Selective Neurodegeneration, Neuropathology and Symptom Profiles in Huntington’s Disease

  • Henry J. WaldvogelEmail author
  • Doris Thu
  • Virginia Hogg
  • Lynette Tippett
  • Richard L. M. Faull
Part of the Advances in Experimental Medicine and Biology book series (AEMB)


Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disease caused by a CAG repeat expansion in exon 1 of the Huntington gene (HD) also known as IT15. Despite thedisease being caused by dysfunctionofasingle gene, expressed as an expanded polyglutamine in the huntingtin protein, there is a major variability in the symptom profile of patients with Huntington’s disease as well as great variability in the neuropathology. The symptoms vary throughout the course of the disease and vary greatly between cases. These symptoms present as varying degrees of involuntary movements, mood, personality changes, cognitive changes and dementia. To determine whether there is a morphological basis for this symptom variability, recent studies have investigated the cellular andneurochemical changes in the striatum and cerebral cortex in the human brain to determine whether there is a link between the pathology in these regions and the symptomatology shown by individual cases. These studies together revealed that cases showing mainly mood symptom profiles correlatedwithmarked degeneration in the striosomal compartment of the striatum, or in the anterior cingulate gyrus of the cerebral cortex. In contrast, in cases with mainly motor symptoms neurodegeneration was especially marked in the primary motor cortex with variable degeneration in both the striosomes and matrix compartments of the striatum. These studies suggest that the variable degeneration of the striatum and cerebral cortex correlates with the variable profiles of Huntington’s disease.


Primary Motor Cortex Medium Spiny Neuron Tandem Repeat Polymorphism Matrix Compartment Receptor Immunostaining 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Illarioshkin SN, Igarashi S, Onodera O et al. Trinucleotide repeat length and rate of progression of Huntington’s disease. Ann Neurol 1994; 36(4):630–635.PubMedCrossRefGoogle Scholar
  2. 2.
    Sharp AH, Ross CA. Neurobiology of Huntington’s disease. Neurobiol Dis 1996; 3(1):3–15.PubMedCrossRefGoogle Scholar
  3. 3.
    Andrew SE, Goldberg YP, Kremer B et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat Genet 1993; 4(4):398–403.PubMedCrossRefGoogle Scholar
  4. 4.
    Claes S, Van Zand K, Legius E et al. Correlations between triplet repeat expansion and clinical features in Huntington’s disease. Arch Neurol 1995; 52(8):749–753.PubMedCrossRefGoogle Scholar
  5. 5.
    Brandt J, Butters N. The neuropsychology of Huntington’s disease. TINS 1986:118–120.CrossRefGoogle Scholar
  6. 6.
    Folstein SE. Huntington’s Disease: A Disorder of Families.Baltimore: John’s Hopkins University Press; 1989.Google Scholar
  7. 7.
    Myers RH, Sax DS, Koroshetz WJ et al. Factors associated with slow progression in Huntington’s disease. Arch Neurol 1991; 48(8):800–804.PubMedCrossRefGoogle Scholar
  8. 8.
    Thompson JC, Snowden JS, Craufurd D et al. Behavior in Huntington’ s disease: dissociating cognition-based and mood-based changes. J Neuropsychiatry Clin Neurosci 2002; 14(1):37–43.PubMedCrossRefGoogle Scholar
  9. 9.
    Zappacosta B, Monza D, Meoni C et al. Psychiatric symptoms do not correlate with cognitive decline, motor symptoms, or CAG repeat length in Huntington’s disease. Arch Neurol 1996; 53(6):493–497.PubMedCrossRefGoogle Scholar
  10. 10.
    Georgiou N, Bradshaw JL, Chiu E et al. Differential clinical and motor control function in a pair of monozygotic twins with Huntington’s disease. Mov Disord 1999; 14(2):320–325.PubMedCrossRefGoogle Scholar
  11. 11.
