Symbol Digit Modalities Test: A valid clinical trial endpoint for measuring cognition in multiple sclerosis.

BACKGROUND: The need for more robust outcomes in multiple sclerosis (MS) clinical trials has been a main priority of the field for decades. Dissatisfaction with existing measures has led to several consensus meetings and initiatives over the past few decades in hopes of defining and gaining acceptance of measures that are valid, reliable, sensitive to change and progression, and most importantly, relevant to those living with MS. The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed for this purpose. OBJECTIVE: The objective of this paper is to describe the results of the MSOAC plan to obtain qualification for a cognitive performance measure that meets these requirements. METHODS: Using data from 14 MS disease-modifying registration trials, we completed a comprehensive examination of the psychometric qualities of the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) with the goal of compiling evidence to support the utilization of one of these measures in future clinical trials. RESULTS AND CONCLUSION: Consistent with the published literature, the SDMT proved superior to the PASAT. The SDMT should be considered the measure of choice for MS trials in assessing cognitive processing speed.

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.

Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis.

Cognitive and motor performance measures are commonly employed in multiple sclerosis (MS) research, particularly when the purpose is to determine the efficacy of treatment. The increasing focus of new therapies on slowing progression or reversing neurological disability makes the utilization of sensitive, reproducible, and valid measures essential. Processing speed is a basic elemental cognitive function that likely influences downstream processes such as memory. The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. Among the MSOAC goals is acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step for these neuroperformance metrics is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are deemed clinically meaningful. This topical review provides an overview of research on one particular cognitive measure, the Symbol Digit Modalities Test (SDMT), recognized as being particularly sensitive to slowed processing of information that is commonly seen in MS. The research in MS clearly supports the reliability and validity of this test and recently has supported a responder definition of SDMT change approximating 4 points or 10% in magnitude.

The Nine-Hole Peg Test as a manual dexterity performance measure for multiple sclerosis.

Impaired manual dexterity is a frequently reported disability in people with multiple sclerosis (MS) and is increasingly prevalent with worsening disease. While various tests and patient-reported outcome measures are available, the Nine-Hole Peg Test (NHPT) is considered as a gold standard measure of manual dexterity and most frequently used in MS research and clinical practice. The MS Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. Among the MSOAC goals are acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step for these neuroperformance metrics is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are deemed clinically meaningful. This article addresses the NHPT, the proposed MSOAC measure for upper extremity function. We find that the NHPT is reliable within and between test sessions, discriminates between healthy subjects and MS patients with different levels of upper limb impairment, and shows high convergent validity with other manual dexterity as well as more comprehensive upper limb measures. Ecological validity is established by its relation to perceived upper limb use in daily life and perceived difficulty in performing activities of daily living. The NHPT is responsive to deterioration in longitudinal studies, and research suggests that a 20% change in test score is commonly used to define clinically meaningful worsening, a definition that needs further validation in all stages of the disease.

Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis.

The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with multiple sclerosis (MS). One of the MSOAC goals is acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful in MS. This article addresses the history, application, and psychometric properties of one such MSOAC metric of ambulation or walking namely, the timed 25-foot walk (T25FW). The T25FW has strong reliability over both brief and long periods of time in MS across a large range of disability levels. The outcome of walking speed from the T25FW has obvious real-world relevance and has correlated strongly with other measures of walking and lower extremity function. The T25FW is responsive for capturing intervention effects in pharmacological and rehabilitation trials and has an established value for capturing clinically meaningful change in ambulation. Directions for future research involve validating clinically meaningful improvements on the T25FW as well as determining whether 20% change is clinically meaningful across the disability spectrum. Researchers might further consider synchronizing accelerometers and motion sensors with the T25FW for capturing walking speed in everyday life and the patient's real environment.

Validity of low-contrast letter acuity as a visual performance outcome measure for multiple sclerosis.

Low-contrast letter acuity (LCLA) has emerged as the leading outcome measure to assess visual disability in multiple sclerosis (MS) research. As visual dysfunction is one of the most common manifestations of MS, sensitive visual outcome measures are important in examining the effect of treatment. Low-contrast acuity captures visual loss not seen in high-contrast visual acuity (HCVA) measurements. These issues are addressed by the MS Outcome Assessments Consortium (MSOAC), including representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. MSOAC goals are acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are clinically meaningful. This review shows that MS and disease-free controls have similar median HCVA, while MS patients have significantly lower LCLA. Deficits in LCLA and vision-specific quality of life are found many years after an episode of acute optic neuritis, even when HCVA has recovered. Studies reveal correlations between LCLA and the Expanded Disability Status Score (EDSS), Multiple Sclerosis Functional Composite (MSFC), retinal nerve fiber layer (RNFL) and ganglion cell layer plus inner plexiform layer (GCL + IPL) thickness on optical coherence tomography (OCT), brain magnetic resonance imaging (MRI), visual evoked potential (VEP), electroretinogram (ERG), pupillary function, and King-Devick testing. This review also concludes that a 7-point change in LCLA is clinically meaningful. The overall goal of this review is to describe and characterize the LCLA metric for research and clinical use among persons with MS.

