Incidence of and risk factors for cognitive impairment in an early Parkinson disease clinical trial cohort

Abstract

Objective: To investigate the incidence of and risk factors for cognitive impairment in a large, well-defined clinical trial cohort of patients with early Parkinson disease (PD).

Methods: The Mini-Mental State Examination (MMSE) was administered periodically over a median follow-up period of 6.5 years to participants in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism trial and its extension studies. Cognitive impairment was defined as scoring 2 standard deviations below age- and education-adjusted MMSE norms.

Results: Cumulative incidence of cognitive impairment in the 740 participants with clinically confirmed PD (baseline age 61.0 +/- 9.6 years, Hoehn-Yahr stage 1-2.5) was 2.4% (95% confidence interval: 1.2%-3.5%) at 2 years and 5.8% (3.7%-7.7%) at 5 years. Subjects who developed cognitive impairment (n = 46) showed significant progressive decline on neuropsychological tests measuring verbal learning and memory, visuospatial working memory, visuomotor speed, and attention, while the performance of the nonimpaired subjects (n = 694) stayed stable. Cognitive impairment was associated with older age, hallucinations, male gender, increased symmetry of parkinsonism, increased severity of motor impairment (except for tremor), speech and swallowing impairments, dexterity loss, and presence of gastroenterologic/urologic disorders at baseline.

Conclusions: The relatively low incidence of cognitive impairment in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism study may reflect recruitment bias inherent to clinical trial volunteers (e.g., younger age) or limitations of the Mini-Mental State Examination-based criterion. Besides confirming known risk factors for cognitive impairment, we identified potentially novel predictors such as bulbar dysfunction and gastroenterologic/urologic disorders (suggestive of autonomic dysfunction) early in the course of the disease.

Figure 1 Kaplan-Meier curve showing the cumulative incidence of cognitive impairment in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism cohort Values below the years indicate the numbers of subjects at risk for cognitive impairment.

Figure 2 Evolution of cognitive test performances over time The plotted values are adjusted group means derived from a mixed-effects regression model that included linear and quadratic terms for time. Subjects who eventually developed cognitive impairment (n = 46) had worse performance at baseline than those who did not develop cognitive impairment (n = 694) (p < 0.003 for all tests) and also had greater decline over time on both verbal and nonverbal tests (p < 0.01 for Selective Reminding Test and New Dot Task; p < 0.05 for Symbol Digit Modalities Test).