    Wexler NS, Lorimer J, Porter J et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. PNAS 2004; 101(10):3498–3503.PubMedCrossRefGoogle Scholar
  12. 12.
    MacMillan JC, Snell RG, Tyler A et al. Molecular analysis and clinical correlations of the Huntington’s disease mutation. Lancet 1993; 342(8877):954–958.PubMedCrossRefGoogle Scholar
  13. 13.
    Telenius H, Kremer B, Goldberg YP et al. Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm. Nat Genet 1994; 6(4):409–414.PubMedCrossRefGoogle Scholar
  14. 14.
    Witjes-Ane MN, Zwinderman AH, Tibben A et al. Behavioural complaints in participants who underwent predictive testing for Huntington’s disease. J Med Genet 2002; 39(11):857–862.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Di Maio L, Squitieri F, Napolitano G et al. Onset symptoms in 510 patients with Huntington’s disease. J Med Genet 1993; 30(4):289–292.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Vonsattel JP, Myers RH, Stevens TJ et al. Neuropathological classification of Huntington’s disease. J Neuropath Exp Neurol 1985; 44:559–577.PubMedCrossRefGoogle Scholar
  17. 17.
    Vonsattel JPG, Difiglia M. Huntington-disease. J Neuropath and Exp Neurol 1998; 57(5):369–384.CrossRefGoogle Scholar
  18. 18.
    Albin RL, Makowiec RL, Hollingsworth ZR et al. Excitatory amino acid binding sites in the basal ganglia of the rat: a quantitative autoradiographic study. Neuroscience 1992; 46:35–48.PubMedCrossRefGoogle Scholar
  19. 19.
    Deng YP, Albin RL, Penney JB et al. Differential loss of striatal projection systems in Huntington’s disease: a quantitative immunohistochemical study. J Chem Neuroanat 2004; 27(3):143–164.PubMedCrossRefGoogle Scholar
  20. 20.
    Faull RL, Waldvogel HJ, Nicholson LF et al. The distribution of GABAA-benzodiazepine receptors in the basal ganglia in Huntington’s disease and in the quinolinic acid-lesioned rat. Prog Brain Res 1993; 99:105–123.PubMedCrossRefGoogle Scholar
  21. 21.
    Glass M, Dragunow M, Faull RLM. The pattern of neurodegeneration in Huntington’s disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington’s disease. Neuroscience 2000; 97(3):505–519.PubMedCrossRefGoogle Scholar
  22. 22.
    Glass M, Failli RL, Dragunow M. Loss of cannabinoid receptors in the substantia nigra in Huntington’s disease. Neuroscience 1993; 56(3):523–527.PubMedCrossRefGoogle Scholar
  23. 23.
    Reiner A, Albin RL, Anderson KD et al. Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci USA 1988; 85(15):5733–5737.PubMedCrossRefGoogle Scholar
  24. 24.
    Ferrante RJ, Kowall NW, Beal MF et al. Morphologic and histochemical characteristics of a spared subset of striatal neurons in Huntington’s disease. J Neuropathol Exp Neurol 1987; 46(1):12–27.PubMedCrossRefGoogle Scholar
  25. 25.
    Vonsattel JP, Ge P, Kelly L. Huntington’s disease. In: Esiri M, Morris JH, editors. The Neuropathology of Dementia. Cambridge: Cambridge University Press UK; 1997:219–240.Google Scholar
  26. 26.
    Allen KL, Waldvogel HJ, Glass M et al. Cannabinoid (CB(1)), GABA(A) and GABA(B) receptor subunit changes in the globus pallidus in Huntington’s disease. J Chem Neuroanat 2009; 37(4):266–281.PubMedCrossRefGoogle Scholar
  27. 27.
    Graybiel AM, Ragsdale CW Jr. Histochemically distinct compartments in the striatum of human, monkeys and cat demonstrated by acetylthiocho linesterase staining. Proc Nat Acad Sci USA 1978; 75(11):5723–5726.PubMedCrossRefGoogle Scholar
  28. 28.
