Speech in prodromal and symptomatic Huntington’s disease as a model of measuring onset and progression in dominantly inherited neurodegenerative diseases

Highlights

• Subtle but apparently genuine changes in speech occur in HD before clinical diagnosis.

• Speech changes in prodromal individuals are largely characterized by timing deficits.

• Limited longitudinal data restricts capacity to predict HD evolution using speech.

Abstract

Subtle motor and cognitive changes can manifest prior to diagnosis in many progressive neurological disorders. Most people with Huntington’s disease (HD) develop dysarthria. Yet, how speech evolves, how the brain regulates speech in HD, and the clinical implications of these changes remain unclear. We reviewed existing literature on speech production in premanifest (PreHD) to symptomatic HD. A search of databases yielded 12 eligible studies. Nine of the twelve studies were included in the meta-analysis. Data suggest that speech in PreHD is characterized by impaired speech agility, phonatory function and speech rate. Over the disease course, speech gradually deteriorates across all subsystems of speech. Our findings indicate subtle changes in speech appear prior to a clinical diagnosis of HD. However, distinct patterns of decline and the magnitude of these deficits require further investigation. Our current understanding of speech impairment in HD relies on small cohort studies. Natural history studies documenting changes from premanifest to end stage may facilitate the development of speech as a marker of disease onset and treatment response.

Introduction

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by an expanded trinucleotide repeat (CAG) in the mutant IT15 huntingtin (Htt) gene (Duyao et al., 1993; Gusella et al., 1983). HD involves premature neuronal cell atrophy in the neostriatum as well as in the wider cortical regions of the brain (Delmaire et al., 2013; Imarisio et al., 2008). No treatment is currently available to delay onset or slow the progression of HD.

The autosomal dominant inheritance of HD allows predictive diagnostic testing, which provides an opportunity for valuable information to be gathered about the natural history of the disease. There is evidence suggesting subtle changes in cognitive and fine motor skills that precede the appearance of chorea in people with the HD gene expansion (i.e., in premanifest HD, or PreHD) (Bechtel et al., 2010; Biglan et al., 2009; Duff et al., 2010; Paulsen et al., 2008; Stout et al., 2011; Tabrizi et al., 2011). These clinical changes may appear more than a decade before the onset of more debilitating symptoms (Ross and Tabrizi, 2011; Tabrizi et al., 2011), at which point the diagnosis of HD is made.

HD is characterized by motor disorder, cognitive decline and psychiatric symptoms (McColgan and Tabrizi, 2018; Roos, 2010; van Duijn et al., 2014). In the context of impairment in both motor and cognitive systems, a breakdown in speech is anticipated given the involvement of these domains in speech production. Preliminary work in this space suggests subtle speech changes appear in PreHD (Kaploun et al., 2011).

There are efforts to develop disease-modifying therapies specifically targeting PreHD, with the understanding that patients may respond to treatment before HD pathology progresses. One of the challenges in preventive HD clinical trials is the lack of objective, sensitive and reliable biological markers to evaluate intervention efficacy (Andre et al., 2014; Mestre et al., 2009; Ross et al., 2014). Speech decline is one of the earliest indicators of disease onset, which suggests it is a potential marker of disease trajectory and/or treatment response (Vogel et al., 2012). However, relatively little is known about the speech phenotype of HD or how speech devolves over the course of the disease. The relationship between speech deficits and neurodegeneration is also unclear as imaging studies on speech functions in HD are rare (Skodda et al., 2016). Here we conducted a comprehensive review and meta-analysis of the literature on speech production in HD.