Included studies fulfilled these criteria: included objective cognitive measures, a comparison group of participants not taking memantine, and provided sufficient data for calculation of effect size. We examined effect sizes across global cognition and five specific neuropsychological domains. Moderator variables examined included neuropsychological domain, diagnostic cohort (PDD, DLB, or mixed PDD-DLB cohort), study design (open label or placebo-controlled), and trial length.
Parkinson's disease (PD) dementia (PDD) and dementia with Lewy bodies (DLB) are common degenerative causes of dementia. Although prevalence and incidence estimates vary because of methodological differences across studies, several systematic reviews of dementia in PD including studies that examined PDD or DLB indicate a point prevalence of 25% to 30% and incidence rates 4 to 6 times that of healthy controls.[1, 2] DLB prevalence estimates indicate it is the second-most common neurodegenerative dementia in the Western world after Alzheimer's disease (AD). Importantly, cumulative prevalence estimates indicate that approximately 75% of PD patients who survive more than 10 years will develop dementia, highlighting the need for efficacious treatment for cognitive deficits.
PDD and DLB are similar in clinical presentation, including parkinsonism, profile of cognitive impairment (i.e., executive dysfunction), and the presence of psychiatric symptoms (e.g., psychosis). However, a PDD diagnosis requires that parkinsonism precedes cognitive impairment for more than 1 year, and cognitive impairment preceding or occurring within 1 year of developing parkinsonism suggests the clinical syndrome of DLB,[4, 5] indicating that these diagnoses may represent a spectrum of disease. Cognitive changes in PDD and DLB have been linked to dopaminergic, cholinergic, and, possibly, noradrenergic and glutamatergic activity.[6, 7] There is particular support for cholinergic dysfunction. Cholinesterase inhibitors have been shown to be beneficial in the treatment of PDD and DLB, and one (rivastigmine) is U.S. Food and Drug Administration approved and recommended for use to treat dementia in PD by an International Parkinson and Movement Disorder Society (MDS) task force on the treatment of nonmotor symptoms in PD. However, the MDS task force concluded that there was insufficient evidence for recommendation of other cholinesterase inhibitors, as well as memantine, which is thought to improve memory through other mechanisms.
With regard to glutamatergic dysfunction, research has demonstrated that glutamate transmission becomes hyperactive after dopamine depletion. Parkinsonian animal models have demonstrated that overactivity of glutamate has a role in the development of parkinsonian syndrome in rats. Research has also shown that abnormal alpha-synuclein affects cortical glutamatergic synapses and is associated with abnormal glutamate binding in patients with DLB versus age-matched controls at autopsy. Glutamate antagonists may alter glutamatergic transmission involving the striatum, subthalamic projections, and thalamocortical pathways. Considering the evidence for glutamatergic dysfunction in DLB patients and in parkinsonian animal models, overactivity of glutamate may contribute to development of PDD and DLB. This suggests that memantine, a partial glutamate receptor antagonist, may be beneficial in decreasing glutamate neurotransmission and preventing excitotoxicity.
Results regarding memantine's effects in PDD and DLB across placebo-controlled trials have varied; however, there were some significant benefits in all studies, and memantine was well tolerated.[14-17] Several meta-analytic reviews assessing safety and efficacy of memantine in PDD and DLB have recently been published.[18, 19] Primary efficacy outcome measures relevant to cognition included the Clinical Global Impression of Change (CGIC) and global cognition as assessed by the Mini–Mental State Examination (MMSE). Results of both meta-analyses revealed that memantine slightly improved overall global impression (i.e., CGIC), but had no significant effects on MMSE scores.
There are several potential explanations for these findings. Although the MMSE has been recommended for use in detecting dementia in PD in the past, the MMSE was designed for AD and may not account for the variable neurocognitive phenotypes observed in PDD and DLB. Although other brief cognitive assessments that cover more cognitive domains have been used in clinical trials and cohort studies (i.e., Montreal Cognitive Assessment; Alzheimer's Disease Assessment Scale–Cognitive Subscale [ADAS-cog]; and Dementia Rating Scale-2 [DRS-2]), these are screening tools for cognitive abilities. A comprehensive neuropsychological evaluation is often desired to increase sensitivity and further describe the phenotype of cognitive impairment. It is possible that memantine has effects on differential neuropsychological domains that may not be adequately assessed on global cognitive measures. Characterization of memantine's potential effects on discrete neurocognitive domains, in addition to global cognition would be useful, and build upon recently published meta-analyses.
Wang et al. meta-analysis examined the effects of memantine in PDD and DLB on global clinical impression, a measure of global cognition, and safety outcomes such as dropouts and adverse events; however, the researchers examined only randomized, placebo-controlled trials. Matsunaga et al. included both open-label and placebo-controlled trials, but did not examine the potential moderating effect of trial type. The design of the trial may moderate potential efficacy of memantine and warrants investigation. Also, whereas the sample composition was reported in these studies, potential moderating effects of sample composition were not investigated. Considering the temporal onset differences and neuropathological variability in PDD versus DLB, sample composition may influence effects observed across studies. Finally, whereas the length of the trial was reported in the previous meta-analyses, potential moderating effects of trial length were not investigated.
