Development of gray matter atrophy in relapsing–remitting multiple sclerosis is not gender dependent: Results of a 5-year follow-up study
Introduction
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disorder of the central nervous system resulting from an interplay between susceptibility genes and environmental factors. MS has been traditionally considered to be more frequent in females and in area more distant from the equator, although studies suggested that latitude gradient is decreasing, while female to male ratio is increasing [1], [2]. More than three decades ago, Confavreux et al. [3] described 1.5:1 female to male ratio, while recent work from Noonan et al. [2] showed 2.6:1 female to male ratio but with ratio ranging from 1.9 to 3.6:1 for the specific age groups evaluated.
Autoimmune diseases are in general, more prevalent in females with some estimates suggesting that >75% of subjects affected by autoimmune diseases are females. [4] This could be due to sex hormone based differences in the immune response [5]. Sex hormone hypothesis in MS is supported by the fact that relapse rate decreases during pregnancy and rebounds in the three months post-pregnancy [6]. Gender differences relative to disease progression were also described, showing a more favorable prognosis in female patients [7], [8]. Although it was hypothesized previously that men are more than twice as likely to pass the disease on to their offspring (so called Carter's effect), [9] recent studies showed equal disease transmission to offspring from the affected mothers and affected fathers [10].
Gender differences were also explored regarding one of the most important genetic risk factors for developing MS, the presence of HLA DRB1*1501 locus but the results are conflicting showing in some studies, increased maternal transmittance, [11] while other studies found no differences in paternal or maternal transmission [12].
Besides clinical and immunological parameters, MRI gender differences between MS patients were also explored on conventional and non-conventional MRI. Some studies found the presence of gadolinium (Gd) enhancing lesions more commonly in females; [13], [14] however, these findings were not confirmed in some other larger studies [15]. Correlation between high estradiol and low progesterone levels with Gd-enhancing lesions has also been described [16]. No gender differences were observed with T2-[15], [17], [18] and T1-lesion volume (LV), [15] although higher T1-LV was described in primary-progressive (PP) males, but not in RRMS or secondary progressive (SP) MS patients [19]. No gender differences were established in cross-sectional or longitudinal brain atrophy studies [15], [17], [20], [21]. However, conflicting results were reported regarding gray matter (GM) atrophy; greater in males [15] or equal in males and females [21]. Non-conventional MRI techniques like magnetization transfer imaging and diffusion-tensor imaging found no gender differences [15]. A longitudinal MRI follow-up study of 45 RRMS patients showed a significant decrease of total brain volume and GM volume as well as an increase in T2-LV in males, while female patients demonstrated a decrease in volume of the frontal subcortical region [22].
Against the background of these conflicting findings, the aim of this study was to evaluate the gender effect on the evolution of MRI lesion, global, tissue specific and regional brain volume changes, with particular emphasis to GM, in a large cohort of RRMS patients who participated in a clinical trial over 5 years.
Section snippets
Methods and patients
One hundred and eighty-one (181) RRMS patients who fulfilled Poser criteria for definite MS [23] had a presence of two or more T2 lesions on baseline MRI, at least two oligoclonal bands in the cerebrospinal fluid, were aged 18–55 years, had Expanded Disability Status Scale (EDSS) ≤ 3.5, had active disease defined by two relapses in the last 12 months or three relapses in the last 24 months prior to the study and were included in the Avonex-Steroid-Azathioprine (ASA) study [24], [25], [26]. In
Clinical variables
Out of 181 patients, there were 39 male and 142 female (M:F ratio 1:3.6). The mean age of study participants at baseline was 29.9 for males and 30.9 for females, while mean disease duration was 69.4 months in males and 63.0 months in the female group. The mean EDSS for both groups was 1.9 at baseline and 2.5 at 5 years. ARR was 0.7 and 0.9 respectively, while disease progression was observed in 56.4% of male and 47.9% of female patients. DMT change occurred in 12 (30.8%) of male and 59 (41.5%)
Discussion
The aim of this study was to explore gender influence on MRI lesion and brain volumetric changes in a cohort of 181 RRMS patients, who were part of the ASA clinical trial over 5-year follow-up period [24], [25], [26]. Baseline and 5-year follow-up clinical characteristics of male and female groups showed no significant differences. Global and tissue-specific brain volume changes showed no significant gender differences over the 5-year follow-up period. Although total SDGM, caudate, putamen,
Study funding
This study was supported by the Czech Ministries of Education and Health (NT13237-4/2012, MSM 0021620849, PRVOUK-P26/LF1/4, RVO-VFN64165/2012) and Biogen Idec Inc.
Conflict of interest
Drs. Gabelic, Bergsland, and Dwyer report no disclosures.
Dr. Dolezal received personal compensation for consulting and educational services from Merck Serono, Biogen Idec, and Novartis.
Drs. Seidl, Vaneckova, and Krasensky received financial support for research activities from Biogen Idec.
Dr. Horakova received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck Serono, Teva and Bayer Shering, as well as support for research activities from Biogen Idec.
Dr. Havrdova received
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2019, NeuroImageCitation Excerpt :The final mesh is then converted into a voxel segmentation and boundary correction is performed as a post-processing step. FIRST has been used for DGM segmentation in a wide variety of clinical applications, including AD (Cherubini et al., 2010; de Jong et al., 2008; Lee et al., 2017; Li et al., 2013; Möller et al., 2015; O’Dwyer et al., 2012; Štěpán-Buksakowska et al., 2014; Unay, 2012; Yi et al., 2016), PD (Acosta-Cabronero et al., 2017; Menke et al., 2014; Sunwoo et al., 2013), HD (van den Bogaard et al., 2013), post-traumatic stress disorder (Veer et al., 2015), schizophrenia (Spoletini et al., 2011), healthy controls (Hibar et al., 2015; Király et al., 2016; Péran et al., 2009; Rentería et al., 2014; T. Tang et al., 2013; Zhang et al., 2013), and most commonly in MS (Amann et al., 2015; Bishop et al., 2017; Chu et al., 2017; Dolezal et al., 2013; Eshaghi et al., 2018; Kim et al., 2017; Popescu et al., 2014; Shiee et al., 2012; Shinohara et al., 2017). In addition the SIENAX pipeline, which is an extended version of the SIENA software (Smith et al., 2002), includes DGM segmentation using FIRST, which has been used in one study for assessing DGM volumes in MS patients (Battaglini et al., 2018).
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