    Holt DJ, Graybiel AM, Saper CB. Neurochemical architecture of the human striatum. J Comp Neurol 1997; 384:1–25.PubMedCrossRefGoogle Scholar
  29. 29.
    Waldvogel HJ, Faull RLM. Compartmentalization of parvalbumin immunoreactivity in the human striatum. Brain Res 1993; 610:311–316.PubMedCrossRefGoogle Scholar
  30. 30.
    Eblen F, Graybiel AM. Highly restricted origin of prefrontal cortical inputs to striosomes in the macaque monkey. J Neurosci 1995; 15(9):5999–6013.PubMedCrossRefGoogle Scholar
  31. 31.
    Gerfen CR. The neostriatal mosaic: multiple levels of compartmental organization. TINS 1992; 15:133–138.PubMedGoogle Scholar
  32. 32.
    Saka E, Goodrich C, Harlan P et al. Repetitive behaviors in monkeys are linked to specific striatal activation patterns. J Neurosci 2004; 24(34):7557–7565.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    White NM, Hiroi N. Preferential localization of self-stimulation sites in striosomes/patches in the rat striatum. Proc Natl Acad Sci USA 1998; 95(11):6486–6491.PubMedCrossRefGoogle Scholar
  34. 34.
    Hedreen JC, Folstein SE. Early loss of neostriatal striosome neurons in Huntington’s disease. JNeuropathol Exp Neurol 1995; 54(1): 105–120.CrossRefGoogle Scholar
  35. 35.
    Morton AJ, Nicholson LF, Faull RL. Compartmental loss of NADPH diaphorase in the neuropil of the human striatum in Huntington’s disease. Neuroscience 1993; 53(1): 159–168.PubMedCrossRefGoogle Scholar
  36. 36.
    Seto-Ohshima A, Emson PC, Lawson E et al. Loss of matrix calcium-binding protein-containing neurons in Huntington’s disease. Lancet 1988; 1234:1252–1254.CrossRefGoogle Scholar
  37. 37.
    Olsen JM, Penney JB, Shoulson I et al. Inhomogeneities of striatal receptor binding in Huntington’s disease. Neurology 1986; 36:342.Google Scholar
  38. 38.
    Augood SJ, Faull RL, Love DR et al. Reduction in enkephalin and substance P messenger RNA in the striatum of early grade Huntington’s disease: a det alled cellular in situ hybridization study. Neuroscience 1996; 72(4): 1023–1036.PubMedCrossRefGoogle Scholar
  39. 39.
    Tippett LJ, Waldvogel HJ, Thomas SJ et al. Striosomes and mood dysfunction in Huntington’s disease. Brain 2007; 130(Pt 1):206–221.PubMedCrossRefGoogle Scholar
  40. 40.
    Alexopoulos GS, Gunning-Dixon FM, Latoussakis V et al. Anterior cingulate dysfunction in geriatric depression. Int J Geriatr Psychiatry 2008; 23(4):347–355.PubMedCrossRefGoogle Scholar
  41. 41.
    Davidson RJ, Pizzagalli D, Nitschke JB et al. Depression: perspectives from affective neuroscience. Annu Rev Psychol 2002; 53:545–574.PubMedCrossRefGoogle Scholar
  42. 42.
    Ebert D, Ebmeier KP. The role of the cingulate gyrus in depression: from functional anatomy to neurochemistry. Biol Psychiatry 1996; 39(12):1044–1050.PubMedCrossRefGoogle Scholar
  43. 43.
    Harrison PJ. The neuropathology of primary mood disorder. Brain 2002; 125(Pt 7):1428–1449.PubMedCrossRefGoogle Scholar
  44. 44.
    Konarski JZ, McIntyre RS, Kennedy SH et al. Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder. Bipolar Disord 2008; 10(1): 1–37.PubMedCrossRefGoogle Scholar
  45. 45.
