Cognitive Effects of Rasagiline in Mild-to-Moderate Stage Parkinson's Disease Without Dementia

While Parkinson’s disease (PD) has historically been defined in terms of its motor symptomatology, nonmotor deficits form an important part of the syndrome. Cognitive deficits can occur in the early stages of PD and are often noted in memory, attention, visuospatial abilities, and executive functioning.¹ These deficits are often subtle and do not rise to the level of impairment necessary for a diagnosis of dementia; however, these deficits are discernable with neuropsychological testing² and may produce subjective complaints of cognitive decline and mild functional difficulties in some patients. In some patients with PD, mild cognitive impairments will worsen over time. The point prevalence for dementia in PD reaches 25%−30%, a rate that is six times greater than in the general population.³

The traditional pharmacological interventions for PD have focused on controlling and alleviating motor symptoms with levodopa and dopamine agonists. These medications treat the symptoms of PD but do not alter the course or progression of the underlying disorder. Rasagiline, an MAO-B inhibitor, showed a potential disease-modifying effect in one study.⁴ In addition to the improvements noted in motor symptoms, there is some indication that rasagiline may be associated with improvements in quality of life⁵ and cognition⁶ as well. Given the positive and intriguing findings seen with treatment with rasagiline, we used a double-blind, placebo-controlled design to study the effects of rasagiline on cognition in nondemented patients with mild-to-moderate stage Parkinson’s over a 6-month period.

Methods

Classification of Evidence

This interventional study provides class 1 evidence regarding the effect of rasagiline on cognition in nondemented patients with mild-to-moderate stage PD during a 26-week, double-blind, placebo-controlled study.

Participants

Fifty participants were recruited from new and existing patients diagnosed with idiopathic PD at the Movement Disorders Clinic at Butler Hospital in Providence, Rhode Island. Forty-five patients completed the study (age: 50–83 years old, mean=68.6 years [SD=8.0]; sex: 34 males, 11 females; education: 8–22 years, mean=15.4 [SD=3.2]; Mini-Mental Status Examination [MMSE] range: 23 to 30/30 points, mean=28.2 [SD=2 points]). Participants enrolled in this study were naive to PD medications, or on levodopa medications, or on dopamine agonist medications. Patients enrolled in the study did not meet DMS-IV criteria for dementia due to PD, were able to speak and read English, had at least 6 years of formal education, were not clinically depressed, had a diagnosis of PD, and had been on stable medication regimens (no new PD medications and no changes to existing PD medication dosages) for the 4 weeks prior to study enrollment. If participants were already taking other Parkinson’s medications at the time of study enrollment, the dosages of those medications remained stable throughout study participation. Changes to existing Parkinson’s medication dosages or addition of other medications to treat PD after study enrollment resulted in removal from study. Participants were allowed to begin non-PD medications or to have changes to their existing non-PD medications if these additions and changes were deemed medically necessary by their providers. Patients were excluded if they were taking any other MAO inhibitor; taking a cognition-enhancing medication, such as a cholinesterase inhibitor medication or memantine; had an MMSE score below 21/30; had significant depression (Beck Depression Inventory−13 item score >7); or had another neurodegenerative disorder besides PD, an unstable cardiac disorder, or clinically significant hepatic, lung, or renal disease.

Standard Protocol Approvals, Registrations, and Patient Consents

The study and all procedures were approved by the institutional review boards of Butler Hospital in Providence, Rhode Island, and Memorial Hospital of Rhode Island in Pawtucket, Rhode Island. All patients provided written informed consent.

Randomization

To facilitate recruitment, we enrolled participants who were of different ages, at various stages of disease severity, and on a variety of different medication regimens. We used statistical methods and urn randomization to control for these differences and ensure that our treatment and control groups were equally balanced on these variables. Following baseline cognitive testing, participants were urn randomized into either the treatment (N=23) or control group (N=22). Urns for this study included Parkinson’s staging and treatment with levodopa or dopamine agonist medications. Thirty-one of our patients were taking a medication for PD at baseline (16 in the treatment group and 15 in the placebo group). Our groups were also balanced on disease staging at baseline using the motor subtest of the Unified Parkinson’s Disease Rating Scale ([UPDRS]⁷ treatment group mean=23.9 [SD=10.7]; placebo group mean=21.7 [SD=9.6]) and the Hoehn-Yahr scale ([H-Y]⁸ treatment group mean=2.0 [SD=0.4]; placebo group mean=1.9 [SD=0.6]).

Procedures

Prior to study enrollment, participants completed a neurological evaluation, the MMSE, and a self-report measure of depression (Beck Depression Inventory−13 item).⁹ Patients who met the inclusion criteria were invited to participate and provided informed consent. Participants in the treatment group received rasagiline 1 mg per day, while control participants received matching placebo. The duration of the study for each participant was 26 weeks.

