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Magnetic Resonance Spectroscopy of Degenerative Brain Diseases pp 103–120Cite as

Magnetic Resonance Spectroscopy in Huntington’s Disease

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Part of the book series: Contemporary Clinical Neuroscience ((CCNE))

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease with complete penetrance. Although the understanding of the cellular mechanisms that drive neurodegeneration in HD and account for the characteristic pattern of neuronal vulnerability is incomplete, defects in energy metabolism, particularly mitochondrial function, represent a common thread in studies of HD pathogenesis in animal models and humans. Here we review the metabolic dysfunction captured by in vivo proton and phosphorus magnetic resonance spectroscopy (MRS) in animal models of HD and human carriers of the mutated huntingtin protein. Having access to a presymptomatic population of individuals gives a unique possibility of approaching early pathophysiological changes in HD. Although longitudinal studies are needed to determine more precisely the time course of these metabolic changes in humans, MRS tools are already used in clinical trials to obtain proof of concepts of the ability of disease-modifying drugs to impact on disease progression in HD.

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References

  1. Squitieri F et al (1994) DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence. Hum Mol Genet 3(12):2103–2114

    CAS  PubMed  Google Scholar 

  2. Pringsheim T et al (2012) The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Mov Disord 27(9):1083–1091

    PubMed  Google Scholar 

  3. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s Disease Collaborative Research Group. (1993) Cell, 72(6):971–983

    Google Scholar 

  4. Langbehn DR et al (2004) A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clin Genet 65(4):267–277

    CAS  PubMed  Google Scholar 

  5. Tibben A (2007) Predictive testing for Huntington’s disease. Brain Res Bull 72(2-3):165–171

    PubMed  Google Scholar 

  6. MacLeod R et al (2013) Recommendations for the predictive genetic test in Huntington’s disease. Clin Genet 83(3):221–231

    CAS  PubMed  Google Scholar 

  7. Tabrizi SJ et al (2009) Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 8(9):791–801

    PubMed  PubMed Central  Google Scholar 

  8. Paulsen JS et al (2008) Detection of Huntington’s disease decades before diagnosis: the Predict-HD study. J Neurol Neurosurg Psychiatry 79(8):874–880

    CAS  PubMed  Google Scholar 

  9. Duff K et al (2007) Psychiatric symptoms in Huntington’s disease before diagnosis: the predict-HD study. Biol Psychiatry 62(12):1341–1346

    PubMed  Google Scholar 

  10. Paulsen JS et al (2005) Depression and stages of Huntington’s disease. J Neuropsychiatry Clin Neurosci 17(4):496–502

    PubMed  Google Scholar 

  11. Paulsen JS et al (2005) Critical periods of suicide risk in Huntington’s disease. Am J Psychiatry 162(4):725–731

    PubMed  Google Scholar 

  12. Reedeker N et al (2011) Incidence, course, and predictors of apathy in Huntington’s disease: a two-year prospective study. J Neuropsychiatry Clin Neurosci 23(4):434–441

    PubMed  Google Scholar 

  13. Montoya A et al (2006) Brain imaging and cognitive dysfunctions in Huntington’s disease. J Psychiatry Neurosci 31(1):21–29

    PubMed  PubMed Central  Google Scholar 

  14. Vonsattel JPG, Keller C, Amaya MDP (2008) Neuropathology of Huntington’s disease. In: Litvan CDAI (ed) Handbook of clinical neurology. Elsevier B. V, Amsterdam

    Google Scholar 

  15. Vonsattel JP, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57(5):369–384

    CAS  PubMed  Google Scholar 

  16. Mitchell IJ, Cooper AJ, Griffiths MR (1999) The selective vulnerability of striatopallidal neurons. Prog Neurobiol 59(6):691–719

    CAS  PubMed  Google Scholar 

  17. Zuccato C, Cattaneo E (2014) Huntington’s disease. Handb Exp Pharmacol 220:357–409

    CAS  PubMed  Google Scholar 

  18. Ross CA et al (2014) Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol 10(4):204–216

    CAS  PubMed  Google Scholar 

  19. Gines S et al (2003) Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington’s disease knock-in mice. Hum Mol Genet 12(5):497–508

