Cholinesterase Inhibitors

Four cholinesterase inhibitors have been approved by the FDA for the treatment of AD: tacrine (1993), donepezil (1995), rivastigmine (2000), and galantamine (2001), but only rivastigmine has been approved for PD dementia (2006). They are all postulated to help correct the cholinergic deficit seen in PD dementia by increasing the amount of acetylcholine (ACh) available for binding to cholinergic receptors in the synaptic cleft. For all the cholinesterase inhibitors, the most common side effects are gastrointestinal distress (nausea, diarrhea, vomiting), fatigue, insomnia, and muscle cramps (157). Rivastigmine tends to also be associated with weight loss and dizziness.

Although all these medications inhibit the action of acetylcholinesterase (AChE), there are subtle differences between these agents, especially with regard to butyrylcholinesterase (BuChE) inhibition and effect on the nicotinic receptors (Table 2). BuChE also breaks down ACh in the synaptic cleft, so inhibition of both BuChE and AChE may theoretically have greater clinical effect in dementia than inhibition of AChE alone. Both tacrine and rivastigmine inhibit BuChE. Cholinergic nicotinic receptor binding is reduced in PD and directly parallels the degree of dementia (158). Galantamine is also an allosteric modulator of presynaptic nicotinic cholinergic receptors. Therefore, by potentiating cholinergic nicotinic transmission, galantamine may be more suited for patients with PD dementia. However, despite these differences between the cholinesterase inhibitors, there have been no comparison trials to suggest that one is superior over another for PD dementia.

Hutchinson and Fazzini (103) reported an open-label trial of tacrine in seven patients with PD dementia. All patients had improvement in hallucinations: five with complete resolution and two with partial improvement. They also had a 7.1-point improvement in mean MMSE scores and an improvement in motor scores. These

TABLE 2 Properties of the Cholinesterase Inhibitors

Property

Tacrine

Donepezil

Rivastigmine

Galantamine

Chemical class

Acridine

Piperidine

Carbamate

Phenanthrene alkaloid

Cholinesterase

AChE and

AChE

AChE and

AChE

selectivity

BuChE

BuChE

Nicotinic ACh

modulator

-

-

allosteric modulation

receptor action

Type of cholin

Noncompetitive

Noncompetitive

Noncompetitive

Competitive reversible;

esterase inhibition

reversible

reversible

reversible;

least potent

most potent

Dose range

5-160 mg

2.5-10 mg

1.5-12mg

4-32 mg

Dosing frequency

qid

qd

bid

Bid or qd with

sustained release

preparation

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

Study

Drug

N

Age

Length PD

Cognitive outcome

Motor response

Hutchinson &

Tacrine

7

74

8

Improved MMSE, VH reduced

UPDRS markedly improved

Fazzini (103)

Werber & Rabey

Tacrine/Donepezil

7/4

75

10

ADAS-cog improved, MMSE

SPES unchanged overall

(166)

nonsignificant improvement

but 5 patients had motor improvement

Bergman &

Donepezil

6

69

5

Improvement on SAPS (5/6)

SAS unchanged

Lerner (105)

Kurita et al. (106)

Donepezil

3

70

12

MMSE improved in 1 patient 16 to 21

Unchanged in 2 patients, tremor worsened in 1

Minettet al. (165)

Donepezil

11 (PDD) 8 (DLB)

ND

ND

Improved MMSE in both groups, no significant change in NPI

No change in mean UPDRS motor scores, 7 patients reported tremor

Reading et al.

Rivastigmine

12

71

12

Improved NPI and MMSE

UPDRS unchanged

(109)

Bullock &

Rivastigmine

5

75

ND

Cognition improved in 2 and

Not formally tested. 2

Cameron (108)

stabilized in 2. 1 patient did not have dementia

patients worsened, 1 improved slightly

Giladi et al. (164)

Rivastigmine

28

75

7

Improved ADAS-cog scores, but not MMSE

UPDRS mildly improved

Aarsland et al.

Galantamine

16

76

13

Global cognitive improvement in

6 patients improved, 4 had

(111)

8 patients, worse in 4

no change, 3 had worsened tremor

Abbreviations-. ADAS-cog, Alzheimer's Diseases Assessment scale-cognitive subscale; DLB, dementia with Lewy bodies; MMSE, Mini-Mental State Examination; ND, not described; PDD, Parkinson's disease with dementia; SAPS, Scale for the Assessment of Positive Symptoms; SAS, Simpson-Angus Scale; UPDRS, Unified Parkinson's Disease Rating Scale; VH, visual hallucinations; SPES, Short Parkinson Evaluation Scale.

Abbreviations-. ADAS-cog, Alzheimer's Diseases Assessment scale-cognitive subscale; DLB, dementia with Lewy bodies; MMSE, Mini-Mental State Examination; ND, not described; PDD, Parkinson's disease with dementia; SAPS, Scale for the Assessment of Positive Symptoms; SAS, Simpson-Angus Scale; UPDRS, Unified Parkinson's Disease Rating Scale; VH, visual hallucinations; SPES, Short Parkinson Evaluation Scale.

Scale, NPI-10, MMSE, verbal fluency, Cognitive Drug Research Computerized Assessment System power of attention tests, and the Clock-Drawing test also improved in the rivastigmine group. In a 24-week open extension of this trial (169), patients on rivastigmine in the original trial maintained their improvement at week 48 of treatment, whereas patients who were previously taking placebo and placed on rivastig-mine (mean 7.7mg/day) experienced a 2.8 improvement in ADAS-cog scores at the end of 24 weeks.

In summary, there is emerging data that cholinesterase inhibitors produce a mild-to-moderate benefit on cognition in PD dementia. Although direct comparison between the different drugs is difficult, rivastigmine is the only approved medication for PD dementia. Other possible approaches to improving cholinergic function in the brain, such as dietary supplementation with cholinergic precursors (lecithin) and administration of cholinergic receptor agonists (bethanechol, milameline, tasaclidine), have not been found to be useful in AD and are unlikely to be tried in patients with PD dementia.

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