Early Biomarkers in Premanifest Huntington's Disease Gene Carriers: a Pilot Study

Huntington's disease (HD) is an autosomal dominant, neurodegenerative, fatal disease caused by a mutation in the hungtingtin (HTT) gene,1 manifesting with neurological, psychiatric and cognitive disorders. The disease causes a severe physical, functional and social impairment, with a great impact on patients' and their care-givers' quality of life. To date, the pathophysiology of HD remains largely unknown. Neuronal degeneration of basal ganglia plays a primary role in causing neuropsychiatric symptoms. Nevertheless, a cortical involvement has been evoked in the genesis of other symptoms of the disease, such as visual system disorders.2 To date only symptomatic treatment is available for motor and psychiatric issues in HD patients. The research field is now focused on investigation of genetic neuroprotective strategies to prevent the progression of the disease.3 The ideal therapeutic goal would be to start the treatment as soon as the disease becomes symptomatic, as the HD mutation is present since the birth. Unfortunately, the age and the symptoms at onset are very variable, mainly related to the mutation size4 but not only. Several other genetic and environmental factors are thought to play a role in the transition from the pre-symptomatic to the symptomatic stage, which remains largely unpredictable.5 Moreover, the diagnosis of symptomatic HD is traditionally based on motor symptoms onset (chorea, dystonia, bradykinesia, coordination issues).6 There are some evidence that subtle structural brain MRI alterations, mild cognitive and psychiatric issues may be present even in the pre-symptomatic stage, suggesting that the symptomatic phase could start before the onset of classical motor symptoms.7 Clinical studies using morphological and functional MRI have recently shown an early involvement of the visual cortex (area visual associative, lateral occipital cortex), which may explain the visuospatial function and visual perception disorders already observed at the pre-symptomatic and initial symptomatic stage of MH.8 The superior colliculus (SC) is a mesencephalic structure involved in the integration of visual stimuli, in the generation of oriented ocular saccades and attention tasks.9 An early dysfunction of SC has been shown in other diseases of the basal ganglia, such as Parkinson's disease (PD)10 and focal dystonia.11 This structure may also be early involved in the pathogenesis of visual disturbances and ocular saccadic changes described in HD.12 To date, there is no data regarding the functional state of SC in response to visual stimuli in HD.

Gait and balance issues in HD are common at the symptomatic stage of the disease, being a major risk of falls along with abnormal involuntary movements.13 They can be present at the early stage of the disease, with a mild severity. To date, no data are available about specific gait assessment in the pre-symptomatic HD carriers. Subtle gait issues resulting in spatiotemporal parameters alteration, not detectable with the standard clinical examination, could be present even in HD asymptomatic gene carriers. New technologies based on 3D virtual reality tools could be of great interest in the diagnosis of very early gait issues in pre-symptomatic HD subjects.

Cognitive issues are also common in HD, ranging from mild cognitive impairment in pre-manifest subjects14 to dementia in the advanced disease.15 Cognitive and emotional impairment is related to the basal ganglia degeneration in HD, progressively involving frontal and subcortical limbic regions.16 Eye-tracking data are known to be good markers of the orientation of attention. Recently, our team has shown that PD is associated in particular with dysfunction of the SC.10,17 At the same time, PD patients have difficulty producing and recognizing facial and vocal emotional expressions and are less reactive to negative stimuli than HS.18 As PD and HD share similar basal ganglia network dysfunctions, they could share also similar cognitive and emotional changes, which may be present from the onset of HD, due to structural and/or functional deficits in frontal and subcortical limbic areas. To date, no study has investigated emotional behavior and orientation reactions correlated with specific functional MRI (fMRI) protocol in pre-symptomatic HD carriers.

Objectives :

The primary objective of our study is to investigate the function of SC in response to visual stimulation using a fMRI in premanifest HD gene carriers (PMGC) compared to healthy subjects (HS). Our main hypothesis is the dysfunction of the SC at the pre-symptomatic stage of the disease (role of SC as an early biomarker of the disease).