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Cholinesterase inhibitors and memantine for Parkinson's disease dementia and Lewy body dementia: A meta-analysis

Recently, several randomized controlled trials on the use of cholinesterase inhibitors or memantine as treatments for cognitive impairment in Parkinson's disease (CIND-PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) were completed. The present study provided a meta-analysis of these studies to evaluate the efficacy of cholinesterase inhibitors and memantine on CIND-PD, PDD and DLB. The Cochrane Library, Pubmed, Embase and Web of Science databases were searched to retrieve eligible studies. As primary efficacy outcomes, cognitive function, global impression, behavioral symptoms and motor function were selected, while falling and adverse events were regarded as safety outcomes. Of note, domain-specific cognitive function was assessed as a primary efficacy outcome and falling as a safety outcome, which, to the best of our knowledge, has not been studied previously in CIND-PD, PDD and DLB. A total of 15 trials were included in the present meta-analysis. The results revealed that treatment with cholinesterase inhibitors resulted in improvements in cognitive function, the clinician's global impression, behavioral symptoms and motor function, in accordance with the results of previous studies. Furthermore, it was revealed that cholinesterase inhibitors had a significant effect on attention, processing speed, executive functions, memory and language; however, they did not improve visuospatial cognition compared with placebos. Memantine had a significant effect on attention, processing speed and executive functions. In addition, cholinesterase inhibitors and memantine did not significantly reduce falling. It was demonstrated that an increased number of adverse events occurred in the pooled cholinesterase inhibitors and memantine group, compared with that in the placebo group (risk ratio (RR)=1.09; 95% confidence interval (CI): 1.04–1.16; P=0.001); however, in the subgroup analysis, only the rivastigmine group experienced significantly more adverse events than the placebo group (85 vs. 73%; RR=1.18; 95% CI: 1.08–1.29; P=0.0001), but donepezil and memantine did not produce any significant adverse events. In conclusion, cholinesterase inhibitors and memantine have an effect not only on global cognitive function and motor function, but also on attention, processing speed, executive functions, memory and language. However, careful monitoring of the side effects of rivastigmine may be required. Further clinical trials are required to verify these conclusions.


