Increased deep gray matter iron is present in clinically isolated syndromes

Objective: Abnormal iron accumulation in MS has been known for decades, however it remains to be established whether iron reflects a cause or epiphenomenon of pathology. The objective of the present study is to determine if iron is increased in the brains of patients with clinically isolated syndromes (CIS) suggestive of early MS.

Methods: Twenty-two patients with a CIS and 16 age- and sex-matched controls underwent 3T MRI studies. Differences in R2*, a metric of iron concentration, were assessed for all voxels throughout the brain. Similar clusters of significant differences were grouped, wherein mean R2* was regressed against a number of parameters, including extended disability status scale (EDSS), age, disease duration, and internal jugular vein (IJV) cross-sectional area (CSA), as measured from magnetic resonance time-of-flight venograms.

Results: Patients had significantly increased R2* in globus pallidus, thalamus, right pulvinar, and cortical areas. Thalamic R2* correlated positively with EDSS. Decreased white matter R2* was detected at various positions in the patient group average. No correlations were found between any changes in R2* and IJV CSA.

Interpretation: Iron is increased in CIS in deep gray matter, suggesting this iron accumulation, well-known in definite MS, occurs early in the disease course. Increases in thalamic iron are associated with worsened clinical status. Decreased white matter R2* may be interpreted as diffuse damage to normal appearing white matter, not often reported in CIS. Observations do not support a role for venous abnormalities in either iron accumulation or white matter damage.