Eye-tracking in Early Manifest Huntington’s Disease: Heterogeneity of Deficits in Inhibitory and Fronto-Executive Control
Main Article Content
Abstract
Objectives: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that affects first basal ganglia and fronto- striatal circuitry. Cognitive decline and inhibitory control deficits are more subtle in the early stages of manifest disease, yet relevant to track disease progression. The current study aims to underpin and characterize the dysfunction of oculomotor inhibitory control mechanisms and executive function through working memory demands on fronto-executive load in a cohort of early manifest HD (Early-HD).
Methods: A comprehensive battery of neuropsychological tests was applied to assess cognitive functioning in 14 Early-HD and 22 Control participants. Oculomotor function was studied using an experimental paradigm comprising four oculomotor tasks: prosaccade, antisaccade, 1- or 2-back memory prosaccade, and 1- or 2-back memory antisaccade. The estimated metrics were success rate, direction errors, timing errors, and the primary saccade latency.
Results: The Early-HD group demonstrated cognitive deficits in visual and verbal memory, executive function, attention, visual perception, and verbal and non-verbal IQ domains. Regarding oculomotor performance, the clinical group had a decreased success rate and increased percentage of direction errors and early premature saccades while exhibiting faster response times than the Control group in the 1- or 2-back memory antisaccade task.
Conclusions: Our results demonstrate overt oculomotor dysfunction in Early-HD since inhibitory control mechanisms are necessary to perform the task. Furthermore, increasing working memory demands and fronto-executive load enhances impulsive response patterns. The dysfunction in goal-oriented oculomotor behavior, including more automatized responses and deficits in inhibition, is present in Early- HD patients with cognitive deficits but who remain functional and autonomous. These findings reinforce the notion that fronto-striatal impairment is a crucial event in HD and that more automatized oculomotor evaluation procedures help identify and stratify deficits in early manifest disease.
Keywords:
Huntington’s disease, manifest stage, oculomotor performance, inhibition, fronto-executive load
Article Details
How to Cite
JÚLIO, Filipa et al.
Eye-tracking in Early Manifest Huntington’s Disease: Heterogeneity of Deficits in Inhibitory and Fronto-Executive Control.
Medical Research Archives, [S.l.], v. 12, n. 7, july 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5577>. Date accessed: 21 dec. 2024.
doi: https://doi.org/10.18103/mra.v12i7.5577.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Phillips W, Shannon KM, Barker RA. The current clinical management of Huntington's disease. Movement Disorders. 2008;23(11):1491-1504.
2. Reilmann R, Leavitt BR, Ross CA. Diagnostic criteria for Huntington's disease based on natural history. Mov Disord. 2014;29(11):1335-1341.
3. Roos RA. Huntington's disease: a clinical review. Orphanet J Rare Dis. 2010;5:40.
4. Ross CA, Aylward EH, Wild EJ, et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol. 2014;10(4):204–216.
5. MacDonald ME, Ambrose CM, Duyao MP, et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993;72(6):971-983.
6. Li SH, Schilling G, Young WS, et al. Huntington's disease gene (IT15) is widely expressed in human and rat tissues. Neuron. 1993;11(5):985-993.
7. Schulte J, Littleton JT. The biological function of the Huntingtin protein and its relevance to Huntington's Disease pathology. Current trends in neurology. 2011;5:65-78.
8. Reilmann R, McGarry A, Grachev ID, et al. Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study. Lancet Neurol. 2019;18(2):165-176.
9. Reilmann R, Anderson KE, Feigin A, et al. Safety and efficacy of laquinimod for Huntington's disease (LEGATO-HD): a multicentre, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Neurol. 2024;23(3):243-255.
10. Van de Roovaart HJ, Nguyen N, Veenstra TD. Huntington's Disease Drug Development: A Phase 3 Pipeline Analysis. Pharmaceuticals (Basel). 2023;16(11).
11. Sampaio C, Borowsky B, Reilmann R. Clinical trials in Huntington's disease: Interventions in early clinical development and newer methodological approaches. Mov Disord. 2014;29(11):1419-1428.
12. keogh SJ, Scahill RI, Owen G, et al. 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 Neurology. 2013;12(7):637–649.
13. Tabrizi SJ, Reilmann R, Roos RAC, et al. Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurology. 2012;11(1):42–53.
14. Keogh R, Frost C, Owen G, et al. Medication Use in Early-HD Participants in Track-HD: an Investigation of its Effects on Clinical Performance. PLoS Curr. 2016;8.
15. Paulsen JS, Long JD, Ross C, et al. Improving Prediction of Huntington Disease Onset with Clinical and Imaging Measures: A 10-Year Prospective Study of Converters. Journal of Neurology Neurosurgery and Psychiatry. 2014;85:A65–A65.
