Skip to main content
SpringerLink
Log in

Myelin Breakdown and Iron Changes in Huntington’s Disease: Pathogenesis and Treatment Implications

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Background

Postmortem and in vivo imaging data support the hypothesis that premature myelin breakdown and subsequent homeostatic remyelination attempts with increased oligodendrocyte and iron levels may contribute to Huntington’s Disease (HD) pathogenesis and the symmetrical progress of neuronal loss from earlier-myelinating striatum to later-myelinating regions. A unique combination of in vivo tissue integrity and iron level assessments was used to examine the hypothesis.

Methods

A method that uses two Magnetic resonance imaging (MRI) instruments operating at different field-strengths was used to quantify the iron content of ferritin molecules (ferritin iron) as well as tissue integrity in eight regions in 11 HD and a matched group of 27 healthy control subjects. Three white matter regions were selected based on their myelination pattern (early to later-myelinating) and fiber composition. These were frontal lobe white matter (Fwm) and splenium and genu of the corpus callosum (Swm and Gwm). In addition, gray matter structures were also chosen based on their myelination pattern and fiber composition. Three striatum structures were assessed [caudate, putamen, and globus pallidus (C, P, and G)] as well as two comparison gray matter regions that myelinate later in development and are relatively spared in HD [Hippocampus (Hipp) and Thalamus (Th)].

Results

Compared to healthy controls, HD ferritin iron levels were significantly increased in striatum C, P, and G, decreased in Fwm and Gwm, and were unchanged in Hipp, Th, and Swm. Loss of tissue integrity was observed in C, P, Fwm, and especially Swm but not Hipp, Th, G, or Gwm. This pattern of findings was largely preserved when a small subset of HD subjects early in the disease process was examined.

Conclusions

The data suggest early in the HD process, myelin breakdown and changes in ferritin iron distribution underlie the pattern of regional toxicity observed in HD. Prospective studies are needed to verify myelin breakdown and increased iron levels are causal factors in HD pathogenesis. Tracking the effects of novel interventions that reduce myelin breakdown and iron accumulation in preclinical stages of HD could hasten the development of preventive treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

AD:

Alzheimer’s disease

C:

Caudate

CNS:

Central nervous system

BDNF:

Brain-derived neurotrophic factor

FDRI:

Field-dependent R 2 increase (an in vivo MRI measure of ferritin iron)

Fwm:

Frontal lobe white matter

G:

Globus pallidus

Gwm:

Genu of the corpus callosum white matter

HD:

Huntington’s disease

Hipp:

Hippocampus

MRI:

Magnetic resonance imaging

P:

Putamen

R 2 :

Transverse relaxation rate (an in vivo MRI measure of myelin breakdown)

Swm:

Splenium of the corpus callosum white matter

Th:

Thalamus

References

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

    PubMed  CAS  Google Scholar 

  2. Li SH, Li XJ (2004) Huntingtin and its role in neuronal degeneration. Neuroscientist 10:467–475

    Article  PubMed  CAS  Google Scholar 

  3. Landles C, Bates GP (2004) Huntingtin and the molecular pathogenesis of Huntington’s disease. Fourth in molecular medicine review series. EMBO Rep 5:958–963

    Article  PubMed  CAS  Google Scholar 

  4. Harper PS, Shaw D (1996) Huntington’s disease: genetic and molecular studies. In: Harper PS (eds) Huntington’s disease 2nd edn. W.B.Saunders, Philadelphia, pp 241–293

    Google Scholar 

  5. Persichetti F, Carlee L, Faber PW, McNeil SM, Ambrose CM, Srinidhi J, Anderson M, Barnes GT, Gusella JF, MacDonald ME (1996) Differential expression of normal and mutant Huntington’s disease gene alleles. Neurobiol Dis 3:183–190

    Article  PubMed  CAS  Google Scholar 

  6. Bartzokis G, Cummings J, Perlman S, Hance DB, Mintz J (1999) Increased basal ganglia iron levels in Huntington disease. Arch Neurol 56:569–574

    Article  PubMed  CAS  Google Scholar 

  7. Bartzokis G, Lu PH, Tishler TA, Perlman S (2006) In vivo assessment of iron in Huntington’s disease and other age-related degenerative brain diseases. In: Sigel A, Sigel H, Sigel RKO (eds) Metal ions in life sciences, vol 1. Wiley, Chichester, pp 151–177

