Abstract
Huntington’s disease (HD) is a neurodegenerative disorder characterised by progressive motor, cognitive and psychiatric symptoms. Objective measurement of disease severity is of increasing importance for detecting symptomatic disease, as well as monitoring disease progression and the response to novel therapeutic interventions. Using a newly-developed infra-red scleral oculometer, we measured saccadic latencies and durations in HD patients exhibiting a broad range of symptoms (n=24) and control subjects of comparable ages (n=20) to see whether these parameters might reflect the presence or severity of HD. Latency distributions were characterised by creating reciprobit plots for each subject, whilst parametric statistics were applied to durations. Compared with the control group, we found the HD group had a significantly increased median latency, and early saccades were more prominent. In addition, HD patients exhibited an increased saccadic duration and variability of duration. Using Bayesian (likelihood) analysis, we obtained saccadic support values for the presence of clinical HD, which correlated with the motor Unified Huntington’s Disease Rating Scale (UHDRS) score in these patients. A sensitivity/specificity analysis of all 44 participants showed that the use of this multivariate support measure was highly successful in predicting HD status, correctly diagnosing 75% of the HD patients, and (95%) of the controls; with a different criterion, these figures were 96 and 15%. Furthermore, we correctly predicted absence of disease in two additional subjects subsequently confirmed to be genetically unaffected. This strongly suggests that multivariate support values derived from saccadic parameters may provide an objective, quantitative biomarker of HD, especially the degree of motor impairment. However, larger longitudinal studies are required to determine whether they can reliably detect the earliest presymptomatic disease, or faithfully reflect disease progression.
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References
Aron AR, Schlaghecken F, Fletcher PC, Bullmore ET, Eimer M, Barker R, Sahakian BJ, Robbins TW (2003) Inhibition of subliminally primed responses is mediated by the caudate and thalamus: evidence from functional MRI and Huntington’s disease. Brain 126:713–723
Bahill AT, Clark MR, Stark L (1975) The main sequence, a tool for studying human eye movements. Math Biosci 24:191–204
Biscaldi M, Fischer B, Stuhr V (1996) Human express saccade makers are impaired at suppressing visually evoked saccades. J Neurophysiol 79:199–214
Blekher TM, Yee RD, Kirkwood SC, Hake AM, Stout JC, Weaver MR, Foroud TM (2004) Oculomotor control in asymptomatic and recently diagnosed individuals with the genetic marker for Huntington’s disease. Vis Res 44:2729–2736
Bollen E, Reulen JPH, Den Heyer JC, Van der Kamp W, Roos RAC, Buruma OJS (1986) Horizontal and vertical saccadic eye movement abnormalities in Huntington’s chorea. J Neurol Sci 74:11–22
Carpenter RHS (1981) In: Fisher DF, Monty RA, Senders JW (eds) Eye movements: cognition and visual perception. Lawrence Erlbaum, Hilsdale, pp 237–246
Carpenter RHS (1988) Movements of the eyes, 2nd edn. Pion, London
Carpenter RHS (1994) SPIC: a PC-based system for rapid measurement of saccadic responses. J Physiol (Proc) 480:4 p
Carpenter RHS (2004) The saccadic system: a neurological microcosm. Adv Clin Neurosci Rehabil 4(1):6–8
Carpenter RHS, Williams MLL (1995) Neural computation of log likelihood in control of saccadic eye movements. Nature 377:59–62
Collewijn H, Went LN, Tamminga EP, Vegter-Van der Vlis M (1988) Oculomotor defects in patients with Huntington’s disease and their offspring. J Neurol Sci 86:307–320
Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M, Folstein S, Ross C, Franz M, Abbott M, Gray J, Conneally P, Young A, Penney J, Hollingsworth J, Shoulson I, Lazzarini A, Falek A, Koroshetz W, Sax D, Bird E, Vonsattel J, Bonilla E, Alvir J, Bickham Conde J, Cha J-H, Dure L, Gomez F, Ramos M, Sanchez-Ramos J, Snodgrass S, de Young M, Wexler N, Moscowitz C, Penchaszadeh G, MacFarlane H, Anderson M, Jenkins B, Srinidhi J, Barnes G, Gusella J, MacDonald M (1993) Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet 4:387–392
Edwards AWF (1972) Likelihood. Cambridge University Press, Cambridge
Hanes DP, Schall JD (1996) Neural control of voluntary movement initiation. Science 274:427–430
Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983
Huntington Study Group (1996) Unified Huntington’s disease rating scale: reliability and consistency. Mov Disord 11:136–142
Lasker AG, Zee DS, Hain TC, Folstein SE, Singer HS (1987) Saccades in Huntington’s disease: initiation defects and distractibility. Neurology 37:364–370
Lasker AG, Zee DS, Hain TC, Folstein SE, Singer HS (1988) Saccades in Huntington’s disease: slowing and dysmetria. Neurology 38:427–431
Lasker AG, Zee DS (1997) Ocular motor abnormalities in Huntington’s disease. Vis Res 37:3639–3645
Leigh RJ, Newman SA, Folstein SE, Lasker AG, Jensen BA (1983) Abnormal ocular motor control in Huntington’s disease. Neurology 33:1268–1275
Leigh RJ, Zee DS (1999) The neurology of eye movements,3rd edn. Oxford University Press, New York
Ober JK, Przedpelska-Ober E, Gryncewicz W, Dylak J, Carpenter RHS, Ober JJ (2003) Hand-held system for ambulatory measurement of saccadic durations of neurological patients. In: Gadja J (ed) Modelling and Measurement in Medicine Komitet Biocybernityki i Inzyneierii Biomedycznej. PAN, Warsaw, pp 187–198
Reddi BAJ, Carpenter RHS (2000) The influence of urgency on decision time. Nat Neurosci 3:827–831
Reddi BAJ, Asrress KN, Carpenter RHS (2003) Accuracy information and response time in a saccadic decision task. J Neurophysiol 90:3538–3546
Tian JR, Zee DS, Lasker AG, Folstein SE (1991) Saccades in Huntington’s disease: predictive tracking and interaction between release of fixation and initiation of saccades. Neurology 41:875–881
Westphal A (1883) Uber eine dem Bilde der cerebrospinalen grauen Degeneration ähniliche Erkrankung des centralen Nervensystem ohne anatomischen Befund nebst einegen Bernerkungen über parodoxe Kontraction. Archiv für Psychiatrie Nervenkrankheiten 14:87–134
Winograd-Gurvich CT, Georgiou-Karistianis N, Evans A, Millist L, Bradshaw JL, Churchyard A, Chiu E, White OB (2003) Hypometric primary saccades and increased variability in visually guided saccades in Huntington’s disease. Neuropsychologia 41:1683–1692
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We would like to thank all the staff and patients at the HD clinic for their support in this work.
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Ali, F.R., Michell, A.W., Barker, R.A. et al. The use of quantitative oculometry in the assessment of Huntington’s disease. Exp Brain Res 169, 237–245 (2006). https://doi.org/10.1007/s00221-005-0143-6
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DOI: https://doi.org/10.1007/s00221-005-0143-6