16. Paulsen JS, Long JD, Ross CA, et al. Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study. Lancet Neurology. 2014;13(12):1193–1201.
17. Paulsen JS, Long JD, Johnson HJ, et al. Clinical and Biomarker Changes in Premanifest Huntington Disease Show Trial Feasibility: A Decade of the PREDICT-HD Study. Front Aging Neurosci. 2014;6:78.
18. Domínguez JF, Stout JC, Poudel G, et al. Multimodal imaging biomarkers in premanifest and early Huntington's disease: 30-month IMAGE-HD data. British Journal of Psychiatry. 2018;208(6):571-578.
19. Huntington-Study-Group. Unified Huntington's Disease Rating Scale: reliability and consistency. Movement Disorders. 1996;11(2):136–142.
20. Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR, International Huntington's Disease Collaborative G. A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length. Clinical Genetics. 2004;65(4):267-277.
21. Langbehn DR, Hayden MR, Paulsen JS, Group P-HIotHS. CAG-repeat length and the age of onset in Huntington disease (HD): a review and validation study of statistical approaches. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2010;153B(2):397–408.
22. Lavrador R, Júlio F, Januário C, Castelo-Branco M, Caetano G. Classification of Huntington’s Disease Stage with Features Derived from Structural and Diffusion-Weighted Imaging. Journal of Personalized Medicine. 2022;12(5):704.
23. Aylward EH. Change in MRI striatal volumes as a biomarker in preclinical Huntington's disease. Brain Research Bulletin. 2007;72(2-3):152–158.
24. Aylward EH, Brandt J, Codori AM, Mangus RS, Barta PE, Harris GJ. Reduced basal ganglia volume associated with the gene for Huntington's disease in asymptomatic at-risk persons. Neurology. 1994;44(5):823–828.
25. Coppen EM, van der Grond J, Roos RAC. Atrophy of the putamen at time of clinical motor onset in Huntington’s disease: a 6-year follow-up study. Journal of Clinical Movement Disorders. 2018;5(1):2.
26. Liu CF, Younes L, Tong XJ, et al. Longitudinal imaging highlights preferential basal ganglia circuit atrophy in Huntington's disease. Brain Commun. 2023;5(5):fcad214.
27. Estevez-Fraga C, Scahill R, Rees G, Tabrizi SJ, Gregory S. Diffusion imaging in Huntington’s disease: comprehensive review. Journal of Neurology, Neurosurgery & Psychiatry. 2021;92(1):62.
28. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP. Neuropathological Classification of Huntingtons-Disease. J Neuropath Exp Neur. 1985;44(6):559–577.
29. Paulsen JS, Long JD. Onset of Huntington's disease: can it be purely cognitive? Mov Disord. 2014;29(11):1342-1350.
30. Biglan KM, Zhang Y, Long JD, et al. Refining the diagnosis of Huntington disease: the PREDICT-HD study. Front Aging Neurosci. 2013;5:12.
31. Harrington DL, Smith MM, Zhang Y, Carlozzi NE, Paulsen JS, Group tP-HIotHS. Cognitive domains that predict time to diagnosis in prodromal Huntington disease. Journal of Neurology, Neurosurgery & Psychiatry. 2012;83(6):612-619.
32. Stout JC, Paulsen JS, Queller S, et al. Neurocognitive Signs in Prodromal Huntington Disease. Neuropsychology. 2011;25(1):1-14.
33. Zimbelman JL, Paulsen JS, Mikos A, Reynolds NC, Hoffmann RG, Rao SM. fMRI detection of early neural dysfunction in preclinical Huntington's disease. Journal of the International Neuropsychological Society. 2007;13(5):758-769.
34. Ross CA, Pantelyat A, Kogan J, Brandt J. Determinants of Functional Disability in Huntington's Disease: Role of Cognitive and Motor Dysfunction. Movement Disorders. 2014;29(11):1351-1358.
35. Dumas EM, van den Bogaard SJ, Middelkoop HA, Roos RA. A review of cognition in Huntington's disease. Frontiers in Bioscience (Schol Ed). 2013;5:1-18.
36. Carvalho JO, Long JD, Westervelt HJ, et al. The impact of oculomotor functioning on neuropsychological performance in Huntington disease. J Clin Exp Neuropsyc. 2016;38(2):217-226.
37. Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. Journal of the American Geriatrics Society. 2005;53(4):695-699.
38. Bechtel N, Scahill RI, Rosas HD, et al. Tapping linked to function and structure in premanifest and symptomatic Huntington disease. Neurology. 2010;75(24):2150-2160.
39. Anderson TJ, MacAskill MR. Eye movements in patients with neurodegenerative disorders. Nat Rev Neurol. 2013;9(2):74-85.
40. Cutsuridis V, Jiang S, Dunn MJ, Rosser A, Brawn J, Erichsen JT. Neural modeling of antisaccade performance of healthy controls and early Huntington's disease patients. Chaos (Woodbury, NY). 2021;31(1):013121.