    Google Scholar 

  8. Jones AL (1996) The Huntington’s disease gene and its protein product. In: Harper PS (eds) Huntington’s disease, 2 edn. W.B.Saunders, Philadelphia, pp 293–316

    Google Scholar 

  9. Mascalchi M, Lolli F, Della Nave R, Tessa C, Petralli R, Gavazzi C, Politi LS, Macucci M, Filippi M, Piacentini S (2004) Huntington disease: volumetric, diffusion-weighted, and magnetization transfer MR imaging of brain. Radiology 232:867–873

    Article  PubMed  Google Scholar 

  10. Jernigan TL, Salmon DP, Butters N, Hesselink JR (1991) Cerebral structure on MRI, Part II: specific changes in Alzheimer’s and Huntington’s diseases. Biol Psychiatry 29:68–81

    Article  PubMed  CAS  Google Scholar 

  11. Aylward EH, Anderson NB, Bylsma FW, Wagster MV, Barta PE, Sherr M, Feeney J, Davis A, Rosenblatt A, Pearlson GD, Ross CA (1998) Frontal lobe volume in patients with Huntington’s disease. Neurology. 50:252–258

    Article  PubMed  CAS  Google Scholar 

  12. Mann DM, Oliver R, Snowden JS (1993) The topographic distribution of brain atrophy in Huntington’s disease and progressive supranuclear palsy. Acta Neuropathol (Berl) 85:553–559

    CAS  Google Scholar 

  13. Rosas HD, Koroshetz WJ, Chen YI, Skeuse C, Vangel M, Cudkowicz ME, Caplan K, Marek K, Seidman LJ, Makris N, Jenkins BG, Goldstein JM (2003) Evidence for more widespread cerebral pathology in early HD: An MRI-based morphometric analysis. Neurology 60:1615–1620

    PubMed  CAS  Google Scholar 

  14. Thieben MJ, Duggins AJ, Good CD, Gomes L, Mahant N, Richards F, McCusker E, Frackowiak RS (2002) The distribution of structural neuropathology in pre-clinical Huntington’s disease. Brain 125:1815–1828

    Article  PubMed  CAS  Google Scholar 

  15. Fennema-Notestine C, Archibald SL, Jacobson MW, Corey-Bloom J, Paulsen JS, Peavy GM, Gamst AC, Hamilton JM, Salmon DP, Jernigan TL (2004) In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease. Neurology 63:989–995

    PubMed  CAS  Google Scholar 

  16. Paulsen JS, Magnotta VA, Mikos AE, Paulson HL, Penziner E, Andreasen NC, Nopoulos PC (2006) Brain structure in preclinical Huntington’s disease. Biol Psychiatry 59:57–63

    Article  PubMed  CAS  Google Scholar 

  17. Reading SA, Yassa MA, Bakker A, Dziorny AC, Gourley LM, Yallapragada V, Rosenblatt A, Margolis RL, Aylward EH, Brandt J, Mori S, van Zijl P, Bassett SS, Ross CA (2005) Regional white matter change in pre-symptomatic Huntington’s disease: a diffusion tensor imaging study. Psychiatry Res 140:55–62

    Article  PubMed  Google Scholar 

  18. Bruyn GW (1973) Neuropathological changes in Huntington’s chorea. In: Barbeau A, Chase TN, Paulson GW (eds) Huntington’s Chorea, vol 1. Raven Press, New York, pp 399–403

    Google Scholar 

  19. Liss L, Paulson GW, Sommer A (1973) Rigid form of Huntington’s chorea: a clinicopathological study of three cases. In: Barbeau A, Chase TN, Paulson GW (eds) Huntington’s Chorea, vol 1. Raven Press, New York, pp 405–424

    Google Scholar 

  20. Klintworth GK (1973) Huntington’s chorea—morphologic contributions of a century. In: Barbeau A, Paulson GW, Chase TN (eds) Advances in neurology. Huntington’s chorea, vol 1. 1872–1972. Raven Press, New York, pp 353–368

    Google Scholar 

  21. de la Monte SM, Vonsattel JP, Richardson EP Jr (1988) Morphometric demonstration of atrophic changes in the cerebral cortex, white matter, and neostriatum in Huntington’s disease. J Neuropathol Exp Neurol 47:516–525

