Magnetic Resonance Spectroscopy in Huntington’s Disease

Part of the Contemporary Clinical Neuroscience book series (CCNE)


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.


Huntington’s disease Caudate Putamen Energy metabolism 


  1. 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):2103–2114CrossRefPubMedGoogle Scholar
  2. 2.
    Pringsheim T et al (2012) The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Mov Disord 27(9):1083–1091CrossRefPubMedGoogle Scholar
  3. 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):971–983Google Scholar
  4. 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):267–277CrossRefPubMedGoogle Scholar
  5. 5.
    Tibben A (2007) Predictive testing for Huntington’s disease. Brain Res Bull 72(2-3):165–171CrossRefPubMedGoogle Scholar
  6. 6.
    MacLeod R et al (2013) Recommendations for the predictive genetic test in Huntington’s disease. Clin Genet 83(3):221–231CrossRefPubMedGoogle Scholar
  7. 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):791–801CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Paulsen JS et al (2008) Detection of Huntington’s disease decades before diagnosis: the Predict-HD study. J Neurol Neurosurg Psychiatry 79(8):874–880CrossRefPubMedGoogle Scholar
  9. 9.
    Duff K et al (2007) Psychiatric symptoms in Huntington’s disease before diagnosis: the predict-HD study. Biol Psychiatry 62(12):1341–1346CrossRefPubMedGoogle Scholar
  10. 10.
    Paulsen JS et al (2005) Depression and stages of Huntington’s disease. J Neuropsychiatry Clin Neurosci 17(4):496–502CrossRefPubMedGoogle Scholar
  11. 11.
    Paulsen JS et al (2005) Critical periods of suicide risk in Huntington’s disease. Am J Psychiatry 162(4):725–731CrossRefPubMedGoogle Scholar
  12. 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):434–441CrossRefPubMedGoogle Scholar
  13. 13.
    Montoya A et al (2006) Brain imaging and cognitive dysfunctions in Huntington’s disease. J Psychiatry Neurosci 31(1):21–29PubMedPubMedCentralGoogle Scholar
  14. 14.
    Vonsattel JPG, Keller C, Amaya MDP (2008) Neuropathology of Huntington’s disease. In: Litvan CDAI (ed) Handbook of clinical neurology. Elsevier B. V, AmsterdamGoogle Scholar
  15. 15.
    Vonsattel JP, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57(5):369–384CrossRefPubMedGoogle Scholar
  16. 16.
    Mitchell IJ, Cooper AJ, Griffiths MR (1999) The selective vulnerability of striatopallidal neurons. Prog Neurobiol 59(6):691–719CrossRefPubMedGoogle Scholar
  17. 17.
    Zuccato C, Cattaneo E (2014) Huntington’s disease. Handb Exp Pharmacol 220:357–409CrossRefPubMedGoogle Scholar
  18. 18.
    Ross CA et al (2014) Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol 10(4):204–216CrossRefPubMedGoogle Scholar
  19. 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):497–508CrossRefPubMedGoogle Scholar
  20. 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):30773–30782CrossRefPubMedGoogle Scholar
  21. 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):2085–2095CrossRefPubMedGoogle Scholar
  22. 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):1161–1167CrossRefPubMedGoogle Scholar
  23. 23.
    Kuwert T et al (1993) Striatal glucose consumption in chorea-free subjects at risk of Huntington’s disease. J Neurol 241(1):31–36CrossRefPubMedGoogle Scholar
  24. 24.
    Browne SE, Beal MF (2004) The energetics of Huntington’s disease. Neurochem Res 29(3):531–546CrossRefPubMedGoogle Scholar
  25. 25.
    Tabrizi SJ et al (1999) Biochemical abnormalities and excitotoxicity in Huntington’s disease brain. Ann Neurol 45(1):25–32CrossRefPubMedGoogle Scholar
  26. 26.
    Cui L et al (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127(1):59–69CrossRefPubMedGoogle Scholar
  27. 27.
    Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1(6):361–370CrossRefPubMedGoogle Scholar
  28. 28.
    Lin J et al (2004) Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 119(1):121–135CrossRefPubMedGoogle Scholar
  29. 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):3019–3025PubMedGoogle Scholar
  30. 30.
    Brouillet E et al (1998) Partial inhibition of brain succinate dehydrogenase is sufficient to initiate striatal degeneration in rat. J Neurochem 70(2):794–805CrossRefPubMedGoogle Scholar
  31. 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):637–649CrossRefPubMedGoogle Scholar
  32. 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):1057–1060CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kar K et al (2013) beta-hairpin-mediated nucleation of polyglutamine amyloid formation. J Mol Biol 425(7):1183–1197CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Pedersen JT, Heegaard NH (2013) Analysis of protein aggregation in neurodegenerative disease. Anal Chem 85(9):4215–4227CrossRefPubMedGoogle Scholar
  35. 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):4181–4192PubMedGoogle Scholar
  36. 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):450–461CrossRefPubMedGoogle Scholar
  37. 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):259–268CrossRefPubMedGoogle Scholar
  38. 38.
    Matthews RT et al (1998) Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington’s disease. J Neurosci 18(1):156–163PubMedGoogle Scholar
