Multiple Sclerosis Phenotypes as a Continuum

(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., 2016.³³