LAUSR

Despite the historical focus on white matter pathology, it is now increasingly recognised that cortical tissue injury is critical to disease outcome. Cortical pathology occurs from the earliest disease stages, predominates in progressive MS, and correlates with physical and cognitive disability [1]. However, our understanding of disease processes operative in the MS cortex remains poor and, in particular, the contribution of BBB dysfunction has been relatively overlooked. A recent radiological study and pathological findings from our group make steps to address these shortcomings and provide fresh insight into the role of BBB dysfunction in cortical pathology. Maranzano et al. undertook a retrospective analysis of serial MRI scans from an early MS cohort. Over a 2-year period, 36% of MS patients had cortical gadolinium (Gd)enhancing lesions, of which 95% were leukocortical [2]. While MRI studies are limited in their ability to detect cortical lesions, these findings importantly corroborate previous histological work showing that a subset of early cortical lesions are associated with BBB disruption [3]. These findings in early disease are substantiated by our work in progressive MS [4]. We have shown that fibrin(ogen), a surrogate marker of BBB disruption, is deposited across the motor cortex. Importantly, levels of fibrin(ogen) correlated with both defective cortical fibrinolysis and neuronal loss, which supports previous work on the proinflammatory and neurotoxic effects of fibrin(ogen) [5]. Given these findings, we propose that cortical BBB disruption might lead to persistent fibrin clots throughout the MS cortex, which may contribute to neurodegeneration and disability progression. Taken together these two studies raise a number of interesting points. Firstly, we found that extracellular fibrin(ogen) is predominantly deposited in deeper cortical layers. The proximity of these layers to the subjacent white matter may implicate the early leukocortical lesions observed by Maranzano et al. as a source of fibrin(ogen). The aberrant fibrinolysis we observed in the MS cortex could enable this early fibrin(ogen) to remain in the cortex for decades and lead to neurodegeneration, particularly in the functionally relevant cortical layer 5 neurons. While this link is appealing, leukocortical lesions were not detected in any appreciable quantity in our cohort, although this may be confounded by postmortem biases. Further, the significant remyelinating capacity of the cortex relative to underlying white matter [6] could lead to the persistence of fibrin(ogen) and neuronal loss long after a lesion has remyelinated. Alternatively, fibrin(ogen) may accumulate over decades through a chronically dysfunctional BBB. Here, traditional Gd-enhancement appears to have limited sensitivity [7] and more sensitive MRI [8, 9] and nuclear imaging techniques [10] may hold promise. Ultimately, development of nuclear imaging techniques with fibrin(ogen) labelling may provide the definitive answer. Secondly, fibrin(ogen) was almost exclusively found in grey matter, often with a sharp border with the clear underlying white matter. Whether there are specific disease mechanisms or vascular changes that facilitate fibrin(ogen) deposition in this distribution requires further investigation. It will also be important to appreciate differences in microenvironment between white and grey matter, and even between different cortical layers, that could alter the metabolism of extravasated fibrin(ogen) over microscopic distances. The role of chronic meningeal inflammation and/or its associated diffusible factors in fibrin(ogen) processing also remains unknown and warrants further study. In summary, these two studies challenge the fundamental concept that BBB disruption is not a feature of MS cortical * Gabriele C. DeLuca [email protected]