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Abstract

Apolipoprotein E (APOE)–ε4 has been associated with an unfavorable course of multiple sclerosis (MS). The mechanisms responsible for this are unclear, although cross-sectional MRI demonstrated a higher extent of “black holes” (BHs) in such patients. Here, we have studied the impact of the APOE genotype on both the longitudinal evolution of focal (BH ratio) and global (brain volume change [BVC]) brain tissue damage. Ninety-nine MS patients underwent ApoE genotyping, clinical examination, and magnetic resonance imaging at baseline and after 2.7 ± 1.1 years to assess lesion load (LL) and BVC. In APOE-ε4 patients, the annual reduction in brain volume was fivefold higher (−0.65 ± 0.61%) than in those without APOE-ε4 (−0.13 ± 0.36%; p = 0.0001). At baseline, T2 LL and T1 LL were non-significantly higher in ε4 carriers, despite a shorter disease duration and absence of significant clinical differences. During follow-up, T1 LL increased from 1.2 ± 2.3ccm to 1.7 ± 2.7ccm in the ε4 group, although T2 LL did not change, leading to a significantly higher increase in the BH ratio [(T1 LL/T2 LL) × 100] from 5.5 to 12.4% (p = 0.005). BH ratio remained almost constant in non-ε4 patients (5.0 vs 5.7%). Accelerated brain tissue loss and a higher proportion of lesions evolving into BH therefore provide magnetic resonance imaging evidence for more pronounced tissue destruction in MS patients with APOE-ε4. Ann Neurol 2004