    Google Scholar 

  22. Peters A, Sethares C (2004) Oligodendrocytes, their progenitors and other neuroglial cells in the aging primate cerebral cortex. Cereb Cortex 14:995–1007

    Article  PubMed  Google Scholar 

  23. Sotrel A, Paskevich PA, Kiely DK, Bird ED, Williams RS, Myers RH (1991) Morphometric analysis of the prefrontal cortex in Huntington’s disease. Neurology 41:1117–1123

    PubMed  CAS  Google Scholar 

  24. Myers RH, Vonsattel JP, Paskevich PA, Kiely DK, Stevens TJ, Cupples LA, Richardson EP Jr, Bird ED (1991) Decreased neuronal and increased oligodendroglial densities in Huntington’s disease caudate nucleus. J Neuropathol Exp Neurol 50:729–742

    PubMed  CAS  Google Scholar 

  25. Gomez-Tortosa E, MacDonald ME, Friend JC, Taylor SA, Weiler LJ, Cupples LA, Srinidhi J, Gusella JF, Bird ED, Vonsattel JP, Myers RH (2001) Quantitative neuropathological changes in presymptomatic Huntington’s disease. Ann Neurol 49:29–34

    Article  PubMed  CAS  Google Scholar 

  26. Bartzokis G (2004) Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease. Neurobiol Aging 25:5–18

    Article  PubMed  CAS  Google Scholar 

  27. Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR (2004) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5:863–873

    Article  PubMed  CAS  Google Scholar 

  28. Dexter DT, Jenner P, Schapira AH, Marsden CD (1992) Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. The Royal Kings and Queens Parkinson’s Disease Research Group. Ann Neurol 32(Suppl 1): S94–S100

    Article  PubMed  CAS  Google Scholar 

  29. Chen JC, Hardy PA, Kucharczyk W, Clauberg M, Joshi JG, Vourlas A, Dhar M, Henkelman RM (1993) MR of human postmortem brain tissue: correlative study between T2 and assays of iron and ferritin in Parkinson and Huntington disease. AJNR Am J Neuroradiol 14:275–281

    PubMed  CAS  Google Scholar 

  30. Youdim MB, Ben-Shachar D, Riederer P (1991) Iron in brain function and dysfunction with emphasis on Parkinson’s disease. Eur Neurol 31(Suppl 1):34–40

    PubMed  Google Scholar 

  31. Connor JR, Benkovic SA (1992) Iron regulation in the brain: histochemical, biochemical, and molecular considerations. Ann Neurol 32(Suppl 1):S51–S61

    Article  PubMed  CAS  Google Scholar 

  32. Connor JR, Menzies SL (1995) Cellular management of iron in the brain. J Neurol Sci 134(Suppl):33–44

    Article  PubMed  CAS  Google Scholar 

  33. Bartzokis G, Tishler TA, Shin I-S, Lu PH, Cummings JL (2004) Brain ferritin iron as a risk factor for age at onset in neurodegenerative diseases. In: LeVine S, Connor J, Schipper H (eds) Redox-active metals in neurological disorders, vol 1012. Ann N Y Acad Sci, New York, pp 224–236

  34. Berg D, Youdim MB (2006) Role of iron in neurodegenerative disorders. Top Magn Reson Imaging 17:5–17

    Article  PubMed  Google Scholar 

  35. Oldendorf WH, Oldendorf W Jr (1988) Basics of magnetic resonance imaging. Martinus Nijhof Publishing, Boston, MA

    Google Scholar 

  36. Kamman RL, Go KG, Brouwer W, Berendsen HJ (1988) Nuclear magnetic resonance relaxation in experimental brain edema: effects of water concentration, protein concentration, and temperature. Magn Reson Med 6:265–274

    Article  PubMed  CAS  Google Scholar 

  37. Bartzokis G, Aravagiri M, Oldendorf WH, Mintz J, Marder SR (1993) Field dependent transverse relaxation rate increase may be a specific measure of tissue iron stores. Magn Reson Med 29:459–464

    Article  PubMed  CAS  Google Scholar 

  38. Bartzokis G, Mintz J, Sultzer D, Marx P, Herzberg JS, Phelan CK, Marder SR (1994) In vivo MR evaluation of age-related increases in brain iron. AJNR Am J Neuroradiol 15:1129–1138

