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Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study.

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  • 1. Department of Neurosurgery, Westmead Hospital, NSW 2145, Australia.
      Authors
    • Kipps CM 1
    (1 author)

ORCIDs linked to this article

Journal of Neurology, Neurosurgery, and Psychiatry, 01 May 2005, 76(5):650-655
https://doi.org/10.1136/jnnp.2004.047993 PMID: 15834021 PMCID: PMC1739615

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A comment on this article appears in "Imaging Huntington's disease (HD) brains--imagine HD trials!" J Neurol Neurosurg Psychiatry. 2005 May;76(5):620.

Abstract 

Background and objectives

Regional cerebral atrophy occurs in carriers of the Huntington's disease (HD) gene mutation before clinical diagnosis is possible. The current inability to reliably measure progression of pathology in this preclinical phase impedes development of therapies to delay clinical onset. We hypothesised that longitudinal statistical imaging would detect progression of structural pathology in preclinical carriers of the HD gene mutation, in the absence of measurable clinical change.

Methods

Thirty subjects (17 preclinical mutation positive, 13 mutation negative) underwent serial clinical and magnetic resonance imaging (MRI) assessments over an interval of 2 years. Statistically significant changes in regional grey and white matter volume on MRI were analysed using tensor based morphometry (TBM). This technique derives a voxel-wise estimation of regional tissue volume change from the deformation field required to warp a subject's early to late T1 images.

Results

Over 2 years, there was progressive regional grey matter atrophy in mutation-positive relative to negative subjects, without significant clinical progression of disease. Significant grey matter volume loss was limited to bilateral putamen and globus pallidus externa (GPe), left caudate nucleus, and left ventral midbrain in the region of the substantia nigra.

Conclusions

While these results are consistent with previous cross sectional pathologic and morphometric studies, significant progression of atrophy in HD before the onset of significant clinical decline is now demonstrable with longitudinal statistical imaging. Such measures could be used to assess the efficacy of potential disease modifying drugs in slowing the progression of pathology before confirmed clinical onset of HD.

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Logo of jnnpsycLink to Publisher's site
J Neurol Neurosurg Psychiatry. 2005 May; 76(5): 650–655.
PMCID: PMC1739615
PMID: 15834021

Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study

C Kipps, A Duggins, N Mahant, L Gomes, J Ashburner, and E McCusker
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Abstract

Background and objectives: Regional cerebral atrophy occurs in carriers of the Huntington's disease (HD) gene mutation before clinical diagnosis is possible. The current inability to reliably measure progression of pathology in this preclinical phase impedes development of therapies to delay clinical onset. We hypothesised that longitudinal statistical imaging would detect progression of structural pathology in preclinical carriers of the HD gene mutation, in the absence of measurable clinical change.

Methods: Thirty subjects (17 preclinical mutation positive, 13 mutation negative) underwent serial clinical and magnetic resonance imaging (MRI) assessments over an interval of 2 years. Statistically significant changes in regional grey and white matter volume on MRI were analysed using tensor based morphometry (TBM). This technique derives a voxel-wise estimation of regional tissue volume change from the deformation field required to warp a subject's early to late T1 images.

Results: Over 2 years, there was progressive regional grey matter atrophy in mutation-positive relative to negative subjects, without significant clinical progression of disease. Significant grey matter volume loss was limited to bilateral putamen and globus pallidus externa (GPe), left caudate nucleus, and left ventral midbrain in the region of the substantia nigra.

Conclusions: While these results are consistent with previous cross sectional pathologic and morphometric studies, significant progression of atrophy in HD before the onset of significant clinical decline is now demonstrable with longitudinal statistical imaging. Such measures could be used to assess the efficacy of potential disease modifying drugs in slowing the progression of pathology before confirmed clinical onset of HD.

