function (g=0.16; 95% CI 0.02-0.29). There was robust evidence for benefit on clinical measures of global cognition across 10 trials (g=0.33; 95% CI 0.19-0.48), especially in PD with mild cognitive impairment (PD-MCI), as well as on individual cognitive domains. Greater CCT dose and PD-MCI population were associated with larger effect sizes, but no statistically significant differences were found between subgroups. There was no significant difference in the efficacy of home-based compared to supervised training. Our findings suggest that CCT is associated with cognitive benefits in PD, including when delivered remotely. Larger, well-powered trials are warranted to examine what specific CCT regimens are most likely to promote cognitive and everyday functioning in the long-term.

Longitudinal changes in task-evoked brain responses in Parkinson's disease patients with and without mild cognitive impairment.

Cognitive deficits are common in Parkinson's disease. Previous cross-sectional research has demonstrated a link between cognitive impairments and fronto-striatal dopaminergic dysmodulation. However, longitudinal studies that link disease progression with altered task-evoked brain activity are lacking. Therefore, our objective was to longitudinally evaluate working-memory related brain activity changes in Parkinson's disease patients with and without mild cognitive impairment (MCI). Patients were recruited within a longitudinal cohort study of incident patients with idiopathic parkinsonism. We longitudinally (at baseline examination and at 12-months follow-up) compared 28 patients with Parkinson's disease without MCI with 11 patients with Parkinson's disease and MCI. Functional MRI blood oxygen level dependent signal was measured during a verbal two-back working-memory task. Patients with MCI under-recruited bilateral medial prefrontal cortex at both time-points (main effect of group: p < 0.001, uncorrected). Critically, a significant group-by-time interaction effect (p < 0.001, uncorrected) was found in the right fusiform gyrus, indicating that working-memory related activity decreased for patients with Parkinson's disease and MCI between baseline and follow-up, while patients without MCI were stable across time-points. The functional connectivity between right fusiform gyrus and bilateral caudate nucleus was stronger for patients without MCI relative to patients with MCI. Our findings support the view that deficits in working-memory updating are related to persistent fronto-striatal under-recruitments in patients with early phase Parkinson's disease and MCI. The longitudinal evolution of MCI in Parkinson's disease translates into additional task-evoked posterior cortical changes.

Persistence of associations between cognitive impairment and motor dysfunction in the early phase of Parkinson's disease.

The relation between cognitive and motor functions in Parkinson's disease is not fully understood. In an incidence population of newly diagnosed drug naïve patients with Parkinson's disease, associations were found between the degree of bradykinesia and postural instability and gait disturbances, measured by the Unified Disease Rating Scale, and different types of cognitive functions. To investigate the stability of these associations over time, we explored the association of differences between baseline and 1-year follow-up in 91 incident cases with Parkinson's disease. The magnitude of change between the two assessments was assessed together with analysis of differences based on which dopaminergic medication was used. Change in bradykinesia was associated with change in working memory and mental flexibility. Changes in postural instability and gait disturbances were associated with change in visuospatial memory. A negative effect of the dopamine agonist pramipexole on phonemic fluency performance was found compared to treatment with other dopaminergic drugs. Change in cognitive and motor functions were associated from time of diagnosis until 1 year after diagnosis. These persisting findings strengthen results from a previous cross-sectional study suggesting similar associations. The effects of dopamine agonists on phonemic fluency should be investigated further.