Abstract

Huntington’s disease (HD) is a progressive, monogenic dominant neurodegenerative disorder caused by repeat expansion mutation in the huntingtin gene. The accumulation of mutant huntingtin protein, forming intranuclear inclusions, subsequently leads to degeneration of medium spiny neurons in the striatum and cortical areas. Genetic testing can identify HD gene carriers before individuals develop overt cognitive, psychiatric, and chorea symptoms. Thus, HD gene carriers can be studied in premanifest stages to understand and track the evolution of HD pathology. While advances have been made, the precise pathophysiological mechanisms underlying HD are unclear. Magnetic resonance imaging (MRI) and positron emission tomography (PET) have been employed to understand HD pathology in presymptomatic and symptomatic disease stages. PET imaging uses radioactive tracers to detect specific changes, at a molecular level, which could be used as markers of HD progression and to monitor response to therapeutic treatments for HD gene expansion carriers (HDGECs). This review focuses on available PET techniques, employed in cross-sectional and longitudinal human studies, as biomarkers for HD, and highlights future potential PET targets. PET studies have assessed changes in postsynaptic dopaminergic receptors, brain metabolism, microglial activation, and recently phosphodiesterase 10A (PDE10A) as markers to track HD progression. Alterations in PDE10A expression are the earliest biochemical change identified in HD gene carriers up to 43 years before predicted symptomatic onset. Thus, PDE10A expression could be a promising marker to track HD progression from early premanifest disease stages. Other PET targets which have been less well investigated as biomarkers include cannabinoid, adenosine, and GABA receptors. Future longitudinal studies are required to fully validate these PET biomarkers for use to track disease progression from far-onset premanifest to manifest HD stages. PET imaging is a crucial neuroimaging tool, with the potential to detect early changes and validate sensitivity of biomarkers for tracking HD pathology. Moreover, continued development of novel PET tracers provides exciting opportunities to investigate new molecular targets, such as histamine and serotonin receptors, to further understand the mechanisms underlying HD pathology.

Highlights

  • Huntington’s disease (HD) is an inherited, neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT) on chromosome 4 [1]

  • Cross-sectional and small longitudinal positron emission tomography (PET) studies have investigated the use of dopamine receptors, brain metabolism, microglial activation, and phosphodiesterase 10A (PDE10A) as potential HD biomarkers

  • Longitudinal studies revealed no changes in glucose metabolism; only metabolic network analysis could be useful for tracking disease progression

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Summary

Introduction

Huntington’s disease (HD) is an inherited, neurodegenerative disorder caused by a CAG (codon that codes for amino acid glutamine) repeat expansion in the huntingtin gene (HTT) on chromosome 4 [1]. The onset of symptoms is inversely associated with the size of the CAG repeat expansion and most commonly occurs at the age of mid-40s [3]. Subclinical changes and pathological processes are thought to precede the initiation of clinical symptoms by several years [4,5,6,7,8,9]. There is currently no cure or disease-modifying therapy for HD, and symptomatic treatment is limited. HD will eventually lead to death, typically 15–20 years following symptomatic onset [10]

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