Brain Atrophy In Multiple Sclerosis Research Articles

Measurement of brain atrophy in multiple sclerosis – a cross-sectional retrospective study

Measurement of brain atrophy in multiple sclerosis – a cross-sectional retrospective study

Smoking is associated with increased lesion volumes and brain atrophy in multiple sclerosis

Cigarette smoking has been linked to higher susceptibility and increased risk of progressive multiple sclerosis (MS). The effects of smoking on MRI characteristics of patients with MS have not been evaluated. To compare the MRI characteristics in cigarette smoker and nonsmoker patients with MS. We studied 368 consecutive patients with MS (age 44.0 +/-SD 10.2 years, disease duration 12.1 +/- 9.1 years) comprising 240 never-smokers and 128 (34.8%) ever-smokers (currently active and former smokers). The average number of packs per day smoked (+/-SD) was 0.95 +/- 0.65, and the mean duration of smoking was 18.0 +/- 9.5 years. All patients obtained full clinical and quantitative MRI evaluation. MRI measures included T1, T2, and gadolinium contrast-enhancing (CE) lesion volumes (LVs) and measures of central, global, and tissue-specific brain atrophy. The associations between smoking status and MRI measurements were assessed in regression analysis. Smoking was associated with increased Expanded Disability Status Scale (EDSS) scores (p = 0.004). The median EDSS scores (interquartile range) in the ever-smoker group and the active-smoker group were both 3.0 (2.0), compared with 2.5 (2.5) in never-smokers. There were adverse associations between smoking and the lesion measures including increased number of CE lesions (p < 0.001), T2 LV (p = 0.009), and T1 LV (p = 0.003). Smoking was associated with decreased brain parenchymal fraction (p = 0.047) and with increases in the lateral ventricle volume (p = 0.001) and third ventricle width (p = 0.023). Smoking is associated with increased blood-brain barrier disruption, higher lesion volumes, and greater atrophy in multiple sclerosis.

Quantification and clinical relevance of brain atrophy in multiple sclerosis: a review

Multiple sclerosis is known to be an inflammatory demyelinating disease characterized mainly by multifocal areas of white matter lesions. Recently, cortical lesions and brain atrophy have emerged as new pathological markers of disease progression. Brain tissue loss can now be easily and reproducibly detected and quantified by MRI, which has led to an increasing amount of research correlating brain tissue loss with other MRI markers, such as white matter lesions, and to clinical disabilities (motor or cognitive), in order to assess its clinical relevance. In this review, we summarize the different MRI-based methods used to quantify whole and regional brain atrophy, and discuss the relevance of brain atrophy in MS through its relationship with characteristic brain lesions, disability and cognition. Lastly, we emphasize the role of brain atrophy in different phenotypes of MS. According to this review of the current literature, the grey matter (GM) atrophy is now well-established in MS and has been found to be strongly associated with clinical and cognitive deterioration. This GM volume loss is characterized by a focal atrophy in the deep grey nuclei but also by diffuse cortical atrophy. Phenotypic variation can be associated with different degrees and regional location of brain atrophy but more investigations are necessary to specify the discrepancies against brain atrophy between the different forms of the disease.

Can rate of brain atrophy in multiple sclerosis be explained by clinical and MRI characteristics?

Introduction Multiple sclerosis (MS) is characterized, besides focal lesions, by brain atrophy. The determinants of atrophy rates in individual patients are poorly understood. Aim This study investigated the predictive value of clinical and magnetic resonance imaging (MRI) factors, including short-term changes thereof, for concurrent and future atrophy evolution using Spearman’s rank correlations and stepwise multiple linear regression. Methods We retrospectively identified a group of 115 active, early relapsing-remitting (RR) patients relatively homogeneous in terms of disease course and MRI activity compared to a second group of 96 patients with broader spectrum of MS phenotypes and inactive scans. All patients had undergone three MRI investigations with interscan intervals of at least 12 and 24 months, respectively. Results In the RR patients, 23% of variance in concurrent atrophy rates (over the first interval) could be explained by the combination of baseline T2 lesion volume and change in EDSS score over the first interval, whereas only 6% in future atrophy rates (over the second interval) was explained. In the heterogeneous group, 20.2% of the variance in future atrophy rates could be explained, but slightly less in concurrent atrophy rates (16.2%). Conclusion We concluded that variance in brain atrophy rates can partially be explained by clinical and MRI measures of disease. Future atrophy rates in individual MS patients are difficult to predict even when including previous atrophy rates.

