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Timothy L. Vollmer, MD
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Weill Medical College of Cornell University

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The link of inflammation and neurodegeneration in progressive MS: STUDY



Progressive multiple sclerosis (MS) is characterized clinically by the accumulation of neurological disability without unequivocal recovery. Understanding the mechanisms that determine entering in this stage of the disease is a great challenge in order to identify potential therapeutic targets. Recent advances in defining more accurately the progressive phenotype of MS, have concluded that differences between primary and secondary progressive forms of disease are relatively quantitative rather than qualitative. In both cases, a large number of molecular and cellular events that might lead to neurodegeneration have been suggested. These include microglia activation, chronic oxidative injury, accumulation of mitochondrial damage in axons, age-related disturbances and dysfunctional axonal transport among others. Commonly, these pathological mechanisms have been considered as a result of inflammatory demyelination but a primary degenerative condition has also been argued. It is now clear that both events contribute to the progression of the disease, however their temporal sequence is still a matter of debate. A detailed knowledge of progressive MS pathogenesis will allow to develop effective treatments for both progression and symptom management that should be based on a combination of anti-inflammatory, regenerative and neuroprotective strategies. In this review, we summarize current data and recent hypothesis about pathological forces that drive progression of damage in MS, i.e. cumulative cortical demyelination and neurodegeneration as well as diffuse alterations (microglia activation, axonal injury and atrophy) throughout white and grey matter in the brain and spinal cord. Finally, we discuss the potential of the aforementioned proposed disease mechanisms with regard to developing suitable therapies to halt the progression in MS pathology.

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disorder of the central nervous system (CNS) and it is the most common cause of non-traumatic neurological disability in young adults [1, 2, 3, 4, 5, 6, 7]. The diagnostic criteria for MS are the clinical course of disease supported by paraclinical laboratory assessments and the demonstration by magnetic resonance imaging (MRI) of dissemination of lesions in space and time. The initial clinical phenotype of MS is frequently characterized by episodes of neurological disturbances followed with residual deficits or full recovery (relapsing-remitting MS, RRMS) and in a minority (10–20 %) by a slowly accumulation of disability from the onset (primary progressive MS, PPMS). Usually with time, a majority of RRMS patients (up to 70 %) transitions into a predominant gradual worsening over exacerbations or relapses (secondary progressive MS, SPMS) [8].

Recently, the classification of the MS phenotypes has been reorganized into categories according to the presence/absence of activity and/or gradual illness progression [9]. Disease activity is defined by clinical relapses and/or lesion activity in CNS imaging and is related to episodes of tissue injury associated with inflammation. Progression is linked to increasing neurologic dysfunction which by current understanding reflects neurodegenerative processes. Progression and activity are very close to one another but conceptually four phenotypes are possible: progression with/without activity; no progression but with activity; and no progression and no activity (stable disease). Thus, SPMS and PPMS are considered parts of the spectrum of progressive MS (PMS) phenotypes and differences between them are relative rather than absolute. Almost no treatment options are available for PMS patients (more than 50 % of people with MS), so a good clinical classification of patients is very important to better design trials for study the value of new therapies [10, 11]. However, the most fundamental issue in developing new treatments for PMS is to understand the pathological events that underpin the disease process.

The pathological mechanisms that drive neurodegeneration in PMS are poorly understood though a large range of disease processes have been proposed as discussed here. Commonly, neurodegeneration has been regarded as a result of inflammatory demyelination due to peripheral immune system activation (the outside-in hypothesis). Recently an explanation of disease progression suggests that inflammatory demyelinating processes in early MS trigger a cascade of events (among others microglia activation, chronic oxidative injury, mitochondrial damage in axons) that lead to neurodegeneration and are amplified by pathogenic mechanisms related to brain ageing and accumulated disease burden [2, 12, 13, 14]. Alternatively, MS can be regarded as a primary degenerative condition which initiates in the myelinating unit (oligodendroglia, their processes and myelin) and results in neuroinflammation (the inside-out hypothesis) [15, 16]. It is highly likely that immune-triggered inflammation in turn drives further damage and degeneration of CNS elements, creating a vicious circle. According to this hypothesis, progression in MS would be present from the beginning of illness and progressive cytodegeneration would underlie all disease processes. Resolution of these conflicting ideas is unresolved, nonetheless both suggest that treatment of PMS, preferable at the early stages of disease, should be based on a combination of anti-inflammatory, regenerative and neuroprotective strategies [11, 17, 18]. Nevertheless, although inflammatory and neurodegenerative events act in concert to induce MS-specific brain damage their relevance changes during the course of chronic disease evolution.

The pathology of MS is defined by a spectrum of tissue alterations in the CNS [2, 6, 19]. Classically include plaques of primary demyelination with oligodendrocyte loss and profound axonal degeneration surrounded by an astrocytic scar formation in the white and gray matter of the brain and spinal cord. These plaques are typically inactive and very frequent in all stages of MS. In contrast, active lesions display a focal disruption of the blood-brain-barrier (BBB) together with inflammatory cells (lymphocytes, macrophages and activated microglia) which are present throughout the lesion or at the periphery in acute or chronic active plaques respectively. In PMS half of focal plaques are characterized by a peripheral small rim composed of a small number of inflammatory cells (slowly expanding pre-existing lesions) whereas damage to BBB is less obvious. In addition to focal plaques, diffuse alterations affecting the normal-appearing CNS with a low-grade on-going inflammation are seen in patients with PMS (Table 1). These changes include microglial activation mild demyelination and axonal-neuronal loss in the context of an inflammatory process partly compartmentalized behind an intact BBB.

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