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Funktionelle Bildgebung kognitiver Prozesse bei M.-Huntington-Patienten und präsymptomatischen Mutationsträgern

Functional imaging of cognitive processes in Huntington’s disease and its presymptomatic mutation carriers

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Zusammenfassung

Kognitive Defizite gehören zu den Kernsymptomen der Huntington-Krankheit (Morbus Huntington, MH). Sie lassen sich in einem frühen Stadium der Erkrankung nachweisen und sind bereits bei präsymptomatischen Mutationsträgern häufig vorhanden. In dieser Übersicht sollen Untersuchungen kognitiver Funktionen von MH-Patienten und von präsymptomatischen Mutationsträgern mittels funktionell bildgebender Verfahren dargestellt und diskutiert werden. Nuklearmedizinische und funktionell magnetresonanztomographische Untersuchungen belegen bei MH-Patienten eine Störung multipler kortikaler und subkortikaler Regionen und ergänzen damit die mittels konventioneller radiologischer Methoden nachweisbaren strukturellen Veränderungen. Bei präsymptomatischen Mutationsträgern kann frühzeitig ein funktionelles Defizit lateral präfrontaler und zingulärer Regionen aufgezeigt werden; eine Überaktivierung posteriorer Areale reflektiert möglicherweise einen kompensatorischen neuronalen Mechanismus vor dem Auftreten manifester kognitiver Defizite. Die Untersuchung präsymptomatischer Mutationsträger mithilfe funktionell bildgebender Verfahren könnte über die Identifizierung funktioneller Biomarker hinaus zur Bestimmung geeigneter klinischer Endpunkte beitragen. Die Bedeutung funktionell bildgebender Verfahren als Instrument zur Verlaufsuntersuchung kognitiver Defizite bei MH-Patienten muss indessen noch anhand entsprechender Studien an geeigneten Kollektiven evaluiert werden.

Summary

Cognitive deficits are among the core symptoms of patients with Huntington’s disease (HD). While impaired attention, visuospatial processing, and memory can be observed during early stages of the illness, HD patients exhibit deficits in executive function on tests requiring planning, problem solving, and cognitive flexibility with progression of the disease. Cognitive dysfunction is already present in individuals who carry the HD gene mutation but remain presymptomatic for motor and cognitive disturbances. This review provides an overview and a discussion of functional neuroimaging findings on cognitive dysfunction in patients with HD and presymptomatic HD gene mutation carriers. In HD patients, currently available evidence suggests a functional deficit of multiple cortical and subcortical regions extending beyond volumetric abnormalities. Early dysfunction of lateral prefrontal and cingulate regions has been shown in individuals with presymptomatic HD, while compensatory responses of posterior brain regions may occur closer to the onset of manifest clinical symptoms. While functional neuroimaging techniques may substantially contribute to defining neurodegenerative disease phenotypes and to identifying neural biomarkers in presymptomatic individuals, the extant data on cognitive function in HD patients and HD gene carriers however is sparse and has to be expanded through further studies.

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Literatur

  1. Paulsen JS, Salmon DP, Monsch AU et al. (1995) Discrimination of cortical from subcortical dementias on the basis of memory and problem-solving tests. J Clin Psychol 51: 48–58

    Article  PubMed  CAS  Google Scholar 

  2. Brandt J, Folstein SE, Folstein MF (1988) Differential cognitive impairment in Alzheimer’s disease and Huntington’s disease. Ann Neurol 23: 555–561

    Article  PubMed  CAS  Google Scholar 

  3. Salmon DP, Filoteo JV (2007) Neuropsychology of cortical versus subcortical dementia syndromes. Seminars in Neurology 27: 7–21

    Article  PubMed  Google Scholar 

  4. Feigin AS, Leenders KL, Moeller JR et al. (2001) Metabolic network abnormalities in early Huntington’s disease: An [18F] FDG PET study. J Nucl Med 42: 1591–1595

    PubMed  CAS  Google Scholar 

  5. Henry JD, Crawford JR, Phillips LH (2005) A meta-analytic review of verbal fluency deficits in Huntington’s disease. Neuropsychology 19: 243–252

    Article  PubMed  Google Scholar 

  6. Montoya A, Price BH, Menear M, Lepage M (2006) Brain imaging and cognitive dysfunctions in Huntington’s disease. J Psychiatry Neurosci 31: 21–29

    PubMed  Google Scholar 

  7. Zakzanis KK (1998) The subcortical dementia of Huntington’s disease. J Clin Exp Neuropsychol 20: 567–578

    Google Scholar 

  8. Lawrence AD, Sahakian BJ, Hodges JR et al. (1996) Executive and mnemonic functions in early Huntington’s disease. Brain 119 (Pt 5): 1633–1645