41. Miranda A, Lavrador R, Julio F, Januario C, Castelo-Branco M, Caetano G. Classification of Huntington's disease stage with support vector machines: A study on oculomotor performance. Behav Res Methods. 2016;48(4):1667-1677.
42. Kipps CM, Duggins AJ, Mahant N, Gomes L, Ashburner J, McCusker EA. Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study. Journal of Clinical and Experimental Neuropsychology. 2005;76(5):650–655.
43. Dalley JW, Everitt BJ, Robbins TW. Impulsivity, compulsivity, and top-down cognitive control. Neuron. 2011;69(4):680-694.
44. Gorges M, Pinkhardt EH, Kassubek J. Alterations of Eye Movement Control in Neurodegenerative Movement Disorders. Journal of Ophthalmology. 2014;2014:11.
45. Rao JA, Harrington DL, Durgerian S, et al. Disruption of response inhibition circuits in prodromal Huntington disease. Cortex. 2014;58:72-85.
46. Bari A, Robbins TW. Inhibition and impulsivity: behavioral and neural basis of response control. Progress in Neurobiology. 2013;108:44-79.
47. Balci F, Day M, Rooney A, Brunner D. Disrupted Temporal control in the R6/2 mouse model of Huntington's Disease. Behavioral Neuroscience. 2009;123(6):1353-1358.
48. Rosenblatt A. Neuropsychiatry of Huntington's disease. Dialogues in Clinical Neuroscience. 2007;9(2):191-197.
49. Manfré G, Doyere V, Bossi S, Riess O, Nguyen HP, El Massioui N. Impulsivity trait in the early symptomatic BACHD transgenic rat model of Huntington disease. Behav Brain Res. 2016;299:6-10.
50. Blekher T, Johnson SA, Marshall J, et al. Saccades in presymptomatic and early stages of Huntington disease. Neurology. 2006;67(3):394-399.
51. Golding CV, Danchaivijitr C, Hodgson TL, Tabrizi SJ, Kennard C. Identification of an oculomotor biomarker of preclinical Huntington disease. Neurology. 2006;67(3):485-487.
52. Robert MPA, Nachev PC, Hicks SL, Golding CVP, Tabrizi SJ, Kennard C. Saccadometry of Conditional Rules in Presymptomatic Huntington's Disease. Annals of the New York Academy of Sciences. 2009;1164(1):444-450.
53. Ali FR, Michell AW, Barker RA, Carpenter RHS. The use of quantitative oculometry in the assessment of Huntington’s disease. Exp Brain Res. 2006;169(2):237-245.
54. Antoniades CA, Xu Z, Mason SL, Carpenter RH, Barker RA. Huntington's disease: changes in saccades and hand-tapping over 3 years. Journal of Neurology. 2010;257(11):1890-1898.
55. Blekher T, 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.
56. Henderson T, Georgiou-Karistianis N, White O, et al. Inhibitory control during smooth pursuit in Parkinson's disease and Huntington's disease. Movement Disorders. 2011;26(10):1893-1899.
57. Patel SS, Jankovic J, Hood AJ, Jeter CB, Sereno AB. Reflexive and Volitional Saccades: Biomarkers of Huntington Disease Severity and Progression. Journal of the Neurological Sciences. 2012;313(1-2):35-41.
58. Turner TH, Goldstein J, Hamilton JM, et al. Behavioral Measures of Saccade Latency and Inhibition in Manifest and Premanifest Huntington’s Disease. Journal of Motor Behavior. 2011;43(4):295-302.
59. 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. Journal of Neurology. 2012;259(2):267-276.
60. 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.
61. Antoniades CA, Altham PM, Mason SL, Barker RA, Carpenter R. Saccadometry: a new tool for evaluating presymptomatic Huntington patients. Neuroreport. 2007;18(11):1133-1136.
62. Peltsch A, Hoffman A, Armstrong I, Pari G, Munoz DP. Saccadic impairments in Huntington’s disease. Exp Brain Res. 2008;186(3):457-469.
63. Wiecki TV, Antoniades CA, Stevenson A, et al. A Computational Cognitive Biomarker for Early-Stage Huntington's Disease. PLoS One. 2016;11(2):e0148409.
64. Mitchell JP, Macrae CN, Gilchrist ID. Working memory and the suppression of reflexive saccades. J Cognitive Neurosci. 2002;14(1):95-103.
65. Van der Stigchel S. The search for oculomotor inhibition: interactions with working memory. Exp Psychol. 2010;57(6):429-435.
66. Júlio F, Caetano G, Januário C, Castelo-Branco M. The effect of impulsivity and inhibitory control deficits in the saccadic behavior of premanifest Huntington’s disease individuals. Orphanet J Rare Dis. 2019;14(1):246.
