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Cognitive impairment occurs in 40% to 60% of those with multiple sclerosis, with devastating effects for some. Subtle abnormalities may already be present in those with clinically isolated syndromes, but impairment tends to be more severe as the disease progresses. Difficulties with memory, information processing, and executive functions are frequent, but other cognitive skills may also be impaired. Standard markers of disease burden (T2 lesion load) do not correlate closely with these deficits, as exemplified by the finding that cognition is equally impaired in those with primary and secondary progressive disease despite very different T2 lesion loads. Searching for better predictors of cognition, Zivadinov et al (this issue, pp 000–000) report that loss of brain parenchyma predicts cognitive decline better than other MRI indices.1 In their 2 year follow up study of 53 patients with early relapsing remitting multiple sclerosis, although T2 and T1 lesion volumes increased during this period, only the progressive loss of brain volume predicted cognitive decline. The 15 patients (28.3%) who declined cognitively lost an average of 8% of brain parenchyma over the study. Cognitive deterioration was not universal in the early stages of the disease, as exemplified by the fact that over two thirds of their patients remained stable or improved over the 2 year period.
In multiple sclerosis the acute inflammatory process initiates a pathological cascade that results in axonal and myelin loss; this loss determines the extent of clinical disability, including cognitive impairment. Axonal and myelin loss is more marked in new lesions and in the active borders of old ones and it may be episodic rather than progressive.2. Finding surrogate markers for this neuropathological process is increasingly important, as disease modifying therapies become available. Newer MRI techniques such as magnetisation transfer, capable of giving information about otherwise normal appearing brain tissue, have been reported to correlate better with cognitive decline than T2 lesion load.3 Fast fluid inversion recovery (fast FLAIR) sequences, which are capable of detecting juxtacortical lesions likely to disrupt important cognitive networks, also hold some promise. But the detection of brain atrophy, and especially its progression over a short period of time, may be particularly useful as it provides a global measure of pathology in the normal appearing brain tissue. The study of Zivadinovet al 1 suggests that brain atrophy occurs early in the disease, at least in some patients, whereas studies in those with well established disease4 point towards an annual rate of cerebral atrophy twice as fast in patients with multiple sclerosis as in age matched controls, and to a closer correlation with physical disability.5
The rate progression of brain atrophy was recently used to assess the impact of interferon β-1b in patients with secondary progressive disease.6 Rates of progression were similar in the drug and placebo arms of the study suggesting that whatever clinical effects were found were likely to be due to the anti-inflammatory/antioedematous effects of the drug rather than its ability to halt progressive axonal and myelin loss. The use of increasingly complex markers of disease activity in trials of new therapeutic agents will help to determine their efficacy, to select those more likely to benefit, and to decide on the optimum timing for their administration.
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