Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex

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Cortical tissue injury is a key pathological feature of progressive multiple sclerosis (MS) and correlates with irreversible physical and cognitive decline.1 A widely held theory states that the progressive stage of MS is characterized by compartmentalization of central nervous system (CNS) inflammation behind an intact blood–brain barrier (BBB).2 According to this view, the inaccessibility of the CNS in progressive disease might explain why immunomodulatory compounds fail to produce clinical benefit. However, there is limited experimental evidence to support this explanation. A greater understanding of the pathogenesis of cortical injury in MS is fundamental for developing novel disease‐modifying drugs that could slow or even halt disability accumulation in the progressive stage.
Meningeal inflammation appears to be a central driver of cortical pathology in MS.3 However, the role of BBB disruption in this process has been relatively overlooked. Given the anatomical relationship between the subarachnoid compartment and penetrating perivascular spaces, BBB disruption and meningeal inflammation could both be intricately linked to the initiation and/or exacerbation of cortical pathology. To date, the evidence of cortical BBB disruption in MS has been limited. Endothelial tight junction abnormalities have been detected in cortical normal‐appearing gray matter (NAGM), a finding suggestive of BBB disruption.4 However, attempts to detect surrogates of BBB disruption, such as extravasated plasma proteins, in postmortem cortical MS tissue have so far failed.5
The serum protein, fibrinogen, is a good surrogate marker of BBB disruption because of its abundance, large size (340 kDa), restriction to the intravascular compartment, and lack of expression in the healthy CNS. Thrombin mediates the polymerization of fibrinogen to insoluble fibrin, and thus helps maintain vascular hemostasis. Plasmin mediates the dissolution of fibrin, a process tightly regulated by plasminogen activator inhibitors (PAIs), such as PAI‐1. It is not currently possible to distinguish between fibrin and fibrinogen in postmortem specimens, largely because of their molecular similarity and shared epitopes, and hence the commonly used term fibrin(ogen). Fibrin(ogen) can stimulate inflammatory sequelae in addition to their role in the coagulation cascade.6
Animal models of MS have implicated fibrin(ogen) deposition and PAI‐1 dysregulation in disease pathogenesis. In experimental autoimmune encephalomyelitis (EAE), fibrinogen extravasation induces activation of microglia and subsequent axonal damage before onset of clinical signs, as well as promoting recruitment of myelin specific T cells.8 Blocking the interaction of fibrinogen with microglia supresses relapsing paralysis,10 and EAE can also be ameliorated by fibrin depletion11 and PAI‐1 inhibition.12
Studies investigating fibrin(ogen) and PAI‐1 in animal models of MS are relevant to understanding MS in humans. Similar to EAE, BBB disruption and deposition of fibrin(ogen) are among the earliest pathological features of human MS and are linked with inflammation and demyelination.13 Proteomic assessment of actively demyelinating plaques further points to specific dysregulation of coagulation proteins.15 PAI‐1 is upregulated in acute white matter (WM) lesions, but also in cerebrospinal fluid (CSF) and serum, where it has been linked to disease activity.16 The potential clinical relevance of elevated PAI‐1 is highlighted by the recent observation that PAI‐1 polymorphisms are linked to MS susceptibility.19 These observations provide a compelling rationale to revisit cortical fibrin(ogen) deposition and PAI‐1 expression and their relationships to neuronal damage in MS postmortem tissue. Assessment of fibrin(ogen) deposition at late stages of MS, wherein cortical parenchymal inflammation is sparse, has not been undertaken to date.
In the current study, we provide unequivocal evidence that fibrin(ogen) deposition is common and extensive in the progressive MS cortex and is significantly associated with the extent of neurodegeneration. We reinforce these findings by showing that cortical PAI‐1 is upregulated in cases with abundant fibrin(ogen) deposition.

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