Sample sizes for brain atrophy outcomes in trials for secondary progressive multiple sclerosis

Progressive brain atrophy in multiple sclerosis (MS) may reflect neuroaxonal and myelin loss and MRI measures of brain tissue loss are used as outcome measures in MS treatment trials. This study investigated sample sizes required to demonstrate reduction of brain atrophy using three outcome measures in a parallel group, placebo-controlled trial for secondary progressive MS (SPMS). Data were taken from a cohort of 43 patients with SPMS who had been followed up with 6-monthly T1-weighted MRI for up to 3 years within the placebo arm of a therapeutic trial. Central cerebral volumes (CCVs) were measured using a semiautomated segmentation approach, and brain volume normalized for skull size (NBV) was measured using automated segmentation (SIENAX). Change in CCV and NBV was measured by subtraction of baseline from serial CCV and SIENAX images; in addition, percentage brain volume change relative to baseline was measured directly using a registration-based method (SIENA). Sample sizes for given treatment effects and power were calculated for standard analyses using parameters estimated from the sample. For a 2-year trial duration, minimum sample sizes per arm required to detect a 50% treatment effect at 80% power were 32 for SIENA, 69 for CCV, and 273 for SIENAX. Two-year minimum sample sizes were smaller than 1-year by 71% for SIENAX, 55% for CCV, and 44% for SIENA. SIENA and central cerebral volume are feasible outcome measures for inclusion in placebo-controlled trials in secondary progressive multiple sclerosis.

Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis

Optical coherence tomography (OCT) noninvasively quantifies retinal nerve fiber layer (RNFL) thickness. Studies show RNFL thinning in multiple sclerosis (MS), and we assessed its association with brain atrophy. RNFL thickness was measured in 40 patients with MS and 15 controls. Brain parenchymal fraction (BPF) and partial brain volumes were estimated from cranial MRI scans using SIENA-X. Multiple linear regression modeling assessed the association between OCT and MRI measures of atrophy. Minimum RNFL thickness and subject age together predict 21% (p = 0.005) of the variance in BPF in all patients with MS and 43% (p = 0.003) of the variance in BPF in the subgroup with relapsing remitting MS (RRMS; n = 20). The partial correlation coefficient between BPF and minimum RNFL thickness, controlling for age, is 0.46 (p = 0.003) in all patients with MS and 0.69 (p = 0.001) in patients with RRMS. These associations are driven by CSF volume but not by gray or white matter volume. There is no significant association of these variables among controls. In multiple sclerosis (MS), retinal nerve fiber layer thickness is associated with brain parenchymal fraction and CSF volume. These data suggest that quantification of axonal thickness in the retina by optical coherence tomography (OCT) provides concurrent information about MRI brain abnormality in MS. OCT should be examined in longitudinal studies to determine if it could be used as an outcome measure in clinical trials of neuroprotective drugs.

Regional brain atrophy development is related to specific aspects of clinical dysfunction in multiple sclerosis

Brain atrophy in multiple sclerosis (MS) is thought to reflect irreversible tissue damage leading to persistent clinical deficit. Little is known about the rate of atrophy in specific brain regions in relation to specific clinical deficits.We determined the displacement of the brain surface between two T1-weighted MRI images obtained at baseline and after a median follow-up time of 2.2 years for 79 recently diagnosed, mildly disabled MS patients. Voxel- and cluster-wise permutation-based statistics were used to identify brain regions in which atrophy development was significantly related to Expanded Disability Status Scale (EDSS), Timed Walk Test (TWT), Paced Auditory Serial Addition Test (PASAT) and 9-Hole Peg Test (HPT). Clusters were considered significant at a corrected cluster-wise p-value of 0.05.Worse EDSS change-score and worse follow-up EDSS were related to atrophy development of periventricular and brainstem regions and right-sided parietal, occipital and temporal regions. Worse PASAT at follow-up was significantly related to atrophy of the ventricles. A worse TWT change-score and worse follow-up TWT were exclusively related to atrophy around the ventricles and of the brainstem. Worse HPT change-score and worse follow-up HPT of either arm were significantly related to the atrophy of widely distributed peripheral regions, as well as atrophy of periventricular and brainstem regions.Our findings suggest that decline in ambulatory function is related to atrophy of central brain regions exclusively, whereas decline in neurologically more complex tasks for coordinated hand function is related to atrophy of both central and peripheral brain regions.

