Elsevier

NeuroImage

Volume 58, Issue 3, 1 October 2011, Pages 724-731
NeuroImage

Imaging genetics in multiple sclerosis: A volumetric and diffusion tensor MRI study of APOE ε4

https://doi.org/10.1016/j.neuroimage.2011.06.024Get rights and content

Abstract

Evidence linking the ε4 allele of APOE to more severe brain MRI abnormalities in multiple sclerosis (MS) has been conflicting and limited to studies of lesion load and whole brain atrophy. The purpose of the present study was to determine whether the ε4 allele of APOE is associated with more extensive brain pathology in MS using structural and diffusion tensor MRI. Using a case–control design, 43 MS patients with the ε4 allele and 47 ε4 negative MS patients underwent structural and diffusion tensor imaging (DTI) at 3T. Hypo- and hyperintense lesion volumes, whole brain and medial temporal volumes, and DTI parameters (fractional anisotropy (FA) and mean diffusivity (MD)) in normal-appearing brain tissue and lesions were compared between the groups. ε4+ and ε4− MS patients were well-matched on demographic characteristics, disease variables, and proportions receiving disease-modifying therapy. ε4+ and ε4− patients did not differ on any MRI or DTI measure. This study refutes a role for the ε4 allele in MRI abnormalities in MS, particularly those linking ε4 to greater T1 hypointense lesion volume and brain atrophy. Previous work on this putative gene–MRI relationship is extended by comparing DTI measures within lesions and normal-appearing brain tissue. A lack of differences in medial temporal regions, areas that have been linked to ε4-associated changes in health and disease, further supports the conclusion that that ε4 is not associated with more subtle MRI markers of brain pathology in MS.

Highlights

► We compared MS patients with and without the APOE ε4 allele by quantitative MRI. ► Imaging parameters were measured in the whole brain and medial temporal lobes (MTL). ► Hypo- orhyperintense lesion volumes did not differ between ε4+ and ε4- MS patients. ► Brain parenchymal fractions(global and MTL) did not differ between the groups. ► DTIin normal-appearing brain tissue and lesions was similar between the groups.

Introduction

The search for disease-modifying genes in multiple sclerosis (MS) is predicated on the notion that heritable factors constitute biomarkers of disease severity. If identified, such biomarkers may assist in predicting disease behavior and informing treatment (Bielekova and Martin, 2004). One of the most studied genes potentially linked to disease severity in MS is the ε4 allele of apolipoprotein E (APOE) (Burwick et al., 2006). Research on APOE in MS has predominantly emphasized the presence or absence of associations of ε4 carriage with clinical measures of disease severity. In contrast, the use of imaging genetic strategies (Bigos and Weinberger, 2010) has been relatively limited (reviewed in Ghaffar and Feinstein, 2010). Brain imaging findings in MS patients carrying ε4 have also been mixed with some studies reporting higher hypointense lesion loads (Enzinger et al., 2004, Fazekas et al., 2000) and/or more brain atrophy (De Stefano et al., 2004, Enzinger et al., 2004) in ε4+ subjects, suggesting more severe tissue damage (Bermel and Bakshi, 2006, van Walderveen et al., 1998). On the other hand, a recent study with a large sample size found no difference in brain volumes between ε4+ and ε4− MS patients (van der Walt et al., 2009). The power derived from the large sample size was offset in part by a number of limitations: the utilization of a single linear measure of brain atrophy (bicaudate ratio), the absence of data on lesion volumes, and the possibility of confounding effects from between-group differences in demographics and disease variables.

The objective of the present study was to clarify the association, if any, between ε4 and brain imaging markers in MS by comparing hypo- and hyperintense lesion volumes and atrophy in the cerebrum and medial temporal regions of ε4+ and ε4− MS subjects. In addition, given the potential importance of APOE in myelin homeostasis (Heise et al., 2010, Ryan et al., 2010, Vance et al., 2000), DTI measures that can reflect white matter myelin content and integrity (Schmierer et al., 2007) were evaluated in normal appearing brain tissue and lesions in both groups.

