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 Huntington's 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.

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 Huntington's 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.

On the origin of oscillopsia during pedunculopontine stimulation.

We report a case of induced oscillopsia caused by deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN). Recent reports have described involuntary oscillopsia during DBS of the PPN that patients have described as trembling vision. Here we substantiate this observation using infra-red eye tracking. It has been suggested that this phenomenon might be used as an indicator of accurate targeting of the PPN with DBS. Our observations suggest that this phenomenon may not be related to a constricted anatomical structure and therefore such practise may be unwise. Scrutiny has led us to believe that the oscillopsia in our patient is not caused by direct stimulation of the oculomotor nerve as suggested in a previous report, but by stimulation of fibres in the uncinate fasciculus of the cerebellum and the superior cerebellar peduncle, which in turn stimulate the saccadic pre-motor neurones in the brainstem.

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.

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

BACKGROUND: Huntington's 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.

White matter connections reflect changes in voluntary-guided saccades in pre-symptomatic Huntington's disease.

Huntington's disease is caused by a known genetic mutation and so potentially can be diagnosed many years before the onset of symptoms. Neuropathological changes have been found in both striatum and frontal cortex in the pre-symptomatic stage. Disruption of cortico-striatal white matter fibre tracts is therefore likely to contribute to the first clinical signs of the disease. We analysed diffusion tensor MR image (DTI) data from 25 pre-symptomatic gene carriers (PSCs) and 20 matched controls using a multivariate support vector machine to identify patterns of changes in fractional anisotropy (FA). In addition, we performed probabilistic fibre tracking to detect changes in 'streamlines' connecting frontal cortex to striatum. We found a pattern of structural brain changes that includes putamen bilaterally as well as anterior parts of the corpus callosum. This pattern was sufficiently specific to enable us to correctly classify 82% of scans as coming from a PSC or control subject. Fibre tracking revealed a reduction of frontal cortico-fugal streamlines reaching the body of the caudate in PSCs compared to controls. In the left hemispheres of PSCs we found a negative correlation between years to estimated disease onset and streamlines from frontal cortex to body of caudate. A large proportion of the fibres to the caudate body originate from the frontal eye fields, which play an important role in the control of voluntary saccades. This type of saccade is specifically impaired in PSCs and is an early clinical sign of motor abnormalities. A correlation analysis in 14 PSCs revealed that subjects with greater impairment of voluntary-guided saccades had fewer fibre tracking streamlines connecting the frontal cortex and caudate body. Our findings suggest a specific patho-physiological basis for these symptoms by indicating selective vulnerability of the associated white matter tracts.

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.

Eye-tracking in amyotrophic lateral sclerosis: A longitudinal study of saccadic and cognitive tasks.

A relative preservation of eye movements is notable in ALS, but saccadic functions have not been studied longitudinally. ALS overlaps with FTD, typically involving executive dysfunction, and eye-tracking offers additional potential for the assessment of extramotor pathology where writing and speaking are both impaired. Eye-tracking measures (including anti-saccade, trail-making and visual search tasks) were assessed at six-monthly intervals for up to two years in a group of ALS (n = 61) and primary lateral sclerosis (n = 7) patients, compared to healthy age-matched controls (n = 39) assessed on a single occasion. Task performance was explored speculatively in relation to resting-state functional MRI (R-FMRI) network connectivity. Results showed that ALS patients were impaired on executive and visual search tasks despite normal basic saccadic function, and impairments in the PLS patients were unexpectedly often more severe. No significant progression was detected longitudinally in either group. No changes in R-FMRI network connectivity were identified in relation to patient performance. In conclusion, eye-tracking offers an objective means to assess extramotor cerebral involvement in ALS. The relative resistance of pure oculomotor function is confirmed, and higher-level executive impairments do not follow the same rate of decline as physical disability. PLS patients may have more cortical dysfunction than has been previously appreciated.

Improving Mobility Performance in Low Vision With a Distance-Based Representation of the Visual Scene.

