Stephen L. Hicks

Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data

BACKGROUND Huntingtons disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects adults in mid-life. Our aim was to identify sensitive and reliable biomarkers in premanifest carriers of mutated HTT and in individuals with early HD that could provide essential methodology for the assessment of therapeutic interventions. METHODS This multicentre study uses an extensive battery of novel assessments, including multi-site 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Blinded analyses were done on the baseline cross-sectional data from 366 individuals: 123 controls, 120 premanifest (pre-HD) individuals, and 123 patients with early HD. FINDINGS The first participant was enrolled in January, 2008, and all assessments were completed by August, 2008. Cross-sectional analyses identified significant changes in whole-brain volume, regional grey and white matter differences, impairment in a range of voluntary neurophysiological motor, and oculomotor tasks, and cognitive and neuropsychiatric dysfunction in premanifest HD gene carriers with normal motor scores through to early clinical stage 2 disease. INTERPRETATION We show the feasibility of rapid data acquisition and the use of multi-site 3T MRI and neurophysiological motor measures in a large multicentre study. Our results provide evidence for quantifiable biological and clinical alterations in HTT expansion carriers compared with age-matched controls. Many parameters differ from age-matched controls in a graded fashion and show changes of increasing magnitude across our cohort, who range from about 16 years from predicted disease diagnosis to early HD. These findings might help to define novel quantifiable endpoints and methods for rapid and reliable data acquisition, which could aid the design of therapeutic trials.

Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis

BACKGROUND TRACK-HD is a prospective observational study of Huntingtons disease (HD) that examines disease progression in premanifest individuals carrying the mutant HTT gene and those with early stage disease. We report 12-month longitudinal changes, building on baseline findings. METHODS we did a 12-month follow-up of patients recruited from the four TRACK-HD study sites in Canada, France, the Netherlands, and the UK. Participants were premanifest individuals (preHD) carrying the mutant HTT gene, patients with early HD, and controls matched by age and sex with the combined preHD and early HD groups. Data were collected by use of 3T MRI and clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Statistical analysis assessed annualised change with the use of linear regression models to estimate differences between groups. FINDINGS 116 preHD individuals, 114 early HD patients, and 115 people in the control group completed follow-up. Four preHD individuals, nine early HD patients, and eight people in the control group did not complete the follow-up. A further nine participants, who completed follow-up assessments, were unable to undergo MRI. After adjustment for demographics, annualised rates of generalised and regional brain atrophy were higher in preHD and early HD groups than in controls. Whole-brain atrophy rates were 0·20% (95% CI 0·05-0·34; p=0·0071) per year higher in preHD participants and 0·60% (0·44-0·76; p<0·0001) in early HD patients, and caudate atrophy rates were 1·37% (0·99-1·75; p<0·0001) per year higher in preHD and 2·86% (2·34-3·39; p<0·0001) in early HD. Voxel-based morphometry revealed grey-matter and white-matter atrophy, even in subjects furthest from predicted disease onset. Quantitative imaging showed statistically significant associations with disease burden, an indicator of disease pathology, and total functional capacity, a widely-used clinical measure of disease severity. Relative to controls, decline in cognition and quantitative motor function was detectable in both pre- and early HD, as was deterioration in oculomotor function in early HD. INTERPRETATION quantitative imaging showed the greatest differentiation across the spectrum of disease and functional measures of decline were sensitive in early HD, with cognitive and quantitative motor impairment also detectable in preHD. We show longitudinal change over 12 months in generalised and regional brain volume, cognition, and quantitative motor tasks in individuals many years from predicted disease onset and show the feasibility of obtaining quantifiable endpoints for future trials.

Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data.

BACKGROUND TRACK-HD is a prospective observational biomarker study in premanifest and early Huntingtons disease (HD). In this report we define a battery of potential outcome measures for therapeutic trials. METHODS We assessed longitudinal data collected at baseline, 12 months, and 24 months at sites in Leiden (Netherlands), London (UK), Paris (France), and Vancouver (Canada). Participants were individuals without HD but carrying the mutant HTT gene (ie, premanifest HD), patients with early HD, and healthy control individuals matched by age and sex to the combined HD groups. Data were collected with 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric assessments. We estimated adjusted, between-group differences in rates of change in these measures and concomitant longitudinal effect sizes. FINDINGS Longitudinal data were available for 116 control individuals, 117 premanifest gene carriers, and 116 participants with early HD. Significantly greater progressive grey-matter, white-matter, whole-brain, and regional atrophy was recorded in the premanifest and early HD groups than in the control group. Effect sizes for atrophy rates between participants with early HD and controls were largest in the caudate (2·04, 95% CI 1·68 to 2·48) and white matter (1·70, 1·40 to 2·08). Functional, quantitative motor, and cognitive measures deteriorated to a greater extent in the early HD group than in controls, with the largest effect size in the symbol digit modality test (1·00, 0·67 to 1·27). In the early HD group, changes in structural imaging and various cognitive and quantitative motor scores were associated with worsening total motor score (TMS) and total functional capacity (TFC). In the premanifest group, despite significant declines in regional and overall brain volumes, few functional variables showed significant 24 month change compared with controls; TMS, emotion recognition, and speeded tapping were exceptions. Premanifest individuals with progression, predefined as an increase in TMS score of 5 points or more, any TFC decline, or a new diagnostic confidence score of 4, exhibited higher rates of brain atrophy and deterioration on some quantitative motor tasks compared with other premanifest participants. INTERPRETATION On the basis of longitudinal effect size, we recommend several objective outcome measures for clinical trials in participants with early HD. Hypothetical treatment effects defined by slower longitudinal changes in these measures would be detectable over a realistic timescale with practical sample sizes. The restricted 24 month cognitive or motor decline in the premanifest sample illustrates the greater challenge in trial design for this group. FUNDING CHDI/HighQ Foundation Inc.

