PURPOSE: Although dysphonia has been shown to be a common sign of Huntington disease (HD), the extent of phonatory dysfunction in gene positive premanifest HD individuals remains unknown. The aim of the current study was to explore the possible occurrence of phonatory abnormalities in prodromal HD. METHOD: Sustained vowel phonations were acquired from 28 premanifest HD individuals and 28 healthy controls of comparable age. Data were analysed acoustically for measures of several phonatory dimensions including airflow insufficiency, aperiodicity, irregular vibration of vocal folds, signal perturbations, increased noise, vocal tremor and articulation deficiency. A predictive model was built to find the best combination of acoustic features and estimate sensitivity/specificity for differentiation between premanifest HD subjects and controls. The extent of voice deficits according to a specific phonatory dimension was determined using statistical decision making theory. The results were correlated to global motor function, cognitive score, disease burden score and estimated years to disease onset. RESULTS: Measures of aperiodicity and increased noise were able to significantly differentiate between premanifest HD individuals and controls (p<0.01). The combination of these aspects of dysphonia led to a sensitivity of 91.5% and specificity of 79.2% to correctly distinguish speakers with premanifest HD from healthy individuals. Some form of disrupted phonatory function was revealed in 68% of our premanifest HD subjects, where 18% had one affected phonatory dimension and 50% showed impairment of two or more dimensions. A relationship between pitch control and cognitive score was also observed (r = -0.50, p = 0.007). CONCLUSIONS: Phonatory abnormalities are detectable even the in premotor stages of HD. Speech investigation may have the potential to provide functional biomarkers of HD and could be included in future clinical trials and therapeutic interventions.

Department of Circuit Theory Faculty of Electrical Engineering Czech Technical University Prague Prague Czech Republic; Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Department of Neurology Huntington Centre NRW St Josef Hospital Ruhr University of Bochum Bochum Germany

Department of Neurology Knappschaftskrankenhaus Ruhr University of Bochum Bochum Germany

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Kremer B, Goldberg P, Andrew SE, Theilmann J, Telenius H, et al. (1994) A worldwide study of the Huntington's disease mutation: The sensitivity and specificity of measuring CAG repeats. New Engl J Med 330: 1401–1406. PubMed

Tabrizi SJ, Langbehn DR, Leavitt BR, Roos RA, Durr A, et al. (2009) Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 8: 791–801. PubMed PMC

Tabrizi SJ, Scahill RI, Owen G, Durr A, Leavitt BR, et al. (2013) Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol 12: 637–649. PubMed

Feigin A, Tang C, Ma Y, Mattis P, Zgaljardic D, et al. (2007) Thalamic metabolism and symptom onset in preclinical Huntington's disease. Brain 130: 2858–2867. PubMed PMC

Stout JC, Paulsen JS, Queller S, Solomon AC, Whitlock KB, et al. (2011) Neurocognitive signs in prodromal Huntington disease. Neuropsychology 25: 1–14. PubMed PMC

Weir DW, Sturrock A, Leavitt BR (2011) Development of biomarkers for Huntington's disease. Lancet Neurol 10: 573–590. PubMed

Beste C, Stock AK, Ness V, Hoffmann R, Lukas C, Saft C (2013) A novel cognitive-neurophysiological state biomarker in premanifest Huntington's disease validated on longitudinal data. Sci Rep 3: 1997. PubMed PMC

Tabrizi SJ, Scahill RI, Durr A, Roos RAC, Leavitt BR, et al. (2011) Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol 10: 31–42. PubMed

Penney JB Jr, Young AB, Shoulson I, Starosta-Rubenstein S, Snodgrass SR, et al. (1990) Huntington's disease in Venezuela: 7 years of follow-up on symptomatic and asymptomatic individuals. Mov Disord 5: 93–99. PubMed

Kirkwood SC, Siemers E, Hodes ME, Conneally PM, Christian JC, Foroud T (2000) Subtle changes among presymptomatic carriers of the Huntington's disease gene. J Neurol Neurosurg Psychiatry 69: 773–779. PubMed PMC

Rusz J, Klempir J, Tykalova T, Baborova E, Cmejla R, et al.. (2014) Characteristics and occurrence of speech impairment in Huntington's disease: possible influence of antipsychotic medication. J Neural Transm: in press. DOI 10.1007/s00702-014-1229-8. PubMed

Hartelius L, Carlstedt A, Ytterberg M, Lillvik M, Laakso K (2003) Speech disorders in mild and moderate Huntington's disease: Results of dysarthria assessment of 19 individuals. J Med Speech-Lang Pa 1: 1–14.

