Innovations In Clinical Neuroscience

HOTTOP Multiple Sclerosis DEC 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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R E V I E W 16 Hot Topics in Multiple Sclerosis [December 2017] secretion of TNF. 41 Levels of sCD14, a marker of macrophageal activity, were higher in patients with PPMS compared to healthy controls, but similar to patients with RRMS in relapses but not in remission. 42 Nevertheless, macrophages (anti-inflammatory M2) are essential for the remyelination by clearing the damaged tissues in the lesions. 40 Dendritic cells can also be found in MS lesions. 32 Dendritic cells from patients with SPMS secrete much higher levels of IL-18 than those from patients with RRMS and healthy controls 43 and induce—in vitro—solely a Th1 cell response not Th1 and Th2 like in RRMS, suggesting a role of dendritic cells in the disease transition into the progressive phase. 44 Based on the similarities between SP and PPMS, a role of dendritic cells in PPMS cannot be excluded. Over the last years, microglial activation (MiA) gained more interest as one of the key mechanisms for neurodegeneration and axonal demise in MS. 30 In PPMS, the microglia were diffusely active in the lesions and in normal-appearing white matter (NAWM) and normal-appearing gray matter (NAGM). 45 Activated microglia in NAWM forms microglial nodules in close proximity to stressed oligodendrocytes and degenerated axons with profound release of oxygen-free radicals. 30 MiA in cortical gray matter of SPMS is caused by the diffusion of inflammatory mediators from the meninges, especially from meningeal B cell infiltration and strongly correlates with clinical disability scores. 46 Similarly, the astrocytes are considered of particular importance in MS. Besides their well-known role in "scar formation," recently the astrocytes have been identified as a potent secretor of different pro-inflammatory cytokines, making them a possible target for therapeutic interventions. 30 White matter damage. Radiologically the white matter pathology in PPMS is divided into three categories as follows. White matter lesions. The well- defined hyperintense T2 WMLs indicate local demyelination of the WM. Histopathologically, the WMLs are either active with hypercellular infiltrate, chronic active, or inactive. Both active and chronic active lesions are characterized by relative preservation of the axons, but the cellular infiltrate differs; in the former, the lymphocytes are the main cells, whereas in the latter the myelin-laden microphages form the mainstay of the lesions. On the other hand, the inactive lesions are characterized by extensive astrogliosis. 47 Diffusely abnormal white matter. Diffusely abnormal white matter (DAWM) refers to the diffuse and subtle signal hyperintensities in the WM. The DAWM in PMS exhibits no acute changes like demyelination or blood–brain barrier (BBB) leakage, nonetheless chronic axonal degeneration and gliosis. DAWM most likely represents degenerative changes secondary to remote focal WM pathologies. 48 Normal-appearing white matter. Normal-appearing white matter exhibits normal signal in the conventional T2 sequences. The NAWM changes include axonal injury without demyelination, low-grade inflammation, microglial, and astrocytic activation without being correlated to the WML load, excluding the possibility that they are "pure" secondary retrograde axonal degeneration. The degree of axonal loss in NAWM, as well as white matter atrophy measurements, correlate with disease severity in SPMS. 49 Gray matter damage (GMD). Gray matter damage emerged over the years as a major determinant of disability and disease progression. 50 GMD involves different lesion types with damage of NAGM. 51 Possible mechanisms are retrospective degenerative changes, inflammatory infiltrate in the meninges, MiA, iron accumulation, and primary oligodendrocytic degeneration. 51 GM atrophy correlate better with the long- term disability than WMLs. 52 THE ROLE OF MITOCHONDRIAL DYSFUNC TION IN PPMS Mitochondrial dysfunction and energy deficits gained interest as a main mechanism of neuronal demise. 53 The mitochondrial dysfunction with subsequent cellular hypoxia is especially relevant for the neurodegeneration of susceptible chronically demyelinated axons commonly found in PMS through energy failure, induction of apoptosis, and enhanced production of oxygen species. 53 Corresponding to that, positive correlation between CSF lactate and disease progression was reported in patients with RRMS. 54 We confirmed a similar correlation in patients with PPMS in a large multicentric CSF cohort including 254 patients with PPMS (unpublished data). A positive correlation between CSF lactate and number of inflammatory MS plaques was reported in another study with 33 clinically isolated syndrome (CIS) patients. 55 Another marker, the level N-acetylaspartate (NAA) measured using MRI spectroscopy, was reduced in patients with MS and correlated to clinical severity of the disease. 56 ROLE OF IRON Iron accumulation in PMS is an age- dependent process leading to free- radicals' release, glutamate toxicity, and exacerbation of the neuronal demise. 57 Iron-induced T2/hypointensities were reported in the GM, WML, and periventricularly around the veins 58 and is correlated with disease progression even better than brain atrophy. 59 Iron deposition in deep gray matter was elevated in patients with SPMS compared to controls. 60 Furthermore, the iron- storage protein "ferritin" and soluble transferrin receptors were elevated in the CSF and serum of patients with SPMS compared to controls. 61 A similar role can be postulated in PPMS. THE MECHANISM OF AXONAL DEGENERATION AND THE REL ATIONSHIP BET WEEN NEUROINFL AMMATION AND NEURODEGENERATION IN PPMS Over the last years, two main hypotheses were postulated to explain the neuronal demise in MS: 62 the inflammation-induced neurodegeneration and the

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