Baseline cognitive testing was performed prior to randomization and treatment and repeated after 26 weeks in the study. The neuropsychological battery was chosen to provide a broad assessment of cognition across multiple domains, including attention, executive functioning, language, visuospatial perception, and memory. Attention was assessed using the Digit Span subtest from the Wechsler Adult Intelligence Scale—Fourth edition.¹⁰ Executive functioning was assessed using the Trail Making Test (TMT) A and B,¹¹ the clock drawing test,¹² verbal fluency tests (F-A-S letter fluency and animal naming),¹³ and the Oral Symbol Digit Modalities Test (OSDM).¹⁴ Language was assessed using the 30-item abbreviated version of the Boston Naming Test,¹⁵ visuospatial perception was assessed using the Judgment of Line Orientation from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS),¹⁶ and motor functioning was assessed using the Purdue Pegboard test (bimanual).¹⁷ Memory was assessed using a 15-item word list learning task (Rey Auditory Verbal Learning Test [RAVLT]).¹³ In addition to the initial neurological evaluation, a medical visit was performed at week 12, and a final neurological evaluation was performed at week 26.

Statistical Analysis

All analyses were performed using PASW Statistics 18. Preliminary t tests were performed to ensure that our groups were equivalent on age, MMSE score, and education level. All of these t tests were nonsignifcant; differences in age between our treatment and placebo groups approached, but did not reach, significance (70.7 rasagiline group versus 66.4 placebo group, p<0.068). To test whether rasagiline produced improvements in cognitive functioning, a series of repeated-measures analyses of variance (ANOVAs) of the raw scores were used to compare our treatment and control groups on the above-described cognitive measures at baseline and after 26 weeks of treatment. Additional repeated-measures ANOVAs were used compare UPDRS motor scores from baseline to final assessment.

Results

Repeated-measures ANOVA comparing pre- and posttreatment scores on tests of attention, executive functioning, visuospatial and language abilities, and memory failed to find significant differences between the rasagiline and control groups. Means and standards deviations for baseline and 26-week cognitive testing are presented in Table 1.

The inclusion criteria for our study were chosen to ensure that our participants did not show significant cognitive impairments at baseline. While all of our participants met the above-described inclusion criteria, we also ran analyses to determine how our participants with PD performed relative to age-matched normative samples. Using published norms, z-scores were calculated for cognitive measures of attention, executive functioning, and memory, and the mean performance for our entire participant pool at baseline was examined. Results indicated that our participant pool’s mean performance was within the average range (e.g., ±1 SD), as compared with published norms for each measure (Table 2).

Rasagiline is an MAO-B inhibitor that is approved for treatment of the motor symptoms of PD. UPDRS change scores were calculated for each participant, and independent sample t test comparison revealed significant group differences with participants who received placebo and those who received rasagiline. The placebo group showed an increase in motor symptoms over the course of the 26-week study (mean=3.36 [SD=5.95]), as compared with those participants who received rasagiline, who showed a decrease in motor symptoms (mean=−1.09 [SD=7.67]); t(43)=–2.17, p=0.04.

Discussion

Cognitive changes are common in PD and can occur at all stages of the disorder. The degeneration of nigrostriatal dopaminergic neurons in PD and the resulting impairments in dopamine transmission likely contribute to the observed cognitive changes.¹⁸ While dopaminergic medications are useful in treating the motor symptoms of PD, their effects on cognition in PD patients have been less clear with some studies finding improvement,¹⁹ some finding impairment,²⁰ and some finding no change²¹ with use. Rasagiline, an MAO inhibitor, enhances dopamine transmission by inhibiting dopamine breakdown and prolonging its synaptic availability. There is also some promise that this medication may show disease-modifying effects.⁴ A recently published study that was performed within the same time frame as our own examined the effects of rasagiline on cognitive functioning in a sample of cognitively impaired, but nondemented, patients with PD. These authors reported significant improvements on a measure of attention and verbal fluency as well as trends favoring the rasagiline group on several other measures.⁶ While these findings are interesting, they should be viewed with some caution due to the high number of statistical tests performed without correction. The purpose of our study was to examine the effect of rasagiline in cognitively unimpaired PD patients using a battery of neuropsychological tests assessing all cognitive domains.

The results of our study found that while participants receiving rasagiline showed some improvements in their motor symptoms, as measured by the UPDRS, no significant changes were found on any of the neuropsychological measures after 6 months of treatment with rasagiline. Further, the participant group who received placebo also did not show significant change on any of the neuropsychological measures over the 6-month course of our study. Finally, the cognitive performance of our treatment and placebo groups did not differ significantly from one another at baseline or after 6 months of study participation.

The strengths of our study include its randomized, double-blind, placebo-controlled design, its extensive neuropsychological assessment of all cognitive domains, and its careful inclusion of cognitively intact participants with PD. Though our sample included both participants who were and who were not receiving medications for PD prior to study enrollment, this was carefully balanced across the placebo and active treatment groups and controlled for the duration of our study. Further, no other cognitively enhancing medications were permitted during the course of our study. Limitations to our study include its relatively small sample size and its short duration. It is important to note that neither of our patient groups showed significant cognitive changes during the 6-month duration of our study. This lack of change, combined with the short duration of our trial, prevents us from drawing conclusions, pro or con, regarding any neuroprotective effects of rasagiline on cognition in persons with PD. As our sample did not include those with significant cognitive impairment or dementia, our results cannot be generalized to those populations.

In summary, rasagiline is an effective treatment for the motor symptoms associated with mild-to-moderate stage PD. Future studies of its possible effects on cognition in PD can include and compare samples of cognitively intact and cognitively impaired individuals. Further, as the rate of cognitive change is less predictable in PD, future investigators may wish to follow study participants for a greater length of time.