Innovations In Clinical Neuroscience

HOTTOP Multiple Sclerosis MAR 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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R E V I E W 14 Hot Topics in Multiple Sclerosis [March 2018] indicate that brain atrophy and cortical and deep GM volume measurements might be useful magnetic resonance imaging (MRI) parameters in predicting MS disease course and progression. MRI IMAGING OF BRAIN ATROPHY MRI measures of global brain atrophy lack pathological specificity, since they might reflect several changes of WM and GM components that are associated with inflammation and neurodegeneration, such as demyelination, axonal damage, neuronal death, astrocyte and microglia proliferation, and physiological fluctuations of the water content. Moreover, the anti-inflammatory DMDs currently used for the treatment of MS differentially act on WM inflammation, thus determining an acceleration of brain volume loss, a phenomenon commonly referred to as "pseudo- atrophy" and assumed to reflect the resolution of inflammation and oedema. This phenomenon might complicate the interpretation of DMD effects, especially in the first two years of therapy. Measurements of percentage brain volume change (PBVC) and brain parenchymal fraction (BPF) over time are among the best-studied and more-used methods for quantifying neurodegeneration in MS. Indeed, the majority of the clinical trials have incorporated BPF or PBVC as a secondary outcome measure of disease progression. PBVC can be obtained by means of the Structural Image Evaluation Using Normalization of Atrophy (SIENA) 39 and its cross-sectional version SIENAX, 40 both included in FSL suite, 41,42 i.e., the most-used methods to extract brain and skull images from the single whole-head input data. These softwares allow tissue- type segmentation, with partial volume estimation, to calculate the total volume of brain tissue and separate estimates of total GM, deep and cortical GM, and WM volumes. 43 BPF is measured as the ratio between the volume of WM + GM and the total intracranial volume WM + GM + ventricular CSF. A meta- analysis of 13 clinical trials—including more than 13,500 RRMS patients and in which brain atrophy was measured as PBVC 44 or BPF 45 —showed that treatment effects on disability progression over two years correlated with the effects observed on both brain atrophy (p=0.001) and T2 lesion volume (p <0.001). 46 Other automated methods are currently available for WM and GM segmentation that allow the assessment of the total cerebral GM volume, the volumes of deep and cortical GM, and the estimation of regional cortical GM volumes. 40,47,48 The results of these automated methods are quite reproducible. 40,49 BPF also can be obtained from Freesurfer and ANTs pipelines or any software providing brain four-tissue segmentation as FSL 43 or SPM. 50 Cortical thickness (CTh) can be calculated with different software tools such as Freesurfer, which includes a surface-based method, 51 or the more recent ANTs with its registration-based DiRECT algorithm. 52,53 GM ATROPHY AND DISABILITY A strong association between physical disability (as measured by means of Expanded Disability Status Scale [EDSS] or timed 25-ft walk [T25FW]) and total, regional, and cortical GM volume has been described with consistent agreement among studies. These associations become more remarkable with disease progression from CIS to SPMS. 54–63 Studies that have demonstrated an association between cerebellar GM loss and the degree of disability in the cerebellar functional system of EDSS are particularly interesting. 60,64 Furthermore, physical disability correlates with both cortical thinning of the frontal, temporal, and parietal lobes 29,30,65,66 and with thalamic atrophy. 26–28 In addition, global GM 61, 62, 65–67 and thalamic atrophy 28,55 have been found to predict EDSS score up to 15–20 years after diagnosis. Several studies have pointed out a correlation between GM loss in the spinal cord and physical disability and disease duration. 68–78 Indeed, spinal cord atrophy was described in the early MS stages 69,70,74 but was much more pronounced in PPMS and SPMS, 76,77 whereas spinal GM volume inversely correlated with physical disability (measured with EDSS, T25FW, and 9-Hole Peg Test scores) in patients with CIS suggestive of MS, and it was more predictive for EDSS or Multiple Sclerosis Functional Composite (MSFC) scores thanothers MRI parameters. 68–70,75–78 Correlations between cognitive impairment and regional, cortical, and total GM volume have also been demonstrated with significant agreement among studies. 79–87 Moreover, associations between specific cognitive domains and various quantitative GM measures (such as thalamic volume, cortical thickness, and total GM volume) were found to be strong independent predictors of cognitive decline. 23,26,34,84,87,88 In summary, brain atrophy and GM (cortical and deep) loss constitute a clinically relevant aspect of MS pathology since the very early disease phases, and, given their association with physical and cognitive disability, definitely should be considered not only a surrogate marker of treatment efficacy but also a primary target of DMDs, especially when the treatment is aimed at reducing disability progression. EFFECTS OF DISEASE- MODIFYING DRUGS ON BRAIN AND GM ATROPHY Glatiramer acetate . The effect of early versus delayed glatiramer acetate (GA) treatment on brain atrophy was analyzed in the open-label phase of the PreCISe trial, 89,90 in which CIS patients with unifocal manifestations and at least two WM T2-lesions were randomized to receive glatiramer acetate 20mg/ day (early treatment, n=198) or placebo (delayed treatment, n=211) for 36 months or until conversion to clinically definite MS, followed by open-label GA treatment for two years. Early GA treatment was associated with less brain atrophy. PBVC from baseline to the last observed values, adjusted for study exposure, was significantly lower with early GA treatment compared with delayed treatment (−0.99% vs. −1.28%,

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