PURPOSE: Severe visual impairment can have a profound impact on personal independence through its effect on mobility. We investigated whether the mobility of people with vision low enough to be registered as blind could be improved by presenting the visual environment in a distance-based manner for easier detection of obstacles. METHODS: We accomplished this by developing a pair of "residual vision glasses" (RVGs) that use a head-mounted depth camera and displays to present information about the distance of obstacles to the wearer as brightness, such that obstacles closer to the wearer are represented more brightly. We assessed the impact of the RVGs on the mobility performance of visually impaired participants during the completion of a set of obstacle courses. Participant position was monitored continuously, which enabled us to capture the temporal dynamics of mobility performance. This allowed us to find correlates of obstacle detection and hesitations in walking behavior, in addition to the more commonly used measures of trial completion time and number of collisions. RESULTS: All participants were able to use the smart glasses to navigate the course, and mobility performance improved for those visually impaired participants with the worst prior mobility performance. However, walking speed was slower and hesitations increased with the altered visual representation. CONCLUSIONS: A depth-based representation of the visual environment may offer low vision patients improvements in independent mobility. It is important for further work to explore whether practice can overcome the reductions in speed and increased hesitation that were observed in our trial.

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.

An eye-tracking version of the trail-making test.

The neurodegenerative disorder amyotrophic lateral sclerosis may render patients unable to speak or write, so that objective assessment of cognitive impairment, which is commonly of a dysexecutive nature, is challenging. There is therefore a need to develop other methods of assessment that utilize other relatively unaffected motor systems. In this proof-of-principle study a novel eye-tracking version of the trail-making test was compared with performance on the standard written version in a group of healthy volunteers. There was good correlation for speed between both versions of Part B (R(2)=0.73), suggesting that this is a viable method to objectively assess cognitive impairment in disorders where patients are unable to speak or write.

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 Huntington's 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.

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 Huntington's 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.

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

When the primary visual cortex (V1) is damaged, there are a number of alternative pathways that can carry visual information from the eyes to extrastriate visual areas. Damage to the visual cortex from trauma or infarct is often unilateral, extensive and includes gray matter and white matter tracts, which can disrupt other routes to residual visual function. We report an unusual young patient, SBR, who has bilateral damage to the gray matter of V1, sparing the adjacent white matter and surrounding visual areas. Using functional magnetic resonance imaging (fMRI), we show that area MT+/V5 is activated bilaterally to visual stimulation, while no significant activity could be measured in V1. Additionally, the white matter tracts between the lateral geniculate nucleus (LGN) and V1 appear to show some degeneration, while the tracts between LGN and MT+/V5 do not differ from controls. Furthermore, the bilateral nature of the damage suggests that residual visual capacity does not result from strengthened interhemispheric connections. The very specific lesion in SBR suggests that the ipsilateral connection between LGN and MT+/V5 may be important for residual visual function in the presence of damage to V1.

Saccadometry of conditional rules in presymptomatic Huntington's disease.

The promise of new treatments for Huntington's disease (HD) has intensified interest in markers of preclinical onset and progression. Recent research has shown that elementary saccadic tasks may exhibit subtle preclinical abnormalities. Other studies have shown cognitive dysfunction to be a major component of early-HD phenotype. It was hypothesized that the synergistic combination of an oculomotor response with a cognitively demanding paradigm might therefore offer a functional marker that could be superior both to simpler saccadic paradigms and to conventional cognitive tests. The performance of 12 early-symptomatic HD patients and 17 presymptomatic gene carriers on three saccadic paradigms were studied: prosaccades, color-cued centrally triggered saccades and a second-order conditional rule task on which the direction of the saccade was cued by the combination of central and peripheral cues. Eye movements were recorded using a highly portable, patient-friendly infrared recording device. The analysis of the latency distributions showed that the second-order conditional rule task could discriminate between clinical groups, had a predictive potential within the presymptomatic group and appeared to be more sensitive than easier tasks. The simplicity of portable saccadometry, combined with the sensitivity of a complex oculomotor task, may therefore offer a promising functional marker in HD.

Oculomotor deficits indicate the progression of Huntington's disease.

The oculomotor deficits associated with Huntington's Disease (HD) are one of the earliest signs of disease onset. They include a marked delay in executing voluntary saccades and a difficulty inhibiting saccades to task-irrelevant stimuli. In addition, HD patients develop a deficit in task-switching, which can be demonstrated by the continued adherence to a rule after it has been recently changed. These deficits are likely to be the result of a progressive neural degeneration of the fronto-striatal system, which is a distinguishing feature of HD neuropathology. It is predicted that as the disease progresses the magnitude of these specific deficits should increase. We tested a cohort of early HD patients and presymptomatic HD gene carriers on a series of oculomotor tasks designed to measure saccade initiation, inhibition and rule switch cost. Saccadic latencies and error rates in early HD patients were found to be systematically higher than controls. Presymptomatic HD subjects showed small increases in saccadic latencies and error rates that were in proportion to the predicted age of disease onset. These results suggest that saccadometry and a cognitively demanding oculomotor task may be useful as an indicator of function in HD.