Iron accumulation in multiple sclerosis: an early pathogenic event

Abstract

Evaluation of: Al-Radaideh AM, Wharton SJ, Lim SY et al. Increased iron accumulation occurs in the earliest stages of demyelinating disease: an ultra-high field susceptibility mapping study in clinically isolated syndrome. Mult. Scler. doi:10.1177/1352458512465135 (2012) (Epub ahead of print).

Iron has been shown to accumulate in deep gray matter structures in many forms of multiple sclerosis (MS), but detecting its presence early in the disease course (e.g., clinically isolated syndrome [CIS]) has been less clear. Here, we review a recent study where MRI scanning at 7 T together with susceptibility mapping was performed to assess iron deposition in CIS and control subjects. Susceptibility indicative of iron deposition was found to be increased in the globus pallidus, caudate, putamen and pulvinar of CIS patients compared with controls. The findings suggest that iron deposition is a pathological change that occurs early in the development of MS. Identifying the mechanisms of iron accumulation and determining whether iron promotes pathogenesis in MS are important areas of future research.

Keywords::

• caudate
• clinically isolated syndrome
• globus pallidus
• iron
• multiple sclerosis
• pulvinar
• putamen
• susceptibility-weighted imaging

Since the initial MRI observation by Drayer et al. [1], there has been a large number of imaging studies (e.g., T2 hypointensity, R2* relaxometry, susceptibility-weighted imaging) that have obtained evidence for increased iron levels in the CNS of patients with multiple sclerosis (MS). Most often, the accumulated iron has been observed by MRI in deep gray matter structures (e.g., caudate, globus pallidus, putamen and/or thalamus) and is present in relapsing–remitting, secondary progressive, adolescent and benign MS [2]. It is unknown whether the accumulated iron has a role in the pathogenesis of MS; however, establishing when iron first accumulates in the course of disease could provide information that has bearing on this question. MRI studies on clinically isolated syndrome (CIS), which is the initial presentation of symptoms associated with a high probability of developing into definite MS, have yielded conflicting results relative to the accumulation of iron [3–5]. Al-Radaideh et al. have utilized a MRI technique with enhanced sensitivity over other procedures to study the deposition of iron in CIS [6].

Summary of methods & results

In the study by Al-Radaideh et al., high-field strength 7 T MRI was used together with T2*-weighted acquisition and postprocessing of data for mapping magnetic susceptibility in 19 patients with CIS and 20 age-matched controls [6]. The acquired data were processed to produce susceptibility-weighted images that were analyzed to detect the accumulation of iron. The measures used the internal capsule as a reference.

Al-Radaideh et al. found that multiple deep gray matter regions (globus pallidus, caudate, putamen and pulvinar) have significantly elevated relative susceptibilities, indicative of greater iron accumulation, in CIS patients compared with controls, and patients in whom CIS has been converted towards definite MS (13 out of 19 patients) had a trend for higher iron levels than for non-converters [6]. Elevated levels of iron were not observed in the thalamus. No correlations were observed between susceptibilities and age, time from the clinical event or Expanded Disability Status Scale score. There was a significant correlation between mean susceptibility values in the caudate and T1 lesion load.

Discussion

It has been known since the 1980s that iron has a propensity to accumulate in the brains of MS patients [1,7,8], but the role that abnormal iron deposits has on the disease course is currently unknown. Elevated levels of detectable iron could occur as an epiphenomenon that develops as a consequence of ongoing pathology (e.g., demyelination, axonal damage and/or neurodegeneration) [3] and have little or no role in contributing to pathogenesis. On the other hand, excess iron could promote or drive pathology. Mishandled iron can catalyze an increased production of reactive oxygen species, which can cause damage to DNA, RNA, mitochondria, proteins, lipids, and so on. Iron within mitochondria, which become altered in MS [9], could facilitate a damaging pro-oxidative environment [10,11] and/or the altered mitochondria could shift the cellular balance of iron leading to iron accumulation [11]. Excess iron is also thought to increase the production of proinflammatory mediators, for example, enhanced cytokine release by iron-loaded, activated macrophages and microglia [2]. Therefore, it is reasonable to consider that abnormal iron deposits could be a source for amplifying cellular damage and thus have a role in disease progression.

Identifying the spatial and temporal deposition of iron in MS could provide valuable clues about its role in disease. In white matter, iron deposits have been observed within and outside the edges of plaques [7,8]. In particular, these deposits have been observed in macrophages, microglia, damaged axons, extravasated red blood cells and as debris, likely as a consequence from demyelination and/or breakdown of red blood cells [2,7,8,12]. These areas of iron deposition are often perivascular and can be associated with ongoing inflammation [8], although inflammation does not always lead to iron deposition as evidenced in a cerebral model of experimental autoimmune encephalomyelitis [13]. Iron deposits may also persist after acute inflammation has subsided [8].

Besides white matter, iron deposits also occur in gray matter, particularly deep gray matter structures – for example, the thalamus, caudate, putamen, globus pallidus and pulvinar. The source and cellular locations of iron deposition in deep gray matter structures are less well understood. Iron deposition in one or more of these structures has been positively correlated with various measures of disease severity, for example, Expanded Disability Status Scale, atrophy and cognitive impairment [2]. Iron accumulation in deep gray matter has also been shown to occur in many forms of MS, that is, relapsing–remitting, secondary progressive, benign and pediatric (adolescent) MS. The observation that iron deposits occur in adolescent MS raises the possibility that iron deposits can occur early in the disease course [14].

