Cognitive impairments in early Parkinson's disease are accompanied by reductions in activity in frontostriatal neural circuitry

Abstract

Studies in patients with Parkinson's disease (PD) suggest that the characteristic motor symptoms of the disorder are frequently accompanied by impairments in cognition that are most profound in tasks of executive function. Neuropsychological deficits are not an inevitable consequence of the disease, yet the reasons underlying cognitive heterogeneity in PD are not well understood. To determine the underlying neural correlate of these cognitive deficits, we used event-related functional magnetic resonance imaging (fMRI) to compare groups of cognitively impaired and unimpaired patients, matched on all other clinical measures. fMRI revealed significant signal intensity reductions during a working-memory paradigm in specific striatal and frontal lobe sites in patients with cognitive impairment compared with those patients who were not cognitively unimpaired. These results demonstrate that cognitive deficits in PD are accompanied by neural changes that are related to, but distinct from, those changes that underlie motoric deficits in these patients. Furthermore, they suggest that fMRI may provide a valuable tool for identifying patients who may benefit from targeted therapeutic strategies.

Figure 1.

Working-memory paradigm. A single trial from the working-memory task. After presentation of four letters and a retention interval of 9–14 sec, a cue signaled one of three prelearned conditions: retrieval, simple manipulation, or complex manipulation. The subject responded with a key press (first response), once the correct solution had been generated in mind, and a second key press (second response) to select from two alternative possibilities.

Figure 2.

Pattern of fMRI activity during the working-memory paradigm. fMRI activity for the combined-subjects (n = 31) random-effects analysis using a one-sample t test corrected for multiple comparisons at p < 0.05, contrasting the period of the task spent retrieving and/or manipulating information within working memory with the period during which maintenance (retention) of the same information was required. Significant activity was observed in the dorsolateral and ventrolateral prefrontal cortices (top and middle panels), the striatum (bottom panels), and posterior association cortices, bilaterally (middle left panel). The color scale represents the T statistic.

Figure 3.

Regional mean fMRI signal during manipulation. The subgroup of patients with executive impairments (▪) demonstrated significant underactivation (p < 0.05) compared with the unimpaired patients (▦) in the frontostriatal ROIs, but not in the posterior association cortices. Control subjects (□) show activation that is broadly similar to the unimpaired patient subgroup. The mean fMRI signal (parameter estimates) reflects the mean of the ROI contrast values. Error bars represent SEM.