Dataset Information

High-dimensional detection of imaging response to treatment in multiple sclerosis.

ABSTRACT: Changes on brain imaging may precede clinical manifestations or disclose disease progression opaque to conventional clinical measures. Where, as in multiple sclerosis, the pathological process has a complex anatomical distribution, such changes are not easily detected by low-dimensional models in common use. This hinders our ability to detect treatment effects, both in the management of individual patients and in interventional trials. Here we compared the ability of conventional models to detect an imaging response to treatment against high-dimensional models incorporating a wide multiplicity of imaging factors. We used fully-automated image analysis to extract 144 regional, longitudinal trajectories of pre- and post- treatment changes in brain volume and disconnection in a cohort of 124 natalizumab-treated patients. Low- and high-dimensional models of the relationship between treatment and the trajectories of change were built and evaluated with machine learning, quantifying performance with receiver operating characteristic curves. Simulations of randomised controlled trials enrolling varying numbers of patients were used to quantify the impact of dimensionality on statistical efficiency. Compared to existing methods, high-dimensional models were superior in treatment response detection (area under the receiver operating characteristic curve?=?0.890 [95% CI?=?0.885-0.895] vs. 0.686 [95% CI?=?0.679-0.693], P???=?0.01). High-dimensional models based on routine, clinical imaging can substantially enhance the detection of the imaging response to treatment in multiple sclerosis, potentially enabling more accurate individual prediction and greater statistical efficiency of randomised controlled trials.

SUBMITTER: Kanber B

PROVIDER: S-EPMC6556513 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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High-dimensional detection of imaging response to treatment in multiple sclerosis.

Kanber Baris B Nachev Parashkev P Barkhof Frederik F Calvi Alberto A Cardoso Jorge J Cortese Rosa R Prados Ferran F Sudre Carole H CH Tur Carmen C Ourselin Sebastien S Ciccarelli Olga O

NPJ digital medicine 20190610

Changes on brain imaging may precede clinical manifestations or disclose disease progression opaque to conventional clinical measures. Where, as in multiple sclerosis, the pathological process has a complex anatomical distribution, such changes are not easily detected by low-dimensional models in common use. This hinders our ability to detect treatment effects, both in the management of individual patients and in interventional trials. Here we compared the ability of conventional models to detec ...[more]

PMID: 31304395

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Project description:BACKGROUND:Recent data from animal models of multiple sclerosis (MS) and from a pilot study indicated a possible beneficial impact of statins on MS. METHODOLOGY/PRINCIPAL FINDINGS:Safety, tolerability and effects on disease activity of atorvastatin given alone or in combination with interferon-beta (IFN-beta) were assessed in a phase II open-label baseline-to-treatment trial in relapsing-remitting MS (RRMS). Patients with at least one gadolinium-enhancing lesion (CEL) at screening by magnetic resonance imaging (MRI) were eligible for the study. After a baseline period of 3 monthly MRI scans (months -2 to 0), patients followed a 9-month treatment period on 80 mg atorvastatin daily. The number of CEL in treatment months 6 to 9 compared to baseline served as the primary endpoint. Other MRI-based parameters as well as changes in clinical scores and immune responses served as secondary endpoints. Of 80 RRMS patients screened, 41 were included, among them 16 with IFN-beta comedication. The high dose of 80 mg atorvastatin was well tolerated in the majority of patients, regardless of IFN-beta comedication. Atorvastatin treatment led to a substantial reduction in the number and volume of CEL in two-sided multivariate analysis (p = 0.003 and p = 0.008). A trend towards a significant decrease in number and volume of CEL was also detected in patients with IFN-beta comedication (p = 0.060 and p = 0.062), in contrast to patients without IFN-beta comedication (p = 0.170 and p = 0.140). Immunological investigations showed no suppression in T cell response but a significant increase in IL-10 production. CONCLUSIONS/SIGNIFICANCE:Our data suggest that high-dose atorvastatin treatment in RRMS is safe and well tolerated. Moreover, MRI analysis indicates a possible beneficial effect of atorvastatin, alone or in combination with IFN-beta, on the development of new CEL. Thus, our findings provide a rationale for phase II/III trials, including combination of atorvastatin with already approved immunomodulatory therapy regimens. TRIAL REGISTRATION:ClinicalTrials.gov NCT00616187.

Project description:So far, only a small number of medications are effective in progressive multiple sclerosis (MS). The sphingosine-1-phosphate-receptor (S1PR)-1,5 modulator siponimod, licensed for progressive MS, is acting both on peripheral immune cells and in the central nervous system (CNS). So far it remains elusive, whether those effects are related to the neurotrophin brain derived neurotrophic factor (BDNF). We hypothesized that BDNF in immune cells might be a prerequisite to reduce disease activity in experimental autoimmune encephalomyelitis (EAE) and prevent neurotoxicity. MOG35-55 immunized wild type (WT) and BDNF knock-out (BDNFko) mice were treated with siponimod or vehicle and scored daily in a blinded manner. Immune cell phenotyping was performed via flow cytometry. Immune cell infiltration and demyelination of spinal cord were assessed using immunohistochemistry. In vitro, effects on neurotoxicity and mRNA regulation were investigated using dorsal root ganglion cells incubated with EAE splenocyte supernatant. Siponimod led to a dose-dependent reduction of EAE scores in chronic WT EAE. Using a suboptimal dosage of 0.45 µg/day, siponimod reduced clinical signs of EAE independent of BDNF-expression in immune cells in accordance with reduced infiltration and demyelination. Th and Tc cells in secondary lymphoid organs were dose-dependently reduced, paralleled with an increase of regulatory T cells. In vitro, neuronal viability trended towards a deterioration after incubation with EAE supernatant; siponimod showed a slight rescue effect following treatment of WT splenocytes. Neuronal gene expression for CCL2 and CX3CL1 was elevated after incubation with EAE supernatant, which was reversed after siponimod treatment for WT, but not for BNDFko. Apoptosis markers and alternative death pathways were not affected. Siponimod exerts both anti-inflammatory and neuroprotective effects, partially related to BDNF-expression. This might in part explain effectiveness during progression in MS and could be a target for therapy.

Dataset Information

High-dimensional detection of imaging response to treatment in multiple sclerosis.

Publications

High-dimensional detection of imaging response to treatment in multiple sclerosis.

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