Reflexive and voluntary saccadic eye movements as biomarker of Huntington’s Disease
Abstract
Introduction. Subtle abnormalities in the preclinical stage of Huntington’s Disease (HD) can be detected using saccadic eye movement assessment reflecting disease progression. This study was aimed to evaluate abnormalities in saccade parameters in asymptomatic carriers and symptomatic HD patients at various stages of HD.
Material and methods. The study enrolled 104 participants, including 14 asymptomatic carriers of HTT mutations, 44 symptomatic HD patients, and 46 control subjects. HD severity was measured using the Unified Huntington’s Disease Rating Scale Total Motor Score (UHDRS–TMS) and Total Functional Capacity Scale (TFC). The evaluation of rapid eye movements (reflexive saccades, anti-saccades, memory-guided saccades) was carried out using ‘Saccadometer Research’.
Results. Measures of reflexive and volitional saccades did not differ between the asymptomatic carriers and controls. Significant latency prolongation and increased physiological variability of latency times, as well as higher error rates among HD patients, were found in all saccade tasks (p < 0.001) compared to the controls. Abnormalities in saccade parameters were more pronounced in the advanced stages of the disease. Latency of saccades and error rate of volitional saccades correlated with the UHDRS–TMS and TFC scores.
Conclusions. The saccade parameters in asymptomatic HD carriers with a long time to disease development were similar to those in the control group. Saccade abnormalities appeared in symptomatic patients at the beginning of the disease, and correlated with HD severity.
Keywords: Huntington’s Diseasesaccadic eye movementsbiomarkers
References
- Vonsattel JP, DiFiglia M, Vonsattel JP, et al. Huntington disease. J Neuropathol Exp Neurol. 1998; 57(5): 369–384.
- O'Keeffe GC, Michell AW, Barker RA, et al. Biomarkers in Huntington's and Parkinson's Disease. Ann N Y Acad Sci. 2009; 1180: 97–110.
- Leigh R, Zee D. The Saccadic System. The Neurology of Eye Movements. 2015: 169–288.
- Petit H, Milbled G, Petit H, et al. Anomalies of conjugate ocular movements in Huntington's chorea: application to early detection. Adv Neurol. 1973; 1: 287–294.
- Leigh RJ, Newman SA, Folstein SE, et al. Abnormal ocular motor control in Huntington's disease. Neurology. 1983; 33(10): 1268–1275.
- Lasker AG, Zee DS, Hain TC, et al. Saccades in Huntington's disease: initiation defects and distractibility. Neurology. 1987; 37(3): 364–370.
- Lasker AG, Zee DS, Hain TC, et al. Saccades in Huntington's disease: slowing and dysmetria. Neurology. 1988; 38(3): 427–431.
- Tian JR, Zee DS, Lasker AG, et al. Saccades in Huntington's disease: predictive tracking and interaction between release of fixation and initiation of saccades. Neurology. 1991; 41(6): 875–881.
- Ali FR, Michell AW, Barker RA, et al. The use of quantitative oculometry in the assessment of Huntington's disease. Exp Brain Res. 2006; 169(2): 237–245.
- Golding CVP, Danchaivijitr C, Hodgson TL, et al. Identification of an oculomotor biomarker of preclinical Huntington disease. Neurology. 2006; 67(3): 485–487.
- Sánchez-Pernaute R, García-Segura JM, del Barrio Alba A, et al. Clinical correlation of striatal 1H MRS changes in Huntington's disease. Neurology. 1999; 53(4): 806–812.
- Siemers E, Foroud T, Bill DJ, et al. Motor changes in presymptomatic Huntington disease gene carriers. Arch Neurol. 1996; 53(6): 487–492.
- Kirkwood SC, Siemers E, Hodes ME, et al. Subtle changes among presymptomatic carriers of the Huntington's disease gene. J Neurol Neurosurg Psychiatry. 2000; 69(6): 773–779.
- Cutsuridis V, Jiang S, Dunn MJ, et al. Neural modeling of antisaccade performance of healthy controls and early Huntington's disease patients. Chaos. 2021; 31(1): 013121.
- Blekher TM, Yee RD, Kirkwood SC, et al. Oculomotor control in asymptomatic and recently diagnosed individuals with the genetic marker for Huntington's disease. Vision Res. 2004; 44(23): 2729–2736.
- Blekher T, Johnson SA, Marshall J, et al. Saccades in presymptomatic and early stages of Huntington disease. Neurology. 2006; 67(3): 394–399.
- Rupp J, Dzemidzic M, Blekher T, et al. Comparison of vertical and horizontal saccade measures and their relation to gray matter changes in premanifest and manifest Huntington disease. J Neurol. 2012; 259(2): 267–276.
- Mazur-Michałek I, Kowalska K, Zielonka D, et al. Structural Abnormalities of the Optic Nerve and Retina in Huntington's Disease Pre-Clinical and Clinical Settings. Int J Mol Sci. 2022; 23(10): 5450.
- Śmiłowska K, van Wamelen D. Atypical motor presentation of Huntington's Disease. Neurol Neurochir Pol. 2023; 57(5): 450–451.
- Zielonka D, Witkowski G, Puch EA, et al. Prevalence of Non-psychiatric Comorbidities in Pre-symptomatic and Symptomatic Huntington's Disease Gene Carriers in Poland. Front Med (Lausanne). 2020; 11(7): 79.
- Langbehn DR, Brinkman RR, Falush D, et al. International Huntington's Disease Collaborative Group. A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length. Clin Genet. 2004; 65(4): 267–277.
- Ober J, Dylak J, Gryncewicz W, et al. Saccadometry – New possibility for monitoring brain functional status. Nauka. 2009; 4: 109–135.
- Rupp J, Dzemidzic M, Blekher T, et al. Abnormal error-related antisaccade activation in premanifest and early manifest Huntington disease. Neuropsychology. 2011; 25(3): 306–318.
- Hicks SL, Robert MPA, Golding CVP, et al. Oculomotor deficits indicate the progression of Huntington's disease. Prog Brain Res. 2008; 171: 555–558.
- Robert MPA, Nachev PC, Hicks SL, et al. Saccadometry of conditional rules in presymptomatic Huntington's disease. Ann N Y Acad Sci. 2009; 1164: 444–450.
- Langbehn DR, Hayden MR, Paulsen JS, et al. and the PREDICT-HD Investigators of the Huntington Study Group. CAG-repeat length and the age of onset in Huntington disease (HD): a review and validation study of statistical approaches. Am J Med Genet B Neuropsychiatr Genet. 2010; 153B(2): 397–408.
- Winder JY, Roos RAC. Premanifest Huntington's disease: Examination of oculomotor abnormalities in clinical practice. PLoS One. 2018; 13(3): e0193866.
- Dursun SM, Burke JG, Andrews H, et al. The effects of antipsychotic medication on saccadic eye movement abnormalities in Huntington's disease. Prog Neuropsychopharmacol Biol Psychiatry. 2000; 24(6): 889–896.
- Green JF, King DJ, Trimble KM. Antisaccade and smooth pursuit eye movements in healthy subjects receiving sertraline and lorazepam. J Psychopharmacol. 2000; 14(1): 30–36.
- Kaczyńska J, Sitek EJ, Witkowski G, et al. Is deep brain stimulation effective in Huntington's Disease? - a systematic literature review. Neurol Neurochir Pol. 2022; 56(4): 299–307.
- Zielonka D, Stawinska-Witoszynska B. Gender Differences in Non-sex Linked Disorders: Insights From Huntington's Disease. Front Neurol. 2020; 11: 571.
