Neurochemical Research

, Volume 32, Issue 10, pp 1655–1664

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

  • George Bartzokis
  • Po H. Lu
  • Todd A. Tishler
  • Sophia M. Fong
  • Bolanle Oluwadara
  • J. Paul Finn
  • Danny Huang
  • Yvette Bordelon
  • Jim Mintz
  • Susan Perlman
Original Paper

DOI: 10.1007/s11064-007-9352-7

Cite this article as:
Bartzokis, G., Lu, P.H., Tishler, T.A. et al. Neurochem Res (2007) 32: 1655. doi:10.1007/s11064-007-9352-7

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.

Keywords

Brain Neurodegeneration Ferritin FDRI Huntingtin BDNF Excitotoxicity Prevention Onset Oligodendrocyte 

Abbreviations

AD

Alzheimer’s disease

C

Caudate

CNS

Central nervous system

BDNF

Brain-derived neurotrophic factor

FDRI

Field-dependent R2 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

R2

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

Swm

Splenium of the corpus callosum white matter

Th

Thalamus

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • George Bartzokis
    • 1
    • 2
    • 3
    • 8
  • Po H. Lu
    • 1
    • 3
  • Todd A. Tishler
    • 1
    • 3
    • 4
  • Sophia M. Fong
    • 1
    • 3
  • Bolanle Oluwadara
    • 1
    • 3
  • J. Paul Finn
    • 5
  • Danny Huang
    • 6
  • Yvette Bordelon
    • 1
  • Jim Mintz
    • 7
  • Susan Perlman
    • 1
  1. 1.Department of NeurologyThe David Geffen School of Medicine at UCLALos AngelesUSA
  2. 2.Laboratory of Neuroimaging, Department of Neurology, Division of Brain MappingUCLALos AngelesUSA
  3. 3.Department of PsychiatryGreater Los Angeles VA Healthcare SystemWest Los AngelesUSA
  4. 4.Neuroscience Interdepartmental Graduate ProgramThe David Geffen School of Medicine at UCLALos AngelesUSA
  5. 5.Department of RadiologyThe David Geffen School of Medicine at UCLALos AngelesUSA
  6. 6.Department of Neurology and Biobehavioral SciencesThe David Geffen School of Medicine at UCLALos AngelesUSA
  7. 7.Department of Psychiatry and Biobehavioral SciencesThe David Geffen School of Medicine at UCLALos AngelesUSA
  8. 8.UCLA Alzheimer’s Disease CenterLos AngelesUSA

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