Prefrontal dopaminergic receptor abnormalities and executive functions in Parkinson's disease

Abstract

The main pattern of cognitive impairments seen in early to moderate stages of Parkinson's disease (PD) includes deficits of executive functions. These nonmotor complications have a significant impact on the quality of life and day-to-day activities of PD patients and are not effectively managed by current therapies, a problem which is almost certainly due to the fact that the disease extends beyond the nigrostriatal system. To investigate the role of extrastriatal dopamine in executive function in PD, PD patients and a control group were studied with positron-emission-tomography using a high-affinity dopamine D2/D3 receptor tracer, [(11) C]FLB-457. All participants were scanned twice while performing an executive task and a control task. Patients were off medication for at least 12 h. The imaging analysis revealed that parkinsonian patients had lower [(11) C]FLB-457 binding than control group independently of task conditions across different brain regions. Cognitive assessment measures were positively correlated with [(11) C]FLB-457 binding in the bilateral dorsolateral prefrontal cortex and anterior cingulate cortex only in control group, but not in PD patients. Within the control group, during the executive task (as compared to control task), there was evidence of reduced [(11) C]FLB-457 binding (indicative of increased dopamine release) in the right orbitofrontal cortex. In contrast, PD patients did not show any reduction in binding during the executive task (as compared with control task). These findings suggest that PD patients present significant abnormalities in extrastriatal dopamine associated with executive processing. These observations provide important insights on the pathophysiology of cognitive dysfunction in PD.

Figure 1

Study design. (a) Each subject underwent two [¹¹C]FLB‐457 PET scans at the same time on two separate days while performing either the active task (retrieval with shift) or the control task (retrieval without shift) of the MCST. Scan order was counterbalanced across subjects. Participants started the MCST five minutes before the radio‐ligand injection and terminated 10 min before the end of the PET scanning with two‐minute breaks between blocks; (b) active task; (c) control task.

Figure 2

Main effect of group on [¹¹C]FLB‐457 binding potential (BP_ND). (a) Voxel‐based analysis showed that the [¹¹C]FLB‐457 BP_ND from both active and control scans were significantly lower in patients with Parkinson's disease (PD) than control group (CG) in various regions (P < 0.05 corrected). (b) Sample BP_ND (spherical VOI, radius 6 mm) was extracted from the statistical peak identified in the voxel‐based analysis, and averaged between control and active tasks. Independent t‐test between CG vs. PD in each VOI also confirmed the lower [¹¹C]FLB‐457 BP_ND in all areas (*P < 0.05).

Figure 3

Correlation between MoCA and [¹¹C]FLB‐457 BP_ND. (a) Voxel‐based analysis showed that the [¹¹C]FLB‐457 BP_ND of active and control scans were positively correlated with MoCA only in control group in the bilateral DLPFC and ACC (P < 0.05 corrected at cluster level, thresholded at P < 0.001 uncorrected), (b) but not in PD (P > 0.05 corrected at cluster level, thresholded at P < 0.001 uncorrected). (c) Sample [¹¹C]FLB‐457 BP_ND (spherical VOI, radius 6 mm) was extracted from the statistical peak identified in the voxel‐based analysis (right DLPFC, BA 46, X = 34 Y = 50 Z = 16). Significant correlation was confirmed with MoCA score only in control group (r = 0.834, P < 0.001), (d) but not in PD (r = 0.024, P > 0.05). The significant difference in correlations was confirmed by Fisher's Z transform (Z = 2.9998, P = 0.0024).

Figure 4

Interaction effect of group × task (PD_active – PD_control – CG_active + CG_control). Voxel‐based analysis showed that the [¹¹C]FLB‐457 BP_ND was differentially affected by task performance between PD and CG in the OFC.

Figure 5

Summary of simple effect of task on [¹¹C]FLB‐457 BP_ND within each group. (a) In control group, performing the active task compared to the control task decreased [¹¹C]FLB‐457 BP_ND in the orbitofrontal cortex (OFC), uncus and fusiform gyrus. In PD, performing the active task compared with control task increased BP_ND in the anterior cingulate cortex (ACC), ventrolateral prefrontal cortex (VLPFC), medial prefrontal cortex (MPFC) and OFC. (b) The [¹¹C]FLB‐457 BP_ND in the OFC (BA 11) was extracted from spherical VOI (X = 24, Y = 26, Z = −24; radius 6 mm) that was identified in the voxel‐based simple effect analysis of task (active vs. control) in control group. The significant reduction of [¹¹C]FLB‐457 BP_ND during active task vs. control task was confirmed in control group (paired‐t test: t(7)=3.57, *P = 0.009), but not in PD (paired‐t test: t(7) = −1.136, P > 0.05). (c) The [¹¹C]FLB‐457 BP_ND in the VLPFC (BA 46/47) was extracted from spherical VOI (X = 42, Y = 48, Z = −6; radius 6 mm) that was identified in the voxel‐based simple effect analysis of task (active vs. control) in PD. The significant increase of [¹¹C]FLB‐457 BP_ND during active task vs. control task was confirmed in PD (paired‐t test: t (7) = 3.839, *P = 0.009), but not in control group (paired‐t test: t(7) = −0.186, P > 0.05).