Struck: Structured Output Tracking with Kernels

Adaptive tracking-by-detection methods are widely used in computer vision for tracking arbitrary objects. Current approaches treat the tracking problem as a classification task and use online learning techniques to update the object model. However, for these updates to happen one needs to convert the estimated object position into a set of labelled training examples, and it is not clear how best to perform this intermediate step. Furthermore, the objective for the classifier (label prediction) is not explicitly coupled to the objective for the tracker (estimation of object position). In this paper, we present a framework for adaptive visual object tracking based on structured output prediction. By explicitly allowing the output space to express the needs of the tracker, we avoid the need for an intermediate classification step. Our method uses a kernelised structured output support vector machine (SVM), which is learned online to provide adaptive tracking. To allow our tracker to run at high frame rates, we (a) introduce a budgeting mechanism that prevents the unbounded growth in the number of support vectors that would otherwise occur during tracking, and (b) show how to implement tracking on the GPU. Experimentally, we show that our algorithm is able to outperform state-of-the-art trackers on various benchmark videos. Additionally, we show that we can easily incorporate additional features and kernels into our framework, which results in increased tracking performance.

Early changes in white matter pathways of the sensorimotor cortex in premanifest Huntington's disease.

Objectives: To investigate the function–structure relationship of white matter within different stages of Huntingtons disease (HD) using diffusion tensor imaging (DTI). Experimental design: From the TRACK‐HD study, an early stage HD group and a premanifest gene carrier group (PMGC) were age‐matched to two healthy control groups; all underwent 3‐T MRI scanning of the brain. Region of interest (ROI) segmentation of the corpus callosum, caudate nucleus, thalamus, prefrontal cortex, and sensorimotor cortex was applied, and the apparent fiber pathways of these regions were analyzed. Functional measures of motor, oculomotor, cognition, and behavior were correlated to DTI measures. Principle observations: In PMGC versus controls, higher apparent diffusion coefficient (ADC) was seen in white matter pathways of the sensorimotor cortex (P < 0.01) and in the ROI of corpus callosum (P < 0.017). In early HD, fiber tract analysis showed higher ADC in pathways of the corpus callosum, thalamus, sensorimotor, and prefrontal region (P < 0.01). ROI analysis showed higher diffusivity in the corpus callosum and caudate nucleus (P < 0.017). Motor, oculomotor, cognition, and probability of onset within 2 and 5 years, correlated well with ADC measures of the corpus callosum (P < 0.01 – P < 0.005), sensorimotor (P < 0.01 – P < 0.005), and prefrontal region (P < 0.01). Conclusions: Disturbances in the white matter connections of the sensorimotor cortex can be demonstrated not only in manifest HD but also in premanifest gene carriers. Connectivity measures are well related to clinical functioning. DTI measures can be regarded as a potential biomarker for HD, due to their ability to objectify changes in brain structures and their role within brain networks. Hum Brain Mapp, 2012.

Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy.

TRACK‐HD is a multicentre longitudinal observational study investigating the use of clinical assessments and 3‐Tesla magnetic resonance imaging as potential biomarkers for future therapeutic trials in Huntingtons disease (HD). The cross‐sectional data from this large well‐characterized dataset provide the opportunity to improve our knowledge of how the underlying neuropathology of HD may contribute to the clinical manifestations of the disease across the spectrum of premanifest (PreHD) and early HD. Two hundred and thirty nine gene‐positive subjects (120 PreHD and 119 early HD) from the TRACK‐HD study were included. Using voxel‐based morphometry (VBM), grey and white matter volumes were correlated with performance in four domains: quantitative motor (tongue force, metronome tapping, and gait); oculomotor [anti‐saccade error rate (ASE)]; cognition (negative emotion recognition, spot the change and the University of Pennsylvania smell identification test) and neuropsychiatric measures (apathy, affect and irritability). After adjusting for estimated disease severity, regionally specific associations between structural loss and task performance were found (familywise error corrected, P < 0.05); impairment in tongue force, metronome tapping and ASE were all associated with striatal loss. Additionally, tongue force deficits and ASE were associated with volume reduction in the occipital lobe. Impaired recognition of negative emotions was associated with volumetric reductions in the precuneus and cuneus. Our study reveals specific associations between atrophy and decline in a range of clinical modalities, demonstrating the utility of VBM correlation analysis for investigating these relationships in HD. Hum Brain Mapp, 2013.