Measuring Brain Atrophy in Multiple Sclerosis

The last decade has seen the development of methods that use conventional magnetic resonance imaging (MRI) to provide sensitive and reproducible assessments of brain volumes. This has increased the interest in brain atrophy measurement as a reliable indicator of disease progression in many neurological disorders, including multiple sclerosis (MS). After a brief introduction in which we discuss the most commonly used methods for assessing brain atrophy, we will review the most relevant MS studies that have used MRI-based quantitative measures of brain atrophy, the clinical importance of these results, and the potential for future application of these measures to understand MS pathology and progression. Despite the number of issues that still need to be solved, the measurement of brain atrophy by MRI is sufficiently precise and accurate. It represents one of most promising in vivo measures of neuroaxonal degeneration in MS, and it should be used extensively in the future to assess and monitor pathological evolution and treatment efficacy in this disease.

Progression of non-age-related callosal brain atrophy in multiple sclerosis: a 9-year longitudinal MRI study representing four decades of disease development

Background: In multiple sclerosis (MS), multiple periventricular lesions are commonly the first findings on MRI. However, most of these MS lesions are clinically silent. The brain atrophy rate has shown...

Magnetic resonance imaging measures of brain atrophy in multiple sclerosis

Magnetic resonance imaging (MRI) has been widely used to diagnose and monitor multiple sclerosis (MS). Although MRI-visible lesions are a key feature of MS, they are thought to correlate poorly with clinical progression. Neurodegeneration is increasingly being recognized as an important factor in the pathogenesis of MS, and MRI measures of brain atrophy have been suggested as surrogate markers of neuroaxonal loss and disease progression. This pathology may be more relevant to the progression of disability than focal inflammation. A number of MRI-based methods have been developed for the measurement of global and regional brain atrophy. Natural-history studies of MS and clinically isolated syndromes suggestive of MS have observed atrophy in these subjects above that seen in controls, over periods ranging from three months to years. Brain atrophy has also been incorporated as an outcome measure in therapeutic trials of disease-modifying treatments. This paper considers neuroaxonal loss and the pathological basis of brain atrophy, methods developed to quantify brain atrophy, the findings of natural-history and therapeutic studies, the relationship of brain atrophy to disability and cognition, and the future research directions and clinical applications of brain atrophy measurements.

Optic nerve atrophy and retinal nerve fibre layer thinning following optic neuritis: Evidence that axonal loss is a substrate of MRI-detected atrophy

Magnetic resonance imaging (MRI) measures of brain atrophy are often considered to be a marker of axonal loss in multiple sclerosis (MS) but evidence is limited. Optic neuritis is a common manifestation of MS and results in optic nerve atrophy. Retinal nerve fibre layer (RNFL) imaging is a non-invasive way of detecting axonal loss following optic neuritis. We hypothesise that if the optic nerve atrophy that develops following optic neuritis is contributed to by axonal loss, it will correlate with thinning of the RNFL. Twenty-five patients were studied at least 1 year after a single unilateral attack of optic neuritis without recurrence, with a selection bias towards incomplete recovery. They had MR quantification of optic nerve cross-sectional area and optic nerve lesion length, as well as optical coherence tomography (OCT) measurement of mean RNFL thickness and macular volume, quantitative visual testing, and visual evoked potentials (VEPs). Fifteen controls were also studied. Significant optic nerve atrophy (mean decrease 30% versus controls), RNFL thinning (mean decrease 33% versus controls), and macular volume loss occurred in patients' affected eyes when compared with patients' unaffected eyes and healthy controls. The optic nerve atrophy was correlated with the RNFL thinning, macular volume loss, visual acuity, visual field mean deviation, and whole field VEP amplitude but not latency. These findings suggest that axonal loss contributes to optic nerve atrophy following a single attack of optic neuritis. By inference, axonal loss due to other post-inflammatory brain lesions is likely to contribute to the global MRI measure of brain atrophy in multiple sclerosis.

