Raj Kapoor

Diffusion tensor imaging in early relapsing-remitting multiple sclerosis

Diffusion tensor magnetic resonance imaging (DTI) indices are abnormal in patients with established multiple sclerosis (MS). The objective of this study was to examine the diffusion characteristics of MS lesions, normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) in MS patients with early relapsing-remitting disease. A further objective was to investigate the relationship between three DTI parameters (fractional anisotropy (FA), mean diffusivity (MD) and volume ratio (VR)) and clinical outcome measures (Kurtzke expanded disability status scale (EDSS) and MS Functional Composite Measure) in early disease. DTI was performed in 28 patients and 27 controls. Analysis was carried out using a region of interest (ROI) approach. ROIs were placed in 12 NAWM and nine NAGM regions. Significant differences were found in FA, MD and VR between lesions and NAWM (P<0.001 for all three DTI parameters). No significant differences were found between patients and controls when examining NAWM or NAGM, although there was a trend for abnormal NAWM FA and VR in some regions. No correlation was found between DTI parameters in lesions, NAWM or NAGM and the clinical outcome measures. The lack of significant DTI abnormality in the NAWM and NAGM may reflect a lack of pathological change or a limited sensitivity of DTI using ROI methodology. Previous studies have shown abnormalities in T1 relaxation time, magnetisation transfer ratio (MTR) and N-Acetyl aspartate (NAA) in this cohort of patients, and as such, DTI using a region of interest (ROI) approach may not be as sensitive as other MR techniques in detecting subtle changes in normal appearing brain tissue in early disease.

Setting a research agenda for progressive multiple sclerosis: The International Collaborative on Progressive MS

Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS.

The EDSS-Plus, an improved endpoint for disability progression in secondary progressive multiple sclerosis

Background: The Expanded Disability Status Scale (EDSS) has wide scientific and regulatory precedent but limited ability to detect clinically relevant disability progression in secondary progressive multiple sclerosis (SPMS) patients, partly due to a lack of meaningful measurement of short-distance ambulatory and upper-extremity function. Objective: To present a rationale for a composite endpoint adding the timed 25-foot walk (T25FW) and 9-Hole Peg Test (9HPT) to EDSS for SPMS disability progression assessment. Methods: Using the International Multiple Sclerosis Secondary Progressive Avonex Clinical Trial (IMPACT) placebo arm (n = 215) data, we analyzed disability progression using a novel progression endpoint, “EDSS-Plus,” defined as progression on ⩾1 of 3 components (EDSS, T25FW, and/or 9HPT) confirmed ⩾24 weeks apart and with a ⩾20% minimum threshold change for T25FW and 9HPT. Results: Over 2 years, subjects classified as T25FW, 9HPT (dominant hand), or 9HPT (non-dominant hand) progressors worsened on average by 103.4%, 69.0%, and 59.2%, respectively, while non-progressors’ times remained largely unchanged. Using EDSS-Plus, 59.5% of the patients had 24-week confirmed disability progression versus 24.7% (EDSS), 41.9% (T25FW), and 34.4% (9HPT (either hand)) on each component alone. Conclusion: The 24-week confirmed minimum worsening of ⩾20% for T25FW and 9HPT clearly separates SPMS progressors from non-progressors. We propose that EDSS-Plus may represent an improved endpoint to identify SPMS disability progression.

MRI Acquisition and Analysis Protocol for In Vivo Intraorbital Optic Nerve Segmentation at 3T

PURPOSE To present a new acquisition and analysis protocol for reliable and reproducible segmentation of the entire intraorbital optic nerve (ION) mean cross-sectional area by means of magnetic resonance imaging (MRI) at 3 tesla (T). METHODS Eight healthy volunteers (mean age 31, five were male) gave written informed consent and both of their IONs were imaged individually using a coronal-oblique T2-weighted fast multidynamic image acquisition scheme; the proposed acquisition scheme has its rationale in combining separately acquired volumes and registering them to account for motion-related artifacts commonly associated with longer acquisitions. Mean cross-sectional area of each ION was measured using a semiautomated image analysis protocol that was based on an active surface model previously described and used for spinal cord imaging. Reproducibility was assessed for repeated scans (scan-rescan) and repeated image analysis performance (intraobserver). RESULTS Mean and SD values of the left ION cross-sectional area for the eight healthy volunteers were 5.0 (±0.7) mm² and for the right ION were 5.3 (±0.8) mm². Mean scan-rescan coefficient of variation (COV) for the left ION was 4.3% and for the right was 4.4%. Mean intraobserver COV for the left ION was 2.1% and for the right was 1.8%. CONCLUSIONS This study presents a new MRI acquisition and analysis protocol for reliable and reproducible in vivo measurement of the entire ION mean cross-sectional area as demonstrated in a pilot study of healthy subjects. The protocol presented here can be used in future studies of the ION in disease state.

The MSOAC approach to developing performance outcomes to measure and monitor multiple sclerosis disability

Background: The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed by the National MS Society to develop improved measures of multiple sclerosis (MS)-related disability. Objectives: (1) To assess the current literature and available data on functional performance outcome measures (PerfOs) and (2) to determine suitability of using PerfOs to quantify MS disability in MS clinical trials. Methods: (1) Identify disability dimensions common in MS; (2) conduct a comprehensive literature review of measures for those dimensions; (3) develop an MS Clinical Data Interchange Standards Consortium (CDISC) data standard; (4) create a database of standardized, pooled clinical trial data; (5) analyze the pooled data to assess psychometric properties of candidate measures; and (6) work with regulatory agencies to use the measures as primary or secondary outcomes in MS clinical trials. Conclusion: Considerable data exist supporting measures of the functional domains ambulation, manual dexterity, vision, and cognition. A CDISC standard for MS (http://www.cdisc.org/therapeutic#MS) was published, allowing pooling of clinical trial data. MSOAC member organizations contributed clinical data from 16 trials, including 14,370 subjects. Data from placebo-arm subjects are available to qualified researchers. This integrated, standardized dataset is being analyzed to support qualification of disability endpoints by regulatory agencies.

Steps towards Collective Sustainability in Biomedical Research

The optimism surrounding multistakeholder research initiatives does not match the clear view of policies that are needed to exploit the potential of these collaborations. Here we propose some action items that stem from the integration between research advancements with the perspectives of patient-advocacy organizations, academia, and industry.

Advanced MRI measures like DTI or fMRI should be outcome measures in future clinical trials – YES

Neuroprotection and repair are two of the biggest unmet therapeutic needs in people with progressive multiple sclerosis (MS). Despite recent positive trials of ocrelizumab and siponimod, the process of drug discovery for these needs remains painfully slow and difficult. This contrasts with the situation in relapsing MS, where there is an efficient pathway for discovering drugs to prevent relapse: the effects of candidate drugs on what has emerged as the dominant underlying pathology (inflammation) can be assessed with an magnetic resonance imaging (MRI) biomarker (lesion activity), which also correlates with meaningful clinical outcome (relapse).1