    PubMed  CAS  Google Scholar 

  39. Vymazal J, Hajek M, Patronas N, Giedd JN, Bulte JW, Baumgarner C, Tran V, Brooks RA (1995) The quantitative relation between T1-weighted and T2-weighted MRI of normal gray matter and iron concentration. J Magn Reson Imaging 5:554–560

    Article  PubMed  CAS  Google Scholar 

  40. Vymazal J, Brooks RA, Patronas N, Hajek M, Bulte JW, Di Chiro G (1995) Magnetic resonance imaging of brain iron in health and disease. J Neurol Sci 134(Suppl 1):19–26

    Article  PubMed  CAS  Google Scholar 

  41. Peters A, Rosene DL, Moss MB, Kemper TL, Abraham CR, Tigges J, Albert MS (1996) Neurobiological bases of age-related cognitive decline in the rhesus monkey. J Neuropathol Exp Neurol 55:861–874

    PubMed  CAS  Google Scholar 

  42. Bartzokis G, Sultzer D, Lu PH, Nuechterlein KH, Mintz J, Cummings J (2004) Heterogeneous age-related breakdown of white matter structural integrity: implications for cortical “disconnection” in aging and Alzheimer’s disease. Neurobiol Aging 25:843–851

    Article  PubMed  CAS  Google Scholar 

  43. Bartzokis G, Lu PH, Geschwind DH, Edwards N, Mintz J, Cummings JL (2006) Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. Arch Gen Psychiatry 63:63–72

    Article  PubMed  CAS  Google Scholar 

  44. Bartzokis G, Beckson M, Hance DB, Marx P, Foster JA, Marder SR (1997) MR evaluation of age-related increase of brain iron in young adult and older normal males. Magn Reson Imaging 15:29–35

    Article  PubMed  CAS  Google Scholar 

  45. Bartzokis G, Sultzer D, Mintz J, Holt LE, Marx P, Phelan CK, Marder SR (1994) In vivo evaluation of brain iron in Alzheimer’s disease and normal subjects using MRI. Biol Psychiatry 35:480–487

    Article  PubMed  CAS  Google Scholar 

  46. Vymazal J, Brooks RA, Baumgarner C, Tran V, Katz D, Bulte JW, Bauminger R, Di Chiro G (1996) The relation between brain iron and NMR relaxation times: an in vitro study. Magn Reson Med 35:56–61

    Article  PubMed  CAS  Google Scholar 

  47. Vymazal J, Zak O, Bulte JW, Aisen P, Brooks RA (1996) T1 and T2 of ferritin solutions: effect of loading factor. Magn Reson Med 36:61–65

    Article  PubMed  CAS  Google Scholar 

  48. Floyd RA, Carney JM (1993) The role of metal ions in oxidative processes and aging. Toxicol Ind Health 9:197–214

    PubMed  CAS  Google Scholar 

  49. Morris CM, Candy JM, Oakley AE, Bloxham CA, Edwardson JA (1992) Histochemical distribution of non-haem iron in the human brain. Acta Anat (Basel) 144:235–257

    CAS  Google Scholar 

  50. Bartzokis G, Sultzer D, Cummings BJ, Holt LE, Hance DB, Henderson VW, Mintz J (2000) In vivo evaluation of brain iron in Alzheimer’s disease and normal controls using magnetic resonance imaging. Arch Gen Psychiatry 57:47–53

    Article  PubMed  CAS  Google Scholar 

  51. Bartzokis G, Tishler TA, Lu PH, Villablanca P, Altshuler LL, Carter M, Huang D, Edwards N, Mintz J (2007) Brain ferritin iron may influence age- and gender-related risks of neurodegeneration. Neurobiol Aging 28:414–423

    Article  PubMed  CAS  Google Scholar 

  52. Bulte JW, Miller GF, Vymazal J, Brooks RA, Frank JA (1997) Hepatic hemosiderosis in non-human primates: quantification of liver iron using different field strengths. Magn Reson Med 37:530–536

    Article  PubMed  CAS  Google Scholar 

  53. Bartzokis G, Cummings JL, Markham CH, Marmarelis PZ, Treciokas LJ, Tishler TA, Marder SR, Mintz J (1999) MRI evaluation of brain iron in earlier- and later-onset Parkinson’s disease and normal subjects. Magn Reson Imaging 17:213–222

    Article  PubMed  CAS  Google Scholar 

  54. Doraiswamy PM, Finefrock AE (2004) Metals in our minds: therapeutic implications for neurodegenerative disorders. Lancet Neurol 3:431–434