Oculomotor dysfunction in amyotrophic lateral sclerosis: a comprehensive review.

Although traditionally regarded as spared, a range of oculomotor dysfunction has been recorded in patients with amyotrophic lateral sclerosis (ALS). Most frequent is ophthalmoparesis, particularly in patients with prolonged survival; however, pursuit, nystagmus, and saccadic impairments have also been reported. The apparent resistance to pathologic involvement of oculomotor (and sphincter) control pathways in most patients with ALS has prompted comparative study to establish the key pathways that underlie motor neuronal vulnerability, with the hope of generating novel therapeutic strategies. Developments in the assessment of oculomotor function, including portable eye-tracking devices, have revealed more subtle impairments in ALS in relation to phenotype, which can now be better understood through parallel elucidation of the normal cerebral oculomotor control network. Given the clinicopathologic overlap between ALS and some types of frontotemporal dementia, the study of oculomotor function has particular value in probing the variable but consistent cognitive impairment seen in ALS and that reflects frontotemporal extramotor cerebral abnormalities. By transcending the requirement to write or speak, loss of which precludes standard neuropsychological testing in some patients with advanced ALS, cognitive tests performed using only oculomotor functions offer additional potential, allowing the study of patients much later in their disease course. The study of oculomotor dysfunction holds significant promise as an additional source of much needed prognostic, monitoring, and mechanistic biomarkers for ALS.

A Depth-Based Head-Mounted Visual Display to Aid Navigation in Partially Sighted Individuals

Independent navigation for blind individuals can be extremely difficult due to the inability to recognise and avoid obstacles. Assistive techniques such as white canes, guide dogs, and sensory substitution provide a degree of situational awareness by relying on touch or hearing but as yet there are no techniques that attempt to make use of any residual vision that the individual is likely to retain. Residual vision can restricted to the awareness of the orientation of a light source, and hence any information presented on a wearable display would have to limited and unambiguous. For improved situational awareness, i.e. for the detection of obstacles, displaying the size and position of nearby objects, rather than including finer surface details may be sufficient. To test whether a depth-based display could be used to navigate a small obstacle course, we built a real-time head-mounted display with a depth camera and software to detect the distance to nearby objects. Distance was represented as brightness on a low-resolution display positioned close to the eyes without the benefit focussing optics. A set of sighted participants were monitored as they learned to use this display to navigate the course. All were able to do so, and time and velocity rapidly improved with practise with no increase in the number of collisions. In a second experiment a cohort of severely sight-impaired individuals of varying aetiologies performed a search task using a similar low-resolution head-mounted display. The majority of participants were able to use the display to respond to objects in their central and peripheral fields at a similar rate to sighted controls. We conclude that the skill to use a depth-based display for obstacle avoidance can be rapidly acquired and the simplified nature of the display may appropriate for the development of an aid for sight-impaired individuals.

Visual activation of extra-striate cortex in the absence of V1 activation.

Research highlights ▶ Gray matter of V1 shows abnormal T1 characteristics and its perfusion is reduced. ▶ Damage is confined to gray matter with no adjacent white matter involvement. ▶ BOLD activation levels in the calcarine sulcus are drastically reduced. ▶ Activation of extrastriate regions to visual stimulation is preserved. ▶ Pathway between LGN and V1 shows degeneration; between LGN and V5/MT is intact.

Simulating prosthetic vision: Optimizing the information content of a limited visual display.

Visual prostheses for the restoration of functional vision are currently under development. To guide prosthesis research and allow for an accurate prognosis of functional gain, simulating the experience of a retinal prosthesis in healthy individuals is desirable. Current simulation paradigms lack crucial aspects of the prosthetic experience such as realistic head- and eye-position-dependent image presentation. We developed a simulation paradigm that used a head-mounted camera and eye tracker to lock the simulation to the point of fixation. We evaluated visual acuity, object recognition and manipulation, and wayfinding under simulated prosthetic vision. We explored three ways of optimizing the information content of the prosthetic visual image: Full-Field representation (wide visual angle, low sampling frequency), Region of Interest (ROI; narrow visible angle, high sampling frequency), and Fisheye (high sampling frequency in the center, progressively lower resolution toward the edges). Full-Field representation facilitated visual search and navigation, whereas ROI improved visual acuity. The Fisheye representation, designed to incorporate the benefits of both Full-Field representation and ROI, performed similarly to ROI with subjects unable to capitalize on the peripheral data. The observation that different image representation conditions prove advantageous for different tasks should be taken into account in the process of designing and testing new visual prosthesis prototypes.