Imaging Correlates of Leukocyte Accumulation and CXCR4/CXCL12 in Multiple Sclerosis

Abstract

Conventional magnetic resonance imaging (MRI) is frequently used to confirm clinical diagnosis of multiple sclerosis (MS), monitor disease evolution, and assess response to treatment. Conventional MRI evaluations show several advantages over clinical assessments, including their more objective nature and increased sensitivity to MS-related changes.^1,2 However, there are only weak or modest correlations between the clinical manifestations of the disease and conventional MRI measures of the disease burden especially in progressive MS.^3-5 T2-weighted sequences depict a wide spectrum of pathological changes in brain tissue and therefore lack specificity. Moreover, T2-weighted images do not show tissue damage occurring in normal-appearing white matter (NAWM) and gray matter, which are known to be extensively injured in the late stages of MS.⁶ More pathologically specific brain imaging methods include magnetic resonance spectroscopy, T1-weighted MRI, diffusion transfer imaging, and magnetization transfer ratio (MTR). Hypointense lesions on T1-weighted MRI (“black holes”) correspond to areas of more significant demyelination, axonal loss, and axonal pathological features in MS tissue.^7-10 The pathological substrates of magnetic resonance–related changes are currently of high interest, in the effort to understand the pathogenesis of disability in patients with MS. Our recent MRI pathological study of MS brain tissue showed that areas abnormal on T2-weighted and T1-weighted MRI with an abnormal MTR (T2/T1/MTR) often correspond to demyelinated lesions with significantly fewer axons but increased axonal swelling and loss of axonal sodium/potassium adenosine triphosphatase.^7,11 Areas abnormal on T2-weighted MRI but with a normal MTR and normal T1-weighted imaging results were associated with less severe tissue damage, less axonal loss, and much less axonal swelling and the presence of axonal sodium/potassium adenosine triphosphatase. The majority of regions abnormal only on T2-weighted imaging (T2 only) featured local microglial activation and were characterized as active or chronic active lesions. T2/T1/MTR regions, which had the most axonal degeneration, were principally chronic inactive lesions. The current study was undertaken to extend these findings, first by detailed analysis of inflammatory elements in the lesions and second by characterizing the CXCR4/CXCL12 system.