Vogel AP, Shirbin C, Andrew J, Churchyard AJ, Stout JC (2012) Speech acoustic markers of early stage and prodromal Huntington disease: A marker of disease onset? Neuropsychologia 50: 3273–3278. PubMed

Rusz J, Klempir J, Baborova E, Tykalova T, Majerova V, et al. (2013) Objective acoustic quantification of phonatory dysfunction in Huntington's disease. PLoS One 8: e65881. PubMed PMC

Skodda S, Schlegel U, Hoffman R, Saft C (2014) Impaired motor speech performance in Huntington's disease. J Neural Transm 121: 399–407. PubMed

Duffy JR (2013) Motor Speech Disorders: Substrates, Differential Diagnosis and Management, 3rd ed., Mosby, St. Louis.

Ramig LA (1986) Acoustic analysis of phonation in patients with Huntington's disease. Preliminary report. Ann Otol Rhinol Laryngol 95: 288–293. PubMed

Coleman R, Anderson D, Lovrien E (1990) Oral motor dysfunction in individuals at risk of Huntington disease. Am J Med Genet 37: 36–39. PubMed

Huntington Study Group (1996) Unified Huntington's Disease Rating Scale: reliability and consistency. Movement Disord 11: 136–142. PubMed

Saft C, Andrich J, Meisel NM, Przuntek H, Muller T (2006) Assessment of simple movements reflects impairments in Huntington's disease. Mov Disord 21: 1208–1212. PubMed

Saft C, Andrich J, Meisel NM, Przuntek H, Muller T (2003) Assessment of complex movements reflects dysfunction in Huntington's disease. J Neurol 250: 1469–1474. PubMed

Penney JB Jr, Vonsattel JP, MacDonald ME, Gusella JF, Myers RH (1997) CAG repeat number governs the development rate of pathology in Huntington's disease. Ann Neurol 41: 689–692. PubMed

Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR, et al. (2004) A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length. Clin Genet 65: 267–277. PubMed

Boersma P, Weenink D (2001) PRAAT, a system for doing phonetics by computer. Glot International 5: 341–345.

Little MA, McSharry PE, Roberts SJ, Costello DA, Moroz IM (2007) Exploiting Nonlinear recurrence and Fractal scaling properties for voice disorder detection. Biomedical Engineering Online 6: 23. PubMed PMC

Kay Elemetrics Corp (2003) Multi-Dimensional Voice Program (MDVP): Software Instroduction Manual. Lincon Park, Kay Elemetrics.

Rusz J, Megrelishvili M, Bonnet C, Okujava M, Brozova H, et al. (2014) A distinct variant of mixed dysarthria reflects parkinsonism and dystonia due to ephedrone abuse. J Neural Transm 121: 655–664. PubMed

Tsanas A, Little MA, McSharry PE, Spielman J, Ramig LO (2012) Novel speech signal processing algorithm for high-accuracy classification of Parkinson's disease. IEEE T Bio-Med Eng 59: 1264–1271. PubMed

Novotny M, Rusz J, Cmejla R, Ruzicka E (2014) Automatic evaluation of articulatory disorders in Parkinson's disease. IEEE/ACM T Audio Speech Lang Process 22: 1366–1378.

Velasco Garcia MJ, Cobeta I, Martin G, Alonso-Navarro H, Jimenez-Jimenez FJ (2011) Acoustic analysis of voice in Huntington's disease. J Voice 25: 208–217. PubMed

Gamboa J, Jimenez-Jimenez FJ, Nieto A, Cobeta I, Vegas A, et al. (1998) Acoustic voice analysis in patients with essential tremor. J Voice 12: 444–452. PubMed

Peck KK, Galgano JF, Branski RC, Bogomolny D, Ho M, et al. (2009) Event-related functional MRI investigation of vocal pitch variation. NeuroImage 44: 175–181. PubMed