Accelerated Evolution of Brain Atrophy and "Black Holes" in MS Patients with APOE-ε4

Department of Neurology, Karl-Franzens University, Graz, Austria.
Annals of Neurology (Impact Factor: 11.91). 04/2004; 55(4):563-9. DOI: 10.1002/ana.20027
Source: PubMed

ABSTRACT Apolipoprotein E (APOE)-epsilon4 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-epsilon4 patients, the annual reduction in brain volume was fivefold higher (-0.65 +/- 0.61%) than in those without APOE-epsilon4 (-0.13 +/- 0.36%; p = 0.0001). At baseline, T(2) LL and T(1) LL were non-significantly higher in epsilon4 carriers, despite a shorter disease duration and absence of significant clinical differences. During follow-up, T(1) LL increased from 1.2 +/- 2.3 ccm to 1.7 +/- 2.7 ccm in the epsilon4 group, although T(2) LL did not change, leading to a significantly higher increase in the BH ratio [(T(1) LL/T(2) LL) x 100] from 5.5 to 12.4% (p = 0.005). BH ratio remained almost constant in non-epsilon4 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-epsilon4.

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    • "Neuroimaging data revealed that accelerated brain-tissue loss and a higher proportion of lesions evolving into " black holes " in MS patients with APOE-ε4. In another investigation Enzinger et al. demonstrated that the annual decrease in brain volume in APOE-ε4 carriers is five-fold higher than non-ε4-carriers [47]. As mentioned earlier, the probability of developing MS in individuals with ε3ε4 genotype is about 2.4 times more than individuals Table 1 The frequency of MS type among males and females. "
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    ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system. Evidences linking apolipoprotein E (APOE) to myelin repair, neuronal plasticity, and cerebral inflammatory processes suggest that it may be relevant in MS. The main goal of this study was to determine whether the APOE genotypes and alleles are associated with MS patients. In total, 147 MS cases and 168 control subjects from Iranian population were genotyped for APOE gene using PCR-RFLP method. The frequency of APOE-ε2ε3 genotype was significantly higher in controls than cases (14.3% vs. 6.1%, P=0.009, OR=0.39) whereas APOE-ε3ε4 genotype frequency was significantly higher in cases compared with controls (8.2% vs. 3.6%, P=0.03, OR=2.4). APOE-ε2 allele frequency in cases was significantly lower than that of controls (4.4% vs. 8.0%, P=0.03, OR=0.52). Also male controls were significantly more likely to have APOE-ε2 allele (7.8% vs. 1%, P=0.01, OR=0.11). APOE-ε4 allele frequency in cases was significantly higher than control group (4.8% versus 2.1%, P=0.03, OR=2.35). It seems that individuals carrying APOE-ε4 allele and/or APOE-ε3ε4 genotype develop MS two times more than non-carriers. Also APOE-ε2ε3 genotype or APOE-ε2 allele may have a protective role against MS development in Iranian population. Further investigation would be warranted to understand the role of APOE alleles and genotypes and risk of MS.
    Journal of the neurological sciences 06/2012; 320(1-2):22-5. DOI:10.1016/j.jns.2012.05.050 · 2.26 Impact Factor
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    • "(b) T1 hypointensities or " black holes " Lesions that appear hypointense on T1-weighted scans are those where severe tissue damage due to demyelination and axonal loss has occurred [26] [27] [28] [29]. A greater accumulation of " black holes " has been associated with the apolipoprotein E (APOE)-ε4 allele [30], thus underpinning its potential as a measure of tissue degeneration. Measuring T1-hypointense lesions has, unfortunately, some major limitations when it comes to monitoring MS evolution that include (1) the fact that the definition of what constitutes a " black hole " is arbitrary and highly operator dependent. "
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    ABSTRACT: A number of recent magnetic resonance imaging studies have challenged the classical view of multiple sclerosis (MS) as a "two-stage" disease where an early inflammatory demyelinating phase with focal macroscopic lesions formed in the white matter (WM) of the central nervous system is followed by a late neurodegenerative phase, which is believed to be a mere consequence of repeated inflammatory insults and irreversible demyelination. These studies have consistently shown the presence of diffuse normal-appearing WM damage, marked gray matter involvement and significant cortical functional reorganization, as well as the occurrence of the neurodegenerative component of MS from the earliest clinical stages of the disease with only a partial relation to MRI markers of inflammatory demyelination. The present review argues that MS can no longer be viewed as a "two-stage" disease, which suggests that the two pathological components are dissociated in time, but rather as a "simultaneous two-component" disease, where the relative contributions of the various pathological processes of the disease to the development of "fixed" disability, their relationship and their evolution over time need to be clarified. This new view of MS should inform the development of future research protocols to define its actual physiopathology and prompt the institution of early treatment which should ideally target not only inflammatory demyelination, but also the neurodegenerative aspects of the disease, as well as promote neuroprotection and enhance reparative mechanisms and adaptive functional reorganization of the cortex.
    Journal of the Neurological Sciences 08/2007; 259(1-2):7-15. DOI:10.1016/j.jns.2006.08.017 · 2.26 Impact Factor
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    • "The different alleles confer different levels of susceptibility to both cardiovascular and neurological diseases. A gene-dosage effect has been shown for apoE4 indicating that it is a major risk factor for the development of Alzheimer disease (Corder et al., 1993); in addition, it is associated with slower recovery from head trauma and stroke and unfavorable course in multiple sclerosis (Enzinger et al., 2004; Mahley and Rall, 2000). ApoE4 is also associated with higher levels of increased total and LDL cholesterol , and consequently, with increased risk of heart disease (Davignon et al., 1988). "
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    ABSTRACT: Compared to other primates, humans live a long time and have large brains. Recent theories of the evolution of human life history stages (grandmother hypothesis, intergenerational transfer of information) lend credence to the notion that selection for increased life span and menopause has occurred in hominid evolution, despite the reduction in the force of natural selection operating on older, especially post-reproductive, individuals. Theories that posit the importance (in an inclusive fitness sense) of the survival of older individuals require them to maintain a reasonably high level of cognitive function (e.g., memory, communication). Patterns of brain aging and factors associated with healthy brain aging should be relevant to this issue. Recent neuroimaging research suggests that, in healthy aging, human brain volume (gray and white matter) is well-maintained until at least 60 years of age; cognitive function also shows only nonsignificant declines at this age. The maintenance of brain volume and cognitive performance is consistent with the idea of a significant post- or late-reproductive life history stage. A clinical model, "the cognitive reserve hypothesis," proposes that both increased brain volume and enhanced cognitive ability may contribute to healthy brain aging, reducing the likelihood of developing dementia. Selection for increased brain size and increased cognitive ability in hominid evolution may therefore have been important in selection for increased lifespan in the context of intergenerational social support networks.
    American Journal of Human Biology 11/2005; 17(6):673-89. DOI:10.1002/ajhb.20439 · 1.93 Impact Factor
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