67. Wild EJ, Tabrizi SJ. Premanifest and early Huntington's disease. In: Bates GP, Tabrizi SJ, Jones L, eds. Huntington's Disease. 4th ed: Oxford University Press; 2014.
68. Garcia-Gorro C, Llera A, Martinez-Horta S, et al. Specific patterns of brain alterations underlie distinct clinical profiles in Huntington's disease. Neuroimage Clin. 2019;23:101900.
69. Mehrabi NF, Waldvogel HJ, Tippett LJ, Hogg VM, Synek BJ, Faull RL. Symptom heterogeneity in Huntington's disease correlates with neuronal degeneration in the cerebral cortex. Neurobiol Dis. 2016;96:67-74.
70. Johnson EB, Ziegler G, Penny W, et al. Dynamics of Cortical Degeneration Over a Decade in Huntington's Disease. Biol Psychiatry. 2021;89(8):807-816.
71. Orth M, Handley OJ, Schwenke C, et al. Observing Huntington's Disease: the European Huntington's Disease Network's REGISTRY. PLoS Curr. 2010;2:RRN1184.
72. Simões MR, Freitas S, Santana I, et al. MoCA. Versão final portuguesa [MoCA 7.1. Portuguese final version]. 2008.
73. Freitas S, Simões MR, Alves L, Santana I. Montreal Cognitive Assessment (MoCA): Normative study for the Portuguese population. J Clin Exp Neuropsyc. 2011;33(9):989-996.
74. Snowden JS, Craufurd D, Thompson J, Neary D. Psychomotor, executive, and memory function in preclinical Huntington's disease. J Clin Exp Neuropsychol. 2002;24(2):133-145.
75. Solomon AC, Stout JC, Weaver M, et al. Ten-year rate of longitudinal change in neurocognitive and motor function in prediagnosis Huntington disease. Mov Disord. 2008;23(13):1830-1836.
76. Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol. 1935;18:643–662.
77. Oldfield RC. The assessment and analysis of handedness: The Edinburgh inventory. Neuropsychologia. 1971;9(1):97-113.
78. Wechsler D. WAIS-III administration and scoring manual. 3rd ed. San Antonio, Texas: The Psychological Corporation; 1997.
79. Wechsler D. WAIS-III: Escala de Inteligência de Wechsler para adultos - Manual. 3rd ed. Portuguese Version [Wechsler Adult Intelligence Scale - WAIS-III]: Cegoc; 2008.
80. Cavaco S, Pinto C, Gonçalves A, Gomes F, Pereira A, Malaquias C. Auditory verbal learning test: dados normativos dos 21 aos 65 anos. Psychologica. 2008;49:208-221.
81. Rey A. Rey verbal learning test. L'examen clinique en psychologie. 2nd ed. Paris: Presses universitaires de France; 1964.
82. Raven J, Raven JC, Court JH. Manual for Raven's progressive matrices and vocabulary scales. Sections 1-7. 1993 ed. Oxford: Oxford Psychologists Press; 1993.
83. Berch DB, Krikorian R, Huha EM. The Corsi Block-Tapping Task: Methodological and Theoretical Considerations. Brain Cognition. 1998;38(3):317-338.
84. Kessels RP, van Zandvoort MJ, Postma A, Kappelle LJ, de Haan EH. The Corsi Block-Tapping Task: standardization and normative data. Applied Neuropsychology. 2000;7(4):252-258.
85. Benton AL. The revised visual retention test : clinical and experimental applications. 4th ed. New York: Psychological Corporation; 1974.
86. Benton AL, Hamsher Kd, Varney NR, Spreen O. Contributions to Neuropsychological Assessment: A Clinical Manual. 1st ed. New York: Oxford University Press; 1983.
87. Lezak MD. Neuropsychological Assessment. 3rd ed. New York: Oxford University Press; 1995.
88. Ardila A, Ostrosky‐Solís F, Bernal B. Cognitive testing toward the future: The example of Semantic Verbal Fluency (ANIMALS). International Journal of Psychology. 2006;41(5):324-332.
89. Snaith RP, Constantopoulos AA, Jardine MY, McGuffin P. A clinical scale for the self-assessment of irritability. The British Journal of Psychiatry. 1978;132(2):164-171.
90. Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatrica Scandinavica. 1983;67(6):361-370.
91. Stout JC, Glikmann-Johnston Y, Andrews SC. Cognitive assessment strategies in Huntington's disease research. J Neurosci Methods. 2016;265:19-24.
92. Papoutsi M, Labuschagne I, Tabrizi SJ, Stout JC. The cognitive burden in Huntington's disease: pathology, phenotype, and mechanisms of compensation. Movement Disorders. 2014;29(5):673-683.
