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The effect of everolimus on neurocognitive aspects of tuberous sclerosis complex

Anurag, Saxena 2021. The effect of everolimus on neurocognitive aspects of tuberous sclerosis complex. PhD Thesis, Cardiff University.
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Tuberous sclerosis complex (TSC) is a multi-system genetic disorder. It is characterised by benign tumour development in many organs, epilepsy and TSC-associated neuropsychiatric disorders, termed TAND that are frequent and have a great impact on the lives of patients and their carers. TSC results from mutations in either TSC1 (encoding TSC1) or TSC2 (encoding TSC2). Loss of functional TSC1 or TSC2 leads to activation of mTORC1 (mammalian target of rapamycin complex 1), a regulator of multiple cellular processes, including cell growth and neuronal function. Everolimus is an inhibitor of mTORC1 and is used in clinical practice for managing TSC-associated tumours and epilepsy. This thesis reports a phase 2, randomised, placebo-controlled trial assessing the safety and efficacy of 6 months of treatment with everolimus in adults with TSC and deficits in memoryand/or executive function. It aimed to determine effect sizes in its placebo and everolimus arms to inform future development of larger trials. Responders were defined as those showing an improvement of ≥1SD in at least one of ten measures of memory and executive function. Microstructural changes in cerebral white matter tracts associated with treatment were assessed using diffusion tensor imaging. Recruitment proved challenging, requiring modification of the original single centre design to a three centre study and revision of eligibility criteria to make them less stringent. Problems with application of one of the eligibility and outcome measures, the 'Test of Everyday Attention', further affected patient numbers for the primary analysis. In the final primary analysis (after adjustment) of 29 participants, 4 of 9 (44.4%) of the placebo group and 14 of 20 (70%) in the everolimus group were responders, satisfying criteria supporting further study as defined in the protocol

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 19 July 2021
Last Modified: 19 Jul 2021 14:55

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