White Matter Changes Underlie Iron’s Impact on Brain Health

If a shortage of iron harms development, yet having too much is linked to cognitive decline and neurodegeneration, what’s the lowdown on how this metal influences brain health? Paul Thompson of the University of California, Los Angeles, and colleagues looked for clues in brain scans and blood tests of healthy young volunteers. They found greater white matter integrity in people with high brain iron. The research, published online January 9 in the Proceedings of the National Academy of Sciences, also correlated healthier brain structure with a genetic polymorphism that confers mild iron excess. The study “links a lot of information about iron regulation to something that’s physically happening in the brain,” Thompson told ARF. However, the big picture remains complex, he and others noted. Iron accumulates in the brains of older adults and in people with neurodegenerative disease, such as Alzheimer’s, yet the impact of the buildup differs with age and other factors.

As part of an ongoing effort to understand how genetic and environmental factors might affect brain health, Thompson’s lab became interested in iron. “We knew iron is needed to make myelin, but we also knew that high iron levels in older people can promote degenerative disease,” he noted. “So we thought that iron might be a good predictor of brain integrity.” With their expertise in magnetic resonance imaging (MRI) techniques, Thompson and colleagues scrutinized brain scans for physical evidence of iron’s impact. His group has used these neuroimaging methods to pick up subtle brain changes related to known AD risk factors. Last year, they reported finding poor white matter integrity in people with the clusterin gene variant associated with increased AD risk (ARF related news story on Braskie et al., 2011).

For the current study, first author Neda Jahanshad and colleagues analyzed brain MRI scans from 615 healthy young adult twins and siblings. Twin studies help researchers discern the contributions of genetic and environmental factors on the outcomes being studied. The researchers examined whether brain structure changes seen by MRI tracked with serum transferrin concentrations, which are thought to be inversely related to brain iron levels. (When iron supplies are low, the liver churns out transferrin to mobilize what little iron is available. When iron levels rise, the liver makes less transferrin.) After controlling for age and sex, participants with lower levels of serum transferrin had better white matter integrity as measured by diffusion tensor imaging (DTI), a newer variation of MRI that is well suited for studying nerve fiber connections. Because the scientists could predict the brain outcome of one twin based on the transferrin levels of his or her sibling, they knew that common genes and/or upbringing were causing the correlation. And since the correlation was more pronounced in identical than fraternal twin pairs, “[we knew] the same genes underlie both traits,” Thompson said.

To tease out the genetic contributions, his team analyzed the participants’ genotyping data, focusing on 20 polymorphisms in the transferrin and hemachromatosis (HFE) genes, which explain some 40 percent of the variance in serum transferrin levels (Benyamin et al., 2009). About 30 percent of study participants carried the H63D variant of HFE, and these folks had lower serum transferrin levels (i.e., more brain iron) and better brain wiring as judged by DTI.

All told, the scientists found that peripheral transferrin is linked to brain integrity, and that common genes—including the HFE H63D polymorphism, which associates with iron overload—influence both traits in these young adults.

However, what iron does across a lifespan is more complicated, said George Bartzokis at UCLA, noting that the current study only looked at people in their twenties. Brain iron increases with age, for example, and men have higher levels than women (Bartzokis et al., 2007) and seem less able to tolerate the buildup, according to Bartzokis’ research. He and his colleagues recently linked poor verbal memory to high hippocampal iron in men, but not in women (Bartzokis et al., 2011).

“The simplest reading of all this might be that it’s really crucial when you’re young to have good iron intake, since you’re building your brain,” Thompson said. “But as you get older, (excess iron) is a double-edged sword.” Biological reactions involving iron produce harmful free radicals, and in old age “your liver becomes less able to handle the iron accumulation, so it just builds up in the brain with no means to clear it,” Thompson said.

How does iron accumulation affect the brain over time? Some studies have reported unusually high levels of iron in the brains of people with Alzheimer’s disease (see Bartzokis et al., 1994), yet a recent meta-analysis found data on brain iron levels in AD patients to be widely varying and inconclusive (Schrag et al., 2011). Research on whether the HFE H63D variant associated with iron overload influences AD risk also seems controversial; some studies found the polymorphism accelerates AD onset (Alizadeh et al., 2009; Sampietro et al., 2001; Combarros et al., 2003), while a meta-analysis points to a protective role (see Lin et al., 2011 and AlzGene HFE H63D meta-analysis).

Further illustrating the complex role of iron in AD, a recent study by Federica Giambattistelli, Campus Bio-Medico University, Rome, and colleagues suggested that the HFE H63D polymorphism may increase AD risk but only in people with signs of liver distress (Giambattistelli et al., 2011). “In other words, the dysfunction of the liver seemed to affect the ‘penetrance’ of the HFE damage,” Giambattistelli noted in an e-mail to ARF. A curious finding in the current study also complicates the iron story—in people with low serum transferrin (high brain iron), some brain regions were smaller, yet others were larger, compared to individuals with high transferrin levels. This pattern initially surprised the authors, who predicted smaller brain volumes in people with low iron. However, Thompson noted, normal brain development involves, at certain points, rises and falls of growth in different regions, which might manifest as thinner cortex and smaller basal ganglia, but larger volumes for some of the deeper structures—“in short, a pattern of apparent losses as well as gains,” Thompson said. Iron may subtly affect these patterns. “And if a person’s development is slower than others, you can also end up with a pattern of excesses and deficits, and the location differs depending on when their brain development was affected.”