93. Hart EP, Dumas EM, Schoonderbeek A, Wolthuis SC, van Zwet EW, Roos RA. Motor dysfunction influence on executive functioning in manifest and premanifest Huntington's disease. Movement Disorders. 2014;29(3):320-326.
94. Lasker AG, Zee DS. Ocular motor abnormalities in Huntington's disease. Vision Res. 1997;37(24):3639-3645.
95. Beglinger LJ, O'Rourke JJF, Wang C, et al. Earliest functional declines in Huntington disease. Psychiatry research. 2010;178(2):414-418.
96. El Massioui N, Lamirault C, Yague S, et al. Impaired Decision Making and Loss of Inhibitory-Control in a Rat Model of Huntington Disease. Front Behav Neurosci. 2016;10:204.
97. Riek HC, Brien DC, Coe BC, et al. Cognitive correlates of antisaccade behaviour across multiple neurodegenerative diseases. Brain Commun. 2023;5(2):fcad049.
98. Rupp J, Blekher T, Jackson J, et al. Progression in prediagnostic Huntington disease. Journal of Neurology Neurosurgery and Psychiatry. 2010;81(4):379-384.
99. PREDICTOM project - Mission and vision. November 6, 2023. Assessed May 8, 2024. https://www.helse-stavanger.no/en/predictom/
2. Reilmann R, Leavitt BR, Ross CA. Diagnostic criteria for Huntington's disease based on natural history. Mov Disord. 2014;29(11):1335-1341.
3. Roos RA. Huntington's disease: a clinical review. Orphanet J Rare Dis. 2010;5:40.
4. Ross CA, Aylward EH, Wild EJ, et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol. 2014;10(4):204–216.
5. MacDonald ME, Ambrose CM, Duyao MP, et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993;72(6):971-983.
6. Li SH, Schilling G, Young WS, et al. Huntington's disease gene (IT15) is widely expressed in human and rat tissues. Neuron. 1993;11(5):985-993.
7. Schulte J, Littleton JT. The biological function of the Huntingtin protein and its relevance to Huntington's Disease pathology. Current trends in neurology. 2011;5:65-78.
8. Reilmann R, McGarry A, Grachev ID, et al. Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study. Lancet Neurol. 2019;18(2):165-176.
9. Reilmann R, Anderson KE, Feigin A, et al. Safety and efficacy of laquinimod for Huntington's disease (LEGATO-HD): a multicentre, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Neurol. 2024;23(3):243-255.
10. Van de Roovaart HJ, Nguyen N, Veenstra TD. Huntington's Disease Drug Development: A Phase 3 Pipeline Analysis. Pharmaceuticals (Basel). 2023;16(11).
11. Sampaio C, Borowsky B, Reilmann R. Clinical trials in Huntington's disease: Interventions in early clinical development and newer methodological approaches. Mov Disord. 2014;29(11):1419-1428.
12. keogh SJ, Scahill RI, Owen G, et al. 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 Neurology. 2013;12(7):637–649.
13. Tabrizi SJ, Reilmann R, Roos RAC, et al. Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurology. 2012;11(1):42–53.
14. Keogh R, Frost C, Owen G, et al. Medication Use in Early-HD Participants in Track-HD: an Investigation of its Effects on Clinical Performance. PLoS Curr. 2016;8.
15. Paulsen JS, Long JD, Ross C, et al. Improving Prediction of Huntington Disease Onset with Clinical and Imaging Measures: A 10-Year Prospective Study of Converters. Journal of Neurology Neurosurgery and Psychiatry. 2014;85:A65–A65.
16. Paulsen JS, Long JD, Ross CA, et al. Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study. Lancet Neurology. 2014;13(12):1193–1201.
17. Paulsen JS, Long JD, Johnson HJ, et al. Clinical and Biomarker Changes in Premanifest Huntington Disease Show Trial Feasibility: A Decade of the PREDICT-HD Study. Front Aging Neurosci. 2014;6:78.
18. Domínguez JF, Stout JC, Poudel G, et al. Multimodal imaging biomarkers in premanifest and early Huntington's disease: 30-month IMAGE-HD data. British Journal of Psychiatry. 2018;208(6):571-578.
19. Huntington-Study-Group. Unified Huntington's Disease Rating Scale: reliability and consistency. Movement Disorders. 1996;11(2):136–142.
20. Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR, International Huntington's Disease Collaborative G. A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length. Clinical Genetics. 2004;65(4):267-277.
21. Langbehn DR, Hayden MR, Paulsen JS, Group P-HIotHS. CAG-repeat length and the age of onset in Huntington disease (HD): a review and validation study of statistical approaches. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2010;153B(2):397–408.
22. Lavrador R, Júlio F, Januário C, Castelo-Branco M, Caetano G. Classification of Huntington’s Disease Stage with Features Derived from Structural and Diffusion-Weighted Imaging. Journal of Personalized Medicine. 2022;12(5):704.
