Cognitive Reserve as a Useful Concept for Early Intervention Research in Multiple Sclerosis

Cognitive Impairment in Multiple SclerosisMultiple sclerosis (MS) is a lifelong progressive neurologic disease typically diagnosed between ages 20 and 40 years: a time when persons are striving to accomplish normative goals of young adulthood (e.g., establishing a career).More than half of MS patients suffer cognitive decline [for review, see Ref.(1)] especially memory problems and cognitive inefficiency (e.g., slowed processing speed, difficulty multi-tasking). Clinico-Pathologic DissociationThere is great variability in cognitive status across MS patients, even among patients with similar patterns of disease burden/progression (2, 3).This is evidenced in part by the relatively modest/incomplete correlation between MS disease burden (e.g., T2 lesion volume, cerebral atrophy) and cognitive functions, whether studied cross-sectionally [e.g., Ref. (2)] or longitudinally [e.g., Ref.(3)].That is, some MS patients are better able to cope with disease burden without cognitive deficits.[Note: there is an important and advancing literature on the relationship between cognition and MRI parameters in persons with MS [e.g., Ref. (4-6)], although a thorough review of this literature is beyond the scope of this opinion piece.In each case, however, the relationship between disease burden and cognitive outcomes remains incomplete.]This dissociation between disease burden and cognitive outcome is common in other neurologic diseases as well, including Alzheimer's disease (AD) (7-9).Indeed, some persons accumulate substantial AD neuropathology (e.g., beta-amyloid) without dementia, whereas other persons suffer dementia at comparable or even lower levels of pathology (8, 9).These observations have motivated the question: how are some people better able to withstand neurologic disease burden without cognitive impairment? Importance of Prediction and Early Intervention to Prevent Cognitive DeclineSystematic reviews report little-to-no efficacy of pharmacological (10) and behavioral (11) treatments for memory impairment in MS patients.As such, the best treatment of cognitive impairment in MS may be the proactive prevention of cognitive decline in the first place.Similarly, treatments for memory impairment in persons with AD have proven largely ineffective, and research has recently shifted toward very early pre-clinical intervention to prevent the onset of dementia (which may represent a point of no return).The science and clinical practice of early intervention/preventative medicine hinges on our ability to accurately identify patients at greatest risk for future cognitive decline or dementia.Targeted enrollment of at-risk patients into early intervention trials will improve statistical power, because beneficial effects of early treatment can only be observed if the