Abstract.
Objective
Objective information about the onset and progression of cognitive impairment in Huntington’s disease (HD) is very important in the light of appropriate outcome measures when conducting clinical trials. Therefore, we evaluated the progression of cognitive functions in HD patients and asymptomatic carriers of the HD mutation (AC) over a 2.5–year period.We also sought to detect the earliest markers of cognitive impairment in AC.
Methods
A prospective study comparing HD patients, clinically asymptomatic HD mutation–carriers (AC) and non–carriers (NC). These groups were examined three times during a period of 2.5 years. At baseline the study sample consisted of 49 subjects. Forty–two subjects (19 HD patients, 12 AC and 11 NC) completed three assessments. A battery of neuropsychological tests measuring intelligence, attention, memory, language, visuospatial perception, and executive functions was performed.
Results
The performance of HD patients deteriorated on the following cognitive tests: Symbol Digit Modalities Test (SDMT), Stroop Colour and Word, Boston Naming Test (BNT), Object and Space Perception and Trail Making Test–B. Longitudinal comparison of AC and NC revealed that performances on SDMT, Block Span, Digit Span Backwards, Hopkins Verbal Learning Test (learning and delayed recall) and Conditional Associative Learning Test are impaired in AC.
Conclusions
Tasks measuring mainly attention, object and space perception and executive functions adequately assess the progression of HD disease. Other cognitive functions do not significantly deteriorate. Furthermore, problems in attention, working memory, verbal learning, verbal long–term memory and learning of random associations are the earliest cognitive manifestations in AC.
Similar content being viewed by others
References
Bates G, Harper P, Jones L (2002) Huntington’s Disease. Third Edition.Oxford: Oxford University Press
Bachoud-Levi AC, Maison P, Bartolomeo P, Boisse MF, Dalla Barba G, Ergis A, et al. (2001) Retest effects and cognitive decline in longitudinal follow- up of patients with early HD. Neurology 56:1052–1058
Bamford KA, Caine ED, Kido DK, Cox C, Shoulson I (1995) A prospective evaluation of cognitive decline in early Huntington’s disease: functional and radiographic correlates. Neurology 45:1867–1873
Ho AK, Sahakian BJ, Robbins TW, Barker RA, Rosser AE, Hodges JR (2002) Verbal fluency in Huntington’s disease: a longitudinal analysis of phonemic and semantic clustering and switching. Neuropsychologia 40:1277–1284
Hodges JR, Salmon DP, Butters N (1990) Differential impairment of semantic and episodic memory in Alzheimer’s and Huntington’s diseases: a controlled prospective study. J Neurol Neurosurg Psychiatry 53:1089–1095
Kirkwood SC, Su JL, Conneally P, Foroud T (2001) Progression of symptoms in the early and middle stages of Huntington disease. Arch Neurol 58:273–278
Snowden J, Craufurd D, Griffiths H, Thompson J, Neary D (2001) Longitudinal evaluation of cognitive disorder in Huntington’s disease. J Int Neuropsychol Soc 7:33–44
Paulsen JS, Zhao H, Stout JC, Brinkman RR, Guttman M, Ross CA, Como P,Manning C, Hayden MR, Shoulson I (2001) Clinical markers of early disease in persons near onset of Huntington’s disease. Neurology 57:658–662
Rich JB, Troyer AK, Bylsma FW, Brandt J (1999) Longitudinal analysis of phonemic clustering and switching during word-list generation in Huntington’s disease. Neuropsychology 13:525–531
Campodonico JR, Codori AM, Brandt J (1996) Neuropsychological stability over two years in asymptomatic carriers of the Huntington’s disease mutation. J Neurol Neurosurg Psychiatry 61:621–624
Giordani B, Berent S, Boivin MJ, Penney JB, Lehtinen S, Markel DS, et al. (1995) Longitudinal neuropsychological and genetic linkage analysis of persons at risk for Huntington’s disease. Arch Neurol 52:59–64
Kirkwood SC, Siemers E, Stout JC, Hodes ME, Conneally PM, Christian JC, et al. (1999) Longitudinal cognitive and motor changes among presymptomatic Huntington disease gene carriers. Arch Neurol 56:563–568
Lemiere J, Decruyenaere M, Evers-Kiebooms G, Vandenbussche E, Dom R (2002) Longitudinal study evaluating neuropsychological changes in socalled asymptomatic carriers of the Huntington’s disease mutation after 1 year. Acta Neurol Scand 106:131–141
Witjes-Ane MN, Vegter-van der Vlis M, van Vugt JP, Lanser JB, Hermans J, Zwinderman AH, van Ommen GJ, Roos RA (2003) Cognitive and motor functioning in gene carriers for Huntington’s disease: a baseline study. J Neuropsychiatry Clin Neurosci 15:7–16