The next step is to see how H63D and other iron-related polymorphisms affect brain measures in larger cohorts—“tens of thousands of people, including elderly,” Thompson said. Toward this end, he and colleagues founded a genetics consortium called ENIGMA, which pooled more than 20,000 brain scans and genome scans from people around the globe. “This is a worldwide effort to find out which genes help or harm our brains as we age, and what they do to the brain,” Thompson said.—Esther Landhuis

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References

News Citations

  1. Neuroimaging Offers a CLU to AD Risk Factor’s Functional Effects

Paper Citations

  1. Braskie MN, Jahanshad N, Stein JL, Barysheva M, McMahon KL, de Zubicaray GI, Martin NG, Wright MJ, Ringman JM, Toga AW, Thompson PM. Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults. J Neurosci. 2011 May 4;31(18):6764-70. PubMed.
  2. Benyamin B, McRae AF, Zhu G, Gordon S, Henders AK, Palotie A, Peltonen L, Martin NG, Montgomery GW, Whitfield JB, Visscher PM. Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels. Am J Hum Genet. 2009 Jan;84(1):60-5. PubMed.
  3. Bartzokis G, Tishler TA, Lu PH, Villablanca P, Altshuler LL, Carter M, Huang D, Edwards N, Mintz J. Brain ferritin iron may influence age- and gender-related risks of neurodegeneration. Neurobiol Aging. 2007 Mar;28(3):414-23. PubMed.
  4. Bartzokis G, Lu PH, Tingus K, Peters DG, Amar CP, Tishler TA, Finn JP, Villablanca P, Altshuler LL, Mintz J, Neely E, Connor JR. Gender and iron genes may modify associations between brain iron and memory in healthy aging. Neuropsychopharmacology. 2011 Jun;36(7):1375-84. PubMed.
  5. Bartzokis G, Sultzer D, Mintz J, Holt LE, Marx P, Phelan CK, Marder SR. In vivo evaluation of brain iron in Alzheimer's disease and normal subjects using MRI. Biol Psychiatry. 1994 Apr 1;35(7):480-7. PubMed.
  6. Schrag M, Mueller C, Oyoyo U, Smith MA, Kirsch WM. Iron, zinc and copper in the Alzheimer's disease brain: a quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion. Prog Neurobiol. 2011 Aug;94(3):296-306. PubMed.
  7. Alizadeh BZ, Njajou OT, Millán MR, Hofman A, Breteler MM, van Duijn CM. HFE variants, APOE and Alzheimer's disease: findings from the population-based Rotterdam study. Neurobiol Aging. 2009 Feb;30(2):330-2. PubMed.
  8. Sampietro M, Caputo L, Casatta A, Meregalli M, Pellagatti A, Tagliabue J, Annoni G, Vergani C. The hemochromatosis gene affects the age of onset of sporadic Alzheimer's disease. Neurobiol Aging. 2001 Jul-Aug;22(4):563-8. PubMed.
  9. Combarros O, García-Román M, Fontalba A, Fernández-Luna JL, Llorca J, Infante J, Berciano J. Interaction of the H63D mutation in the hemochromatosis gene with the apolipoprotein E epsilon 4 allele modulates age at onset of Alzheimer's disease. Dement Geriatr Cogn Disord. 2003;15(3):151-4. PubMed.
  10. Lin M, Zhao L, Fan J, Lian XG, Ye JX, Wu L, Lin H. Association between HFE polymorphisms and susceptibility to Alzheimer's disease: a meta-analysis of 22 studies including 4,365 cases and 8,652 controls. Mol Biol Rep. 2011 Jun 24; PubMed.
  11. Giambattistelli F, Bucossi S, Salustri C, Panetta V, Mariani S, Siotto M, Ventriglia M, Vernieri F, Dell'Acqua ML, Cassetta E, Rossini PM, Squitti R. Effects of hemochromatosis and transferrin gene mutations on iron dyshomeostasis, liver dysfunction and on the risk of Alzheimer's disease. Neurobiol Aging. 2011 Apr 20; PubMed.

External Citations

  1. clusterin
  2. H63D
  3. ENIGMA

Further Reading

Papers

  1. Giambattistelli F, Bucossi S, Salustri C, Panetta V, Mariani S, Siotto M, Ventriglia M, Vernieri F, Dell'Acqua ML, Cassetta E, Rossini PM, Squitti R. Effects of hemochromatosis and transferrin gene mutations on iron dyshomeostasis, liver dysfunction and on the risk of Alzheimer's disease. Neurobiol Aging. 2011 Apr 20; PubMed.
  2. Bartzokis G, Lu PH, Tingus K, Peters DG, Amar CP, Tishler TA, Finn JP, Villablanca P, Altshuler LL, Mintz J, Neely E, Connor JR. Gender and iron genes may modify associations between brain iron and memory in healthy aging. Neuropsychopharmacology. 2011 Jun;36(7):1375-84. PubMed.
  3. Bartzokis G, Tishler TA, Lu PH, Villablanca P, Altshuler LL, Carter M, Huang D, Edwards N, Mintz J. Brain ferritin iron may influence age- and gender-related risks of neurodegeneration. Neurobiol Aging. 2007 Mar;28(3):414-23. PubMed.

Primary Papers

  1. Jahanshad N, Kohannim O, Hibar DP, Stein JL, McMahon KL, de Zubicaray GI, Medland SE, Montgomery GW, Whitfield JB, Martin NG, Wright MJ, Toga AW, Thompson PM. Brain structure in healthy adults is related to serum transferrin and the H63D polymorphism in the HFE gene. Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):E851-9. PubMed.

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