Functional Brain Activity and Presynaptic Dopamine Uptake in Patients with Parkinson's Disease and Mild Cognitive Impairment: a Cross-sectional Study

Background: Many patients with Parkinson's disease have mild cognitive impairment (MCI). Deficits in executive functions and working memory suggest dysfunctional frontostriatal brain circuitry. We aimed to assess brain responses during a working memory task in a cohort of newly diagnosed drug-naive patients with Parkinson's disease with and without MCI.

Methods: Participants were recruited within a prospective cohort study of incident patients with idiopathic parkinsonism, including Parkinson's disease. Between Jan 1, 2004, and April 30, 2009, all physicians in the Umeå catchment area were requested to refer all individuals with suspected parkinsonism to the Department of Neurology at Umeå University. Included patients fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease. Control individuals were matched on the basis of age and sex with the first 50 patients included in the study. Participants who scored 1·5 SDs or more below the population mean on at least two cognitive measures were diagnosed with MCI. The primary outcome measures were functional MRI blood-oxygen-level-dependent signal and SPECT presynaptic uptake. Functional MRI was done during a verbal two-back working memory task. Presynaptic dopamine SPECT was done to assess presynaptic striatal dopaminergic system integrity. Event-related transient analyses of functional MRI data were done for the whole brain and for frontostriatal regions of interest, and semi-quantitative SPECT analyses were done for striatal regions of interest.

Findings: Compared with controls (n=24), patients with Parkinson's disease (n=77) had under-recruitment in an extensive brain network including bilateral striatal and frontal regions (p<0·001). Within the Parkinson's disease group, patients with Parkinson's disease and MCI (n=30) had additional under-recruitment in the right dorsal caudate nucleus (p=0·005) and the bilateral anterior cingulate cortex (p<0·001) compared with patients with Parkinson's disease without MCI (n=26). In patients with Parkinson's disease and MCI, SPECT uptake in the right caudate was lower than in patients with Parkinson's disease without MCI (p=0·008) and correlated with striatal functional MRI blood-oxygen-level-dependent signal (r=0·32, p=0·031).

Interpretation: These altered brain responses in patients with Parkinson's disease and MCI suggest that cognitive impairment is linked to frontostriatal dysfunction.

Funding: Swedish Medical Research Council, Swedish Parkinson Foundation, Swedish Parkinson's Disease Association, Umeå University, Kempe Foundation, Foundation for Clinical Neuroscience at Umeå University Hospital, Västerbotten County Council (ALF), King Gustaf V's and Queen Victoria's Freemason Foundation, Knut and Alice Wallenberg Foundation, and Swedish Brain Power.