    Article  PubMed  CAS  Google Scholar 

  55. Ke Y, Ming Qian Z (2003) Iron misregulation in the brain: a primary cause of neurodegenerative disorders. Lancet Neurol 2:246–253

    Article  PubMed  CAS  Google Scholar 

  56. Lamantia AS, Rakic P (1990) Cytological and quantitative characteristics of four cerebral commissures in the rhesus monkey. J Comp Neurol 291:520–537

    Article  PubMed  CAS  Google Scholar 

  57. Kemper T (1994) Neuroanatomical and neuropathological changes during aging and dementia. In: Albert M, Knoefel J (eds) Clinical neurology of aging 2nd edn. Oxford University Press, New York, pp 3–67

    Google Scholar 

  58. Yakovlev PI, Lecours AR (1967) Regional development of the brain in early life. Blackwell Scientific Publications, Boston, pp 3–70

    Google Scholar 

  59. Hallgren B, Sourander P (1958) The effect of age on the non-haemin iron in the human brain. J Neurochem 3:41–51

    Article  PubMed  CAS  Google Scholar 

  60. Hotelling H (1940) The selection of variates for use in prediction with some comments on the general problem of nuisance parameters. Ann Math Stat 11:271–283

    Google Scholar 

  61. Steiger JH (1980) Tests for comparing elements of a correlation matrix. Psychol Bull 87:245–251

    Article  Google Scholar 

  62. Hartman BK, Agrawal HC, Agrawal D, Kalmbach S (1982) Development and maturation of central nervous system myelin: comparison of immunohistochemical localization of proteolipid protein and basic protein in myelin and oligodendrocytes. Proc Natl Acad Sci USA 79:4217–4220

    Article  PubMed  CAS  Google Scholar 

  63. Trotter JL, Wegescheide CL, Garvey WF (1984) Regional studies of myelin proteins in human brain and spinal cord. Neurochem Res 9:133–146

    Article  PubMed  CAS  Google Scholar 

  64. Schwob VS, Clark HB, Agrawal D, Agrawal HC (1985) Electron microscopic immunocytochemical localization of myelin proteolipid protein and myelin basic protein to oligodendrocytes in rat brain during myelination. J Neurochem 45:559–571

    Article  PubMed  CAS  Google Scholar 

  65. Tolwani RJ, Cosgaya JM, Varma S, Jacob R, Kuo LE, Shooter EM (2004) BDNF overexpression produces a long-term increase in myelin formation in the peripheral nervous system. J Neurosci Res 77:662–669

    Article  PubMed  CAS  Google Scholar 

  66. Du Y, Fischer TZ, Lee LN, Lercher LD, Dreyfus CF (2003) Regionally specific effects of BDNF on oligodendrocytes. Dev Neurosci 25:116–126

    Article  PubMed  CAS  Google Scholar 

  67. Djalali S, Holtje M, Grosse G, Rothe T, Stroh T, Grosse J, Deng DR, Hellweg R, Grantyn R, Hortnagl H, Ahnert-Hilger G (2005) Effects of brain-derived neurotrophic factor (BDNF) on glial cells and serotonergic neurones during development. J Neurochem 92:616–627

    Article  PubMed  CAS  Google Scholar 

  68. Gauthier LR, Charrin BC, Borrell-Pages M, Dompierre JP, Rangone H, Cordelieres FP, De Mey J, MacDonald ME, Lessmann V, Humbert S, Saudou F (2004) Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118:127–138

    Article  PubMed  CAS  Google Scholar 

  69. Canals JM, Pineda JR, Torres-Peraza JF, Bosch M, Martin-Ibanez R, Munoz MT, Mengod G, Ernfors P, Alberch J (2004) Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington’s disease. J Neurosci 24:7727–7739

    Article  PubMed  CAS  Google Scholar 

  70. O’Kusky J, Colonnier M (1982) Postnatal changes in the number of astrocytes, oligodendrocytes, and microglia in the visual cortex (area 17) of the macaque monkey: a stereological analysis in normal and monocularly deprived animals. J Comp Neurol 210:307–315

    Article  PubMed  CAS  Google Scholar 

  71. Bartzokis G (2004) Quadratic trajectories of brain myelin content: unifying construct for neuropsychiatric disorders. Neurobiol Aging 25:49–62