Semi-automatic brain region extraction (SABRE) reveals superior cortical and deep gray matter atrophy in MS

In multiple sclerosis (MS), atrophy occurs in various cortical and subcortical regions. However, it is unclear whether this is mostly due to gray (GM) or white matter (WM) loss. Recently, a new semi-automatic brain region extraction (SABRE) technique was developed to quantify parenchyma volume in 13 hemispheric regions. This study utilized SABRE and tissue segmentation to examine whether regional brain atrophy in MS is mostly due to GM or WM loss, correlated with disease duration, and moderated by disease course. We studied 68 MS patients and 39 normal controls with 1.5 T brain MRI. As expected, MS diagnosis was associated with significantly lower ( P < 0.001) regional brain parenchymal fractions (RBPFs). While significant findings emerged in 11 GM comparisons, only four WM comparisons were significant. The largest mean RBPF percent differences between groups (MS < NC) were in the posterior basal ganglia/thalamus region (−19.3%), superior frontal (−15.7%), and superior parietal (−14.3%) regions. Logistic regression analyses showed GM regions were more predictive of MS diagnosis than WM regions. Eight GM RBPFs were significantly correlated ( P < 0.001) with disease duration compared to only one WM region. Significant trends emerged for differences in GM, but not WM between secondary progressive (SP) and relapsing–remitting MS patients. Percent differences in GM between the two groups were largest in superior frontal (−9.9%), medial superior frontal (−6.5%), and superior parietal (−6.1%) regions, with SP patients having lower volumes. Overall, atrophy in MS is diffuse and mostly related to GM loss particularly in deep GM and superior frontal–parietal regions.

Steroids and brain atrophy in multiple sclerosis

In this review, we focus on different pathogenetic mechanisms of corticosteroids that induce short- and long-term brain volume fluctuations in a variety of systemic conditions and disorders, as well as on corticosteroid-induced immunomodulatory, immunosuppressive and anti-inflammatory mechanisms that contribute to the slowdown of brain atrophy progression in patients with multiple sclerosis (MS). It appears that chronic low-dose treatment with corticosteroids may contribute to irreversible loss of brain tissue in a variety of autoimmune diseases. This side effect of steroid therapy is probably mediated by steroid-induced protein catabolism mechanism. Evidence is mounting that high-dose corticosteroids may induce reversible short-term brain volume changes due to loss of intracellular water and reduction of abnormal vascular permeability, without there having been axonal loss. Other apoptotic and selective inhibiting mechanisms have been proposed to explain the nature of corticosteroid-induced brain volume fluctuations. It has been shown that chronic use of high dose intravenous methylprednisolone (IVMP) in patients with MS may limit brain atrophy progression over the long-term via different immunological mechanisms, including downregulation of adhesion molecule expression on endothelial cells, decreased cytokine and matrix metalloproteinase secretion, decreased autoreactive T-cell-mediated inflammation and T-cell apoptosis induction, blood–brain barrier closure, demyelination inhibition and, possibly, remyelination promotion. Studies in nonhuman primates have confirmed that short-term brain volume fluctuations may be induced by corticosteroid treatment, but that they are inconsistent, potentially reversible and probably dependent upon individual susceptibility to the effects of corticosteroids. Further longitudinal studies are needed to elucidate pathogenetic mechanisms contributing to brain volume fluctuations in autoimmune diseases and multiple sclerosis.

Microglial imaging with positron emission tomography and atrophy measurements with magnetic resonance imaging in multiple sclerosis: a correlative study

The objectives of the present study were to assess brain atrophy in multiple sclerosis (MS) patients during different disease stages and to investigate by PET and [11C]PK11195, a marker of microglial activation, the relationship between inflammation, atrophy and clinically relevant measures. Eight healthy subjects and 22 MS patients were included. Semiquantitative [11C]PK11195 uptake values, with normalization on cortical grey matter, were measured for magnetic resonance imaging T2- and T1-lesions and normal appearing white matter (NAWM). As atrophy index we used the ratio of the amount of white and grey matter divided by the ventricular size, using an optimized a priori based segmentation algorithm (SPM99). Atrophy was significantly greater in MS patients compared to age-matched controls. A significant correlation was found between brain atrophy and both disease duration and disability, as measured with the Expanded Disability Status Scale. For NAWM, [11C]PK11195 uptake increased with the amount of atrophy, while T2-lesional [11C]PK11195 uptake values decreased according to increasing brain atrophy. The present study suggests that brain atrophy, correlating with disease duration and disability, is directly related to NAWM and T2-lesional inflammation as measured by microglial activation.