    Thu DC, Oorschot DE, Tippett LJ et al. Cell loss in the motor and cingulate cortex correlates with symptomatology in Huntington’s disease. Brain 2010; 133(Pt 4):1094–1110.PubMedCrossRefGoogle Scholar
  46. 46.
    Cudkowicz M, Kowall NW. Degeneration of pyramidal projection neurons in Huntington’s disease cortex. Ann Neurol 1990; 27:200–204.PubMedCrossRefGoogle Scholar
  47. 47.
    Hedreen JC, Peyser CE, Folstein SE et al. Neuronal loss in layers V and VI of cerebral cortex in Huntington’s disease. Neurosci Lett 1991; 133(2):257–261.PubMedCrossRefGoogle Scholar
  48. 48.
    Heinsen H, Strik M, Bauer M et al. Cortical and striatal neurone number in Huntington’s disease. Acta Neuropathol 1994; 88(4):320–333.PubMedCrossRefGoogle Scholar
  49. 49.
    Macdonald V, Halliday G. Pyramidal cell loss in motor cortices in Huntington’s disease. Neurobiol Dis 2002; 10(3):378–386.PubMedCrossRefGoogle Scholar
  50. 50.
    Macdonald V, Halliday GM, Trent RJ et al. Significant loss of pyramidal neurons in the angular gyrus of patients with Huntington’s disease. Neuropathol Appl Neurobiol 1997; 23(6):492–495.PubMedCrossRefGoogle Scholar
  51. 51.
    Selemon LD, Rajkowska G, Goldman-Rakic PS. Evidence for progression in frontal cortical pathology in late-stage Huntington’s disease. J Comp Neurol 2004; 468(2): 190–204.PubMedCrossRefGoogle Scholar
  52. 52.
    Rosas HD, Feigin AS, Hersch SM. Using advances in neuroimaging to detect, understand and monitor disease progression in Huntington’s disease. NeuroRx 2004; l(2):263–272.CrossRefGoogle Scholar
  53. 53.
    Rosas HD, Hevelone ND, Zaleta AK et al. Regional cortical thinning in preclinical Huntington disease and its relationship to cognition. Neurology 2005; 65(5):745–747.PubMedCrossRefGoogle Scholar
  54. 54.
    Rosas HD, Koroshetz WJ, Chen YI et al. Evidence for more widespread cerebral pathology in early HD: an MRI-based morphometric analysis. Neurology 2003; 60(10): 1615–1620.PubMedCrossRefGoogle Scholar
  55. 55.
    Rosas HD, Liu AK, Hersch S et al. Regional and progressive thinning of the cortical ribbon in Huntington’s disease. Neurology 2002; 58(5):695–701.PubMedCrossRefGoogle Scholar
  56. 56.
    Rosas HD, Salat DH, Lee SY et al. Cerebral cortex and the clinical expression of Huntington’s disease: complexity and heterogeneity. Brain 2008; 131(Pt 4): 1057–1068.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Hodges A, Strand AD, Aragaki AK et al. Regional and cellular gene expression changes in human Huntington’s disease brain. Hum Mol Genet 2006; 15(6):965–977.PubMedCrossRefGoogle Scholar
  58. 58.
    Luthi-Carter R, Strand A, Peters NL et al. Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum Mol Genet 2000; 9(9):1259–1271.PubMedCrossRefGoogle Scholar
  59. 59.
    Cattaneo E, Rigamonti D, Goffredo D et al. Loss of normal huntingtin function: new developments in Huntington’s disease research. Trends Neurosci 2001; 24(3):182–188.PubMedCrossRefGoogle Scholar
  60. 60.
    Cha JH. Transcriptional dysregulation in Huntington’s disease. Trends Neurosci 2000; 23(9):387–392.PubMedCrossRefGoogle Scholar
  61. 61.