Section snippets

Patient screening, enrolment, and matching

Details of patient screening, enrolment, and matching of this sample are described previously (Ghaffar et al., 2010). Briefly, patients with a diagnosis of multiple sclerosis by the modified Macdonald criteria (Polman et al., 2005) were recruited between July 2006 and September 2008 from two tertiary care MS clinics (St. Michael's Hospital and Sunnybrook Health Sciences Centre, Toronto, ON). APOE genotype was determined as described previously (Ghaffar et al., 2010). Exclusion criteria

Demographics and disease variables

The 43 ε4+ and 47 ε4− MS patients were well-matched with respect to age, gender, disease course, disease duration, EDSS, MSFC, proportion receiving disease modifying medication, and depressive symptom scores (Table 1). Genotypic frequencies were as follows: 33 ε3/ε4, 39 e3/e3, 8 ε2/ε3, 6 ε2/ε4, and 4 ε4/ε4. ε4+ and ε4− groups did not differ with respect to carriage of the ε2 allele (14% vs. 17%, χ2 = 0.161, p = 0.668, OR (95% CI) = 0.79 (0.25–2.50)).

Global (whole brain) MRI and DTI variables in APOE ε4+ and ε4− MS patients

The 43 ε4+ and 47 ε4− MS patients did not differ in

Discussion

The purpose of this study was to compare MRI volumes and DTI metrics in lesions and in normal-appearing brain tissue of APOE ε4+ versus APOE ε4− MS patients while controlling for demographic and disease variables. MRI and DTI measures were compared at two levels, namely the whole brain and the medial temporal lobes. The results showed no differences between the two groups on any of the MRI and DTI parameters examined: BPF, NAWM volume, NAGM volume, hypointense lesion volume, hyperintense lesion

Conclusions

In conclusion, this study refutes a role of the ε4 allele as a significant determinant of MRI volumes and DTI variables in MS at the level of the whole brain and the medial temporal lobes. These data complement and extend recent cognitive studies of ε4 in MS. Whether the same conclusions regarding ε4 in MS can be drawn longitudinally remains to be determined.

The following are the supplementary materials related to this article.

Disclosures

OG served as a consultant on the Editorial Board of Cerebrio (a continuing medical education company); received travel expenses and/or honoraria for lectures or educational activities not funded by industry; received salary support and research stipend from the Canadian Institutes of Health Research; and receives salary support and research stipend from Sunnybrook Health Sciences Centre and Ontario Shores Centre for Mental Health Sciences.

NJL, GMS, and MR have nothing to disclose.

POC served on

Funding and role of the funding source

This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) to AF. OG was supported by a CIHR Fellowship and the CIHR Michael Bisby Award. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. AF had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

References (46)

  • T.E. Behrens et al.

    Characterization and propagation of uncertainty in diffusion-weighted MR imaging

    Magn. Reson. Med.

    (2003)
  • B. Bielekova et al.

    Development of biomarkers in multiple sclerosis

    Brain

    (2004)
  • R.M. Burwick et al.

    APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers

    Neurology

    (2006)
  • N. Cherbuin et al.

    Neuroimaging and APOE genotype: a systematic qualitative review

    Dement. Geriatr. Cogn. Disord.

    (2007)
  • G.R. Cutter et al.

    Development of a multiple sclerosis functional composite as a clinical trial outcome measure

    Brain

    (1999)
  • N. De Stefano et al.

    Influence of apolipoprotein E epsilon4 genotype on brain tissue integrity in relapsing–remitting multiple sclerosis

    Arch. Neurol.

    (2004)
  • C. Enzinger et al.

    Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele

    Arch. Neurol.

    (2003)
  • C. Enzinger et al.

    Accelerated evolution of brain atrophy and "black holes" in MS patients with APOE-epsilon 4

    Ann. Neurol.

    (2004)
  • F. Faul et al.

    G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences

    Behav. Res. Methods

    (2007)
  • F. Fazekas et al.

    Apolipoprotein E genotype related differences in brain lesions of multiple sclerosis

    J. Neurol. Neurosurg. Psychiatry

    (2000)
  • A. Feinstein et al.

    Diffusion tensor imaging abnormalities in cognitively impaired multiple sclerosis patients

    Mult. Scler.

    (2010)
  • O. Ghaffar et al.

    APOE epsilon4 and cognitive dysfunction in multiple sclerosis: a review

    J. Neuropsychiatry Clin. Neurosci.

    (2010)
  • O. Ghaffar et al.

    APOE epsilon4 and the cognitive genetics of multiple sclerosis

    Neurology

    (2010)
  • Cited by (4)

    View full text