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Selected References

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  • DeKosky Steven T, Marek Kenneth. Looking backward to move forward: early detection of neurodegenerative disorders. Science. 2003 Oct 31;302(5646):830–834. [Abstract] [Google Scholar]
  • González-González MC, Trujillo MJ, Rodríguez de Alba M, García-Hoyos M, Lorda-Sánchez I, Díaz-Recasens J, Ayuso C, Ramos C. Huntington disease-unaffected fetus diagnosed from maternal plasma using QF-PCR. Prenat Diagn. 2003 Mar;23(3):232–234. [Abstract] [Google Scholar]
  • McCusker E, Richards F, Sillence D, Wilson M, Trent RJ. Huntington's disease: neurological assessment of potential gene carriers presenting for predictive DNA testing. J Clin Neurosci. 2000 Jan;7(1):38–41. [Abstract] [Google Scholar]
  • Kirkwood SC, Siemers E, Bond C, Conneally PM, Christian JC, Foroud T. Confirmation of subtle motor changes among presymptomatic carriers of the Huntington disease gene. Arch Neurol. 2000 Jul;57(7):1040–1044. [Abstract] [Google Scholar]
  • Kirkwood SC, Siemers E, Stout JC, Hodes ME, Conneally PM, Christian JC, Foroud T. Longitudinal cognitive and motor changes among presymptomatic Huntington disease gene carriers. Arch Neurol. 1999 May;56(5):563–568. [Abstract] [Google Scholar]
  • Smith MA, Brandt J, Shadmehr R. Motor disorder in Huntington's disease begins as a dysfunction in error feedback control. Nature. 2000 Feb 3;403(6769):544–549. [Europe PMC free article] [Abstract] [Google Scholar]
  • Rothwell JC. Huntington's disease. A predictor of pathology. Nature. 2000 Feb 3;403(6769):495–496. [Abstract] [Google Scholar]
  • Lawrence AD, Hodges JR, Rosser AE, Kershaw A, ffrench-Constant C, Rubinsztein DC, Robbins TW, Sahakian BJ. Evidence for specific cognitive deficits in preclinical Huntington's disease. Brain. 1998 Jul;121(Pt 7):1329–1341. [Abstract] [Google Scholar]
  • Albin RL, Reiner A, Anderson KD, Dure LS, 4th, Handelin B, Balfour R, Whetsell WO, Jr, Penney JB, Young AB. Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington's disease. Ann Neurol. 1992 Apr;31(4):425–430. [Abstract] [Google Scholar]
  • Gómez-Tortosa E, MacDonald ME, Friend JC, Taylor SA, Weiler LJ, Cupples LA, Srinidhi J, Gusella JF, Bird ED, Vonsattel JP, et al. Quantitative neuropathological changes in presymptomatic Huntington's disease. Ann Neurol. 2001 Jan;49(1):29–34. [Abstract] [Google Scholar]
  • Thieben MJ, Duggins AJ, Good CD, Gomes L, Mahant N, Richards F, McCusker E, Frackowiak RSJ. The distribution of structural neuropathology in pre-clinical Huntington's disease. Brain. 2002 Aug;125(Pt 8):1815–1828. [Abstract] [Google Scholar]
  • Dedeoglu Alpaslan, Kubilus James K, Yang Lichuan, Ferrante Kimberly L, Hersch Steven M, Beal M Flint, Ferrante Robert J. Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington's disease transgenic mice. J Neurochem. 2003 Jun;85(6):1359–1367. [Europe PMC free article] [Abstract] [Google Scholar]
  • Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med. 2000 Jul;6(7):797–801. [Abstract] [Google Scholar]
  • A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease. Neurology. 2001 Aug 14;57(3):397–404. [Abstract] [Google Scholar]
  • Kassubek J, Juengling FD, Kioschies T, Henkel K, Karitzky J, Kramer B, Ecker D, Andrich J, Saft C, Kraus P, et al. Topography of cerebral atrophy in early Huntington's disease: a voxel based morphometric MRI study. J Neurol Neurosurg Psychiatry. 2004 Feb;75(2):213–220. [Europe PMC free article] [Abstract] [Google Scholar]
  • Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP., Jr Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol. 1985 Nov;44(6):559–577. [Abstract] [Google Scholar]
  • Lange H, Thörner G, Hopf A, Schröder KF. Morphometric studies of the neuropathological changes in choreatic diseases. J Neurol Sci. 1976 Aug;28(4):401–425. [Abstract] [Google Scholar]
  • Reiner A, Albin RL, Anderson KD, D'Amato CJ, Penney JB, Young AB. Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5733–5737. [Europe PMC free article] [Abstract] [Google Scholar]
