Outcome measures and Biomarkers for Hereditary Spastic Paraplegia

Abstract

Hereditary Spastic Paraplegia (HSP) is an inherited neurodegenerative condition leading to impaired mobility and reduced quality of life. There is no curative treatment and an urgent need for standardised outcome measures to demonstrate efficacy of novel treatment options. The aim of this thesis is to identify outcome measures and biomarkers for HSP clinical trials.

In Chapter 1, a scoping review revealed heterogeneity of pre-existing outcome measures and biomarkers used and limited evidence for validity and reliability in HSP. Based on the findings, a core outcome set should include a clinician rated outcome measure, patient reported outcome measure (PROM), and a biomarker.

In Chapter 2, a systematic review of motor evoked potentials (MEP) in HSP did not support it as a biomarker for disease severity. Clinical evaluation of a set of outcome measures supported Scale for Assessment and Rating of Ataxia as a supplement to the Spastic Paraplegia Rating Scale in patients with HSP and prominent ataxia symptoms. Short Form-36, a generic PROM, did not capture HSP-specific quality of life issues, and MEP findings did not correlate with clinically relevant outcome measures. This study highlighted the need for an HSP-specific PROM and biomarker.

In Chapter 3, flow cytometry showed reduced levels of acetylated α-tubulin in HSP-SPAST peripheral blood mononuclear cells compared to controls. These findings support further investigation of acetylated α-tubulin as a potential biomarker for HSP-SPAST and measure of treatment response.

In Chapter 4, patients with HSP, carers, and HSP clinicians were consulted using a modified Delphi process and cognitive interviews to develop HSP-specific items for an HSP-specific quality of life survey (HSPQoL). The HSPQoL was found to be valid and reliable.

This thesis provides crucial evidence to inform choice of outcome measures and biomarkers in HSP clinical trials and discusses avenues for future research.