Baro F (1973) A neuropsychological approach to early detection of Huntington’s chorea. Adv Neurol 1:1329–1338
Blackmore L, Simpson SA, Crawford JR (1995) Cognitive performance in UK sample of presymptomatic people carrying the gene for Huntington’s disease. J Med Genet 32:358–362
Bradshaw JL, Phillips JG, Dennis C, Attingley JB, Andrews D, Chiu E, et al. (1992) Initiation and execution of movement sequences in those suffering from and at-risk of developing Huntington’s disease. J Clin Exp Neuropsychol 14:179–192
de Boo GM, Tibben A, Lanser JB, Jennekens-Schinkel A, Hermans J, Maat-Kievit A, et al. (1997) Early cognitive and motor symptoms in identified carriers of the gene for Huntington disease. Arch Neurol 54:1353–1357
de Boo GM, Tibben A, Lanser JB, Jennekens- Schinkel A, Hermans J, Vegtervan der Vlis M, et al. (1997) Intelligence indices in people with a high/low risk for developing Huntington’s disease. J Med Genet 34:564–568
de Boo GM, Tibben AA, Hermans JA, Jennekens-Schinkel A, Maat-Kievit A, Roos RA (1999) Memory and learning are not impaired in presymptomatic individuals with an increased risk of Huntington’s disease. J Clin Exp Neuropsychol 21:831–836
Diamond R, White RF, Myers RH, Mastromauro C, Koroshetz WJ, Butters N, et al. (1992) Evidence of presymptomatic cognitive decline in Huntington’s disease. J Clin Exp Neuropsychol 14:961–975
Foroud T, Siemers E, Kleindorfer D, Bill DJ, Hodes ME, Norton JA, et al. (1995) Cognitive scores in carriers of Huntington’s disease gene compared to noncarriers. Ann Neurol 37:657–664
Gomez-Tortosa E, del Barrio A, Barroso T, Garcia Ruiz PJ (1996) Visual processing disorders in patients with Huntington’s disease and asymptomatic carriers. J Neurol 243:286–292
Hahn-Barma V, Deweer B, Durr A, Dode C, Feingold J, Pillon B, et al. (1998) Are cognitive changes the first symptoms of Huntington’s disease? A study of gene carriers. J Neurol Neurosurg Psychiatry 64:172–177
Jason GW, Pajurkova EM, Suchowersky O, Hewitt J, Hilbert C, Reed J, et al. (1988) Presymptomatic neuropsychological impairment in Huntington’s disease. Arch Neurol 45:769–773
Jason GW, Suchowersky O, Pajurkova EM, Graham L, Klimek ML, Garber AT, et al. (1997) Cognitive manifestations of Huntington disease in relation to genetic structure and clinical onset. Arch Neurol 54:1081–1088 942
Josiassen RC, Curry LM, Mancall EL (1983) Development of neuropsychological deficits in Huntington’s disease. Arch Neurol 40:791–796
Kirkwood SC, Siemers E, Bond C, Conneally PM, Christian JC, Foroud T (2000) Confirmation of subtle motor changes among presymptomatic carriers of the Huntington disease gene. Arch Neurol 57:1040–1044
Lawrence AD, Hodges JR, Rosser AE, Kershaw A, French-Constant C, Rubinsztein DC, et al. (1998) Evidence for specific cognitive deficits in preclinical Huntington’s disease. Brain 121: 1329–1341
Lundervold AJ, Reinvang I (1995) Variability in cognitive function among persons at high genetic risk of Huntington’s disease. Acta Neurol Scand 91:462–469
Oepen G, Mohr U, Willmes K, Thoden U (1985) Huntington’s disease: visuomotor disturbance in patients and offspring. J Neurol Neurosurg Psychiatry 48:426–433
Rosenberg NK, Sorensen SA, Christensen AL (1995) Neuropsychological characteristics of Huntington’s disease carriers: a double blind study. J Med Genet 32:600–604
Rothlind JC, Brandt J, Zee D, Codori AM, Folstein S (1993) Unimpaired verbal memory and oculomotor control in asymptomatic adults with the genetic marker for Huntington’s disease. Arch Neurol 50:799–802
Snowden JS, Craufurd D, Thompson J, Neary D (2002) Psychomotor executive and memory function in preclinical Huntington’s disease. J Clin Exp Neuropsychol 24:133–145
Strauss ME, Brandt J (1986) Attempt at preclinical identification of Huntington’s disease using the WAIS. J Clin Exp Neuropsychol 8:210–208
Strauss ME, Brandt J (1990) Are there neuropsychologic manifestations of the gene for Huntington’s disease in asymptomatic at-risk individuals? Arch Neurol 47:905–908
Witjes-Ané MN (2003) The evolution of cognitive,motor and behavioural characteristics in ‘presymptomatic’ carriers for Huntington’s disease-A prospective study. Leiden: Universiteit Leiden
Georgiou-Karistianis N, Smith E, Bradshaw JL, Chua P, Lloyd J, Churchyard A, Chiu E (2003) Future directions in research with presymptomatic individuals carrying the gene for Huntington’s disease. Brain Res Bull 59:331–338
Huntington study group.Unified Huntington’s disease rating scale: reliability and consistency (1996) Huntington study group. Mov Disord 11:136–142
