Brain atrophy in clinically early relapsing–remitting multiple sclerosis

Abstract

Brain atrophy measured by MRI is a potentially useful tool for monitoring disease progression in multiple sclerosis. The location, extent and mechanisms of brain atrophy in early disease are not well documented. Using quantitative MRI, this study investigated whole brain, grey and white matter atrophy in clinically early relapsing-remitting multiple sclerosis and its relationship to lesion measures. Data came from 27 normal control subjects (14 females and 13 males, mean age 36.1 years) and 26 subjects with clinically definite multiple sclerosis (18 females and eight males, mean age 35.1 years, mean delay from first symptom to scan 1.8 years, median Expanded Disability Status Scale score 1.0). All had three-dimensional fast spoiled gradient recall (3D FSPGR), T(1)-weighted pre- and post-gadolinium-enhanced and T(2)-weighted scans. The 3D FSPGR images were automatically segmented into grey and white matter and cerebrospinal fluid using SPM99. 3D FSPGR hypo-intense, T(2) hyper-intense, T(1) hypo-intense and T(1) post-gadolinium-enhancing lesion volumes were determined by semi-automatic lesion segmentation. The SPM99 output was combined with the 3D FSPGR lesion segmentations to quantify tissue volumes as fractions of total intracranial volumes, producing values for the brain parenchymal fraction (BPF), white matter fraction (WMF) and grey matter fraction (GMF). Comparing multiple sclerosis with control subjects, BPF, GMF and WMF were significantly reduced (P < 0.001 for all tissue fractions). Using Pearson correlations, T(2) hyper-intense and T(1) hypo-intense lesion volumes were inversely related to BPF (T(2) r = -0.78, P < 0.001; T(1) r = -0.59, P = 0.002) and GMF (T(2) r = -0.73, P < 0.001; T(1) r = -0.53, P = 0.006), but not WMF (T(2) r = -0.30, P = 0.134; T(1) r = -0.26, P = 0.199). T(1) post-gadolinium-enhancing lesion volumes were not correlated with any fractional volumes. These results indicate that significant brain atrophy, affecting both grey and white matter, occurs early in the clinical course of multiple sclerosis. The lack of correlation between lesion load measures and WMF suggests that pathological changes in white matter may occur by mechanisms which are at least partly independent from overt lesion genesis in early multiple sclerosis.

Focal cortical atrophy in multiple sclerosis: Relation to lesion load and disability

“…We observed a significant negative correlation between mean cortical thickness and the total volume of WM lesions, confirming previous studies that used a volumetric approach (Ge et al, 2001;Chard et al, 2002;De Stefano et al, 2003). We found that the correlation between the TWMLL and cortical thickness was statistically significant at almost every vertex of the surface model after correcting for multiple comparisons.…”

“…However, it is also possible that these gray matter regions are somehow intrinsically more vulnerable to direct involvement by the disease; indeed, histopathological studies have demonstrated that the cingulate gyrus, temporal lobe, and insula generally show a higher prevalence of cortical demyelinated lesions than other areas (Bö et al, 2003;Vercellino et al, 2005;Kutzelnigg and Lassmann, 2006). Two studies on relatively small numbers (n = 30 and 26) of MS patients reported a correlation between fractional GM volume and total WM lesion volume, but not disability (Ge et al, 2001;Chard et al, 2002). However, another report in a larger patient group (n = 65) did uncover a correlation between GM volume and EDSS (De Stefano et al, 2003).…”

“…However, more recent studies have demonstrated the presence of gray matter (GM) lesions (Peterson et al, 2001;Geurts et al, 2005) and brain atrophy (Chard et al, 2002;Anderson et al, 2006). Total brain atrophy can be viewed as a surrogate marker of the destructive pathological processes taking place in MS and can be observed with magnetic resonance imaging (MRI) by measuring the brain parenchymal fraction, a normalized measure that represents the sum of both gray matter (GM) and WM atrophy (Chard et al, 2002).…”

“…However, more recent studies have demonstrated the presence of gray matter (GM) lesions (Peterson et al, 2001;Geurts et al, 2005) and brain atrophy (Chard et al, 2002;Anderson et al, 2006). Total brain atrophy can be viewed as a surrogate marker of the destructive pathological processes taking place in MS and can be observed with magnetic resonance imaging (MRI) by measuring the brain parenchymal fraction, a normalized measure that represents the sum of both gray matter (GM) and WM atrophy (Chard et al, 2002). In addition to establishing global brain atrophy as a pathological feature of the disease, studies have focused separately on the atrophy of cortical GM by measuring decreases in normalized cortical volumes (De Stefano et al, 2003), by means of an ordinal visual scale (Bakshi et al, 2001), or by directly measuring cortical thickness in vivo (Sailer et al, 2003;Chen et al, 2004).…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…However, neuroimaging studies revealed microglia activation with minimal inflammatory cell infiltrates in proximity of cortical axonal transections [19]; this gray matter abnormality occurs surprisingly early and correlates much better with permanent disability, demonstrating that microglia activation in gray matter correlates with neuron loss and MS onset ( [37,51,201,230]). …”