Grant: Operating Grant: Joint Programme on Neurodegenerative Disease Research (JPND)

Neurodegenerative disorders (NDDs) are devastating and a big burden on affected patients, their families and society at large. To help change the currently relentlessly progressive course of NDDs, likely interventions early in the course of NDDs are critical. It is equally critical to develop tools to measure disease progression in these early stages to test the impact of therapeutic interventions aiming to slow down the progression of NDDs or even arrest progression. However, identifying people at an early stage of developing a neurodegenerative disorder is not easy. In this proposal, we focus on NDDs caused by genetic alterations, here is a genetic change that consists of an expansion of a repeated stretch of DNA, collectively known as repeat expansion disorders (REDs). These disorders result over time in clinical impairments in all who inherit the repeat expansion (fully penetrant disorders). We favour the hypothesis that the driver of disease progression in REDs is the further increase of the repeat expansion in vulnerable cells of the body ('somatic expansion - SE'), e.g. neurons in defined brain regions, eventually resulting in clinical symptoms and signs. Other genes determine the rate of somatic expansion and can be measured in the blood, in particular if observing SE of longer periods. Subtle speech impairments are an early sign and can be measured quantitatively using acoustic speech analysis using target acoustic parameters (TAPs) as biomarkers. TAPs will be compared with other candidate biomarkers for early disease progression such as the rate of atrophy of the brain measured quantitatively and a marker in blood that reflects damage to neurons called NfL. Changes of these measures are promising candidate early progression markers. We hypothesize that people with larger SEs will show faster rates of progression in these markers, thus establishing an important disease mechanism, SE, as a traceable and potentially treatable mechanism of these group of NDDs.