Combined insular and striatal dopamine dysfunction are associated with executive deficits in Parkinson's disease with mild cognitive impairment

The ability to dynamically use various aspects of cognition is essential to daily function, and reliant on dopaminergic transmission in cortico-striatal circuitry. Our aim was to investigate both striatal and cortical dopaminergic changes in patients with Parkinson's disease with mild cognitive impairment, who represent a vulnerable group for the development of dementia. We hypothesized severe striatal dopamine denervation in the associative (i.e. cognitive) region and cortical D2 receptor abnormalities in the salience and executive networks in Parkinson's disease with mild cognitive impairment compared with cognitively normal patients with Parkinson's disease and healthy control subjects. We used positron emission tomography imaging with dopaminergic ligands C-11-dihydrotetrabenazine, to investigate striatal dopamine neuron integrity in the associative subdivision and C-11-FLB 457, to investigate cortical D2 receptor availability in patients with Parkinson's disease (55-80 years of age) with mild cognitive impairment (n = 11), cognitively normal patients with Parkinson's disease (n = 11) and age-matched healthy control subjects (n = 14). Subjects were administered a neuropsychological test battery to assess cognitive status and determine the relationship between dopaminergic changes and cognitive performance. We found that patients with mild cognitive impairment had severe striatal dopamine depletion in the associative (i.e. cognitive) subdivision as well as reduced D2 receptor availability in the bilateral insula, a key cognitive hub, compared to cognitively normal patients and healthy subjects after controlling for age, disease severity and daily dopaminergic medication intake. Associative striatal dopamine depletion was predictive of D2 receptor loss in the insula of patients with Parkinson's disease with mild cognitive impairment, demonstrating interrelated striatal and cortical changes. Insular D2 levels also predicted executive abilities in these patients as measured using a composite executive z-score obtained from neuropsychological testing. Furthermore we assessed cortical thickness to ensure that D2 receptor changes were not confounded by brain atrophy. There was no difference between groups in cortical thickness in the insula, or any other cortical region of interest. These findings suggest that striatal dopamine denervation combined with insular D2 receptor loss underlie mild cognitive impairment in Parkinson's disease and in particular decline in executive function. Furthermore, these findings suggest a crucial and direct role for dopaminergic modulation in the insula in facilitating cognitive function.