    Article  PubMed  Google Scholar 

  9. Butters N, Sax D, Montgomery K, Tarlow S (1978) Comparison of the neuropsychological deficits associated with early and advanced Huntington’s disease. Arch Neurol 35: 585–589

    PubMed  CAS  Google Scholar 

  10. Brandt J, Butters N (1986) The neuropsychology of Huntington’s disease. Trends Neurosci 9: 118–220

    Article  Google Scholar 

  11. Snowden J, Craufurd D, Griffiths H et al. (2001) Longitudinal evaluation of cognitive disorder in Huntington’s disease. J Int Neuropsychol Soc 7: 33–44

    Article  PubMed  CAS  Google Scholar 

  12. Ward J, Sheppard JM, Shpritz B et al. (2006) A four-year prospective study of cognitive functioning in Huntington’s disease. J Int Neuropsychol Soc 12: 445–454

    PubMed  Google Scholar 

  13. Lemiere J, Decruyenaere M, Evers-Kiebooms G et al. (2004) Cognitive changes in patients with Huntington’s disease (HD) and asymptomatic carriers of the HD mutation--a longitudinal follow-up study. J Neurol 251: 935–942

    Article  PubMed  CAS  Google Scholar 

  14. Witjes-Ane MN, Vegter-van der Vlis M, Vugt JP van et al. (2003) Cognitive and motor functioning in gene carriers for Huntington’s disease: a baseline study. J Neuropsychiatry Clin Neurosci 15: 7–16

    PubMed  Google Scholar 

  15. 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

    Article  PubMed  CAS  Google Scholar 

  16. Cope MT, Georgiou N, Bradshaw JL et al. (1996) Simon effect and attention in Parkisnon’s disease: a comparison with Huntington’s disease and Tourette’s syndrome. J Clin Exp Neuropsychol 18: 276–290

    Article  PubMed  CAS  Google Scholar 

  17. Georgiou N, Bradshaw JL, Phillips JG et al. (1995) The Simon effect and attention deficits in Gilles de la Tourette’s syndrome and Huntington’s disease. Brain 118 (Pt 5): 1305–1318

    Article  PubMed  Google Scholar 

  18. Montoya A, Pelletier M, Menear M et al. (2006) Episodic memory impairment in Huntington’s disease: a meta-analysis. Neuropsychologia 44: 1984–1994

    Article  PubMed  Google Scholar 

  19. Nehl C, Ready RE, Hamilton J, Paulsen JS (2001) Effects of depression on working memory in presymptomatic Huntington’s disease. J Neuropsychiatry Clin Neurosci 13: 342–346

    PubMed  CAS  Google Scholar 

  20. Royall DR, Lauterbach EC, Cummings JL et al. (2002) Executive control function: a review of its promise and challenges for clinical research. A report from the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci 14: 377–405

    PubMed  Google Scholar 

  21. Miller EK (2000) The prefrontal cortex and cognitive control. Nat Rev Neurosci 1: 59–65

    Article  PubMed  CAS  Google Scholar 

  22. Milner B (1963) Effects of different brain lesions on card sorting. Arch Neurol 9: 90

    Google Scholar 

  23. Stroop JR (1935) Studies of interference in serial verbal reactions. J Exp Psychol Learn Mem Cogn 18: 643–662

    Google Scholar 

  24. Carpenter PA, Just MA, Reichle ED (2000) Working memory and executive function: evidence from neuroimaging. Curr Opin Neurobiol 10: 195–199

    Article  PubMed  CAS  Google Scholar 

  25. Lange KW, Sahakian BJ, Quinn NP et al. (1995) Comparison of executive and visuospatial memory function in Huntington’s disease and dementia of Alzheimer type matched for degree of dementia. J Neurol Neurosurg Psychiatry 58: 598–606

    PubMed  CAS  Google Scholar 

  26. Watkins LH, Rogers RD, Lawrence AD et al. (2000) Impaired planning but intact decision making in early Huntington’s disease: implications for specific fronto-striatal pathology. Neuropsychologia 38: 1112–1125

    Article  PubMed  CAS  Google Scholar 

  27. Josiassen RC, Curry LM, Mancall EL (1983) Development of neuropsychological deficits in Huntington’s disease. Arch Neurol 40: 791–796

    PubMed  CAS  Google Scholar 

  28. Weinberger DR, Berman KF, Iadarola M et al. (1988) Prefrontal cortical blood flow and cognitive function in Huntington’s disease. J Neurol Neurosurg Psychiatry 51: 94–104