In the current study, we conduct a quantitative meta-analysis of existing studies examining memantine treatment in PDD and DLB. Our analysis included all available studies to evaluate the cognitive effects of memantine in PDD and DLB. A meta-analytic approach allows for the combination of results across studies and provides a more powerful estimate of true population differences. We examined both global cognition and neuropsychological changes across five commonly accepted domains (reaction time, executive functioning, memory, language, and visuospatial functions) in PDD and DLB compared to control groups (either placebo-controlled or open-label trials with a group not taking memantine). Furthermore, we sought to identify the impact of various potential clinical moderator variables, including potential effects of sample composition (i.e., PDD only, DLB only, or mixed cohorts), type of trial (i.e., open-label vs. placebo-controlled), and trial length (i.e. number of weeks), on memantine's efficacy.
The current meta-analysis builds and expands upon recent quantitative reviews of memantine's effects in PDD or DLB,[18, 19] in that a broader range of neurocognitive functions was examined and the possible contributions of sample composition, trial type, and trial length on the impact/effect size of the treatment were also explored. Although the meta-analysis indicated significant heterogeneity across studies, when cognition was viewed broadly, specific neuropsychological domains did not account for variability in effect sizes across studies. There was, however, a trend toward larger effects being observed on tests tapping global cognitive functions.
Although the effects on cognition are small, there are examples in the literature showing positive outcomes from treatment with memantine. For example, memantine may be considered as a reasonable treatment option, particularly considering evidence for its good safety and tolerability profile. Additionally, several recent studies have demonstrated memantine's benefits on quality of life and rapid eye movement behavior disorder in these populations. A recent open-label extension of a placebo-controlled trial included in the present meta-analysis evaluated the effects of memantine on survival. After 36-month follow-up, patients in the memantine group had a longer survival compared to patients in the placebo group. Within the active treatment group, survival analysis 36 months from baseline showed that responders during the controlled phase of the study had higher rates of survival compared with nonresponders. Although longer survival may not always be a useful indicator of therapeutic benefit in a chronic dementing illness, this finding suggests a potential disease-modifying effect of memantine in PDD and DLB and merits long-term evaluation in a larger study sample.
The trend for larger effects regarding global cognitive functions may have its basis in the heterogeneity of the illness itself. That is, PD, PDD, and DLB are heterogeneous disorders with regard to individual symptom presentation as well as cognitive dysfunction observed.[6, 32] It seems possible that global measures “cast a wider net” and are able to capture this individual variability or heterogeneity better than a focal neuropsychological test. With the press toward a more person-centered or “precision medicine” approach, measures that are able to detail subtle changes in an individual's cognition may be better able to capture the efficacy of any pharmacological intervention. For example, “intraindividual variability” or IIV has been shown to confer unique predictive information about cognitive functioning beyond mean performance and is specific to an individual. Preliminary studies have suggested that elevated IIV is a characteristic of PD[34, 35] and may be predictive of the development of dementia. Considering evidence that memantine leads to improvements in quality of life as well as evidence for a strong association between quality of life and cognition in demented and nondemented PD patients,[36-38] it is reasonable to hypothesize that improvements in quality of life are likely to be accompanied by improvements in cognition. Future studies of cognitive function in PD that utilize this type of person-centered methodology may help to resolve the conflicting findings between improved quality of life after memantine treatment and the lack of observable cognitive improvement.
Moderator analysis revealed significant moderating effects of sample composition and trial type. In previous meta-analyses, Wang et al. detected substantial heterogeneity in observed effects when PDD and DLB were evaluated together, but potential moderating effects of sample composition were not examined. In the current study, effect sizes for mixed cohorts were significantly larger than DLB-only cohorts; however, effect sizes for mixed cohorts were not significantly larger than PDD-only cohorts. There were no significant differences in effect sizes for PDD-only versus DLB-only cohorts. These findings suggest that using mixed cohorts may influence effect sizes and efficacy. Our results indicate that in the context of the significant moderating effect of sample composition, future trials of memantine may benefit from inclusion of only PDD or DLB subjects. If both PDD and DLB subjects are included in future trials, independent analyses are suggested for PDD and DLB subjects.
With regard to trial type, Matsunaga et al. meta-analysis included both open-label and placebo-controlled trials, but did not examine the potential moderating effect of trial type. Placebo-controlled trials have typically been the gold standard of pharmacological research; however, this rigorous research design often excludes subjects with substantial medical comorbidity and does not allow concomitant medication treatments. Because medical comorbidity and collateral medication use are common in clinical practice, placebo-controlled studies have been critiqued as lacking external validity. Along this same line, open-label trials in PD have been shown to be influenced by physician biases and expectation of benefit owing to knowledge of receiving active medication. In reference to the latter controversies, the finding of larger effect sizes in open-label studies likely reflect the contributions of both drug and placebo effects and reinforce the contention that randomized, placebo-controlled trials are recommended when possible.
Limitations of the current meta-analysis include the number of eligible studies for inclusion, the variety of neuropsychological measures used across studies, and inability to examine level of education as a potential moderator variable owing to inconsistent reporting of education level across studies. Education level should be recorded in future trials to allow for this analysis. Overall, memantine may be a feasible treatment option, considering the beneficial effects observed in trials examining safety profile, quality of life, and sleep disturbances. Although the effectiveness of memantine on improvement in cognition is quite small, larger prospective, multicenter studies may further assess potential benefits of memantine on cognition in PDD and DLB utilizing person-centered approaches to neuropsychological assessment and data analysis. If a comprehensive neuropsychological battery is used in a trial, the present results suggest that assessment of global cognition, rather than discrete neuropsychological domains, may better capture effects of memantine on cognition because of the heterogeneity of cognitive deficits across PDD and DLB patients.