Imaging genetics in multiple sclerosis: A volumetric and diffusion tensor MRI study of APOE ε4
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)
- et al.
The measurement and clinical relevance of brain atrophy in multiple sclerosis
Lancet Neurol.
(2006) - et al.
Imaging genetics — days of future past
NeuroImage
(2010) - et al.
Semiautomatic brain region extraction: a method of parcellating brain regions from structural magnetic resonance images
NeuroImage
(2004) - et al.
A global optimisation method for robust affine registration of brain images
Med. Image Anal.
(2001) - et al.
A robust method for extraction and automatic segmentation of brain images
NeuroImage
(2002) - et al.
Neuropsychological assessment, quantitative MRI and ApoE gene polymorphisms in a series of MS patients treated with IFN beta-1b
J. Neurol. Sci.
(2006) - et al.
Diffusion tensor imaging of post mortem multiple sclerosis brain
NeuroImage
(2007) - et al.
The synthesis and transport of lipids for axonal growth and nerve regeneration
Biochim. Biophys. Acta
(2000) - et al.
User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability
NeuroImage
(2006) - et al.
Beck Depression Inventory (BDI)—II Manual
(1996)
Characterization and propagation of uncertainty in diffusion-weighted MR imaging
Magn. Reson. Med.
Development of biomarkers in multiple sclerosis
Brain
APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers
Neurology
Neuroimaging and APOE genotype: a systematic qualitative review
Dement. Geriatr. Cogn. Disord.
Development of a multiple sclerosis functional composite as a clinical trial outcome measure
Brain
Influence of apolipoprotein E epsilon4 genotype on brain tissue integrity in relapsing–remitting multiple sclerosis
Arch. Neurol.
Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele
Arch. Neurol.
Accelerated evolution of brain atrophy and "black holes" in MS patients with APOE-epsilon 4
Ann. Neurol.
G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences
Behav. Res. Methods
Apolipoprotein E genotype related differences in brain lesions of multiple sclerosis
J. Neurol. Neurosurg. Psychiatry
Diffusion tensor imaging abnormalities in cognitively impaired multiple sclerosis patients
Mult. Scler.
APOE epsilon4 and cognitive dysfunction in multiple sclerosis: a review
J. Neuropsychiatry Clin. Neurosci.
APOE epsilon4 and the cognitive genetics of multiple sclerosis
Neurology
Cited by (4)
Imaging Phenotypes in Multiple Sclerosis
2015, Neuroimaging Clinics of North AmericaCitation Excerpt :However, in large meta-analyses including thousands of patients with MS and controls, an effect of ApoE variation in MS susceptibility has not been proved.53,54 Although most of the imaging studies assessing the influence of ApoE on MS severity could not show significant associations,28,55–60 some studies have reported more brain damage in carriers of the ϵ4 allele (Table 3).61–64 In a study consisting of 99 patients with RR MS,63 MR imaging was performed at 2 points in time with a minimum interval of 2 years.
Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis
2019, Multiple Sclerosis JournalMorphometry and genetics
2018, Neuromethods