    PubMed  CAS  Google Scholar 

  29. Monsch AU, Bondi MW, Butters N et al. (1994) A comparison of category and letter fluency in Alzheimer’s dieases and Huntington’s disease. Neuropsychology 8: 2530

    Article  Google Scholar 

  30. Ho AK, Sahakian BJ, Brown RG et al. (2003) Profile of cognitive progression in early Huntington’s disease. Neurology 61: 1702–1706

    PubMed  CAS  Google Scholar 

  31. Solomon AC, Stout JC, Johnson SA et al. (2007) Verbal episodic memory declines prior to diagnosis in Huntington’s disease. Neuropsychologia 45: 1767–1776

    Article  PubMed  Google Scholar 

  32. Hahn-Barma V, Deweer B, Durr A 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

    PubMed  CAS  Google Scholar 

  33. Lawrence AD, Hodges JR, Rosser AE et al. (1998) Evidence for specific cognitive deficits in preclinical Huntington’s disease. Brain 121 (Pt 7): 1329–1341

    Article  PubMed  Google Scholar 

  34. Brandt J, Shpritz B, Codori AM et al. (2002) Neuropsychological manifestations of the genetic mutation for Huntington’s disease in presymptomatic individuals. J Int Neuropsychol Soc 8: 918–924

    Article  PubMed  CAS  Google Scholar 

  35. Walter H, Riepe M, Grön G (1999) Funktionelle Bildgebung als klinisches Instrument in der Psychiatrie. Nervenheilkunde 18: 322–331

    Google Scholar 

  36. Rosas HD, Feigin AS, Hersch SM (2004) Using advances in neuroimaging to detect, understand, and monitor disease progression in Huntington’s disease. NeuroRx 1: 263–272

    Article  PubMed  CAS  Google Scholar 

  37. Walter H (2004) Funktionelle Bildgebung in Psychiatrie und Psychotherapie. Methodische Grundlagen und klinische Anwendungen. Schattauer, Stuttgart

  38. Aylward EH (2007) Change in MRI striatal volumes as a biomarker in preclinical Huntington’s disease. Brain Res Bull 72: 152–158

    Article  PubMed  CAS  Google Scholar 

  39. Kuwert T, Lange HW, Boecker H et al. (1993) Striatal glucose consumption in chorea-free subjects at risk of Huntington’s disease. J Neurol 241: 31–36

    Article  PubMed  CAS  Google Scholar 

  40. Lawrence AD, Weeks RA, Brooks DJ et al. (1998) The relationship between striatal dopamine receptor binding and cognitive performance in Huntington’s disease. Brain 121: 1343–1355

    Article  PubMed  Google Scholar 

  41. Weeks RA, Piccini P, Harding AE, Brooks DJ (1996) Striatal D1 and D2 dopamine receptor loss in asymptomatic mutation carriers of Huntington’s disease. Ann Neurol 40: 49–54

    Article  PubMed  CAS  Google Scholar 

  42. Turjanski N, Weeks R, Dolan R et al. (1995) Striatal D1 and D2 receptor binding in patients with Huntington’s disease and other choreas. A PET study. Brain 118 (Pt 3): 689–696

    Article  PubMed  Google Scholar 

  43. Goldberg TE, Berman KF, Mohr E, Weinberger DR (1990) Regional cerebral blood flow and cognitive function in Huntington’s disease and schizophrenia. A comparison of patients matched for performance on a prefrontal-type task. Arch Neurol 47: 418–422

    PubMed  CAS  Google Scholar 

  44. Deckel AW, Weiner R, Szigeti D et al. (2000) Altered patterns of regional cerebral blood flow in patients with Huntington’s disease: a SPECT study during rest and cognitive or motor activation. J Nucl Med 41: 773–780

    PubMed  CAS  Google Scholar 

  45. Feigin AS, Ghilardi MF, Huang C et al. (2006) Preclinical Huntington’s disease: compensatory brain responses during learning. Ann Neurol 59: 53–59

    Article  PubMed  Google Scholar 

  46. Beglinger LJ, Nopoulos PC, Jorge RE et al. (2005) White matter volume and cognitive dysfunction in early Huntington’s disease. Cogn Behav Neurol 18: 102–107

    Article  PubMed  Google Scholar 

  47. Kassubek J, Juengling FD, Ecker D, Landwehrmeyer GB (2005) Thalamic atrophy in Huntington’s disease co-varies with cognitive performance: a morphometric MRI analysis. Cereb Cortex 15: 846–853

