Huntington disease: natural history, biomarkers and prospects for therapeutics

Abstract

Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic testing, with estimation of years to predicted onset, enabling the entire range of disease natural history to be studied. Structural neuroimaging biomarkers show that progressive regional brain atrophy begins many years before the emergence of diagnosable signs and symptoms of HD, and continues steadily during the symptomatic or 'manifest' period. The continued development of functional, neurochemical and other biomarkers raises hopes that these biomarkers might be useful for future trials of disease-modifying therapeutics to delay the onset and slow the progression of HD. Such advances could herald a new era of personalized preventive therapeutics. We describe the natural history of HD, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features. Building on this information, we review recent progress in the development of biomarkers for HD, and potential future roles of these biomarkers in clinical trials.

An image‐based model of brain volume biomarker changes in Huntington's disease

“…4A–D) allow the EBM staging to be related to potential thresholds for motor and cognitive onset. Example thresholds are chosen to reflect values that separate pre‐HD and HD subjects according to the longitudinal data published by2: Figure 2. For thresholds of TMS > 15, SDMT < 40, and Stroop < 100, the EBM predicts motor and cognitive onset for subjects with stage >13.…”

“…Symptoms typically begin in early adult life and the disease is usually fatal, with a median survival rate of 18 years after motor onset 2. Despite the disease being identifiable by a single genetic marker – an expanded cytosine‐adenine‐guanine (CAG) repeat in the huntingtin gene3 – an effective disease‐modifying treatment has yet to be found.…”

Structural and functional brain network correlates of depressive symptoms in premanifest Huntington's disease

“…Huntington's disease is a progressive neurodegenerative disease caused by a dominantly inherited CAG repeat expansion in the huntingtin gene on chromosome 4 [Ross et al, 2014]. It is characterized by cognitive, motor and neuropsychiatric impairment.…”

Allosteric activation of M 4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

“…HD is characterized by a prediagnostic phase that includes subtle changes in personality, cognition, and motor function, followed by a more severe symptomatic stage initially characterized by hyperkinesia (chorea), motor incoordination, deterioration of cognitive abilities, and psychiatric symptoms. At later stages of disease progression, patients experience dystonia, rigidity, and bradykinesia, and ultimately death (3)(4)(5)(6)(7). The cortex and striatum are the most severely affected brain regions in HD and, interestingly, an increasing number of reports suggest that alterations in cortical and striatal physiology are present in prediagnostic individuals and in young HD mice (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”