Clinical implications of early caudate dysfunction in Parkinson's disease

Abstract

Objective: Although not typical of Parkinson's disease (PD), caudate dopaminergic dysfunction can occur in early stages of the disease. However, its frequency and longitudinal implications in large cohorts of recently diagnosed patients remain to be established. We investigated the occurrence of caudate dopaminergic dysfunction in the very early phases of PD (<2 years from diagnosis) using ¹²³I-FP-CIT single photon emission CT and determined whether it was associated with the presence or subsequent development of cognitive impairment, depression, sleep and gait problems.

Methods: Patients with PD and healthy controls were identified from the Parkinson's Progression Markers Initiative (PPMI) database. We defined a clinically significant caudate dysfunction as ¹²³I-FP-CIT binding <-2 SDs compared with the controls' mean and categorised three groups accordingly (no reduction, unilateral reduction, bilateral reduction). All statistical analyses were adjusted for mean putamen binding.

Results: At baseline, 51.6% of 397 patients had normal caudate dopamine transporter binding, 26.0% had unilateral caudate involvement, 22.4% had bilaterally impaired caudate.Compared with those with a baseline normal caudate function, at the4-year follow-up patients with a baseline bilateral caudate involvement showed a higher frequency of cognitive impairment (p<0.001) and depression (p<0.001), and worse cognitive (p<0.001), depression (<0.05) and gait (<0.001) ratings. Significant caudate involvement was observed in 83.9% of the population after 4 years (unilateral 22.5%, bilateral 61.4%).

Conclusions: Early significant caudate dopaminergic denervation was found in half of the cases in the PPMI series. Baseline bilateral caudate involvement was associated with increased risk of developing cognitive impairment, depression and gait problems over the next 4 years.

Keywords: caudate; cognitive impairment; depression; gait problems; parkinson’s disease.

Figure 1

Pie chart representing the three groups of patients at baseline (A) and follow-up (B) classified according to their baseline caudate ¹²³I-FP-CIT SPECT binding compared with healthy controls. Patients with Parkinson’s disease (baseline, n=397; follow-up, n=267) were categorised into three groups based on their baseline caudate specific binding ratios compared with healthy controls: no reduced ¹²³I-FP-CIT binding in either caudate (PD-NC); ¹²³I-FP-CIT caudate binding reduced below −2 SDs of the controls’ mean in one caudate only (PD-UC); ¹²³I-FP-CIT caudate binding bilaterally reduced below −2 SDs of controls’ mean (PD-BC). The percentage of each subgroup in the PD cohort is displayed on the corresponding pie slice. PD, Parkinson’s disease.

Figure 2

Boxplots showing differences in outcomes in PD subgroups (n=323) at the 4-year follow-up. (A) MoCA, (B) GDS and (C) Gait Index score. PD-NC: Parkinson’s disease patients with no reduced caudate ¹²³I-FP-CIT binding compared with the controls’ mean at baseline. PD-UC: Parkinson’s disease patients with reduced baseline caudate ¹²³I-FP-CIT binding below −2 SDs of the controls’ mean in one caudate only. PD-BC: Parkinson’s disease patients with reduced baseline caudate ¹²³I-FP-CIT binding below −2 SDs of the controls’ mean in both caudate nuclei. (A) Bar charts representing mean MoCA scores with 95% CIs at the 4-year follow-up. (B) Bar charts representing mean GDS scores with 95% CIs at the 4-year follow-up. (C) Boxes and whiskers representing distributions of the gait index scores (product of MDS-UPDRS II subitems 2.12 and 2.13) at the 4-year follow-up. Boxes: 25th to 75th percentiles; whiskers 95th percentile. *P<0.05, **p<0.001. GDS, Geriatric Depression Score; MoCA, Montreal Cognitive Assessment score; PD, Parkinson’s disease.