Multiple Sclerosis Outcome Assessments Consortium: Genesis and initial project plan.

The need for improved clinical outcome measures in multiple sclerosis trials has been recognized for two decades, but only recently has the Food and Drug Administration (FDA) created a pathway for qualification of new clinician-reported outcome (ClinRO) assessments. Additionally, drug development in multiple sclerosis (MS) has been extraordinarily active, with numerous disease-modifying drugs now on the market. This shifting therapeutic landscape, along with the unmet need for drugs to treat the progressive forms of MS and the changing expectations of clinicians, patients, and payers, have led to the call for more sensitive and meaningful disability progression measures. In response to these drivers, the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was launched. A public-private partnership, MSOAC aims to accelerate the development of new therapies for MS by generating new tools for measuring outcomes in clinical trials. At the first annual MSOAC/FDA meeting, a regulatory path was outlined for qualifying a new tool for assessing efficacy in registration trials of MS. The European Medicines Agency (EMA) and FDA will provide parallel consultation and review. The consensus approach with engagement by all of the stakeholders, prominently including patients with MS, should also increase acceptance of the measure by clinicians and patients.

Thermodynamics of Zn2+ binding to Cys2His2 and Cys2HisCys zinc fingers and a Cys4 transcription factor site.

The thermodynamics of Zn(2+) binding to three peptides corresponding to naturally occurring Zn-binding sequences in transcription factors have been quantified with isothermal titration calorimetry (ITC). These peptides, the third zinc finger of Sp1 (Sp1-3), the second zinc finger of myelin transcription factor 1 (MyT1-2), and the second Zn-binding sequence of the DNA-binding domain of glucocorticoid receptor (GR-2), bind Zn(2+) with Cys(2)His(2), Cys(2)HisCys, and Cys(4) coordination, respectively. Circular dichroism confirms that Sp1-3 and MyT1-2 have considerable and negligible Zn-stabilized secondary structure, respectively, and indicate only a small amount for GR-2. The pK(a)'s of the Sp1-3 cysteines and histidines were determined by NMR and used to estimate the number of protons displaced by Zn(2+) at pH 7.4. ITC was also used to determine this number, and the two methods agree. Subtraction of buffer contributions to the calorimetric data reveals that all three peptides have a similar affinity for Zn(2+), which has equal enthalpy and entropy components for Sp1-3 but is more enthalpically disfavored and entropically favored with increasing Cys ligands. The resulting enthalpy-entropy compensation originates from the Zn-Cys coordination, as subtraction of the cysteine deprotonation enthalpy results in a similar Zn(2+)-binding enthalpy for all three peptides, and the binding entropy tracks with the number of displaced protons. Metal and protein components of the binding enthalpy and entropy have been estimated. While dominated by Zn(2+) coordination to the cysteines and histidines, other residues in the sequence affect the protein contributions that modulate the stability of these motifs.

The genetic signature of perineuronal oligodendrocytes reveals their unique phenotype.

Oligodendrocytes--best known for assembling central nervous system myelin--can be categorized as precursors, myelin-forming cells and non-myelinating perineuronal cells. Perineuronal oligodendrocytes have been well characterized morphologically and ultrastructurally, but knowledge about their function remains scanty. It has been proposed that perineuronal oligodendrocytes support neurons and, following injury, transform into myelin-synthesizing cells. Recent findings implicating perineuronal oligodendrocytes in cytoarchitectural abnormalities in the prefrontal cortex of schizophrenia and other psychiatric disorders shed new light on these cells. We have obtained the genetic signature of perineuronal oligodendrocytes by identifying gene expression differences between oligodendrocyte subpopulations using cell-specific tags, microarray technology, quantitative time-resolved polymerase chain reaction and bioinformatics tools. We show that perineuronal cells are the progeny of oligodendrocyte progenitors and, hence, are members of the oligodendrocyte lineage. Physiologically they exhibit a novel phenotype. Their expression of PDGFR-αß and its growth factor ligand PDGF-CC sets them apart from members of their lineage as this receptor precludes their response to the same growth factors that act on myelinating cells. Their coordinate expression and context-specific usage of transcription factors Olig2, Ascl1 and Pax6, together with the prominent presence of transcription factors Pea3, Lhx2 and Otx2--not hitherto linked to the oligodendrocyte lineage--suggested a cell with features that blur the boundary between a neuron and a glial cell. But they also maintain a reservoir of untranslated transcripts encoding major myelin proteins presumably for a demyelinating episode. This first molecular characterization of perineuronal oligodendrocytes revealed the striking difference between the myelinating and non-myelinating phenotypes.

A tool for examining the role of the zinc finger myelin transcription factor 1 (Myt1) in neural development: Myt1 knock-in mice.