van der Ploeg HM, Defares PB Spielberger CD (1979) Handleiding bij de Zelf-BeoordelingsVragenlijst. Lisse: Swets en Zeitlinger
Bouman TK, Luteijn F, Albersnagel FA, van der Ploeg FA (1985) Enige ervaringen met de Beck Depression Inventory. Gedrag – Tijdschrift Voor Psychologie 13:13–24
Quinn N, Brown R, Craufurd D, Goldman S, Hodges J, Kieburtz K, et al. (1996) Core assessment program for intracerebral transplantation in Huntington’s disease (capit-hd). Mov Disord 11:143–150
Nelson HE (1982) National Adult Reading Test Manual. National Hospital London
Schmand B, Lindeboom J, van Harskamp F (1992) Nederlandse leestest voor volwassenen. Lisse: Swets en Zeitlinger
Stinissen J, Willems PJ, Coetsier P, Hulsman WL (1981) WAIS Dutch adaptation Wechsler Adult Intelligence Scale. Lisse, The Netherlands: Swets & Zeitlinger
Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental state: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198
Smith A (1982) Symbol Digit Modalities Test (SDMT) Manual (Revised). Los Angeles:Western Psychological Services
Stroop JR (1935) Studies of interference in serial verbal reaction. J Exp Psychology 18:643–662
Brandt J (1991) The Hopkins Verbal Learning Test: development of a new memory test with six equivalent forms. Clin Neuropsychol 5:125–141
Benedict RH, Schretlen D, Groninger L, Brandt J (1998) The Hopkins Verbal Learning Test – Revised: Normative data and analysis of inter-form and test-retest reliability. Clin Neuropsychol 12:43–55
Wilson BA, Cockburn J, Baddeley A (1985) The Rivermead Behavioral Memory Test. Reading, England//Gaylord, MI: Thames Valley Test Co; National Rehabilitation Services
Milner B (1971) Interhemispheric differences in the localization of psychological processes in man. Br Med Bull 27:272–277
Kaplan EF, Goodglass H, Weintraub S (1983) The Boston Naming Test. Philadelphia: Lea&Febiger
De Renzi E, Vignolo LA (1962) The Token test: a sensitive test to detect disturbances in aphasics. Brain 85:665–678
Warrington EK, James M (1991) Visual Object and Space Perception Battery. Bury, St. Edmunds, Suffolk, England//Gaylord, MI: Thames Valley Test Co; National Rehabilitation Services
Heaton RK, Chelune GJ, Talley JL,Kay Gary G, Curtiss G (1993) Wisconsin Card Sorting Test Manual: revised and expanded.Odessa: Psychological Assessment Resources, Inc
Nelson HE (1976) A modified card sorting test sensitive to frontal lobe defects. Cortex 12:313–324
Reitan RM (1958) Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills 8:271–276
Spreen O, Strauss E (1991) A compendium of neuropsychological tests. New York: Oxford University Press
Petrides M, Milner B (1982) Deficits on subject-ordered tasks after frontaland temporal-lobe lesions in man. Neuropsychologia 20:249–262
Taylor AE, Saint-Cyr JA, Lang AE (1990) Memory and learning in early Parkinson’s disease: evidence for a “frontal lobe syndrome”. Brain Cogn 13:211–232
Siesling S, van Vugt JP, Zwinderman KA, Kieburtz K, Roos RA (1998) Unified Huntington’s disease rating scale: a follow up. Mov Disord 13:915–919
Starkstein SE, Brandt J, Folstein S, Strauss M, Berthier ML, Pearlson GD, et al. (1988) Neuropsychological and neuroradiological correlates in Huntington’s disease. J Neurol Neurosurg Psychiatry 51:1259–1263
Bermel RA, Bakshi R, Tjoa C, Srinivas RP, Jacobs L (2002) Bicaudate ratio as a magnetic resonance imaging marker of brain atrophy in multiple sclerosis. Arch Neurol 59:275–280
Cummings JL (1995) Anatomic and behavioral aspects of frontal-subcortical circuits. Ann N Y Acad Sci 769:1–13
Podoll K, Caspary P, Lange HW, Noth J (1988) Language functions in Huntington’s disease. Brain 111:1475–1503
Hodges JR, Salmon DP, Butters N (1991) The nature of the naming deficit in Alzheimer’s and Huntington’s disease. Brain 114:1547–1558
Butters N, Sax DS, Montgomery K, Tarlow S (1978) Comparison of the neuropsychological deficits associated with early and advanced Huntington’s disease. Arch Neurol 35:585–589
Caine ED, Hunt RD, Weingarnter H, Ebert MH (1978) Huntington’s dementia. Clinical and neuropsychological features. Arch Gen Psychiatry 35:378–384
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lemiere, J., Decruyenaere, M., Evers-Kiebooms, G. et al. Cognitive changes in patients with Huntington’s disease (HD) and asymptomatic carriers of the HD mutation. J Neurol 251, 935– 942 (2004). https://doi.org/10.1007/s00415-004-0461-9
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s00415-004-0461-9