    CAS  PubMed  Google Scholar 

  20. Milakovic T, Johnson GV (2005) Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant huntingtin. J Biol Chem 280(35):30773–30782

    CAS  PubMed  Google Scholar 

  21. Antonini A et al (1996) Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington’s disease. Brain 119(Pt 6):2085–2095

    PubMed  Google Scholar 

  22. Grafton ST et al (1992) Serial changes of cerebral glucose metabolism and caudate size in persons at risk for Huntington’s disease. Arch Neurol 49(11):1161–1167

    CAS  PubMed  Google Scholar 

  23. Kuwert T et al (1993) Striatal glucose consumption in chorea-free subjects at risk of Huntington’s disease. J Neurol 241(1):31–36

    CAS  PubMed  Google Scholar 

  24. Browne SE, Beal MF (2004) The energetics of Huntington’s disease. Neurochem Res 29(3):531–546

    CAS  PubMed  Google Scholar 

  25. Tabrizi SJ et al (1999) Biochemical abnormalities and excitotoxicity in Huntington’s disease brain. Ann Neurol 45(1):25–32

    CAS  PubMed  Google Scholar 

  26. Cui L et al (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127(1):59–69

    CAS  PubMed  Google Scholar 

  27. Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1(6):361–370

    PubMed  Google Scholar 

  28. Lin J et al (2004) Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 119(1):121–135

    CAS  PubMed  Google Scholar 

  29. Palfi S et al (1996) Chronic 3-nitropropionic acid treatment in baboons replicates the cognitive and motor deficits of Huntington’s disease. J Neurosci 16(9):3019–3025

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Brouillet E et al (1998) Partial inhibition of brain succinate dehydrogenase is sufficient to initiate striatal degeneration in rat. J Neurochem 70(2):794–805

    CAS  PubMed  Google Scholar 

  31. Tabrizi SJ et al (2013) 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 Neurol 12(7):637–649

    PubMed  Google Scholar 

  32. Mochel F et al (2010) Dietary anaplerotic therapy improves peripheral tissue energy metabolism in patients with Huntington’s disease. Eur J Hum Genet 18(9):1057–1060

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kar K et al (2013) beta-hairpin-mediated nucleation of polyglutamine amyloid formation. J Mol Biol 425(7):1183–1197

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Pedersen JT, Heegaard NH (2013) Analysis of protein aggregation in neurodegenerative disease. Anal Chem 85(9):4215–4227

    CAS  PubMed  Google Scholar 

  35. Beal MF et al (1993) Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J Neurosci 13(10):4181–4192

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Jenkins BG et al (1996) Non-invasive neurochemical analysis of focal excitotoxic lesions in models of neurodegenerative illness using spectroscopic imaging. J Cereb Blood Flow Metab 16(3):450–461

    CAS  PubMed  Google Scholar 

  37. Dautry C et al (1999) Serial 1H-NMR spectroscopy study of metabolic impairment in primates chronically treated with the succinate dehydrogenase inhibitor 3-nitropropionic acid. Neurobiol Dis 6(4):259–268

    CAS  PubMed  Google Scholar 

  38. Matthews RT et al (1998) Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington’s disease. J Neurosci 18(1):156–163

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Henry PG et al (2002) Decreased TCA cycle rate in the rat brain after acute 3-NP treatment measured by in vivo 1H-[13C] NMR spectroscopy. J Neurochem 82(4):857–866

    CAS  PubMed  Google Scholar 

  40. Mochel F et al (2012) Early alterations of brain cellular energy homeostasis in Huntington disease models. J Biol Chem 287(2):1361–1370

    CAS  PubMed  Google Scholar 

  41. Tkac I et al (2001) Metabolic changes in quinolinic acid-lesioned rat striatum detected non- invasively by in vivo 1H NMR spectroscopy. J Neurosci Res 66(5):891–898

    CAS  PubMed  Google Scholar 

  42. Jenkins BG et al (2000) Nonlinear decrease over time in N-acetyl aspartate levels in the absence of neuronal loss and increases in glutamine and glucose in transgenic Huntington’s disease mice. J Neurochem 74(5):2108–2119