Introduction
The most common types of dementia are Alzheimer's dementia (AD) and Parkinson's disease dementia (PDD), while dementia with Lewy bodies (DLB) is the second most common type of dementia, accounting for 15-20% of the global incidence of dementia (1)(2)(3). PDD and DLB are characterized by accumulation of Lewy bodies in brain cells (4). From a clinical and neuropathological perspective, DLB and PDD are similar conditions with the same features, namely dementia, parkinsonism, hallucinations and fluctuations of attention or arousal (5). They may be distinguished on the basis of the relative timing of dementia and Parkinsonism. Several meta-analyses have been performed to examine the efficacy and safety of cholinesterase inhibitors and memantine, or each drug separately, on CIND-PD, PDD and DLB (6)(7)(8)(9). The studies reported that cholinesterase inhibitors and memantine improve the global impression, cognitive function, psychiatric symptoms or motor function. They evaluated cognitive function via the use of certain screening tests, including the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). To the best of our knowledge, no previous meta-analysis has focused on cognitive domains, including attention, processing speed, executive functions, memory and language. The present study hypothesized that cholinesterase inhibitors and memantine may also improve the patients' cognitive domains in addition to global cognitive function, which may further prove their efficacy. In addition, falls are a common and severe complication of PD patients and seriously affect their daily safety, prognosis and quality of life (10), and thus, the effect of cholinesterase inhibitors and memantine on falls was also investigated.
Selection criteria. Randomized, placebo-controlled trials that assessed the efficacy of cholinesterase inhibitors in patients with CIND-PD, DLB and PDD were selected for the present meta-analysis. The inclusion criteria were as follows: Patients with PD were included if they fulfilled the UK PD Society Brain Bank clinical diagnostic criteria for PD or clinically definite and probable PD diagnosis (11)(12)(13)(14), and if they subsequently developed dementia, met the Diagnostic and Statistical Manual of Mental Disorders fourth edition/revised fourth edition or the Movement Disorders Society criteria at least 1 year after the onset of PD symptoms (15); DLB patients were included if they met the consensus guidelines for the clinical and pathological diagnosis of DLB or revised consensus criteria (16).
Data extraction and quality assessment. Two authors independently selected trials for inclusion in the meta-analysis and extracted information on the study design, patient selection criteria, drug doses, trial durations, primary and secondary outcomes, discontinuations and adverse events in each trial. Disagreements were resolved by discussion with other team members or by contacting the original investigators, who were all sent emails with requests to provide the exact data. For any missing standard deviation data, which were not obtainable from the primary investigators, estimated values calculated using the formula no. 8.5.2.3 in the Cochrane handbook were used in the analysis (17). The Cochrane criteria were used to assess risk of bias (18), and Grades of Recommendation, Assessment, Development and Evaluation (GRADE) Profiler software (version 3.6; Cochrane, London, UK) was used to evaluate the quality of the studies according to the GRADE methods (19).
Statistical analysis. The meta-analysis was performed using RevMan software (version 5.3; Cochrane), employing the inverse variance method. Heterogeneity was assessed using the Chi-squared and I 2 statistical tests, and considered significant if P<0.05 and I 2 >50% was obtained by the former and the latter test, respectively. If I 2 >50%, a sensitivity analysis was performed to determine the reasons for heterogeneity. In this commonly used sensitivity analysis method, each study included is eliminated one by one, followed by effect-size calculation, or the inclusion criteria are changed or certain types of literature are removed prior to effect volume combination. For continuous data, mean differences (MD) or standardized mean differences (SMD) were used in combination with the effect-size (Hedges'g) data. For dichotomous data, the risk ratio (RR) was estimated along with associated 95% confidence interval (CI). Overall, SMD and RR with 95% CI were estimated with Mantel-Haenszel fixed-effects (20) or DerSimonian-Laird random-effects models (21). When it was confirmed that there was no heterogeneity, pooled SMD and RR were calculated according to the Mantel-Haenszel fixed-effects model (P>0.05 or I 2 <50%). If there was evidence of heterogeneity, pooled SMD and RR were calculated according to the DerSimonian-Laird random-effects model (P<0.05 or I 2 >50%). Begg's funnel plots were drawn to evaluate publication bias.

Results
Study selection and characteristics. A total of 2,135 records of trials for the treatment of PD-CIND, PDD or DLB were retrieved from the Cochrane Library, Pubmed, Embase and Web of Science. Of these studies, a large quantity was not relevant, including studies regarding other diseases or interventions, or duplications. A total of 237 records were considered suitable after screening the titles and abstracts. Finally, of the 237 full-text articles, only 15 trials [six donepezil (22)(23)(24)(25)(26)(27), five rivastigmine (10,(28)(29)(30)(31) and four memantine trials (32)(33)(34)(35)] were included in the present meta-analysis. The flow chart for the selection of studies is presented in Fig. 1 and the details of each included article are presented in Table I. The methodological quality of all studies evaluated using the Cochrane risk of bias criteria is provided in Fig. 2.
Falling. A considerable number of patients experience falls as a complication of PDD and five of the trials included (10,25,29,32,35) reported on the quantity of falling. As presented in Fig. 8, the meta-analysis revealed that cholinesterase inhibitors and memantine did not significantly reduce falling compared with the placebo (RR=0.74; 95% CI: 0.51-1.08; P=0.12), thereby demonstrating that treatment with the drugs did not significantly prevent falls.
Publication bias. The publication bias regarding cognitive and motor function was determined by drawing Begg's funnel plots ( Fig. 10A and B). The shape of the funnel plots exhibited no obvious asymmetry, which indicated the absence of significant heterogeneity between these selected studies, and the pooled results were not influenced by publication bias.

Sensitivity analysis.
A sensitivity analysis was conducted to assess the stability of the results by sequential removal of individual studies. The heterogeneity (I 2 =75%) in global cognitive function is shown in Fig. 3, the study by Li et al (10) did not provide the mean differences with SDs, but rather electing to report the mean and SDs prior to and following treatment, which may have resulted in data conversion-associated errors.
Following the exclusion of the study, the analysis results did not change. In Fig. 4A, numerous trials that examined cognitive domains were then assessed (I 2 =78%), it was found that the results did not change following the sequential removal of individual studies. The authors of the current study estimated that there was variability in measurement precision.

