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Myelin breakdown and iron changes in Huntington's disease: pathogenesis and treatment implications
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.
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“Alterations in brain iron metabolism with increased iron accumulation were identified by MRI in the striata of patients with Huntington’s disease194 and in particular the basal ganglia (caudate nucleus, putamen, and globus pallidus).195,196”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [194]
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Metadata
- Authors
- Bartzokis, G., Lu, P. H., Tishler, T. A., Fong, S. M., Oluwadara, B., Finn, J. P., Huang, D., Bordelon, Y., Mintz, J., & Perlman, S.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Bartzokis, George
- Venue
- Neurochemical Research
- Published
- 2007-05-05
- Volume
- 32
- Issue
- 10
- Pages
- 1655-1664
- ISSN
- 0364-3190 (ISSN-L)
- 1573-6903
- OpenAlex
- W1986646115
- Cited by
- 238
- References
- 94
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 9 · 2023: 10 · 2022: 14 · 2021: 14 · 2020: 11 · 2019: 14 · 2018: 14 · 2017: 10 · 2016: 9 · 2015: 24 · 2014: 16 · 2013: 18 · 2012: 18
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neurochemical Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health (5r03mh051928-02)
- National Institute on Aging (R01AG027342, P50AG016570, AG 16570)
- National Institute of Mental Health (MH6357-01A1, MH 51928, MH066029-01A2, R01MH066029)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- Huntington's disease, myelin breakdown, tissue integrity, remyelination, oligodendrocytes, striatum, corpus callosum, white matter, pathogenesis, preclinical disease, iron accumulation, MRI field strength
- MeSH terms
- Adult, Aged, Brain, Brain Chemistry, Data Interpretation, Statistical, Female, Ferritins, Humans, Huntington Disease, Image Processing, Computer-Assisted, Iron, Magnetic Resonance Imaging, Male, Middle Aged, Myelin Sheath
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