    CAS  PubMed  Google Scholar 

  43. Mangiarini L et al (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87(3):493–506

    CAS  PubMed  Google Scholar 

  44. Jenkins BG et al (2005) Effects of CAG repeat length, HTT protein length and protein context on cerebral metabolism measured using magnetic resonance spectroscopy in transgenic mouse models of Huntington’s disease. J Neurochem 95(2):553–562

    CAS  PubMed  Google Scholar 

  45. van Dellen A et al (2000) N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington’s disease mice. Neuroreport 11(17):3751–3757

    PubMed  Google Scholar 

  46. Jenkins BG et al (1998) 1H NMR spectroscopy studies of Huntington’s disease: correlations with CAG repeat numbers. Neurology 50(5):1357–1365

    CAS  PubMed  Google Scholar 

  47. Tkac I et al (2007) Neurochemical changes in Huntington R6/2 mouse striatum detected by in vivo 1H NMR spectroscopy. J Neurochem 100(5):1397–1406

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Zacharoff L et al (2012) Cortical metabolites as biomarkers in the R6/2 model of Huntington’s disease. J Cereb Blood Flow Metab 32(3):502–514

    CAS  PubMed  Google Scholar 

  49. Zacharoff L et al. (2010) Biochemical changes in Q140 striatum precedes progressive volume loss. In: Proceedings of the society for neuroscience. San Diego, CA

    Google Scholar 

  50. Zacharoff L et al. (2011) Striatum specific lactate change in BACHD model of Huntington’s disease. In: Proceedings of the society for neuroscience. Washington, DC.

    Google Scholar 

  51. Heikkinen T et al (2012) Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington’s disease. PLoS One 7(12), e50717

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Wheeler VC et al (1999) Length-dependent gametic CAG repeat instability in the Huntington’s disease knock-in mouse. Hum Mol Genet 8(1):115–122

    CAS  PubMed  Google Scholar 

  53. Wheeler VC et al (2000) Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice. Hum Mol Genet 9(4):503–513

    CAS  PubMed  Google Scholar 

  54. Tkac I et al (2012) Homeostatic adaptations in brain energy metabolism in mouse models of Huntington disease. J Cereb Blood Flow Metab 32(11):1977–1988

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Mochel F et al (2012) Abnormal response to cortical activation in early stages of Huntington disease. Mov Disord 27(7):907–910

    CAS  PubMed  Google Scholar 

  56. Kim J et al (2010) Reduced creatine kinase as a central and peripheral biomarker in Huntington’s disease. Biochim Biophys Acta 1802(7-8):673–681

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Wheeler VC et al (2002) Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice. Hum Mol Genet 11(6):633–640

    CAS  PubMed  Google Scholar 

  58. Chaumeil MM et al (2012) pH as a biomarker of neurodegeneration in Huntington’s disease: a translational rodent-human MRS study. J Cereb Blood Flow Metab 32(5):771–779

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Cui W et al (2013) Non-invasive measurement of cerebral oxygen metabolism in the mouse brain by ultra-high field 17O MR spectroscopy. J Cereb Blood Flow Metab 33(12):1846–1849

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Nikas JB, Keene CD, Low WC (2010) Comparison of analytical mathematical approaches for identifying key nuclear magnetic resonance spectroscopy biomarkers in the diagnosis and assessment of clinical change of diseases. J Comp Neurol 518(20):4091–4112

    CAS  PubMed  Google Scholar 

  61. Nikas JB, Low WC (2011) Application of clustering analyses to the diagnosis of Huntington disease in mice and other diseases with well-defined group boundaries. Comput Methods Programs Biomed 104(3):e133–e147

    PubMed  PubMed Central  Google Scholar 

  62. Hess AT et al (2011) Real-time motion and B0 corrected single voxel spectroscopy using volumetric navigators. Magn Reson Med 66(2):314–323

    PubMed  PubMed Central  Google Scholar 

  63. Keating B, Ernst T (2012) Real-time dynamic frequency and shim correction for single-voxel magnetic resonance spectroscopy. Magn Reson Med 68(5):1339–1345

