We report the results of a small randomized, double-blind, placebo-controlled trial to investigate the effects of the drug memantine on cognitive outcome measures in young adults with DS. We used a carefully selected set of neuropsychological outcomes to test our primary hypothesis that memantine might improve hippocampal-dependent function in individuals with DS. This hypothesis was based on preclinical studies in a mouse model of DS. We found a significant effect of 16 weeks of memantine treatment on one secondary memory outcome measure associated with the primary hypothesis, the CVLT-II. Additionally, we found effects with P-values <0.10 for one of the primary outcome measures, the PAL Stages, and for one of the secondary/discriminant outcome measures, the DAS-II Recall of Digits. These findings should warrant further investigation with the use of a larger sample size. Memantine therapy was well tolerated in our participant cohort, with only mild and infrequent adverse events noted. Given our findings, it would be premature to make any recommendations on the clinical usefulness of memantine as a therapeutic agent for the amelioration of the cognitive deficits associated with DS. This trial now joins a group of very few placebo-controlled trials to be performed on individuals with DS and was a necessary step toward the establishment of a bridge between the preclinical work with animal models of DS and the much more ambitious project of investigating various pharmacotherapies to improve the quality of life of individuals with DS.
Ultimately, the most clinically relevant measures for the evaluation of the efficacy of medications directed at enhancing the cognitive capabilities of individuals with intellectual disability of any cause are those assessing adaptive and daily living skills. These are the practical, everyday skills that affect independence and social competence. However, these skills also take several years to mature, even in the population of typically developing individuals. Hence, it would have been unrealistic to expect any funding agency or pharmaceutical company to finance the implementation of the large-scale and prolonged study that would be required to demonstrate efficacy in adaptive and daily living skills at an exploratory stage of investigation (see Costa24
for a recent review on this subject). Accordingly, the design of the present study was based on modest, but realistic goals.
The finding of improved CVLT-II scores in the group of participants with DS treated with memantine in the present study merits further consideration. The CVLT-II is one of the five most common assessment instruments used by clinical neuropsychologists in North America.25
The construct validity of the CVLT-II as a measure of episodic verbal learning and memory has garnered considerable support in the neuropsychological literature,26, 27
and it has been used to assess the levels of severity and recovery in neurological disorders including AD, tumors, traumatic brain injury, stroke and epilepsy affecting the medial temporal lobe26, 28, 29, 30, 31
and neuropsychiatric afflictions such as posttraumatic stress disorder and chronic depression.32, 33, 34
The CVLT-II is commonly used to evaluate verbal memory, and consists of the presentation of a word list that is longer than the average working memory span.34
Correct encoding, storage and consolidation are needed for long-term memory, and these processes have been shown to be heavily dependent on the function of hippocampus/temporal lobes. In healthy, typically developing individuals, it is generally assumed that successful verbal learning of a supraspan word list also depends on the development of a strategy, and should therefore rely on the frontal lobes as well. Finally, attention deficits or interference may also contribute to disturbed recall. In pathologic conditions, such as in amnesia or memory impairment, subjects are unlikely to develop alternative learning strategies, which make the test even more dependent on the functioning of hippocampus/medial temporal lobes. Indeed, there is general agreement on the role of the medial temporal lobes in episodic/long-term consolidation, and most researchers agree that verbal memory generally depends more on left-side structures.35
Although it would have been interesting to characterize serial position effects and subjective clustering strategies associated with the CVLT-II performance by individuals with DS in the present study, the use of the short form of the CVLT-II (which has 9 items instead of 16) has limited the potential usefulness of such analysis. The finding of a borderline significant effect on the DAS-II Recall of Digits is also intriguing and deserves future investigation, because of this measure's dependence on prefrontal cortex function.
In spite of its broad use in clinical and experimental neuropsychology, in the present work, we chose not to describe the CVLT-II as a primary measure, but instead as a ‘secondary measure associated with the primary hypothesis'. This was consciously done because, in the strictest sense of the term, a primary measure of a clinical trial should be one from which the a priori
power calculations are performed for the estimation of the necessary sample size to detect significance at a pre-established level of power. The only two measures that fit this description in the present trial were the PAL and PRM. Previously published mean and s.d. data were already available from the work of Pennington et al.7
at the time this study was conceived. However, no CVLT-II assessments in individuals with DS were available in the literature. Therefore, we were unable to make any statistical estimation of sample sizes based on expected effect sizes. Now, the data showed here will allow us and others to design trials in which the CVLT-II will feature as the (or at least one of the) primary measure(s).