    Article  CAS  Google Scholar 

  72. LeVine SM, Macklin WB (1990) Iron-enriched oligodendrocytes: a reexamination of their spatial distribution. J Neurosci Res 26:508–512

    Article  PubMed  CAS  Google Scholar 

  73. Quintana C, Bellefqih S, Laval JY, Guerquin-Kern JL, Wu TD, Avila J, Ferrer I, Arranz R, Patino C (2006) Study of the localization of iron, ferritin, and hemosiderin in Alzheimer’s disease hippocampus by analytical microscopy at the subcellular level. J Struct Biol 153:42–54

    Article  PubMed  CAS  Google Scholar 

  74. Dwork AJ (1995) Effects of diet and development upon the uptake and distribution of cerebral iron. J Neurol Sci 134(Suppl 1):45–51

    Article  PubMed  CAS  Google Scholar 

  75. Connor JR, Menzies SL (1996) Relationship of iron to oligodendrocytes and myelination. Glia 17:83–93

    Article  PubMed  CAS  Google Scholar 

  76. Erb GL, Osterbur DL, LeVine SM (1996) The distribution of iron in the brain: a phylogenetic analysis using iron histochemistry. Brain Res Dev Brain Res 93:120–128

    Article  PubMed  CAS  Google Scholar 

  77. Hill JM, Switzer RC (1984) The regional distribution and cellular localization of iron in the rat brain. Neuroscience 11:595–603

    Article  PubMed  CAS  Google Scholar 

  78. Sapp E, Kegel KB, Aronin N, Hashikawa T, Uchiyama Y, Tohyama K, Bhide PG, Vonsattel JP, DiFiglia M (2001) Early and progressive accumulation of reactive microglia in the Huntington disease brain. J Neuropathol Exp Neurol 60:161–172

    PubMed  CAS  Google Scholar 

  79. Pavese N, Gerhard A, Tai YF, Ho AK, Turkheimer F, Barker RA, Brooks DJ, Piccini P (2006) Microglial activation correlates with severity in Huntington disease: a clinical and PET study. Neurology 66:1638–1643

    Article  PubMed  CAS  Google Scholar 

  80. Mehlhase J, Gieche J, Widmer R, Grune T (2006) Ferritin levels in microglia depend upon activation: modulation by reactive oxygen species. Biochim Biophys Acta 1763:854–859

    Article  PubMed  CAS  Google Scholar 

  81. Zhang X, Surguladze N, Slagle-Webb B, Cozzi A, Connor JR (2006) Cellular iron status influences the functional relationship between microglia and oligodendrocytes. Glia 54:795–804

    Article  PubMed  CAS  Google Scholar 

  82. O’Kusky J, Colonnier M (1982) A laminar analysis of the number of neurons, glia, and synapses in the visual cortex (area 17) of adult macaque monkeys. J Comp Neurol 210:278–290

    Article  PubMed  CAS  Google Scholar 

  83. Bartzokis G, Beckson M, Lu PH, Nuechterlein KH, Edwards N, Mintz J (2001) Age-related changes in frontal and temporal lobe volumes in men: a magnetic resonance imaging study. Arch Gen Psychiatry 58:461–465

    Article  PubMed  CAS  Google Scholar 

  84. Bartzokis G (2002) Schizophrenia: breakdown in the well-regulated lifelong process of brain development and maturation. Neuropsychopharmacology 27:672–683

    Article  PubMed  Google Scholar 

  85. Bartzokis G (2005) Brain myelination in prevalent neuropsychiatric developmental disorders: primary and comorbid addiction. Adolesc Psychiatry 29:55–96

    Google Scholar 

  86. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44:559–577

    PubMed  CAS  Google Scholar 

  87. Crapper McLachlan DR, Dalton AJ, Kruck TP, Bell MY, Smith WL, Kalow W, Andrews DF (1991) Intramuscular desferrioxamine in patients with Alzheimer’s disease [published erratum appears in Lancet 1991 Jun 29;337(8757):1618] [see comments]. Lancet 337:1304–1308

    Article  PubMed  CAS  Google Scholar 

  88. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny R, Li QX, Tammer A, Carrington D, Mavros C, Volitakis I, Xilinas M, Ames D, Davis S, Beyreuther K, Tanzi RE, Masters CL (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60:1685–1691

