Multiple Sclerosis Phenotypes as a Continuum: The Role of Neurologic Reserve

Abstract

Purpose of review: This review presents the hypothesis that loss of neurologic reserve explains onset of progressive multiple sclerosis (PrMS).

Recent findings: Evidence supporting the separate classification of PrMS and relapsing multiple sclerosis (RMS) is limited and does not explain PrMS or the response of these patients to therapy.

Summary: We argue that multiple sclerosis (MS) progresses along a continuum from RMS to PrMS, with differing levels of neurologic reserve accounting for phenotypic differences. In early MS, inflammation causes brain atrophy with symptoms buffered by neurologic reserve. As brain loss from normal aging and MS continues, reserve is depleted and effects of subclinical MS disease activity and aging are unmasked, manifesting as PrMS. Most therapies show limited benefit in PrMS; patients are older, have fewer inflammatory events, and the effects of aging cause continued loss of neurologic function, even if inflammation is terminated. Loss of neurologic reserve means patients with PrMS cannot recover function, unlike patients with RMS.

Figure 1. Inflammatory Activation in Early MS Leads to Astrocyte Activation, Demyelination, and Neuronal Destruction

(A) The dura mater and subarachnoid space of the brain are well connected to the circulation, filled with blood vessels and lymphatic vessels across which immune cells, such as B and T lymphocytes, can enter and exit the CNS. (B) Autoreactive B cells and T cells mature in the lymph nodes, including the deep cervical lymph nodes, and enter the circulation, where (C) these cells cross the blood-brain barrier and enter the CNS. Effector functions of autoreactive B cells include antibody and cytokine production, and antigen presentation to T cells, which further drives CNS inflammation. The proinflammatory cytokines released by these cells drive the activation of CNS resident cells, including astrocytes.^e49 The inflammatory processes mediated by activated astrocytes include the release of TNF-α, production of reactive oxygen species including NO (via iNOS) and other toxic intermediates, leading to oligodendrocyte damage and apoptosis, neuronal/axonal damage, and the loss of astrocytes themselves. Oligodendrocyte damage may be compounded by the fact that some patients with MS can be predisposed to factors that inhibit oligodendrocyte maturation, and loss of normal astrocyte function may also affect the blood-brain barrier, microglial activation, and neuronal damage. Indeed, repair in lesions is accompanied not only by regeneration of oligodendrocytes but the reappearance and maturation of astrocytes. Of interest, the role of astrocytes was elucidated by studies with the S1PRm fingolimod. S1PRms are also thought to be potentially neuroprotective in the CNS through their direct effects on astrocytes, as well as neurons and oligodendrocytes.^e49 Autoreactive B cells are able to leave the CNS, crossing the blood-brain barrier by draining through the deep cervical lymph nodes and on into the peripheral lymphatic system, where further rounds of maturation and clonal expansion can occur before repopulating the CNS and driving pathologic process further. iNOS = inducible nitric oxide synthase; NO = nitric oxide; S1PRm = sphingosine-1 phosphate receptor modulator; TNF = tumor necrosis factor.

Figure 2. The Concept of Brain/Neurologic Reserve in MS^,

(A) Cross-sectional relationships between components of reserve and performance. This model provides a roadmap for the nomenclature and expected relationships among reserve-related constructs at a specific point in time. Going counterclockwise from left, genetic and inborn factors refer to inborn or background determinants of brain function (e.g., single nucleotide polymorphisms). These factors are the only direct causes of (innate) brain reserve, which represents a patient's potential brain structure (e.g., head size, intracranial volume, synapse count, and CNS structure). Regardless of a patient's brain reserve, the patient's neuronal network function represents the present level of functioning of a patient (e.g., functional connectivity as measured by functional magnetic resonance imaging). Then, the combination of a patient's present neuronal network function, environmental factors (e.g., socioeconomic adversity or advantage and stressful events), and disease burden (e.g., diagnosis, symptoms, treatment side effects, and progressive disability) determines the patient's expected performance on a task. Finally, the difference between observed and expected performance is affected by the person's expected performance, (acquired) reserve and reserve-related person characteristics. Reserve and reserve-related person characteristics are each hypothesized to lead to larger differences between observed and expected performance, but through different mechanisms. Whereas reserve relates specifically to compensatory or protective brain function, reserve-related person characteristics refer to attitudes, values, or socioemotional skills that are posited to enhance an individual's resilience in the face of adversity and/or disease. Both reserve and reserve-related person characteristics are posited to be directly affected by the individual's past and current reserve-building activities. Such activities are hypothesized to include a multidimensional array of activities that promote brain health, including cultural/intellectual pursuits, physical activity, social/community participation, spiritual/religious practices, and dietary/lifestyle habits. (B) Brain reserve as a function of normal aging and in MS. In healthy people, brain reserve is initially high, but slowly declines as people age. Only at advanced ages would cognitive/brain health be affected by the loss of brain reserve. In people with MS, brain reserve can initially buffer/compensate for the effects of disease (preclinical phase). However, in MS, brain reserve is depleted more rapidly by the effects of aging and disease processes. Brain reserve is lowered to a level at which it can no longer compensate and the impact of disease on cognitive/brain health becomes apparent, manifesting as disease progression. (C) As described above, brain reserve buffers/slows disease progression. Patients with lower levels of brain reserve may progress through all the classically defined stages of disease progression, with overt “unbuffered” symptoms at each stage that are easily diagnosed (top line). Those with intermediate levels of brain reserve may appear asymptomatic for longer, with the disease progressing in the background before the loss of reserve manifests as overt relapsing-remitting symptoms before progressive disease (middle line). Patients with very high brain reserve may appear functionally asymptomatic even while the clinical effects of the relapsing phase are ongoing, buffered until disease processes overcome reserve and manifest overtly as primary progressive disease (bottom line). MS = multiple sclerosis. Adapted from (A) Schwartz et al., 2016.

Figure 3. Rates of Brain Atrophy in MS and in Normal Aging and Rates of Disability Worsening in RRMS and SPMS^,

Stacked histograms showing the trend of brain atrophy slopes by age in HCs (red) and MS-specific atrophy (blue). The total rate of atrophy in patients with MS is represented by the total height of each histogram bar (combining colors). For SIENA (A) and the thalamus (B), the contribution of MS-specific atrophy and normal aging to the total atrophy slope changed significantly across decades, whereas normal aging was stable across decades in the caudate (C) and the putamen (D). The rates of disability worsening in RRMS and SPMS are depicted in (E), in which mean annualized EDSS scores indicate that disability worsening is significantly higher in patients with SPMS in the first 3 years after initiating treatment than in those with RRMS. Data are annualized to allow comparison between time epochs of different duration. *p < 0.5, **p < 0.01, ***p < 0.001, Mann-Whitney U test. EDSS = Expanded Disability Status Scale; HC = healthy control; MS = multiple sclerosis; RRMS = relapsing-remitting MS; SIENA = structural image evaluation using normalization of atrophy; SPMS = secondary progressive MS. Adapted from (A–D) Azevedo et al., 2019, and (E) Coles et al., 2006.