A novel cognitive-neurophysiological state biomarker in premanifest Huntington's disease validated on longitudinal data

Institute for Cognitive Neuroscience, Biopsychology, Ruhr-University Bochum, Germany.
Scientific Reports (Impact Factor: 5.58). 05/2013; 3:1797. DOI: 10.1038/srep01797
Source: PubMed


In several neurodegenerative diseases, like Huntington's disease (HD), treatments are still lacking. To determine whether a treatment is effective, sensitive disease progression biomarkers are especially needed for the premanifest phase, since this allows the evaluation of neuroprotective treatments preventing, or delaying disease manifestation. On the basis of a longitudinal study we present a biomarker that was derived by integrating behavioural and neurophysiological data reflecting cognitive processes of action control. The measure identified is sensitive enough to track disease progression over a period of only 6 month. Changes tracked were predictive for a number of clinically relevant parameters and the sensitivity of the measure was higher than that of currently used parameters to track prodromal disease progression. The study provides a biomarker, which could change practice of progression diagnostics in a major basal ganglia disease and which may help to evaluate potential neuroprotective treatments in future clinical trials.

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Available from: Vanessa Neß, Oct 14, 2015
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    • "Typically patients present in mid life with an array of motor signs including chorea and bradykinesia as well as psychiatric and cognitive impairments [6]. Many studies have sought to identify the earliest changes in HD and subtle impairments in motor and cognitive function before predicted disease onset have been reported [7,8]. Others have sought to more objectively track disease progression once the disease has become manifest and this includes a range of motor, cognitive and imaging approaches [4,9]. "
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    ABSTRACT: Current clinical assessments of motor function in Huntington's Disease (HD) rely on subjective ratings such as the Unified Huntington's Disease Rating scale (UHDRS). The ability to track disease progression using simple, objective, inexpensive, and robust measures would be beneficial. One objective measure of motor performance is hand-tapping. Over the last 14 years we have routinely collected, using a simple device, the number of taps made by the right and left hand over 30 seconds in HD patients attending our NHS clinics. Here we report on a longitudinal cohort of 237 patients, which includes patients at all stages of the disease on a wide range of drug therapies. Hand tapping in these patients declines linearly at a rate of 5.1 taps per year (p < 0.0001; 95% CI = 3.8 to 6.3 taps), and for each additional year of age patients could perform 0.9 fewer taps (main effect of age: p = 0.0007; 95% CI = 0.4 to 1.4). Individual trajectories can vary widely around this average rate of decline, and much of this variation could be attributed to CAG repeat length. Genotype information was available for a subset of 151 patients, and for each additional repeat, patients could perform 5.6 fewer taps (p < 0.0001; 95% CI = 3.3 to 8.0 taps), and progressed at a faster rate of 0.45 fewer taps per year (CAG by time interaction: p = 0.008; 95% CI = 0.12 to 0.78 taps). In addition, for each unit decrease in Total Functional Capacity (TFC) within individuals, the number of taps decreased by 6.3 (95% CI = 5.4 to 7.1, p < 0.0001). Hand tapping is a simple, robust, and reliable marker of disease progression. As such, this simple motor task could be a useful tool by which to assess disease progression as well therapies designed to slow it down.
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    ABSTRACT: We report brain imaging and genetic diagnosis in a family from Wuhan, China, with a history of Huntington's disease. Among 17 family members across three generations, four patients (II2, II6, III5, and III9) show typical Huntington's disease, involuntary dance-like movements. Magnetic resonance imaging found lateral ventricular atrophy in three members (II2, II6, and III5). Moreover, genetic analysis identified abnormally amplified CAG sequence repeats (> 40) in two members (III5 and III9). Among borderline cases, with clinical symptoms and brain imaging features of Huntington's disease, two cases were identified (II2 and II6), but shown by mutation analysis for CAG expansions in the important transcript 15 gene, to be non-Huntington's disease. Our findings suggest that clinical diagnosis of Huntington's disease requires a combination of clinical symptoms, radiological changes, and genetic diagnosis.
    Neural Regeneration Research 02/2014; 9(4):440-6. DOI:10.4103/1673-5374.128258 · 0.22 Impact Factor
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    ABSTRACT: Background Brain dysfunction precedes clinical manifestation of Huntington’s disease (HD) by decades. This study was aimed to determine whether resting EEG is altered in preclinical HD mutations carriers (pre-HD). Methods We examined relative power of broad traditional EEG bands as well as 1-Hz sub-bands of theta and alpha from the resting-state EEG of 29 pre-HD individuals and of 29 age-matched normal controls. Results The relative power of the narrow sub-band in the border of theta-alpha (7-8 Hz) was significantly reduced in pre-HD subjects as compared to normal controls, while the alterations in relative power of the broad frequency bands were not significant. In pre-HD subjects, the number of CAG repeats in the huntingtin (HTT) gene as well as the disease burden score (DBS) showed a positive correlation with relative power of the delta and theta frequency bands and their sub-bands and a negative correlation with alpha band relative power and the differences of relative power of the 7-8 Hz and 4-5 Hz frequency sub-bands. Conclusion The obtained results suggest that EEG alterations in pre-HD individuals may be related to the course of the pathological process and to HD endophenotype. Analysis of the narrow EEG bands was found to be more useful for assessing EEG alterations in pre-HD individuals than a more traditional approach using broad bandwidths.
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