    Article  PubMed  Google Scholar 

  48. Kirsch P, Lis S, Esslinger C et al. (2006) Brain activation during mental maze solving. Neuropsychobiology 54: Epub Sep 11

    Article  Google Scholar 

  49. Clark VP, Lai S, Deckel AW (2002) Altered functional MRI responses in Huntington’s disease. Neuroreport 13: 703–706

    Article  PubMed  Google Scholar 

  50. Voermans NC, Petersson KM, Daudey L et al. (2004) Interaction between the human hippocampus and the caudate nucleus during route recognition. Neuron 43: 427–435

    Article  PubMed  CAS  Google Scholar 

  51. Kim JS, Reading SA, Brashers-Krug T et al. (2004) Functional MRI study of a serial reaction time task in Huntington’s disease. Psychiatry Res 131: 23–30

    Article  PubMed  Google Scholar 

  52. Georgiou-Karistianis N, Sritharan A, Farrow M et al. (2007) Increased cortical recruitment in Huntington’s disease using a Simon task. Neuropsychologia 45: 1791–1800

    Article  PubMed  Google Scholar 

  53. Thiruvady DR, Georgiou-Karistianis N, Egan GF et al. (2007) Functional connectivity of the prefrontal cortex in Huntington’s disease. J Neurol Neurosurg Psychiatry 78: 127–133

    Article  PubMed  CAS  Google Scholar 

  54. Reading SA, Dziorny AC, Peroutka LA et al. (2004) Functional brain changes in presymptomatic Huntington’s disease. Ann Neurol 55: 879–883

    Article  PubMed  Google Scholar 

  55. Paulsen JS, Zimbelman JL, Hinton SC et al. (2004) fMRI biomarker of early neuronal dysfunction in presymptomatic Huntington’s Disease. AJNR 25: 1715–1721

    PubMed  Google Scholar 

  56. Zimbelman JL, Paulsen JS, Mikos AE et al. (2007) fMRI detection of early neural dysfunction in preclinical Huntington’s disease. J Int Neuropsychol Society 13: 758–769

    Google Scholar 

  57. Monchi O, Petrides M, Petre V et al. (2001) Wisconsin Card Sorting revisited: distinct neural circuits participating in different stages of the task identified by event-related functional magnetic resonance imaging. J Neurosci 21: 7733–7741

    PubMed  CAS  Google Scholar 

  58. Walter H, Wolf RC (2002) Von der Hypofrontalität zur dynamischen Dysfunktion. FMRT Studien bei Patienten mit Schizophrenie. Nervenheilkunde 21: 392–399

    Google Scholar 

  59. Wolf RC, Vasic N, Walter H (2006) Differential activation of ventrolateral prefrontal cortex during working memory retrieval. Neuropsychologia 44: 2558–2563

    Article  PubMed  Google Scholar 

  60. Baddeley A (1996) The fractionation of working memory. Proc Natl Acad Sci USA 93: 13468–13472

    Article  PubMed  CAS  Google Scholar 

  61. Baddeley A (2003) Working memory: looking back and looking forward. Nat Rev Neurosci 4: 829–839

    Article  PubMed  CAS  Google Scholar 

  62. Goldman-Rakic PS (1996) The prefrontal landscape: implications of functional architecture for understanding human mentation and the central executive. Philos Trans R Soc Lond B Biol Sci 351: 1445–1453

    Article  PubMed  CAS  Google Scholar 

  63. Wolf RC, Vasic N, Höse A et al. (2007) Changes over time in frontotemporal function in patients with schizophrenia during working memory performance. Schizophr Res 91: 141–150

    Article  PubMed  Google Scholar 

  64. Rypma B, Prabhakaran V, Desmond JE et al. (1999) Load-dependent roles of frontal brain regions in the maintenance of working memory. Neuroimage 9: 216–226

    Article  PubMed  CAS  Google Scholar 

  65. Lawrence AD, Watkins LH, Sahakian BJ et al. (2000) Visual object and visuospatial cognition in Huntington’s disease: implications for information processing in corticostriatal circuits. Brain 123 (Pt 7): 1349–1364

    Article  PubMed  Google Scholar 

  66. Wolf RC, Vasic N, Schönfeldt-Lecuona C et al. (2007) Cortical dysfunction in patients with Huntington’s disease during working memory performance. Hum Brain Mapping (in press)

  67. Wolf RC, Vasic N, Schönfeldt-Lecuona CL et al. (2007) Dorsolateral prefrontal cortex dysfunction in presymptomatic Huntington’s disease: evidence from event-related fMRI. Brain 130: 2845–2857