23. Aylward EH. Change in MRI striatal volumes as a biomarker in preclinical Huntington's disease. Brain Research Bulletin. 2007;72(2-3):152–158.
24. Aylward EH, Brandt J, Codori AM, Mangus RS, Barta PE, Harris GJ. Reduced basal ganglia volume associated with the gene for Huntington's disease in asymptomatic at-risk persons. Neurology. 1994;44(5):823–828.
25. Coppen EM, van der Grond J, Roos RAC. Atrophy of the putamen at time of clinical motor onset in Huntington’s disease: a 6-year follow-up study. Journal of Clinical Movement Disorders. 2018;5(1):2.
26. Liu CF, Younes L, Tong XJ, et al. Longitudinal imaging highlights preferential basal ganglia circuit atrophy in Huntington's disease. Brain Commun. 2023;5(5):fcad214.
27. Estevez-Fraga C, Scahill R, Rees G, Tabrizi SJ, Gregory S. Diffusion imaging in Huntington’s disease: comprehensive review. Journal of Neurology, Neurosurgery & Psychiatry. 2021;92(1):62.
28. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP. Neuropathological Classification of Huntingtons-Disease. J Neuropath Exp Neur. 1985;44(6):559–577.
29. Paulsen JS, Long JD. Onset of Huntington's disease: can it be purely cognitive? Mov Disord. 2014;29(11):1342-1350.
30. Biglan KM, Zhang Y, Long JD, et al. Refining the diagnosis of Huntington disease: the PREDICT-HD study. Front Aging Neurosci. 2013;5:12.
31. Harrington DL, Smith MM, Zhang Y, Carlozzi NE, Paulsen JS, Group tP-HIotHS. Cognitive domains that predict time to diagnosis in prodromal Huntington disease. Journal of Neurology, Neurosurgery & Psychiatry. 2012;83(6):612-619.
32. Stout JC, Paulsen JS, Queller S, et al. Neurocognitive Signs in Prodromal Huntington Disease. Neuropsychology. 2011;25(1):1-14.
33. Zimbelman JL, Paulsen JS, Mikos A, Reynolds NC, Hoffmann RG, Rao SM. fMRI detection of early neural dysfunction in preclinical Huntington's disease. Journal of the International Neuropsychological Society. 2007;13(5):758-769.
34. Ross CA, Pantelyat A, Kogan J, Brandt J. Determinants of Functional Disability in Huntington's Disease: Role of Cognitive and Motor Dysfunction. Movement Disorders. 2014;29(11):1351-1358.
35. Dumas EM, van den Bogaard SJ, Middelkoop HA, Roos RA. A review of cognition in Huntington's disease. Frontiers in Bioscience (Schol Ed). 2013;5:1-18.
36. Carvalho JO, Long JD, Westervelt HJ, et al. The impact of oculomotor functioning on neuropsychological performance in Huntington disease. J Clin Exp Neuropsyc. 2016;38(2):217-226.
37. Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. Journal of the American Geriatrics Society. 2005;53(4):695-699.
38. Bechtel N, Scahill RI, Rosas HD, et al. Tapping linked to function and structure in premanifest and symptomatic Huntington disease. Neurology. 2010;75(24):2150-2160.
39. Anderson TJ, MacAskill MR. Eye movements in patients with neurodegenerative disorders. Nat Rev Neurol. 2013;9(2):74-85.
40. Cutsuridis V, Jiang S, Dunn MJ, Rosser A, Brawn J, Erichsen JT. Neural modeling of antisaccade performance of healthy controls and early Huntington's disease patients. Chaos (Woodbury, NY). 2021;31(1):013121.
41. Miranda A, Lavrador R, Julio F, Januario C, Castelo-Branco M, Caetano G. Classification of Huntington's disease stage with support vector machines: A study on oculomotor performance. Behav Res Methods. 2016;48(4):1667-1677.
42. Kipps CM, Duggins AJ, Mahant N, Gomes L, Ashburner J, McCusker EA. Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study. Journal of Clinical and Experimental Neuropsychology. 2005;76(5):650–655.
43. Dalley JW, Everitt BJ, Robbins TW. Impulsivity, compulsivity, and top-down cognitive control. Neuron. 2011;69(4):680-694.
44. Gorges M, Pinkhardt EH, Kassubek J. Alterations of Eye Movement Control in Neurodegenerative Movement Disorders. Journal of Ophthalmology. 2014;2014:11.
45. Rao JA, Harrington DL, Durgerian S, et al. Disruption of response inhibition circuits in prodromal Huntington disease. Cortex. 2014;58:72-85.
46. Bari A, Robbins TW. Inhibition and impulsivity: behavioral and neural basis of response control. Progress in Neurobiology. 2013;108:44-79.