  39. 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):857–866CrossRefPubMedGoogle Scholar
  40. 40.
    Mochel F et al (2012) Early alterations of brain cellular energy homeostasis in Huntington disease models. J Biol Chem 287(2):1361–1370CrossRefPubMedGoogle Scholar
  41. 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):891–898CrossRefPubMedGoogle Scholar
  42. 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):2108–2119CrossRefPubMedGoogle Scholar
  43. 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):493–506CrossRefPubMedGoogle Scholar
  44. 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):553–562CrossRefPubMedGoogle Scholar
  45. 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):3751–3757CrossRefPubMedGoogle Scholar
  46. 46.
    Jenkins BG et al (1998) 1H NMR spectroscopy studies of Huntington’s disease: correlations with CAG repeat numbers. Neurology 50(5):1357–1365CrossRefPubMedGoogle Scholar
  47. 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):1397–1406CrossRefPubMedPubMedCentralGoogle Scholar
  48. 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):502–514CrossRefPubMedGoogle Scholar
  49. 49.
    Zacharoff L et al. (2010) Biochemical changes in Q140 striatum precedes progressive volume loss. In: Proceedings of the society for neuroscience. San Diego, CAGoogle Scholar
  50. 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. 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), e50717CrossRefPubMedPubMedCentralGoogle Scholar
  52. 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):115–122CrossRefPubMedGoogle Scholar
  53. 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):503–513CrossRefPubMedGoogle Scholar
  54. 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):1977–1988CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Mochel F et al (2012) Abnormal response to cortical activation in early stages of Huntington disease. Mov Disord 27(7):907–910CrossRefPubMedGoogle Scholar
  56. 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):673–681CrossRefPubMedPubMedCentralGoogle Scholar
  57. 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):633–640CrossRefPubMedGoogle Scholar
  58. 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):771–779CrossRefPubMedPubMedCentralGoogle Scholar
  59. 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):1846–1849CrossRefPubMedPubMedCentralGoogle Scholar
  60. 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):4091–4112CrossRefPubMedGoogle Scholar
  61. 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–e147CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Hess AT et al (2011) Real-time motion and B0 corrected single voxel spectroscopy using volumetric navigators. Magn Reson Med 66(2):314–323CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Keating B, Ernst T (2012) Real-time dynamic frequency and shim correction for single-voxel magnetic resonance spectroscopy. Magn Reson Med 68(5):1339–1345CrossRefPubMedPubMedCentralGoogle Scholar
  64. 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):20–25CrossRefPubMedGoogle Scholar
  65. 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):27–30CrossRefPubMedPubMedCentralGoogle Scholar
  66. 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):2689–2695CrossRefPubMedGoogle Scholar
  67. 67.
    Sanchez-Pernaute R et al (1999) Clinical correlation of striatal 1H MRS changes in Huntington’s disease. Neurology 53(4):806–812CrossRefPubMedGoogle Scholar
  68. 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):167–173CrossRefPubMedGoogle Scholar
  69. 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):1033–1040CrossRefPubMedGoogle Scholar
  70. 70.
    Sturrock A et al (2010) Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease. Neurology 75(19):1702–1710CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Padowski JM et al (2014) Neurochemical correlates of caudate atrophy in Huntington’s disease. Mov Disord 29(3):327–335CrossRefPubMedPubMedCentralGoogle Scholar
  72. 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):2230–2239CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Unschuld PG et al (2012) Brain metabolite alterations and cognitive dysfunction in early Huntington’s disease. Mov Disord 27(7):895–902CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Ruocco HH et al (2007) Evidence of thalamic dysfunction in Huntington disease by proton magnetic resonance spectroscopy. Mov Disord 22(14):2052–2056CrossRefPubMedGoogle Scholar
  75. 75.
    van Oostrom JC et al (2007) 1H magnetic resonance spectroscopy in preclinical Huntington disease. Brain Res 1168:67–71CrossRefPubMedGoogle Scholar
  76. 76.
    Gomez-Anson B et al (2007) Decreased frontal choline and neuropsychological performance in preclinical Huntington disease. Neurology 68(12):906–910CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127ParisFrance
  2. 2.Département de GénétiqueSalpêtrière University HospitalParisFrance
  3. 3.Groupe de Recherche Clinique NeurométaboliqueUniversité Pierre and Marie CurieParisFrance
  4. 4.Department of NeuroscienceUniversity of MinnesotaMinneapolisUSA
  5. 5.Department of Radiology, Center for Magnetic Resonance ResearchUniversity of MinnesotaMinneapolisUSA

Personalised recommendations