CIS is the first occurrence of demyelinating symptoms associated with a strong likelihood of conversion to definite MS. In a previous study, iron deposition levels were examined in CIS using 3T MRI and R2* mapping; no evidence of enhanced iron deposition was observed compared with healthy control subjects [3]. Owing to the lack of increased deposition in CIS, and the fact that iron deposition was significantly elevated in relapsing–remitting MS compared with CIS, the authors suggested that iron accumulation is an epiphenomenon of the disease process, although they did not exclude the possibility that once iron accumulates, it could still promote oxidative damage [3]. In other studies, 1.5 T MRI revealed that the left head of the caudate had a significantly reduced T2 hypointensity, which is indicative of iron, in CIS patients compared with healthy controls [4], and a 3 T system using susceptibility-weighted imaging revealed greater signal attenuation, indicative of iron, in the putamen and pulvinar nucleus [5]. Taken together, these studies paint an ambiguous picture about iron in CIS; that is, is iron significantly elevated in CIS patients relative to age-matched controls, and if so, in which structures?

The high-field strength susceptibility mapping used by Al-Radaideh et al. [6] has greater sensitivity over other techniques to detect iron (e.g., T2 hypointensity, R2* relaxometry) as the susceptibility variation can enhance the contrast of iron deposits relative to background [15] and the sensitivity of iron susceptibility effects increases with the magnetic field strength [16]. Furthermore, since an increasing iron content results in greater phase differences, there is a correlation between iron concentration and signal intensity, which enables quantification [17]. The advantages of their technique likely accounted for the significant findings by Al-Radaideh et al., that is, that CIS patients have increased susceptibilities relative to controls in multiple deep gray matter regions [6]. Even though significant differences were obtained, it is relevant to note that there was still considerable overlap in susceptibility levels between the CIS and control groups indicating that iron accumulation is not a prerequisite for CIS in all affected individuals or that more subtle changes such as iron redistribution [2] are present but not detected by their method. Although iron accumulation likely accounts for the elevated susceptibilities, Al-Radaideh et al. noted that the susceptibilities could also be influenced by differences in myelination [6]; this could be a confounding factor, especially in MS where demyelination and remyelination are present. An interrelated factor is the use of the internal capsule as an internal reference. Myelin and axonal pathology can occur in this region in CIS and MS. Moreover, the internal capsule has a trend to display changes in MRI signals (i.e., T2 hypointensity which can be confused with iron deposition) following neuronal degeneration in gray matter structures [18]. Taken together, a larger study of CIS patients is warranted, perhaps comparing values obtained using several different reference structures.

Al-Radaideh et al. suggest that deep gray matter structures may be sensitive to inflammation occurring in other CNS regions and imply that during the earlier phases of MS, deep gray matter structures are responding by accumulating iron [6]. Accumulation of iron has been observed in the thalamus following traumatic injury to the cortex [18], suggesting that a demyelinating lesion and/or axonal damage in a fiber tract in MS could similarly affect deep gray matter structures. As deep gray matter structures lose incoming and outgoing fibers, trophic support would decrease, which could lead to greater stress on cellular constituents such as mitochondria [19]. Alternatively, demyelination results in a loss of the concentration of sodium channels at the nodes of Ranvier, and the repositioning of ion channels and pumps results in an increased energy demand and hence increased mitochondrial function within axons [9]. Blood flow and oxygen availability are also reduced in the CNS of MS patients [2]. These stresses could result in mitochondrial changes that include biogenesis, resulting in enhanced accumulation of iron [2,10,11]. In future studies, it will be relevant to determine if mitochondrial changes are associated with deep gray matter accumulation of iron in CIS.

Although iron accumulation may occur early in the disease course, the question remains whether iron deposition has a prominent role in the evolution of disease. Multiple studies have found an association between iron levels and various measures of disability [2]; however, one study found no difference in the amount of iron accumulation between benign MS and secondary progressive MS, despite the greater disability in the latter group [20]. This result could be interpreted to indicate that levels of iron deposition do not correlate with advancing disability; thus, increased iron accumulation could be due to a multitude of factors such as duration of disease, age of the patient, lesion burden, lesion location and/or sensitivity of measurement. It would be interesting to see if the more sensitive methodology used by Al-Radaideh et al. [6] would obtain a different result between benign and secondary progressive MS.

Five-year view

Determining the factors that account for iron accumulation in MS and whether iron contributes to the development and progression of disability will be important next steps in MS research. It is likely that iron accumulation occurs by different mechanisms in white and gray matter structures. If iron does promote pathology in MS, then it is likely that its role in pathogenesis will also differ between white and gray matter structures. Addressing these mechanisms will be pertinent for future studies. Moreover, addressing the role of iron in relation to mitochondria could be relevant to furthering the understanding of neurodegeneration in MS [2,11].

Key issues

• • Iron accumulates in both white and gray matter structures in multiple sclerosis (MS).

• • Increased iron deposition is present in various forms of MS, that is, relapsing–remitting MS, secondary-progressive MS, benign MS and adolescent MS.

• • Utilization of high magnetic field strength together with susceptibility-weighted mapping sensitivity revealed evidence for greater iron accumulation in several deep gray matter structures of clinically isolated syndrome patients compared with control subjects.

• • The presence of elevated levels of iron in clinically isolated syndrome indicates that iron accumulation is present at the earliest stages of MS.

• • It is unknown whether or not iron has a pathogenic role in the development and/or progression of MS.

• • Identifying how abnormal iron accumulation intersects with other pathogenic events in MS is an area of future research.

Financial & competing interest disclosure

SM LeVine has ongoing communications and a grant/contract in development with ApoPharma, Inc. and current funding from the Heartland Border Walk for MS. SG Lynch is an investigator in multicenter trials and receives support from Biogen IDEC, Genzyme, Teva, Novartis, Actelion, Hoffman-La Roche, Genentech, Accorda and Opexa. SG Lynch also receives support from grants from the National Multiple Sclerosis Society and the NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.