Assessing Cognitive Improvement in People with Down Syndrome: Important Considerations for Drug-Efficacy Trials

Abstract

Experimental research over just the past decade has raised the possibility that learning deficits connected to Down syndrome (DS) might be effectively managed by medication. In the current chapter, we touch on some of the work that paved the way for these advances and discuss the challenges associated with translating them. In particular, we highlight sources of phenotypic variability in the DS population that are likely to impact performance assessments. Throughout, suggestions are made on how to detect meaningful changes in cognitive-adaptive function in people with DS during drug treatment. The importance of within-subjects evaluation is emphasized.

Young children with Down syndrome show normal development of circadian rhythms, but poor sleep efficiency: a cross-sectional study across the first 60 months of life

“…Much of the cognitive profile seen in people with DS can be traced mechanistically to changes in the developmental trajectory of the frontotemporal regions of the brain, including the hippocampus. Neuropsychological research has supported this relationship by repeatedly documenting a disproportionate weakness in performance on cognitive tasks that are dependent on hippocampal function in those with DS [1], [2], [3].…”

“…Down syndrome (DS) emerges out of the biological sequelae produced by an extra copy of all or part of human chromosome 21 (Hsa21; trisomy-21) [1]. In addition to well-documented functional strengths, individuals with this condition face many challenges throughout their lifespan.…”

Cognitive Enhancement

“…Cognitive enhancement in special populations often involves children, as in the case of Autism Spectrum Disorder (reviewed in Vahabzadeh et al 2015) and Down syndrome (reviewed in Fernandez and Reeves 2015). Improvement in social cognition is a primary goal for Autism Spectrum Disorder, and many candidate medications are available for testing.…”

“…So, the naming of these drugs is in itself an issue going forward. Nevertheless, with the advances in science today, there is the real possibility that cognitive enhancers will have a significant impact on society, especially in view of the likelihood that such drugs will gain traction as lifestyle-type medicines having broad reach across not only ill but healthy individuals (Forlini et al 2013;Cabrera 2015). It is possible with correct communication and discussion between policy makers, regulatory authorities, physicians, and disease area experts that many of the ethical issues that are associated with cognition can be addressed and be made open to the general public in an informative and educative manner.…”

A non-mosaic humanized mouse model of Down syndrome, trisomy of a nearly complete long arm of human chromosome 21 in mouse chromosome background

“…There are a number of technical arguments for a new DS model to meet these challenges, but perhaps the most compelling global issue relates to pre-clinical drug testing. Potential treatments in Ts65Dn mice have yielded an embarrassment of riches with at least a dozen potential single gene targets whose ablation alleviates cognitive deficits and more than a dozen pharmaceuticals or nutriceuticals reporting promising effects (12). For example, the recent clinical trial by Roche of the GABA-α5 antagonist RG1662 gave serious weight to experiments in Ts65Dnand other trisomic mice showing that normalization of the balance of inhibitory and excitatory inputs to hippocampus could improve several hippocampal-based behavioral paradigms as well as long term potentiation (LTP), all of which are impaired in Ts65Dn and other DS models (7,(13)(14)(15).…”