Ergun Uc on Cognitive Impairment in Early Parkinson's Disease

November 4, 2009


Ergun Y. Uc, MD, is the first author of a publication from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) cohort in the November 3, 2009, issue of Neurology (2009;73:1469-1477), entitled "Incidence of and risk factors for cognitive impairment in an early Parkinson disease clinical trial cohort." Uc is Associate Professor of Neurology at the Department of Neurology of the University of Iowa and at the Neurology Service of the VA Medical Center of Iowa City.

Jose E. Cavazos, MD, PhD, FAAN, discussed the study with Uc. Dr. Cavazos serves as Associate Professor of Neurology, Pharmacology and Physiology at the University of Texas Health Science Center at San Antonio, and is a member of the Editorial Board of the Science section of Prior to this publication, what were the known incidence, risk factors, and predictors for future cognitive impairment when patients were diagnosed with Parkinson's disease?

Uc: Cognitive impairment is common in patients with Parkinson's disease (PD), even in the early stages. Mild cognitive impairment is seen in about 20 percent of patients at the time of diagnosis, and affects more than 50 percent of cases overall. The risk of dementia in PD (PDD) is increased four to six-fold, affecting 30 to 40 percent of all cases with PD, and up to 80 percent of PD patients can become demented 15 years after diagnosis. The prevalence and incidence of dementia in published reports varies, depending on the age, severity of Parkinsonism, and baseline cognitive function of the studied population. The annual incidence of PDD ranges between 42.6 and 112.5 cases per 1,000 person-years, depending on the baseline characteristics (e.g., age, disease severity) or setting (hospital vs. community based). The only community-based incident PD study on PDD reported that about 10 percent of patients developed dementia when tested again about 3.5 years after diagnosis (Williams-Gray et al., 2007).

Known risk factors for PDD include advanced age, increased severity of Parkinsonism (especially when postural instability and gait disorder are present), symmetry of the signs of Parkinsonism, presence of hallucinations, male gender, depression, and poor performance on baseline cognitive tests. Keep in mind that the definitions of PDD, cognitive impairment, and mild cognitive impairment may vary from study to study. What are the advantages of studying the incidence of, and risk factors and predictors for, cognitive decline in the DATATOP cohort?

Uc: The DATATOP cohort is one of the largest and best-studied early PD cohorts in the world, starting with the untreated (pre-levodopa) phase and with a long follow-up period (up to 7.6 years with extension studies). The DATATOP protocol included frequent and periodical neuropsychological testing throughout the study, enabling us to study the incidence of cognitive impairment and its risk factors in early PD in a relatively accurate manner. Identifying important risk factors for cognitive impairment in early PD will allow clinicians to target those at highest risk when a disease-modifying treatment for cognitive dysfunction/dementia becomes available. Furthermore, this study gives us a glimpse of how participants in early PD trials might be evolving cognitively compared to the general PD population. Please summarize the findings of your study.

Uc: The cumulative incidence of cognitive impairment (defined as scoring two standard deviations below age—and education-adjusted MMSE norms) on clinically confirmed PD (740 out of 800 subjects) was 2.4 percent (95 percent CI: 1.2–3.5 percent) at two years and 5.8 percent (3.7–7.7 percent) at five years. Subjects who developed cognitive impairment based on the MMSE criterion showed significant progressive decline on all longitudinally available neuropsychological tests (both verbal and non-verbal abilities), while the performance of the non-impaired subjects stayed stable. Univariate analyses showed that 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 (difficulties in ADLs requiring manual dexterity), presence of gastroenterologic/urologic disorders at baseline, and lower performance on neuropsychological tests. Multivariate analyses showed that neuropsychological test results, bulbar dysfunction factor, and baseline gastrointestinal disorder are significant risk factors. When neuropsychological test results were excluded from consideration in the multivariate analysis, hallucinations and bulbar dysfunction factor were the most significant risk factors.

Although probably higher than the general population, the incidence of cognitive impairment in the DATATOP study was relatively low compared to community- and hospital-based studies in PD. This relatively low incidence may reflect recruitment bias inherent to clinical trial volunteers (e.g., younger age, higher education, better general health) or limitations of the MMSE-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. What should we tell a newly diagnosed PD patient regarding possible future cognitive impairment?

Uc: Cognitive impairment is a common and potentially disabling non-motor manifestation of PD across all stages of PD. Even early in the course, cognitive impairment can affect performance at work and critical activities of daily living such as driving. Later in the course, dementia can limit medical and surgical treatment options for Parkinsonism, and become an independent risk factor for nursing home placement and mortality. Patients, their caregivers, and health care providers should have an increased awareness of cognitive impairment in PD so that it can be recognized early, and social, professional, and treatment adjustments can be made at every stage of the disease.

PD is a heterogenous disease and knowing risk factors for cognitive impairment as outlined in our study and the literature can help focusing clinical care and research on patients at high risk for cognitive impairment. What do you hope to see in future research studies?

Uc: Our study shows that secondary analyses of existing clinical trial databases can be useful to identify new information. I hope that our study encourages further "data mining" efforts on existing clinical trial and cohort databases in PD. With increased awareness of the frequency, severity, and impact of cognitive impairment in PD, I hope that more research efforts will be concentrated on this disabling aspect of PD. Animal models of PD may need to incorporate cognitive impairment. Protocols of cohort studies or clinical trials in PD may need to go beyond using typical motor manifestations as outcome measures and also include sensitive, detailed testing on non-motor aspects of PD such as cognitive impairment as outcome measures to capture multiple aspects of disability. Clinical trials with detailed protocols testing novel treatment and neuroprotection approaches (pharmacological, behavioral) on mild cognitive impairment and dementia in PD are needed.

Author Disclosures

Dr. Uc has received speaker honoraria for activities not sponsored by industry, has served as a grant reviewer for the Parkinson Study Group, and he receives research support from the NIH, the US Department of Veterans Affairs, and the Parkinson Disease Foundation.

Within the past 24 months, Dr. Cavazos received personal compensation for his work as a scientific board advisor for UCB Pharma and Ortho McNeil, and as a consultant for GXC Global. In the same period, he served as an editorial board member of Epilepsy Research and as Web Content chair of the American Epilepsy Society. Within the past five years, he received grant funding from NIH (NINDS) and VA (Merit review award).