47. Balci F, Day M, Rooney A, Brunner D. Disrupted Temporal control in the R6/2 mouse model of Huntington's Disease. Behavioral Neuroscience. 2009;123(6):1353-1358.
48. Rosenblatt A. Neuropsychiatry of Huntington's disease. Dialogues in Clinical Neuroscience. 2007;9(2):191-197.
49. Manfré G, Doyere V, Bossi S, Riess O, Nguyen HP, El Massioui N. Impulsivity trait in the early symptomatic BACHD transgenic rat model of Huntington disease. Behav Brain Res. 2016;299:6-10.
50. Blekher T, Johnson SA, Marshall J, et al. Saccades in presymptomatic and early stages of Huntington disease. Neurology. 2006;67(3):394-399.
51. Golding CV, Danchaivijitr C, Hodgson TL, Tabrizi SJ, Kennard C. Identification of an oculomotor biomarker of preclinical Huntington disease. Neurology. 2006;67(3):485-487.
52. Robert MPA, Nachev PC, Hicks SL, Golding CVP, Tabrizi SJ, Kennard C. Saccadometry of Conditional Rules in Presymptomatic Huntington's Disease. Annals of the New York Academy of Sciences. 2009;1164(1):444-450.
53. Ali FR, Michell AW, Barker RA, Carpenter RHS. The use of quantitative oculometry in the assessment of Huntington’s disease. Exp Brain Res. 2006;169(2):237-245.
54. Antoniades CA, Xu Z, Mason SL, Carpenter RH, Barker RA. Huntington's disease: changes in saccades and hand-tapping over 3 years. Journal of Neurology. 2010;257(11):1890-1898.
55. Blekher T, 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.
56. Henderson T, Georgiou-Karistianis N, White O, et al. Inhibitory control during smooth pursuit in Parkinson's disease and Huntington's disease. Movement Disorders. 2011;26(10):1893-1899.
57. Patel SS, Jankovic J, Hood AJ, Jeter CB, Sereno AB. Reflexive and Volitional Saccades: Biomarkers of Huntington Disease Severity and Progression. Journal of the Neurological Sciences. 2012;313(1-2):35-41.
58. Turner TH, Goldstein J, Hamilton JM, et al. Behavioral Measures of Saccade Latency and Inhibition in Manifest and Premanifest Huntington’s Disease. Journal of Motor Behavior. 2011;43(4):295-302.
59. 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. Journal of Neurology. 2012;259(2):267-276.
60. 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.
61. Antoniades CA, Altham PM, Mason SL, Barker RA, Carpenter R. Saccadometry: a new tool for evaluating presymptomatic Huntington patients. Neuroreport. 2007;18(11):1133-1136.
62. Peltsch A, Hoffman A, Armstrong I, Pari G, Munoz DP. Saccadic impairments in Huntington’s disease. Exp Brain Res. 2008;186(3):457-469.
63. Wiecki TV, Antoniades CA, Stevenson A, et al. A Computational Cognitive Biomarker for Early-Stage Huntington's Disease. PLoS One. 2016;11(2):e0148409.
64. Mitchell JP, Macrae CN, Gilchrist ID. Working memory and the suppression of reflexive saccades. J Cognitive Neurosci. 2002;14(1):95-103.
65. Van der Stigchel S. The search for oculomotor inhibition: interactions with working memory. Exp Psychol. 2010;57(6):429-435.
66. Júlio F, Caetano G, Januário C, Castelo-Branco M. The effect of impulsivity and inhibitory control deficits in the saccadic behavior of premanifest Huntington’s disease individuals. Orphanet J Rare Dis. 2019;14(1):246.
67. Wild EJ, Tabrizi SJ. Premanifest and early Huntington's disease. In: Bates GP, Tabrizi SJ, Jones L, eds. Huntington's Disease. 4th ed: Oxford University Press; 2014.
68. Garcia-Gorro C, Llera A, Martinez-Horta S, et al. Specific patterns of brain alterations underlie distinct clinical profiles in Huntington's disease. Neuroimage Clin. 2019;23:101900.
69. Mehrabi NF, Waldvogel HJ, Tippett LJ, Hogg VM, Synek BJ, Faull RL. Symptom heterogeneity in Huntington's disease correlates with neuronal degeneration in the cerebral cortex. Neurobiol Dis. 2016;96:67-74.
70. Johnson EB, Ziegler G, Penny W, et al. Dynamics of Cortical Degeneration Over a Decade in Huntington's Disease. Biol Psychiatry. 2021;89(8):807-816.
71. Orth M, Handley OJ, Schwenke C, et al. Observing Huntington's Disease: the European Huntington's Disease Network's REGISTRY. PLoS Curr. 2010;2:RRN1184.