  • Mann DM, Oliver R, Snowden JS. The topographic distribution of brain atrophy in Huntington's disease and progressive supranuclear palsy. Acta Neuropathol. 1993;85(5):553–559. [Abstract] [Google Scholar]
  • Halliday GM, McRitchie DA, Macdonald V, Double KL, Trent RJ, McCusker E. Regional specificity of brain atrophy in Huntington's disease. Exp Neurol. 1998 Dec;154(2):663–672. [Abstract] [Google Scholar]
  • Roos RA, Pruyt JF, de Vries J, Bots GT. Neuronal distribution in the putamen in Huntington's disease. J Neurol Neurosurg Psychiatry. 1985 May;48(5):422–425. [Europe PMC free article] [Abstract] [Google Scholar]
  • Graveland GA, Williams RS, DiFiglia M. Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington's disease. Science. 1985 Feb 15;227(4688):770–773. [Abstract] [Google Scholar]
  • de la Monte SM, Vonsattel JP, Richardson EP., Jr Morphometric demonstration of atrophic changes in the cerebral cortex, white matter, and neostriatum in Huntington's disease. J Neuropathol Exp Neurol. 1988 Sep;47(5):516–525. [Abstract] [Google Scholar]
  • Aylward EH, Anderson NB, Bylsma FW, Wagster MV, Barta PE, Sherr M, Feeney J, Davis A, Rosenblatt A, Pearlson GD, et al. Frontal lobe volume in patients with Huntington's disease. Neurology. 1998 Jan;50(1):252–258. [Abstract] [Google Scholar]
  • Harris GJ, Codori AM, Lewis RF, Schmidt E, Bedi A, Brandt J. Reduced basal ganglia blood flow and volume in pre-symptomatic, gene-tested persons at-risk for Huntington's disease. Brain. 1999 Sep;122(Pt 9):1667–1678. [Abstract] [Google Scholar]
  • Aylward EH, Codori AM, Barta PE, Pearlson GD, Harris GJ, Brandt J. Basal ganglia volume and proximity to onset in presymptomatic Huntington disease. Arch Neurol. 1996 Dec;53(12):1293–1296. [Abstract] [Google Scholar]
  • Aylward EH, Codori AM, Rosenblatt A, Sherr M, Brandt J, Stine OC, Barta PE, Pearlson GD, Ross CA. Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington's disease. Mov Disord. 2000 May;15(3):552–560. [Abstract] [Google Scholar]
  • Grafton ST, Mazziotta JC, Pahl JJ, St George-Hyslop P, Haines JL, Gusella J, Hoffman JM, Baxter LR, Phelps ME. Serial changes of cerebral glucose metabolism and caudate size in persons at risk for Huntington's disease. Arch Neurol. 1992 Nov;49(11):1161–1167. [Abstract] [Google Scholar]
  • Aylward EH, Sparks BF, Field KM, Yallapragada V, Shpritz BD, Rosenblatt A, Brandt J, Gourley LM, Liang K, Zhou H, et al. Onset and rate of striatal atrophy in preclinical Huntington disease. Neurology. 2004 Jul 13;63(1):66–72. [Abstract] [Google Scholar]
  • Ashburner J, Andersson JL, Friston KJ. Image registration using a symmetric prior--in three dimensions. Hum Brain Mapp. 2000 Apr;9(4):212–225. [Abstract] [Google Scholar]
  • Freeborough PA, Fox NC. Modeling brain deformations in Alzheimer disease by fluid registration of serial 3D MR images. J Comput Assist Tomogr. 1998 Sep-Oct;22(5):838–843. [Abstract] [Google Scholar]
  • Ashburner J, Friston KJ. Voxel-based morphometry--the methods. Neuroimage. 2000 Jun;11(6 Pt 1):805–821. [Abstract] [Google Scholar]
  • Hedreen JC, Folstein SE. Early loss of neostriatal striosome neurons in Huntington's disease. J Neuropathol Exp Neurol. 1995 Jan;54(1):105–120. [Abstract] [Google Scholar]
  • Albin RL. Selective neurodegeneration in Huntington's disease. Ann Neurol. 1995 Dec;38(6):835–836. [Abstract] [Google Scholar]
  • 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 May;44(5):823–828. [Abstract] [Google Scholar]
  • Lasker AG, Zee DS. Ocular motor abnormalities in Huntington's disease. Vision Res. 1997 Dec;37(24):3639–3645. [Abstract] [Google Scholar]
  • Rosas HD, Liu AK, Hersch S, Glessner M, Ferrante RJ, Salat DH, van der Kouwe A, Jenkins BG, Dale AM, Fischl B. Regional and progressive thinning of the cortical ribbon in Huntington's disease. Neurology. 2002 Mar 12;58(5):695–701. [Abstract] [Google Scholar]
  • Jenkins BG, Rosas HD, Chen YC, Makabe T, Myers R, MacDonald M, Rosen BR, Beal MF, Koroshetz WJ. 1H NMR spectroscopy studies of Huntington's disease: correlations with CAG repeat numbers. Neurology. 1998 May;50(5):1357–1365. [Abstract] [Google Scholar]
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