Molecular Imaging Markers to Track Huntington’s Disease Pathology

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.

Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease

“…In Huntington’s disease occurrence of such very early changes is supported by the observation of early deficits in premanifest Huntington’s disease mutation carriers, such as loss of phosphodiesterase 10A in the occipital lobe up to 47 years prior to disease onset (summarized in Wilson et al, 2017 ). Also, the ability to perform complex visuospatial orientation, such as visual search, seems to be altered even in pre-manifest stages far from clinical diagnosis ( Labuschagne et al, 2016 ).…”

Inhibition of endocannabinoid degradation rectifies motivational and dopaminergic deficits in the Q175 mouse model of Huntington’s disease

“…Striatal medium spiny neuron degeneration represents the canonical, histopathological hallmark of HD [8,9]. However, before gross neurodegeneration and motor symptoms present, alterations in neurochemical transmission arise during periods when patients primarily exhibit psychiatric impairments [10]. Disruptions in endocannabinoid (eCB) and dopamine system function are prominent neuropathologies in HD that present early and worsen across disease progression [11][12][13].…”

Huntington’s Disease: A Review of the Known PET Imaging Biomarkers and Targeting Radiotracers

“…It progresses with fatal and devastating psychiatric, cognitive and motor impairments, caused by mutant huntingtin (mHTT) protein expression. Some excellent reviews on the molecular imaging of HD have been published, however focusing primarily on clinical data [2][3][4][5]. This review is divided according to HD biomarkers thought to be most affected by the pathology.…”