As the fields of pharmacotherapeutics for DS and other defined central nervous system disorders associated with cognitive and intellectual disabilities move forward, an important question to ponder is the translatability of behavioral measures obtained in an animal model (generally a rodent species) into neuropsychological measures from human studies. In the original collaboration between the research teams led by Drs Bruce Pennington and Lynn Nadel,7
their emphasis on tests with a significant visuospatial memory component, such as the PAL and PRM, was based on the premise that these types of tests were more likely to have similar construct validity between mouse and human studies. However, here the most promising measure of hippocampus-dependent function was the CVLT-II, which obviously cannot be assessed in mice. It is not unreasonable to argue that, evolutionarily, verbal episodic memory has acquired a disproportionate importance in the human medial temporal lobe, compared with visuospatial memory and the formation of cognitive maps.
In addition to its small sample size, short duration of the treatment and the use of multiple statistical comparisons without adjusting the P
-value, this study has a few other limitations. For example, participant selection was biased toward a subgroup of young adults with DS who were generally healthy, verbal and with no, or very few, behavioral issues. One of the consequences of this bias was the production of an ~2:1 imbalance in the female/male ratio in our sample. This can be explained by the observation that, in average, adolescent and young adult women with DS have been reported to function at a higher cognitive level and display less maladaptive behaviors and psychiatric disorders than their male counterparts.36, 37
Also, although extreme care was taken in the selection of participants and caregivers, we acknowledge the very small, but real, possibility that a few caregivers might have removed the study medication from the bottles without giving them to the participants.
In selecting the age range, our goal was to avoid the potential confound of neurodevelopment during the 16-week time window between the baseline neuropsychological evaluation and the posttreatment assessment, while also minimizing any superimposing effect of neurodegeneration on these measures. The pitfalls represented by recruiting participants of advanced age and concomitant health issues were seen recently in the study by Hanney et al.
named ‘Memantine for dementia in adults older than 40 years with Down's syndrome' (MEADOWS). This study was a randomized, double-blind, placebo-controlled trial to assess safety and efficacy of memantine on the treatment of cognitive decline associated with dementia in individuals with DS. Although 1-year-long treatment with memantine was well tolerated in this participant cohort, efficacy data were completely negative. The design of the MEADOWS trial preceded many important recent findings in the field of DS research; therefore, it did not benefit from newly available information. For example, neuropsychological assessments of hippocampus-dependent measures were not included in the protocol. Additionally, it is plausible to assume that, by the time treatment began, various irreversible pathological cellular cascades were already triggered and the disease process might have reached a point of no return (see Costa39
for a more complete set of comments on the MEADOWS trial). Therefore, an investigation of the potential neuroprotective role of memantine in young, healthy adults with DS cannot be discarded in light of the present evidence.
Because of the novel nature of some of the findings in the present study, it would be prudent to proceed with caution and our results should be reproduced in a larger sample of participants before an even larger, phase III multicenter trial can be planned. Although memantine therapy has proven safe and well tolerated here and in the MEADOWS trial, given the expression of increased anxiety in some participants in both trials, a dose-finding trial may also be warranted. Eventually, we also would like to design future trials specifically to include younger, school-age children, similar to what has been done recently by Kishnani et al.
where these authors investigated the potential usefulness of the anticholinesterase drug donepezil for treatment of cognitive dysfunction in children with DS aged 10–17 years. At present, however, very little clinical (or even preclinical) safety data on memantine are available for pediatric participants. Finally, it would be important to explore the usefulness of electrophysiological, imaging and/or biochemical biomarkers in future studies. Such biomarkers would not only provide potential surrogate end points in addition to neuropsychological measures, but also might allow for a more inclusive recruitment in future studies. One could argue, for example, that individuals who are nonverbal and/or display significant behavioral issues are exactly those who might benefit the most from therapies directed at enhancing cognitive abilities in individuals with DS.