Pathologic and imaging correlates of cognitive deficits in multiple sclerosis: changing the paradigm of diagnosis and prognosis.

From 1868, when Charcot first described the clinical features and the pathologic correlates, up till the present day, multiple sclerosis (MS) has commonly been characterized by the symptoms caused by inflammatory plaques in the white matter of the brain and spinal cord. Early use of magnetic resonance imaging (MRI) to diagnose MS focused on detecting these white matter lesions. By the 1990s, researchers recognized that many patients with MS have cognitive deficits that can cause severe disability, and also determined the associated pathology; these findings shed more light on both the pathogenesis and progression. Since 2004, several lines of evidence have shown that the extent of white matter plaques identified on MRI does not correlate well with cognitive deficits. High-resolution MRI and advances in immunohistochemical techniques have enabled detection of cortical demyelination early in the course, correlating with cognitive deficits. Late in the course, pathologic changes in normal-looking white and gray matter correlate more closely with progressive cognitive deficits than with visual, sensory, and motor symptoms. This finding implies the need to redefine the disease and its progression. In this review, we discuss the histopathologic studies of cortical plaques in MS and early indications about their role in disease definition and progression, describe the role of high-resolution MRI in staging and determining progression of cognitive symptoms, and discuss how advances in these areas are forcing us to rethink diagnosis and determination of progression.

APOE ε4 is associated with exacerbation of cognitive decline in patients with multiple sclerosis.

BACKGROUND: : In previous studies we and others have demonstrated an association with apolipoprotein (APOE) ε4 genotype and the presence of cognitive deficits in multiple sclerosis (MS). In this follow-up study, we have assessed whether APOE ε4 status exacerbates progression of cognitive deficits in MS. METHODS: : A total of 197 patients with MS were assessed for APOE genotype, and baseline cognitive performance was measured using a standardized battery of tests. One hundred seventy patients (86.3%) were clinically followed up for 1 year and were assessed for progression of cognitive deficits. RESULTS: : The APOE ε4 allele was present in 24.7% of patients. During 1-year follow-up, significant progression of cognitive deficits was found in APOE ε4 carriers (P=0.001) after logistic regression analysis controlling for sex, ethnicity, age, education, disease duration, severity, and subtype. CONCLUSIONS: : APOE ε4 carriers with MS have worsening progression of cognitive deficits than noncarriers. APOE ε4 carrier status predicts cognitive decline in verbal learning and memory.

Cognitive impairment in neurological diseases: lessons from apolipoprotein E.

Apolipoprotein E4 (ApoE4) has been considered to have detrimental effects on the age of onset and progression in Alzheimer's disease. Evidence continues to accumulate regarding the effects of ApoE isoforms in a number of other neurological diseases. Recent studies demonstrate an increase in cognitive deficits in ApoE4 patients with traumatic brain injury, cerebrovascular disease, and delirium. Evidence of the role ApoE isoforms played in cognition in multiple sclerosis has illuminated the neurodegenerative aspects of this disease. It further provides evidence of the effect neuroinflammation has in increasing susceptibility to cognitive decline in younger patients. Determining where these diverse diseases intersect and diverge in their relationship to ApoE provides insight into the two-hit mechanism in cognitive decline.