Gray matter atrophy is related to long‐term disability in multiple sclerosis

Fisniku, Leonora; Chard, Declan; Jackson, Jessica L.; Anderson, Valerie; Altmann, Daniel R.; Miszkiel, Katherine; Thompson, Alan J.; Miller, David H.

doi:10.1002/ana.21423

Cited by 454 publications

(413 citation statements)

References 41 publications

(66 reference statements)

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“…Little damage may cause large changes in network topology. Third, given the observed specific effects of different types of damage, functional connectivity changes in the beginning of the disease might be different compared to later stages of the disease, as it is known from empirical data that thalamic atrophy is present in the earliest phases of the disease (Minagar et al, 2013), while cortical atrophy is thought to be more prominent and developing in patterns in later stages (Fisniku et al, 2008). Whether the supposed sequential occurrence of thalamic and cortical atrophy is driven by one of the changes remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Explaining the heterogeneity of functional connectivity findings in multiple sclerosis: An empirically informed modeling study

Tewarie

Steenwijk

Brookes

et al. 2018

Human Brain Mapping

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To understand the heterogeneity of functional connectivity results reported in the literature, we analyzed the separate effects of grey and white matter damage on functional connectivity and networks in multiple sclerosis. For this, we employed a biophysical thalamo‐cortical model consisting of interconnected cortical and thalamic neuronal populations, informed and amended by empirical diffusion MRI tractography data, to simulate functional data that mimic neurophysiological signals. Grey matter degeneration was simulated by decreasing within population connections and white matter degeneration by lowering between population connections, based on lesion predilection sites in multiple sclerosis. For all simulations, functional connectivity and functional network organization are quantified by phase synchronization and network integration, respectively. Modeling results showed that both cortical and thalamic grey matter damage induced a global increase in functional connectivity, whereas white matter damage induced an initially increased connectivity followed by a global decrease. Both white and especially grey matter damage, however, induced a decrease in network integration. These empirically informed simulations show that specific topology and timing of structural damage are nontrivial aspects in explaining functional abnormalities in MS. Insufficient attention to these aspects likely explains contradictory findings in multiple sclerosis functional imaging studies so far.

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Section: Discussionmentioning

confidence: 99%

Explaining the heterogeneity of functional connectivity findings in multiple sclerosis: An empirically informed modeling study

Tewarie

Steenwijk

Brookes

et al. 2018

Human Brain Mapping

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“…While Gd + lesions reflect transient inflammatory events, changes in T2/ FLAIR lesion numbers and volumes are measures of cumulative lesion formation and can be used in lieu of Gd + lesion counts [26]. The relationship to future disability is only modest [27], and other measures that reflect global and gray matter changes have been shown to be better predictors of long-term outcomes [28,29]. Despite this evidence, MRI outcomes for exploratory Phase II studies of MS therapies continue to use Gd + lesions and T2 volumes.…”

Section: Mri As a Surrogate Markermentioning

confidence: 99%

“…Measures of specific tissue types reveal that there are distinct atrophy rates in gray matter versus white matter regions in the brain, and that while white matter regions show a steady decrease, gray matter atrophy accelerates over time and is a more sensitive predictor of future disability [28,29]. There is emerging evidence that the appearance of white matter lesions is linked to subsequent cortical gray matter changes, although the specific location of the lesions may influence the degree of gray matter change detected [79].…”

Section: Fig 1 Serial Cerebral Magnetic Resonance (Mr) Images Demonmentioning

confidence: 99%

Neuroimaging in Multiple Sclerosis: Neurotherapeutic Implications

Sicotte

2011

Neurotherapeutics

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Summary: Imaging techniques, in particular magnetic resonance imaging (MRI), play an important role in the diagnosis and management of multiple sclerosis (MS) and related demyelinating diseases. Findings on MRI studies of the brain and spinal cord are critical for MS diagnosis, are used to monitor treatment response and may aid in predicting disease progression in individual patients. In addition, results of imaging studies serve as essential biomarkers in clinical trials of putative MS therapies and have led to important insights into disease pathophysiology. Although they are useful tools and provide in vivo measures of disease-related activity, there are some important limitations of MRI findings in MS, including the non-specific nature of detectable white matter changes, the poor correlation with clinical disability, the limited sensitivity and ability of standard measures of gadolinium enhancing lesions and T2 lesions to predict future clinical course, and the lack of validated biomarkers of long term outcomes. Advancements that hold promise for the future include new techniques that are sensitive to diffuse changes, the increased use of higher field scanners, measures that capture disease related changes in gray matter, and the use of combined structural and functional imaging approaches to assess the complex and evolving disease process that occurs during the course of MS.

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“…This process begins very early in MS. Rapid rates of brain atrophy have been observed in CIS patients who convert to MS, 10,11 and rapid brain atrophy continues throughout the disease. Like all disease-severity measures, atrophy rates vary across MS patients, and the rate of atrophy during RRMS is only weakly correlated with relapses or Expanded Disability Status Scale (EDSS) score.…”

Section: Irreversible Axon and Myelin Injury Occurs Early In The Courmentioning

confidence: 99%

“…Accelerated gray matter atrophy occurs in patients at all stages of MS as well 14 and correlates better with disability than other MRI measures. 11 The picture emerges of a disease that is pathologically active from onset, in which CNS tissue may be damaged or destroyed without obvious clinical manifestations during early disease stages. Over time, with cumulative brain tissue injury and the additive effects of aging, a threshold is surpassed beyond which neurologic function fails and progressive disability ensues.…”

Section: Irreversible Axon and Myelin Injury Occurs Early In The Courmentioning

confidence: 99%

Controversy: To Treat or Not to Treat in Clinically Isolated Syndrome

Herndon¹

2009

International Journal of MS Care

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99The decision whether to treat or not to treat patients presenting with a clinically isolated syndrome suggestive of multiple sclerosis (MS) can be a difficult one. If the results of magnetic resonance imaging (MRI) are normal, most clinicians would not treat, as the risk of development of MS is low. If the MRI is abnormal, however, the decision is considerably more difficult. At present, we do not have any good markers that would allow us to determine which individuals will go on to develop MS and which individuals will remain stable.An advantage of early treatment is a 15% to 20% further reduction in attack frequency over and above the approximately 30% decrease that occurs with later treatment. This has been a consistent finding with early treatment with the interferons and glatiramer acetate. Nevertheless, with early treatment we are subjecting many patients to a regimen that will not help them in order to improve the outcome in those who will develop clinically definite MS. This "medicalizes" those patients, who will suffer the same side effects as those who need the medication.On the other hand, the placebo patients from the phase 3 trials who were treated with their second attack subsequently have more attacks than those treated early, and probably more disability. The long-term subcutaneous interferon beta-1b (Betaseron) results showed a much higher 17-year mortality rate in those receiving placebo than in those treated with either low-dose or high-dose Betaseron in the phase 3 trial.

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Gray matter atrophy is related to long‐term disability in multiple sclerosis

Abstract: In MS patients with a relatively long and homogeneous disease duration, GM atrophy is more marked than WM atrophy, and reflects disease subtype and disability to a greater extent than WM atrophy or lesions.

Cited by 454 publications

References 41 publications

Explaining the heterogeneity of functional connectivity findings in multiple sclerosis: An empirically informed modeling study

Explaining the heterogeneity of functional connectivity findings in multiple sclerosis: An empirically informed modeling study

Neuroimaging in Multiple Sclerosis: Neurotherapeutic Implications

Controversy: To Treat or Not to Treat in Clinically Isolated Syndrome

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