    PubMed  PubMed Central  Google Scholar 

  64. Deelchand DK, Iltis I, Henry PG (2014) Improved quantification precision of human brain short echo-time 1H magnetic resonance spectroscopy at high magnetic field: a simulation study. Magn Reson Med 72(1):20–25

    CAS  PubMed  Google Scholar 

  65. Harms L et al (1997) Decreased N-acetyl-aspartate/choline ratio and increased lactate in the frontal lobe of patients with Huntington’s disease: a proton magnetic resonance spectroscopy study. J Neurol Neurosurg Psychiatry 62(1):27–30

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Jenkins BG et al (1993) Evidence for impairment of energy metabolism in vivo in Huntington’s disease using localized 1H NMR spectroscopy. Neurology 43(12):2689–2695

    CAS  PubMed  Google Scholar 

  67. Sanchez-Pernaute R et al (1999) Clinical correlation of striatal 1H MRS changes in Huntington’s disease. Neurology 53(4):806–812

    CAS  PubMed  Google Scholar 

  68. Taylor-Robinson SD et al (1996) Proton magnetic resonance spectroscopy in Huntington’s disease: evidence in favour of the glutamate excitotoxic theory. Mov Disord 11(2):167–173

    CAS  PubMed  Google Scholar 

  69. Hoang TQ et al (1998) Quantitative proton-decoupled 31P MRS and 1H MRS in the evaluation of Huntington’s and Parkinson’s diseases. Neurology 50(4):1033–1040

    CAS  PubMed  Google Scholar 

  70. Sturrock A et al (2010) Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease. Neurology 75(19):1702–1710

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Padowski JM et al (2014) Neurochemical correlates of caudate atrophy in Huntington’s disease. Mov Disord 29(3):327–335

    CAS  PubMed  PubMed Central  Google Scholar 

  72. van den Bogaard SJ et al (2011) Exploratory 7-Tesla magnetic resonance spectroscopy in Huntington’s disease provides in vivo evidence for impaired energy metabolism. J Neurol 258(12):2230–2239

    PubMed  PubMed Central  Google Scholar 

  73. Unschuld PG et al (2012) Brain metabolite alterations and cognitive dysfunction in early Huntington’s disease. Mov Disord 27(7):895–902

    PubMed  PubMed Central  Google Scholar 

  74. Ruocco HH et al (2007) Evidence of thalamic dysfunction in Huntington disease by proton magnetic resonance spectroscopy. Mov Disord 22(14):2052–2056

    PubMed  Google Scholar 

  75. van Oostrom JC et al (2007) 1H magnetic resonance spectroscopy in preclinical Huntington disease. Brain Res 1168:67–71

    PubMed  Google Scholar 

  76. Gomez-Anson B et al (2007) Decreased frontal choline and neuropsychological performance in preclinical Huntington disease. Neurology 68(12):906–910

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, 75013, Paris, France

    Fanny Mochel M.D., Ph.D.

  2. Département de Génétique, Salpêtrière University Hospital, 75013, Paris, France

    Fanny Mochel M.D., Ph.D.

  3. Groupe de Recherche Clinique Neurométabolique, Université Pierre and Marie Curie, Paris, France

    Fanny Mochel M.D., Ph.D.

  4. Department of Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA

    Janet M. Dubinsky Ph.D.

  5. Department of Radiology, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, 55455, USA

    Pierre-Gilles Henry Ph.D.

Authors
  1. Fanny Mochel M.D., Ph.D.
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  2. Janet M. Dubinsky Ph.D.
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  3. Pierre-Gilles Henry Ph.D.
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Corresponding author

Correspondence to Fanny Mochel M.D., Ph.D. .

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Editors and Affiliations

  1. University of Minnesota Medical School, Center Magnetic Resonance Research University of Minnesota Medical School, Minneapolis, MN, USA

    Gülin Öz

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Mochel, F., Dubinsky, J.M., Henry, PG. (2016). Magnetic Resonance Spectroscopy in Huntington’s Disease. In: Öz, G. (eds) Magnetic Resonance Spectroscopy of Degenerative Brain Diseases. Contemporary Clinical Neuroscience. Springer, Cham. https://doi.org/10.1007/978-3-319-33555-1_6

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