References for this Review were identified through searches of PubMed with the search terms “autopsy”, “histopathology”, “multiple sclerosis”, “MRI”, “pathology”, “post-mortem”, “lesions”, “normal-appearing white matter”, “grey matter”, “spinal cord”, “cerebellum”, “hippocampus”, “thalamus”, and “iron” from Jan 1, 2013, to Oct 31, 2018. Articles were also identified through searches of the authors' own files. Only papers published in English were reviewed. The final reference list was generated
ReviewAssociation between pathological and MRI findings in multiple sclerosis
Introduction
Pathological assessment is the gold standard in multiple sclerosis for understanding the processes involved in the disease and its progression, and for the identification of possible future therapeutic targets. MRI is a particularly suitable technology for in-vivo evaluation of pathology, because of its high sensitivity in revealing abnormalities related to multiple sclerosis and in monitoring disease progression and the effects of treatment. The association between multiple sclerosis pathology and MRI findings needs to be continuously verified to improve the technique's specificity in detecting pathological features in this disorder. MRI or other imaging methods with a high specificity for multiple sclerosis pathology could be applied longitudinally after their specificity has been verified.
In 2012, a review paper1 based on a workshop held by a group of international experts in neuropathology and neuroimaging in multiple sclerosis summarised the evidence from correlative pathological MRI studies available at that time. The aim was to discuss concordant data, but also to highlight controversies, identify emerging pathological and MRI findings, and open questions for future research. This discussion included the need to improve imaging specificity, the acquisition of high-resolution images, the combination of MRI methods, and the assessment of specific disease processes (eg, remyelination and iron abnormalities). Improvement of MRI technologies and wider availability of MRI scanners since 2012 has allowed better understanding and MRI monitoring of specific pathological processes related to multiple sclerosis, including not only the presence of central vein sign and hypointense rim, the heterogeneous damage in different CNS regions, and iron accumulation, but also mechanisms of tissue recovery.
This Review summarises the advances in MRI techniques and how the measures they provide correlate with the pathological substrates of multiple sclerosis. In particular, white matter and grey matter lesions, normal-appearing brain tissue abnormalities, damage of relevant structures (eg, spinal cord, thalamus, cerebellum, and hippocampus), and iron accumulation were discussed during a second workshop (Nov 23–24, 2017, Milan, Italy), since they represent the main areas of progress in filling the gap between pathology and MRI findings. Emerging pathological and MRI findings that, in combination, might enhance our understanding of disease pathophysiology and help identify reliable in-vivo markers for monitoring different aspects of multiple sclerosis are also discussed.
Section snippets
White matter lesions
Focal white matter lesions, characterised by inflammation and demyelination, are the most obvious hallmarks of multiple sclerosis histopathology. The inflammatory lesion infiltrate mainly consists of blood-derived monocytes and microglia (for simplicity subsequently termed here as phagocytes), T cells, and B cells.2 In active and demyelinating lesions, commonly found at the beginning of the disease—as documented in biopsy studies in which the onset of symptoms provides an estimate of lesion
Grey matter lesions
The extent of grey matter demyelination in multiple sclerosis varies considerably between patients and can be widespread, especially during the chronic phase. In the neocortex, the proportion of tissue affected by demyelination ranges between 15% and 40% on histological inspection, whereas an average of 30% demyelination is reported for the deep grey matter, mesencephalon, hippocampus, cerebellar cortex, and spinal cord grey matter, with outliers of nearly complete demyelination of the grey
Spinal cord
Spinal cord pathology is common in multiple sclerosis and, compared with brain pathology, more likely to be clinically apparent. Acute symptoms and signs at onset and the chronic loss of function, particularly of the lower limbs, correlate to some extent with findings in pathology specimens in which blood–brain barrier damage, inflammation, demyelination, gliosis, and neuro-axonal loss, have been reported.30, 71, 72
A post-mortem study of 13 patients with multiple sclerosis and five healthy
Normal-appearing brain tissue
Pathologically, normal-appearing white matter has been defined as white matter that appears normal macroscopically and shows normal myelination microscopically, is at least 10 mm away from a plaque's edge, and is differentiated from diffusely abnormal or dirty-appearing white matter, which includes areas of diffuse myelin pallor with ill-defined borders.87 Normal-appearing grey matter has been defined as a region with no evidence of demyelination using immunohistochemistry.34 Regarding MRI, the
Thalamus, cerebellum, and hippocampus
Pathological and MRI studies have consistently demonstrated an early involvement of the thalamus, cerebellum, and hippocampus. Damage to these structures is clinically relevant, since it is strongly associated with locomotor disability and cognitive impairment.94, 95, 96 Other clinically relevant structures are the brainstem and the hypothalamus; however, they have not been discussed during the workshop and are therefore outside the scope of this Review.
The thalamus can show considerable
Iron pathology
The notion of abnormal distribution of brain iron in patients with multiple sclerosis dates back more than 35 years with the observation of iron accumulation around demyelinated multiple sclerosis plaques, using Perls' staining for ferric iron.114 Subsequent studies showed that decreased T2 signal intensity in deep grey matter structures correlated with the amount of iron indicated by Perls' staining in healthy post-mortem brains,115 and that decreased signal intensity on T2-weighted images was
Conclusions and future directions
Over the past 5 years, there have been many advances in MRI measures that reflect pathological findings in patients with multiple sclerosis. Among them, the evaluation of leptomeningeal enhancement and of the lesional central vein sign have been proposed to improve the diagnostic investigation of patients with suspected multiple sclerosis.58 The assessment of microstructural abnormalities and iron accumulation has increased our understanding of the mechanisms responsible for the clinical
Search strategy and selection criteria
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