The Parkinson's-Reversing Breakthrough

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Abbreviations: ACh, acetylcholine; AChE, acetylcholinesterase; BuChE, butyrylcholinesterase.

Abbreviations: ACh, acetylcholine; AChE, acetylcholinesterase; BuChE, butyrylcholinesterase.

results suggested that cholinesterase inhibitors could improve neuropsychiatric features in PD without motor deterioration. However, in other studies, tacrine was associated with fulminant hepatotoxicity, which has limited its use.

The accumulation of evidence that cholinesterase inhibitors were effective for the cognitive and behavioral sequelae of DLB without significant motor side effects rejuvenated interest in these compounds for treating dementia in PD (159-163). Subsequently, multiple open-label reports in PD dementia emerged and are summarized in Table 3 (103,105-106,108-109,111,164-166). Unfortunately, variability in the trial designs, inclusion criteria, and assessment measures make it difficult to compare studies. Overall, however, it appears that the cholinesterase inhibitors result in mild improvements in cognition without change in parkinsonian features. The few studies that reported motor deterioration noticed an effect mainly on tremor.

In a randomized, double-blind, placebo-controlled trial (167), 14 individuals with PD and cognitive impairment received either donepezil (5 or 10mg/d) or placebo in a cross-over design of two sequential periods lasting 10 weeks each. Patients had a history of cognitive decline at least one year after the onset of parkin-sonism (3.0 ± 2.6 years) to decrease the likelihood of enrolling patients with DLB. The entire cohort had a mean age of 71 years, average duration of PD 10.8 years, and a mean levodopa dose of 485 mg/day. Patients had to have a MMSE score between 16 and 26. In addition, all patients had to have a decline in memory and at least one other category of cognitive function. After 10 weeks of treatment, donepezil improved the MMSE score by 2.1, but the placebo group did not improve (0.3). Furthermore, the clinician's interview based impression of change (ClBlC) was greater for the donepezil group when compared to placebo. Motor function did not worsen during donepezil treatment, and no carry-over effect was noted.

There have been two other double-blind, placebo-controlled trials of donepezil in PD patients. Leroi et al. (168) randomized 16 patients to donepezil (2.5-10 mg/d) or placebo. Patients had to meet DSM-IV criteria for either dementia or cognitive impairment secondary to PD. Seven patients were placed on donepezil therapy for a mean duration of 15.2 weeks. There was no difference between the two groups at the final visit in terms of MMSE or DRS scores, but the donepezil group had a 60% improvement in the DRS memory subscore, compared to a 12.5% improvement in the placebo arm. Four of the donepezil treated patients withdrew from the study, one from worsening parkinsonism. However, there were no significant group differences in the UPDRS scores from baseline to the final visit. The second trial used a crossover design in 22 PD subjects with dementia (107). Patients had to have a MMSE score between 17 and 26, and meet DSM-IV criteria for dementia in order to be included in the study. Each treatment period was 10 weeks with a six-week washout between the two periods. Patients on donepezil had a nonsignificant improvement in their ADAS-cog scores (primary outcome measure), but had a two-point improvement on their MMSE score and on overall clinical impression.

There are no placebo-controlled trials reported for galantamine at this time. However, a large double-blind, placebo-controlled trial of rivastigmine for dementia in PD has been reported (110). This study enrolled 541 patients with mild-to-moderate dementia and PD, and randomized them to rivastigmine (mean dose 8.6 mg/d) or placebo for 24 weeks. About 410 subjects completed the study with dropouts primarily due to nausea, vomiting, and tremor. There was a significant improvement in the primary outcome measures for the rivastigmine group: ADAS-cog score at 24 weeks (2.1 ± 8.2) and the overall clinical impression. Secondary efficacy variables, Alzheimer's Disease Cooperative Study-Activities of Daily Living

TABLE 3 Summary of Open-label studies of Cholinesterase Inhibitors for Dementia in Parkinson's Disease



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