Executive Function Deficits in Adults with Tuberous Sclerosis Complex: Implications for Clinical Practice and Clinical Trials

Background: Tuberous Sclerosis Complex (TSC) is a genetic disorder with multi-system involvement. The lifetime prevalence rates of TSC-associated neuropsychiatric disorders (TAND) are in the region of 90% and lead to significant burden of disease. TAND includes a range of neuropsychological manifestations, including executive deficits. There are, however, few studies that have investigated executive skills in the disorder, either by group-wise comparisons or by examining the profile of executive deficits. There has also been interest in clinical trials with neurocognition as primary outcome in TSC and other genetic disorders, but given the novelty of the field, much is still unknown in terms of selection and analysis of neurocognitive outcomes, such as of executive functions.

Objectives: The aim of this study was to examine four components of executive skills in normally-intelligent adults with or without TSC and to analyze findings in two different ways – a group-wise analysis, and an individual profile analysis. We hypothesized that the TSC group would perform significantly worse than a non-TSC control group, and that a specific set of executive deficits to target in trials may be identified.

Methods: The sample consisted of 21 adults with TSC and a gender-, age- and performance IQ-matched control sample of 18 non-TSC adults. Four subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB) were used to assess simple spatial working memory (SSP task), self-ordered spatial working memory (SWM task), planning (SoC task), and attentional set-shifting (IDED task). Data were analysed for group difference. In addition, the individual profiles of the TSC group were examined to identify the rates and pattern of clinical executive deficits (performance <5th Percentile).

Results: Results showed significant group-wise differences on the Spatial Span (SSP) task and the Between Error Score of Spatial Working Memory (SWM), but not on the other tasks. Individual profile analysis revealed different results. None of the TSC participants were impaired on the spatial span (SSP) task, ten percent (10%) were impaired on the self-ordered spatial working memory (SWM) task, 20% on the planning (SoC) task, and 30% on the extra-dimensional aspects of the set-shifting (IDED) task. Overall 52% of TSC individuals scored in the impaired range on one or more of the executive function tasks.

Conclusions: We confirmed that a significant proportion of adults with TSC presented with clinically significant deficits on various executive functions, but without a pattern that suggested a ‘target’ executive deficit. Interestingly, group-wise comparisons gave a different impression of executive weaknesses in TSC. The study highlighted the importance not only of performing group-wise comparisons but also of investigating profiles of clinical deficits in those with TSC and other genetic disorders. Findings suggest that the variability of neuropsychological profiles, and the differences between ‘group-based’ and individual profile analysis should be considered in determining clinical trial design and analysis methods of molecularly-targeted trials with neurocognition as primary outcome in TSC and other genetic disorders.