72. Simões MR, Freitas S, Santana I, et al. MoCA. Versão final portuguesa [MoCA 7.1. Portuguese final version]. 2008.
73. Freitas S, Simões MR, Alves L, Santana I. Montreal Cognitive Assessment (MoCA): Normative study for the Portuguese population. J Clin Exp Neuropsyc. 2011;33(9):989-996.
74. Snowden JS, Craufurd D, Thompson J, Neary D. Psychomotor, executive, and memory function in preclinical Huntington's disease. J Clin Exp Neuropsychol. 2002;24(2):133-145.
75. Solomon AC, Stout JC, Weaver M, et al. Ten-year rate of longitudinal change in neurocognitive and motor function in prediagnosis Huntington disease. Mov Disord. 2008;23(13):1830-1836.
76. Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol. 1935;18:643–662.
77. Oldfield RC. The assessment and analysis of handedness: The Edinburgh inventory. Neuropsychologia. 1971;9(1):97-113.
78. Wechsler D. WAIS-III administration and scoring manual. 3rd ed. San Antonio, Texas: The Psychological Corporation; 1997.
79. Wechsler D. WAIS-III: Escala de Inteligência de Wechsler para adultos - Manual. 3rd ed. Portuguese Version [Wechsler Adult Intelligence Scale - WAIS-III]: Cegoc; 2008.
80. Cavaco S, Pinto C, Gonçalves A, Gomes F, Pereira A, Malaquias C. Auditory verbal learning test: dados normativos dos 21 aos 65 anos. Psychologica. 2008;49:208-221.
81. Rey A. Rey verbal learning test. L'examen clinique en psychologie. 2nd ed. Paris: Presses universitaires de France; 1964.
82. Raven J, Raven JC, Court JH. Manual for Raven's progressive matrices and vocabulary scales. Sections 1-7. 1993 ed. Oxford: Oxford Psychologists Press; 1993.
83. Berch DB, Krikorian R, Huha EM. The Corsi Block-Tapping Task: Methodological and Theoretical Considerations. Brain Cognition. 1998;38(3):317-338.
84. Kessels RP, van Zandvoort MJ, Postma A, Kappelle LJ, de Haan EH. The Corsi Block-Tapping Task: standardization and normative data. Applied Neuropsychology. 2000;7(4):252-258.
85. Benton AL. The revised visual retention test : clinical and experimental applications. 4th ed. New York: Psychological Corporation; 1974.
86. Benton AL, Hamsher Kd, Varney NR, Spreen O. Contributions to Neuropsychological Assessment: A Clinical Manual. 1st ed. New York: Oxford University Press; 1983.
87. Lezak MD. Neuropsychological Assessment. 3rd ed. New York: Oxford University Press; 1995.
88. Ardila A, Ostrosky‐Solís F, Bernal B. Cognitive testing toward the future: The example of Semantic Verbal Fluency (ANIMALS). International Journal of Psychology. 2006;41(5):324-332.
89. Snaith RP, Constantopoulos AA, Jardine MY, McGuffin P. A clinical scale for the self-assessment of irritability. The British Journal of Psychiatry. 1978;132(2):164-171.
90. Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatrica Scandinavica. 1983;67(6):361-370.
91. Stout JC, Glikmann-Johnston Y, Andrews SC. Cognitive assessment strategies in Huntington's disease research. J Neurosci Methods. 2016;265:19-24.
92. Papoutsi M, Labuschagne I, Tabrizi SJ, Stout JC. The cognitive burden in Huntington's disease: pathology, phenotype, and mechanisms of compensation. Movement Disorders. 2014;29(5):673-683.
93. Hart EP, Dumas EM, Schoonderbeek A, Wolthuis SC, van Zwet EW, Roos RA. Motor dysfunction influence on executive functioning in manifest and premanifest Huntington's disease. Movement Disorders. 2014;29(3):320-326.
94. Lasker AG, Zee DS. Ocular motor abnormalities in Huntington's disease. Vision Res. 1997;37(24):3639-3645.
95. Beglinger LJ, O'Rourke JJF, Wang C, et al. Earliest functional declines in Huntington disease. Psychiatry research. 2010;178(2):414-418.
96. El Massioui N, Lamirault C, Yague S, et al. Impaired Decision Making and Loss of Inhibitory-Control in a Rat Model of Huntington Disease. Front Behav Neurosci. 2016;10:204.
97. Riek HC, Brien DC, Coe BC, et al. Cognitive correlates of antisaccade behaviour across multiple neurodegenerative diseases. Brain Commun. 2023;5(2):fcad049.
98. Rupp J, Blekher T, Jackson J, et al. Progression in prediagnostic Huntington disease. Journal of Neurology Neurosurgery and Psychiatry. 2010;81(4):379-384.
99. PREDICTOM project - Mission and vision. November 6, 2023. Assessed May 8, 2024. https://www.helse-stavanger.no/en/predictom/