    Article  PubMed  Google Scholar 

  89. Shin RW, Kruck TP, Murayama H, Kitamoto T (2003) A novel trivalent cation chelator feralex dissociates binding of aluminum and iron associated with hyperphosphorylated tau of Alzheimer’s disease. Brain Res 961:139–146

    Article  PubMed  CAS  Google Scholar 

  90. Kaur D, Yantiri F, Rajagopalan S, Kumar J, Mo JQ, Boonplueang R, Viswanath V, Jacobs R, Yang L, Beal MF, DiMonte D, Volitaskis I, Ellerby L, Cherny RA, Bush AI, Andersen JK (2003) Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson’s disease. Neuron 37:899–909

    Article  PubMed  CAS  Google Scholar 

  91. Nguyen T, Hamby A, Massa SM (2005) Clioquinol down-regulates mutant huntingtin expression in vitro and mitigates pathology in a Huntington’s disease mouse model. Proc Natl Acad Sci USA 102:11840–11845

    Article  PubMed  CAS  Google Scholar 

  92. Newman MB, Arendash GW, Shytle RD, Bickford PC, Tighe T, Sanberg PR (2002) Nicotine’s oxidative and antioxidant properties in CNS. Life Sci 71:2807–2820

    Article  PubMed  CAS  Google Scholar 

  93. Finefrock AE, Bush AI, Doraiswamy PM (2003) Current status of metals as therapeutic targets in Alzheimer’s disease. J Am Geriatr Soc 51:1143–1148

    Article  PubMed  Google Scholar 

  94. Mi S, Miller RH, Lee X, Scott ML, Shulag-Morskaya S, Shao Z, Chang J, Thill GLevesque M, Zhang M, Hession C, Sah D, Trapp B, He Z, Jung V, McCoy JM, Pepinsky RB (2005) LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci 8:745–751

    Article  PubMed  CAS  Google Scholar 

  95. Youdim MB, Stephenson G, Ben Shachar D (2004) Ironing iron out in Parkinson’s disease and other neurodegenerative diseases with iron chelators: a lesson from 6-hydroxydopamine and iron chelators, desferal and VK-28. Ann NY Acad Sci 1012:306–325

    Article  PubMed  CAS  Google Scholar 

  96. Bartzokis G, Lu PH, Mintz J (2004) Quantifying age-related myelin breakdown with MRI: novel therapeutic targets for preventing cognitive decline and Alzheimer’s disease. J Alzheimers Dis 6:S53–S59

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by NIMH grants (MH51928; MH6357-01A1; and MH066029-01A2); an NIA Alzheimer’s Disease Center Grant (AG 16570); funds received from the State of California, Department of Health Services, contract No. 013608-001; the Sidell-Kagan Foundation; and a Merit Review Grant from the Department of Veterans Affairs.

Author information

Authors and Affiliations

  1. Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA

    George Bartzokis, Po H. Lu, Todd A. Tishler, Sophia M. Fong, Bolanle Oluwadara, Yvette Bordelon & Susan Perlman

  2. Laboratory of Neuroimaging, Department of Neurology, Division of Brain Mapping, UCLA, Los Angeles, CA, 90095, USA

    George Bartzokis

  3. Department of Psychiatry, Greater Los Angeles VA Healthcare System, West Los Angeles, CA, 90073, USA

    George Bartzokis, Po H. Lu, Todd A. Tishler, Sophia M. Fong & Bolanle Oluwadara

  4. Neuroscience Interdepartmental Graduate Program, The David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA

    Todd A. Tishler

  5. Department of Radiology, The David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA

    J. Paul Finn

  6. Department of Neurology and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA

    Danny Huang

  7. Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA

    Jim Mintz

  8. UCLA Alzheimer’s Disease Center, 10911 Weyburn Avenue Suite 200, Los Angeles, CA, 90095-7226, USA

    George Bartzokis

Authors
  1. George Bartzokis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Po H. Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Todd A. Tishler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sophia M. Fong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bolanle Oluwadara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Paul Finn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Danny Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yvette Bordelon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jim Mintz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Susan Perlman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George Bartzokis.

Additional information

Special issue dedicated to Dr. Moussa Youdim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bartzokis, G., Lu, P.H., Tishler, T.A. et al. Myelin Breakdown and Iron Changes in Huntington’s Disease: Pathogenesis and Treatment Implications. Neurochem Res 32, 1655–1664 (2007). https://doi.org/10.1007/s11064-007-9352-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-007-9352-7

Keywords

Search

Navigation