    Article  PubMed  Google Scholar 

  68. Wolf RC, Walter H (2005) Evaluation of a novel event-related parametric fMRI paradigm investigating prefrontal function. Psychiatry Res Neuroimaging 140: 73–83

    Article  Google Scholar 

  69. Langbehn DR, Brinkman RR, Falush D et al. (2004) A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAg lenghth. Clin Genet 65: 267–277

    Article  PubMed  CAS  Google Scholar 

  70. Ashburner J, Friston KJ (2000) Voxel-based morphometry – the methods. Neuroimage 11: 805–821

    Article  PubMed  CAS  Google Scholar 

  71. Ogawa S, Lee TM, Kay AR, Tank DW (1990) Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci USA 87: 9868–9872

    Article  PubMed  CAS  Google Scholar 

  72. Ciarmiello A, Cannella M, Lastoria S et al. (2006) Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington’s disease. J Nucl Med 47: 215–222

    PubMed  CAS  Google Scholar 

  73. Rosas HD, Tuch DS, Hevelone ND et al. (2006) Diffusion tensor imaging in presymptomatic and early Huntington’s disease: Selective white matter pathology and its relationship to clinical measures. Mov Disord 21: 1317–1325

    Article  PubMed  Google Scholar 

  74. Rosas HD, Hevelone ND, Zaleta AK et al. (2005) Regional cortical thinning in preclinical Huntington disease and its relationship to cognition. Neurology 65: 745–747

    Article  PubMed  CAS  Google Scholar 

  75. Paulsen JS, Magnotta VA, Mikos AE et al. (2006) Brain structure in preclinical Huntington’s disease. Biol Psychiatry 59: 57–63

    Article  PubMed  CAS  Google Scholar 

  76. DiProspero NA, Chen EY, Charles V et al. (2004) Early changes in Huntington’s disease patient brains involve alterations in cytoskeletal and synaptic elements. J Neurocytol 33: 517–533

    Article  PubMed  Google Scholar 

  77. Arnsten AF, Li B (2005) Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry 57: 1377–1384

    Article  PubMed  CAS  Google Scholar 

  78. Manoach DS (2003) Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings. Schizophr Res 60: 285–298

    Article  PubMed  Google Scholar 

  79. Callicott JH, Mattay VS, Verchinski BA et al. (2003) Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. Am J Psychiatry 160: 2209–2215

    Article  PubMed  Google Scholar 

  80. Walter H, Vasic N, Höse A et al. (2007) Working memory dysfunction in schizophrenia compared to healthy controls and patients with depression: evidence from event-related fMRI. NeuroImage 35: 1551–1561

    Article  PubMed  Google Scholar 

  81. Hale ST, Bookheimer SY, McGough JJ et al. (2007) Atypical brain activation during simple and complex levels of processing in adult ADHD. Journal of Attention Disorders published online on May 9: doi:10.1177/1087054706294101

  82. Wolf RC, Vasic N, Walter H (2006) The concept of working memory in schizophrenia: current evidence and future perspectives. Fortschr Neurol Psychiatr 74: 449–468

    Article  PubMed  CAS  Google Scholar 

  83. Callicott JH, Egan MF, Mattay VS et al. (2003) Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia. Am J Psychiatry 160: 709–719

    Article  PubMed  Google Scholar 

  84. Kipps CM, Duggins AJ, Mahant N et al. (2007) Progresion of structural neuropathology in preclinical Huntington’s disease: a tensor based morphometry study. J Neurol Neurosurg Psychiatry 76: 650–655

    Article  Google Scholar 

  85. Deckel AW, Cohen D, Duckrow R (1998) Cerebral blood flow velocity decreases during cognitive stimulation in Huntington’s disease. Neurology 51: 1576–1583

    PubMed  CAS  Google Scholar 

  86. Sternberg S (1966) High-speed scanning in human memory. Science 153: 652–654

    Article  PubMed  CAS  Google Scholar 

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  1. Abteilung Psychiatrie III, Universitätsklinik, Leimgrubenweg 12–14, 89075, Ulm, Deutschland

    R.C. Wolf, N. Vasic & C. Schönfeldt-Lecuona

  2. Neurologische Klinik, Universität Ulm, Ulm, Deutschland

    D. Ecker & G.B. Landwehrmeyer

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  1. R.C. Wolf
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  2. N. Vasic
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  3. C. Schönfeldt-Lecuona
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Wolf, R., Vasic, N., Schönfeldt-Lecuona, C. et al. Funktionelle Bildgebung kognitiver Prozesse bei M.-Huntington-Patienten und präsymptomatischen Mutationsträgern. Nervenarzt 79, 408–420 (2008). https://doi.org/10.1007/s00115-007-2390-1

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