    Morton AJ, Faull RL, Edwardson JM. Abnormalities in the synaptic vesicle fusion machinery in Huntington’s disease. Brain Res Bull 2001; 56(2):111–117.PubMedCrossRefGoogle Scholar
  62. 62.
    Petersen A, Mani K, Brundin P. Recent advances on the pathogenesis of Huntington’s disease. Exp Neurol 1999; 157(1):1–18.PubMedCrossRefGoogle Scholar
  63. 63.
    Rosas HD, Salat DH, Lee SY et al. Complexity and heterogeneity: what drives the ever-changing brain in Huntington’s disease? Ann N Y Acad Sci 2008; 1147:196–205.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Zuccato C, Cattaneo E. Role of brain-derived neurotrophic factor in Huntington’s disease. Prog Neurobiol 2007; 81(5–6):294–330.PubMedCrossRefGoogle Scholar
  65. 65.
    Cepeda C, Wu N, Andre VM et al. The corticostriatal pathway in Huntington’s disease. Prog Neurobiol 2007; 81(5–6):253–271.PubMedCrossRefGoogle Scholar
  66. 66.
    Strand AD, Baquet ZC, Aragaki AK et al. Expression profiling of Huntington’s disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration. J Neurosci 2007;27(43):11758–11768.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Molyneaux BJ, Arlotta P, Menezes JR et al. Neuronal subtype specification in the cerebral cortex. Nat Rev Neurosci 2007; 8(6):427–437.PubMedCrossRefGoogle Scholar
  68. 68.
    Cummings DM, Andre VM, Uzgil BO et al. Alterations in cortical excitation and inhibition in genetic mouse models of Huntington’s disease. J Neurosci 2009; 29(33): 10371–10386.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Andre VM, Cepeda C, Venegas A et al. Altered cortical glutamate receptor function in the R6/2 model of Huntington’s disease. J Neurophysiol 2006; 95(4):2108–2119.PubMedCrossRefGoogle Scholar
  70. 70.
    Laforet GA, Sapp E, Chase K et al. Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington’s disease. J Neurosci 2001;21(23):9112–9123.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Sapp E, Schwarz C, Chase K et al. Huntingtin localization in brains of normal and Huntington’s disease patients. Ann Neurol 1997; 42(4):604–612.PubMedCrossRefGoogle Scholar
  72. 72.
    Gu X, Andre VM, Cepeda C et al. Pathological cell-cell interactions are necessary for striatal pathogenesis in a conditional mouse model of Huntington’s disease. Mol Neurodegener 2007; 2:8.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Gu X, Li C, Wei W et al. Pathological cell-cell interactions elicited by a neuropathogenic form of mutant Huntingtin contribute to cortical pathogenesis in HD mice. Neuron 2005; 46(3):433–444.PubMedCrossRefGoogle Scholar
  74. 74.
    Spampanato J, Gu X, Yang XW et al. Progressive synaptic pathology of motor cortical neurons in a BAC transgenic mouse model of Huntington’s disease. Neuroscience 2008; 157(3):606–620.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Van Roon-Mom WM, Hogg VM, Tippett LJ et al. Aggregate distribution in frontal and motor cortex in Huntington’s disease brain. Neuroreport 2006; 17(6):667–670.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Henry J. Waldvogel
    • 1
    • 2
    Email author
  • Doris Thu
    • 3
  • Virginia Hogg
    • 2
    • 4
  • Lynette Tippett
    • 2
    • 4
  • Richard L. M. Faull
    • 1
    • 2
  1. 1.Department of Anatomy with Radiology, Faculty of Medical and Health SciencesUniversity of AucklandAucklandNew Zealand
  2. 2.Centre for Brain ResearchUniversity of AucklandAucklandNew Zealand
  3. 3.Brain Mind InstituteEcole Polytechnique Federale de LausanneLausanneSwitzerland
  4. 4.Department of PsychologyUniversity of AucklandAucklandNew Zealand

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