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Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study.

ABSTRACT: Although the association between cytosine-adenine-guanine (CAG) repeat length and age at onset of Huntington's disease is well known, improved prediction of onset would be advantageous for clinical trial design and prognostic counselling. We compared various measures for tracking progression and predicting conversion to manifest Huntington's disease.In this prospective observational study, we assessed the ability of 40 measures in five domains (motor, cognitive, psychiatric, functional, and imaging) to predict time to motor diagnosis of Huntington's disease, accounting for CAG repeat length, age, and the interaction of CAG repeat length and age. Eligible participants were individuals from the PREDICT-HD study (from 33 centres in six countries [USA, Canada, Germany, Australia, Spain, UK]) with the gene mutation for Huntington's disease but without a motor diagnosis (a rating below 4 on the diagnostic confidence level from the 15-item motor assessment of the Unified Huntington's Disease Rating Scale). Participants were followed up between September, 2002, and July, 2014. We used joint modelling of longitudinal and survival data to examine the extent to which baseline and change of measures analysed separately was predictive of CAG-adjusted age at motor diagnosis.1078 individuals with a CAG expansion were included in this analysis. Participants were followed up for a mean of 5·1 years (SD 3·3, range 0·0-12·0). 225 (21%) of these participants received a motor diagnosis of Huntington's disease during the study. 37 of 40 cross-sectional and longitudinal clinical and imaging measures were significant predictors of motor diagnosis beyond CAG repeat length and age. The strongest predictors were in the motor, imaging, and cognitive domains: an increase of one SD in total motor score (motor domain) increased the risk of a motor diagnosis by 3·07 times (95% CI 2·26-4·16), a reduction of one SD in putamen volume (imaging domain) increased risk by 3·32 times (2·37-4·65), and a reduction of one SD in Stroop word score (cognitive domain) increased risk by 2·32 times (1·88-2·87).Prediction of diagnosis of Huntington's disease can be improved beyond that obtained by CAG repeat length and age alone. Such knowledge about potential predictors of manifest Huntington's disease should inform discussions about guidelines for diagnosis, prognosis, and counselling, and might be useful in guiding the selection of participants and outcome measures for clinical trials.US National Institutes of Health, US National Institute of Neurological Disorders and Stroke, and CHDI Foundation.

SUBMITTER: Paulsen JS

PROVIDER: S-EPMC4373455 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study.

Paulsen Jane S JS Long Jeffrey D JD Ross Christopher A CA Harrington Deborah L DL Erwin Cheryl J CJ Williams Janet K JK Westervelt Holly James HJ Johnson Hans J HJ Aylward Elizabeth H EH Zhang Ying Y Bockholt H Jeremy HJ Barker Roger A RA

The Lancet. Neurology 20141103 12

<h4>Background</h4>Although the association between cytosine-adenine-guanine (CAG) repeat length and age at onset of Huntington's disease is well known, improved prediction of onset would be advantageous for clinical trial design and prognostic counselling. We compared various measures for tracking progression and predicting conversion to manifest Huntington's disease.<h4>Methods</h4>In this prospective observational study, we assessed the ability of 40 measures in five domains (motor, cognitive ...[more]

PMID: 25453459

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Project description:Huntington's disease is an inherited neurodegenerative disease that causes motor, cognitive and psychiatric impairment, including an early decline in ability to recognize emotional states in others. The pathophysiology underlying the earliest manifestations of the disease is not fully understood; the objective of our study was to clarify this. We used functional magnetic resonance imaging to investigate changes in brain mechanisms of emotion recognition in pre-manifest carriers of the abnormal Huntington's disease gene (subjects with pre-manifest Huntington's disease): 16 subjects with pre-manifest Huntington's disease and 14 control subjects underwent 1.5 tesla magnetic resonance scanning while viewing pictures of facial expressions from the Ekman and Friesen series. Disgust, anger and happiness were chosen as emotions of interest. Disgust is the emotion in which recognition deficits have most commonly been detected in Huntington's disease; anger is the emotion in which impaired recognition was detected in the largest behavioural study of emotion recognition in pre-manifest Huntington's disease to date; and happiness is a positive emotion to contrast with disgust and anger. Ekman facial expressions were also used to quantify emotion recognition accuracy outside the scanner and structural magnetic resonance imaging with voxel-based morphometry was used to assess the relationship between emotion recognition accuracy and regional grey matter volume. Emotion processing in pre-manifest Huntington's disease was associated with reduced neural activity for all three emotions in partially separable functional networks. Furthermore, the Huntington's disease-associated modulation of disgust and happiness processing was negatively correlated with genetic markers of pre-manifest disease progression in distributed, largely extrastriatal networks. The modulated disgust network included insulae, cingulate cortices, pre- and postcentral gyri, precunei, cunei, bilateral putamena, right pallidum, right thalamus, cerebellum, middle frontal, middle occipital, right superior and left inferior temporal gyri, and left superior parietal lobule. The modulated happiness network included postcentral gyri, left caudate, right cingulate cortex, right superior and inferior parietal lobules, and right superior frontal, middle temporal, middle occipital and precentral gyri. These effects were not driven merely by striatal dysfunction. We did not find equivalent associations between brain structure and emotion recognition, and the pre-manifest Huntington's disease cohort did not have a behavioural deficit in out-of-scanner emotion recognition relative to controls. In addition, we found increased neural activity in the pre-manifest subjects in response to all three emotions in frontal regions, predominantly in the middle frontal gyri. Overall, these findings suggest that pathophysiological effects of Huntington's disease may precede the development of overt clinical symptoms and detectable cerebral atrophy.

Project description:Huntington's disease (HD) is a genetic neurodegenerative disorder that affects not only the motor but also the cognitive domain. In particular, cognitive symptoms such as impaired executive skills and deficits in recognizing other individuals' mental state may emerge many years before the motor symptoms. This study was aimed at testing two cognitive hypotheses suggested by previous research with a new Stroop task created for the purpose: 1) the impairment of emotion recognition in HD is moderated by the emotions' valence, and 2) inhibitory control is impaired in HD. Forty manifest and 20 pre-manifest HD patients and their age- and gender-matched controls completed both the traditional "Stroop Color and Word Test" (SCWT) and the newly created "Stroop Emotion Recognition under Word Interference Task" (SERWIT), which consist in 120 photographs of sad, calm, or happy faces with either congruent or incongruent word interference. On the SERWIT, impaired emotion recognition in manifest HD was moderated by emotion type, with deficits being larger in recognizing sadness and calmness than in recognizing happiness, but it was not moderated by stimulus congruency. On the SCWT, six different interference scores yielded as many different patterns of group effects. Overall our results corroborate the hypothesis that impaired emotion recognition in HD is moderated by the emotions' valence, but do not provide evidence for the hypothesis that inhibitory control is impaired in HD. Further research is needed to learn more about the psychological mechanisms underlying the moderating effect of emotional valence on impaired emotion recognition in HD, and to corroborate the hypothesis that the inhibitory processes involved in Stroop tasks are not impaired in HD. Looking beyond this study, the SERWIT promises to make important contributions to disentangling the cognitive and the psychomotor aspects of neurological disorders. The research was approved by the Ethics Committee of the "Istituto Leonarda Vaccari", Rome on January 24, 2018.

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Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study.

Publications

Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study.

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