Interplay Between Age and Neuroinflammation in Multiple Sclerosis: Effects on Motor and Cognitive Functions

Abstract

Aging is one of the main risk factors for the development of many neurodegenerative diseases. Emerging evidence has acknowledged neuroinflammation as potential trigger of the functional changes occurring during normal and pathological aging. Two main determinants have been recognized to cogently contribute to neuroinflammation in the aging brain, i.e., the systemic chronic low-grade inflammation and the decline in the regulation of adaptive and innate immune systems (immunosenescence, ISC). The persistence of the inflammatory status in the brain in turn may cause synaptopathy and synaptic plasticity impairments that underlie both motor and cognitive dysfunctions. Interestingly, such inflammation-dependent synaptic dysfunctions have been recently involved in the pathophysiology of multiple sclerosis (MS). MS is an autoimmune neurodegenerative disease, typically affecting young adults that cause an early and progressive deterioration of both cognitive and motor functions. Of note, recent controlled studies have clearly shown that age at onset modifies prognosis and exerts a significant effect on presenting phenotype, suggesting that aging is a significant factor associated to the clinical course of MS. Moreover, some lines of evidence point to the different impact of age on motor disability and cognitive deficits, being the former most affected than the latter. The precise contribution of aging-related factors to MS neurological disability and the underlying molecular and cellular mechanisms are still unclear. In the present review article, we first emphasize the importance of the neuroinflammatory dependent mechanisms, such as synaptopathy and synaptic plasticity impairments, suggesting their potential exacerbation or acceleration with advancing age in the MS disease. Lastly, we provide an overview of clinical and experimental studies highlighting the different impact of age on motor disability and cognitive decline in MS, raising challenging questions on the putative age-related mechanisms involved.

Keywords: aging; cognition; experimental autoimmune encephalomyelitis; multiple sclerosis; neurodegeneration; neuroinflammation; synaptic plasticity; synaptopathy.

Figure 1

Key neuroinflammatory processes occurring in the central nervous system (CNS) of multiple sclerosis (MS) patients influenced by aging. Immune cell infiltration from the periphery, mainly through the blood–brain barrier, is a prominent feature of early-stage MS (top panel). Peripheral innate and adaptive immune cells, along with activated CNS-resident microglia and astrocytes, promote demyelination, axonal injury and synaptopathy mainly through action of soluble inflammatory (IL-1β, Interleukin-1β; TNF, tumor necrosis factor; IFN-γ, interferon-γ; IL-17, interleukin-17) and neurotoxic mediators. Neuronal damage can be completely or partly resolved due to remyelination, resolution of inflammation and neuroprotective/reparative mechanisms (growth factors). Furthermore, additional mechanisms, from local synaptic plasticity to brain rewiring, intervene to functionally compensate synaptic loss (long-term potentiation, LTP). With advancing years, premature aging processes such as peripheral immunosenescence (ISC) and inflammaging may lead to age-related changes in the blood. Neuronal senescence and unusual microglia (primed) activation as well as astrogliosis (IL-1β; IL-6; TNF; granulocyte–macrophage colony-stimulating factor, GM-CSF; CC-chemokine ligand 2, CCL2) might contribute at exacerbating MS neuroinflammatory processes (synaptopathy, impaired synaptic plasticity, reduced production of brain derived neurotrophic factor (BDNF) and insuline-like growth factor (IGF-1)). Later on (bottom panel), immune cell infiltration wanes, perhaps due to adaptive immune cell exhaustion from chronic antigen exposure. However, chronic CNS-intrinsic inflammation, and other processes influenced by age (such as oxidative stress, mitochondrial injury, iron accumulation and excitotoxicity) might contribute at exacerbating early pathological processes leading to neurodegeneration. Further microglial recruitment and activation might be induced by interaction with astrocytes releasing CCL2 and GM-CSF as occur during aging. Astrocytes can prevent remyelination at sites of neuroaxonal injury by inhibiting progenitor cells from developing into mature oligodendrocyte cells (ODCs). RNS, reactive nitrogen species; ROS, reactive oxygen species.

Figure 2

Sequence of pathological and reparative events occurring during MS disease course, leading to severe neurological impairments. With advancing aging, neurodegenerative and neuroinflammatory processes are exacerbated causing severe cognitive and motor deficits. Inflammation is present at all stages of the disease, starting from an early phase dominated by peripheral immune cells invasion into the CNS to a progressive and chronic CNS inflammation. Since the early phase of the relapsing/remitting forms demyelination, synaptopathy and axonal damage occur causing progressive neurodegeneration. To avoid brain damage and to functionally compensate for eventual deficits of synaptic inputs, mechanisms of neuroprotection, remyelination and synaptic plasticity intervene. The transition from relapsing-remitting course MS (RRMS) to secondary progressive MS (SPMS) is likely to be the point at which the compensatory brain plasticity reserve bypassing of neuronal injury is exhausted. Usually after the fifth decade, regardless of the preceding disease course and severity, the inevitability and the rate of neurological decline are highly consistent.