Discussion
The present meta-analysis assessed the efficacy and safety of cholinesterase inhibitors and memantine in the treatment of CIND-PD, PDD and DLB, which contained four new more articles than a previous meta-analysis (9). To the best of our knowledge, the present study was the first meta-analysis to report on the effect of cholinesterase inhibitors and memantine in subjects with CIND-PD, PDD and DLB, including cognitive domains (attention, processing speed, executive functions, memory, visuospatial cognition and language). The results indicated that cholinesterase inhibitors had beneficial effects on attention, processing speed, executive functions, memory and language, but did not improve visuospatial cognition when compared with the placebo. Furthermore, memantine was revealed to improve attention, processing speed and executive functions. However, cholinesterase inhibitors and memantine did not significantly reduce falling. Compared with the placebo, more adverse events occurred in the pooled cholinesterase inhibitors and memantine group than in the placebo group. However, a subgroup analysis indicated that only the rivastigmine group experienced significantly more adverse events than the placebo group, while donepezil and memantine did not produce any significant adverse events. Consistent with the results of previous meta-analyses, the present study indicated that donepezil was beneficial for DLB  Manabe et al (36) observed that 10 mg donepezil improved BPSD in DLB. Mori et al (37) reported that increasing the dose of donepezil from 5 to 10 mg enhanced the effect in improving cognitive function in DLB with little influence on the safety. Ukai et al (38) reported that donepezil was highly effective against visual hallucinations in DLB. Galanthamine is another cholinesterase inhibitor. To date, the potential benefits of galanthamine have remained insufficiently demonstrated, except for an open-label trial. Litvinenko et al (39) reported that galanthamine improved cognitive function, behavioral symptoms, daily activity and the number of falls. Galanthamine treatment was not associated with any significant adverse events when compared with the placebo.
The results of the present meta-analysis revealed that memantine only had a minor side effect on the participants; however, this is in contrast to the meta-analysis by Matsunaga et al (6). This discrepancy may have been due to the fact that the analysis of the present study included two further trials, which may have provided more accurate results. Larsson et al (40) reported that memantine decreases the probable rapid eye movement sleep behavioral disorder in patients with DLB and PDD.
Safety is as important as the efficacy of the interventions in clinical studies. All of the three drugs assessed in the present study adhered to certain safety standards; however, rivastigmine produced more adverse events compared with those in the placebo group. Of note, donepezil and memantine did not produce any significant adverse events compared with the placebo. None of the drugs improved or    aggravated the symptoms of Parkinsonism compared with the placebo. Emre et al (41) reported that in a 76-week, prospective, open-label, randomized study in PDD patients aged 50 to 85 years, rivastigmine exhibited long-term safety.
Of note, the present meta-analysis had several limitations. First, even though 15 trials were included, the number of participants was small, and the results may not sufficiently allow for making any final conclusions. Furthermore, a complete evaluation of all interventions applied was impossible due to a lack of data. In addition, most of the trials included were relatively short, and more long-term trials with relatively longer follow-up periods similar to that by Li et al (10) lasting 12 months, are required for further evaluation. In addition, in the cognitive domains analysis with I 2 =78%, variation in at times overlapping interventions, heterogeneity in outcomes assessed and low number of controls were of greatest concern. The studies examined were performed across multiple countries with instruments that may appear to be similar, prima facie, but may substantially differ in how they sequentially remove individual studies (42). The authors of the current study combined different doses of the same drug for analysis, thus this may lead to biased results; this must be taken into consideration and eliminated in future studies.
In conclusion, cholinesterase inhibitors provide a benefit not only regarding global cognitive function, CGIC and behavioral symptoms, but also in cognitive domains.  cholinesterase inhibitors and memantine are associated with good safety outcomes, with only the rivastigmine group exhibiting significant adverse events compared with the placebo group. However, considering the limitations of the present study, the results may not sufficiently support the use of cholinesterase inhibitors and memantine as treatments for CIND-PD, PDD and DLB. Further clinical trials on a larger scale are imperative to better assess the efficacy and safety of cholinesterase inhibitors and memantine in CIND-PD, PDD and DLB.