Neuronal cell injury precedes brain atrophy in multiple sclerosis

<h3>Introduction</h3> Bacterial vaginosis (BV) and vaginal microbiota disruption during pregnancy are associated with increased risk of spontaneous preterm birth (SPTB), but clinical trials of BV treatment during pregnancy have shown little or no benefit. An alternative hypothesis is that vaginal bacteria present around conception may lead to SPTB by compromising the protective effects of cervical mucus, colonising the endometrial surface before fetal membrane development, and causing low-level inflammation in the decidua, placenta and fetal membranes. This protocol describes a prospective case-cohort study addressing this hypothesis. <h3>Methods and analysis</h3> HIV-seronegative Kenyan women with fertility intent are followed from preconception through pregnancy, delivery and early postpartum. Participants provide monthly vaginal specimens during the preconception period for vaginal microbiota assessment. Estimated date of delivery is determined by last menstrual period and first trimester obstetrical ultrasound. After delivery, a swab is collected from between the fetal membranes. Placenta and umbilical cord samples are collected for histopathology. Broad-range 16S rRNA gene PCR and deep sequencing of preconception vaginal specimens will assess species richness and diversity in women with SPTB versus term delivery. Concentrations of key bacterial species will be compared using quantitative PCR (qPCR). Taxon-directed qPCR will also be used to quantify bacteria from fetal membrane samples and evaluate the association between bacterial concentrations and histopathological evidence of inflammation in the fetal membranes, placenta and umbilical cord. <h3>Ethics and dissemination</h3> This study was approved by ethics committees at Kenyatta National Hospital and the University of Washington. Results will be disseminated to clinicians at study sites and partner institutions, presented at conferences and published in peer-reviewed journals. The findings of this study could shift the paradigm for thinking about the mechanisms linking vaginal microbiota and prematurity by focusing attention on the preconception vaginal microbiota as a mediator of SPTB.

Association of fatigue and brain atrophy in multiple sclerosis

Functional imaging studies have demonstrated a relationship between fatigue and altered cerebral activation patterns in multiple sclerosis patients, but no relationship between fatigue and brain atrophy has been demonstrated. We hypothesized that the subjective complaint of fatigue would predict the severity of destructive brain pathology. We assessed the relationship between fatigue and brain atrophy longitudinally in a cohort of 134 patients previously enrolled in a 2-year clinical trial of interferon β-1a and re-evaluated 8 years after randomization into the trial. Brain atrophy was measured using the brain parenchymal fraction (BPF), and disability was measured using the Multiple Sclerosis Functional Composite at baseline, year 2 and year 8. Fatigue was measured using the Sickness Impact Profile's Sleep and Rest Scale (SIPSR) at baseline, year 2 and year 8. Linear regression analyses were used to assess the relationship between changes in fatigue and atrophy progression . Worsening fatigue on the SIPSR during the initial 2 years was significantly associated with progressive brain atrophy over the subsequent 6 years. The relationships between fatigue and brain atrophy were independent of changes in disability, mood, or other MRI characteristics. This suggests that the subjective complaint of fatigue is linked to destructive pathologic processes in RRMS patients.

Correction for intracranial volume in analysis of whole brain atrophy in multiple sclerosis: the proportion vs. residual method

Two techniques that correct (normalize) regional and whole brain volumes according to head size—the proportion method (tissue-to-intracranial volume ratio) and the residual method (regression-based predicted brain tissue volumes)—are used pervasively in neuroimaging research, but have received little critical evaluation or direct comparison. Using a quantitatively derived MRI data set of patients with multiple sclerosis ( n = 18) and age-/sex-matched normal controls ( n = 18), we introduced various types of error into estimates of intracranial volume (ICV) and absolute parenchymal volume (APV) to observe how this error affected the final outcome of normalized brain measures and their ability to detect group differences, as computed by a proportion (brain parenchymal fraction [BPF]) and residual method (predicted parenchymal volume [PPV]). The results indicated that systemic error in ICV and APV values considerably affected BPF means based on the proportion method, except with dependent-related systematic APV error, but essentially did not change statistical power associated with group differences in BPF. Random error altered BPF means to a much smaller extent, but was associated with moderate reductions in statistical power. On the other hand, PPV estimates based on the residual method were unaffected by these same ICV and APV errors, except with dependent-related systematic APV error, and were not associated with reductions in statistical power. Our findings suggest that head size correction of brain regions with the residual method generally may provide advantages over the proportion method.

