Background The optimal design and outcome measures for preventive clinical trials in neurodegenerative diseases are unknown. Objective To examine measures that may be associated with disease in the largest cohort ever recruited of prediagnosed individuals carrying the gene expansion for Huntington disease (HD). Design The Predict-HD study is a multicenter observational research study in progress at 17 sites in the United States, 4 in Canada, and 3 in Australia. Setting Genetics and HD outpatient clinics. Participants Five hundred five at-risk individuals who had previously undergone elective DNA analyses for the CAG expansion in the HD gene (predictive testing) and did not currently have a clinical diagnosis of HD. Main Outcome Measures Basal ganglia volumes on magnetic resonance images, estimated probability of diagnosis (based on CAG repeat length), performances on 21 standardized cognitive tasks, total scores on 3 scales of psychiatric distress, and motor diagnosis based on the Unified Huntington's Disease Rating Scale. Results Several variables showed progressive decline as the diagnostic ratings advanced toward manifest disease. Estimated probability of diagnosis was associated with Unified Huntington's Disease Rating Scale prediagnostic stages and varied from 15% in persons with no motor abnormalities to nearly 40% in those with abnormalities suggestive of probable disease. Striatal volumes, cognitive performances, and even psychiatric ratings declined significantly with motor manifestations of disease. Conclusions The documentation of biological and refined clinical markers suggests several clinical end points for preventive clinical trials. Longitudinal study is critical to further validate possible markers for prediagnosed HD.

https://jamanetwork.com/journals/jamaneurology/articlepdf/791574/noc50266.pdf

Preparing for preventive clinical trials: the Predict-HD study.

Ocular motor abnormalities in 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.

/pdf/white-matter-connections-reflect-changes-in-voluntary-guided-bzspq1e9tg.pdf

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

OBJECTIVES To compare the neurological and psychometric characteristics of presymptomatic gene carriers and non-gene carriers who are at risk for developing Huntington9s disease so as to characterise early signs of disease and to identify markers of neurological function that could be used to assess the impact of experimental therapies on the progression of disease, even among those who are clinically presymptomatic. METHODS A sample of people at risk for Huntington9s disease was genotyped and evaluated using subscales of the Wechsler adult intelligence scale–revised (WAIS-R), a quantified neurological rating scale, and computerised physiological measures including speed of movement and reaction time. RESULTS Genotyping and clinical examination determined that 171 participants were presymptomatic gene carriers (PSGCs) and 414 participants were non-gene carriers (NGCs). The PSGCs performed significantly worse when compared with the NGCs on the digit symbol, picture arrangement, and arithmetic subscales of the WAIS-R (p CONCLUSIONS Among Huntington9s disease gene carriers, subtle cognitive and motor deficits precede the onset of sufficient neurological abnormality to warrant a clinical diagnosis of Huntington9s disease.

https://jnnp.bmj.com/content/jnnp/69/6/773.full.pdf

Subtle changes among presymptomatic carriers of the Huntington's disease gene

Summary Different aspects of attention, e.g. phasic alertness, vigilance, divided attention, response flexibility, response inhibition and intermodal integration, were investigated with a computerized test-battery in a group of 20 patients with Huntington's disease and 27 healthy controls. Huntington's disease patients are not impaired in reacting to task-contingent external stimulation in the phasic alertness task, but the self-generated maintenance of attention as measured by the vigilance task, is disturbed. The simultaneous monitoring of different input-channels in the divided attention task and the ability to operate with information given to different modalities in the intermodal integration task are severely affected. The performance of Huntington's disease patients in the response flexibility task, in which internal cued shifts are required, is impaired. Huntington's disease patients are also impaired in reacting selectively to go/no-go stimuli in the response inhibition task. It is suggested that a number of ‘higher’ cognitive deficits described in Huntington's disease might, at least partly, be due to basic attentional disturbances.

N. Beenen

Papers

The diagnostic value of eye movement recording in patients with Huntington's disease and their offspring