Neuronal cell injury precedes brain atrophy in multiple sclerosis.

Global brain atrophy estimated using MRI and whole brain N-acetylaspartate (WBNAA) concentration measured with proton MR spectroscopy were obtained in 42 patients with relapsing-remitting multiple sclerosis and 41 matched control subjects. Patients exhibited cross-sectional atrophy (0.5%; p = 0.033) and WBNAA decline (1.8%/y; p = 0.005) vs disease duration. The 3.6-fold rate disparity between the two processes suggests that neuronal/axonal dysfunction (N-acetylaspartate decline) precedes parenchyma loss, not its consequence (i.e., is an earlier, more sensitive specific metric of the ongoing disease activity).

Interventions for the prevention of brain atrophy in multiple sclerosis : current status.

The assessment of brain volume changes on serial magnetic resonance imaging (MRI) scans can provide an objective measure of the neurodegenerative component of multiple sclerosis (MS) pathology. Results from placebo-controlled and crossover clinical trials indicate that immunomodulating (e.g. recombinant interferon-beta [IFNbeta]-1a [Rebif] and IFNbeta-1b [Betaferon] and glatiramer acetate [Copaxone]) and immunosuppressive (e.g. cladribine and alemtuzumab) treatments for relapsing-remitting (RR) and secondary progressive MS lack substantial efficacy in preventing the development of brain atrophy, despite the marked effects of these treatments on clinical and MRI outcomes of disease activity. A modest but significant treatment effect on brain atrophy has been reported for patients with RRMS only in one trial of IFNbeta-1a (Avonex) and in another study of long-term corticosteroid therapy.Failure to find a significant treatment benefit in preventing brain atrophy might be the result of inadequate trial designs, including their relatively short durations, which may not be adequate to reveal beneficial effects in a chronic disease like MS. Alternatively, such a failure might indicate that treatments proven to be effective in reducing MS-related inflammation are unable to act with the same efficacy on the most severe and disabling pathological substrates of the disease. The modest correlation between MRI enhancement frequency and brain atrophy observed in the placebo groups of several trials also fits with the concept that the suppression of inflammatory activity in MS is not fully and rapidly associated with a similar effect on the global neurodegenerative process of the disease.

Is gadolinium enhancement predictive of the development of brain atrophy in multiple sclerosis? A review of the literature.

Several studies have demonstrated that brain atrophy can be detected over relatively short intervals from the earliest stages of multiple sclerosis (MS). Reviewing the published data, the authors highlight some hypothetical pathological mechanisms proposed as determinants of brain atrophy. Using the terms multiple sclerosis, MRI (magnetic resonance imaging), and brain atrophy, 181 citations were identified. The authors considered only studies with prospective designs with natural-course MS patients and/or placebo-treated patients of therapeutic trials, in which patients underwent baseline and follow-up scans with a T1-weighted gadolinium diethylenetriamine penta-acetic acid sequence (0.1 mmol/kg body weight), and correlation analyses between Gd enhancement activity and brain atrophy progression. Five hundred thirty-two patients of 5 natural history studies and 5 therapeutic trial studies participated in the review process. The main observation was that in patients with a relapsing-remitting (RR) disease course, there was a correlation between Gd enhancement activity and brain atrophy progression. This correlation was not influenced by any other demographic and clinical additional data considered in the review process. Examination of the pathological mechanisms proposed in the reviewed studies led the authors to believe that inflammation is only in part responsible for the development of brain atrophy. This conclusion may have an implication for the strategies of tissue protection advocated in the early stages of the RR course and strengthen recent evidence indicating that anti-inflammatory immunomodulatory agents and immunosuppressive treatments, which predominantly act against the inflammatory component of disease activity, may not have similar effects on progressive tissue loss, either in RR or progressive MS.