The Myt1 family of transcription factors is unique among the many classes of zinc finger proteins in how the zinc-stabilized fingers contact the DNA helix. To examine the function of Myt1 in the developing nervous system, we generated mice in which Myt1 expression was replaced by an enhanced Green Fluorescent Protein fused to a Codon-improved Cre recombinase as a protein reporter. Myt1 knock-in mice die at birth, apparently due to improper innervation of their lungs. Elimination of Myt1 did not significantly affect the number or distribution of neural precursor cells that normally express Myt1 in the embryonic spinal cord. Nor was the general pattern of differentiated neurons altered in the embryonic spinal cord. The Myt1 knock-in mice should provide an important tool for identifying the in vivo targets of Myt1 action and unraveling the role of this structurally distinct zinc finger protein in neural development.

Mouse transmembrane BAX inhibitor motif 3 (Tmbim3) encodes a 38 kDa transmembrane protein expressed in the central nervous system.

Cell survival proteins play an important role throughout nervous system development, normal physiological processes, and pathological conditions. Transmembrane BAX inhibitor motif 3 (TMBIM3, also known as GRINA), is a member of a family of proteins that contain a conserved BAX inhibitor-1 motif. This family of proteins includes several members that have been shown to protect cells from apoptosis. In this study, the authors show that TMBIM3 is expressed in the brain including high levels in the hippocampus. Biochemical and sequence analysis of TMBIM3 demonstrates that the rat, murine, and human genes encode an approximately 38 kDa protein with a predicted seven transmembrane domain topology. A Tmbim3 knockout mouse line did not have an obvious phenotype, but may prove useful in future studies of this family of proteins.

Effective Data Sharing as a Conduit for Advancing Medical Product Development.

INTRODUCTION: Patient-level data sharing has the potential to significantly impact the lives of patients by optimizing and improving the medical product development process. In the product development setting, successful data sharing is defined as data sharing that is actionable and facilitates decision making during the development and review of medical products. This often occurs through the creation of new product development tools or methodologies, such as novel clinical trial design and enrichment strategies, predictive pre-clinical and clinical models, clinical trial simulation tools, biomarkers, and clinical outcomes assessments, and more. METHODS: To be successful, extensive partnerships must be established between all relevant stakeholders, including industry, academia, research institutes and societies, patient-advocacy groups, and governmental agencies, and a neutral third-party convening organization that can provide a pre-competitive space for data sharing to occur. CONCLUSIONS: Data sharing focused on identified regulatory deliverables that improve the medical product development process encounters significant challenges that are not seen with data sharing aimed at advancing clinical decision making and requires the commitment of all stakeholders. Regulatory data sharing challenges and solutions, as well as multiple examples of previous successful data sharing initiatives are presented and discussed in the context of medical product development.

Standardized Data Structures in Rare Diseases: CDISC User Guides for Duchenne Muscular Dystrophy and Huntington's Disease.

Interest in drug development for rare diseases has expanded dramatically since the Orphan Drug Act was passed in 1983, with 40% of new drug approvals in 2019 targeting orphan indications. However, limited quantitative understanding of natural history and disease progression hinders progress and increases the risks associated with rare disease drug development. Use of international data standards can assist in data harmonization and enable data exchange, integration into larger datasets, and a quantitative understanding of disease natural history. The US Food and Drug Administration (FDA) requires the use of Clinical Data Interchange Consortium (CDISC) Standards in new drug submissions to help the agency efficiently and effectively receive, process, review, and archive submissions, as well as to help integrate data to answer research questions. Such databases have been at the core of biomarker qualification efforts and fit-for-purpose models endorsed by the regulators. We describe the development of CDISC therapeutic area user guides for Duchenne muscular dystrophy and Huntington's disease through Critical Path Institute consortia. These guides describe formalized data structures and controlled terminology to map and integrate data from different sources. This will result in increased standardization of data collection and allow integration and comparison of data from multiple studies. Integration of multiple data sets enables a quantitative understanding of disease progression, which can help overcome common challenges in clinical trial design in these and other rare diseases. Ultimately, clinical data standardization will lead to a faster path to regulatory approval of urgently needed new therapies for patients.

Data Sharing Goals for Nonprofit Funders of Clinical Trials.

Sharing clinical trial data can provide value to research participants and communities by accelerating the development of new knowledge and therapies as investigators merge data sets to conduct new analyses, reproduce published findings to raise standards for original research, and learn from the work of others to generate new research questions. Nonprofit funders, including disease advocacy and patient-focused organizations, play a pivotal role in the promotion and implementation of data sharing policies. Funders are uniquely positioned to promote and support a culture of data sharing by serving as trusted liaisons between potential research participants and investigators who wish to access these participants' networks for clinical trial recruitment. In short, nonprofit funders can drive policies and influence research culture. The purpose of this paper is to detail a set of aspirational goals and forward thinking, collaborative data sharing solutions for nonprofit funders to fold into existing funding policies. The goals of this paper convey the complexity of the opportunities and challenges facing nonprofit funders and the appropriate prioritization of data sharing within their organizations and may serve as a starting point for a data sharing toolkit for nonprofit funders of clinical trials to provide the clarity of mission and mechanisms to enforce the data sharing practices their communities already expect are happening.

Correction: Data Sharing Goals for Nonprofit Funders of Clinical Trials.

[This corrects the article DOI: 10.2196/23011.].

Tubulin polymerization-promoting protein (TPPP/p25) is critical for oligodendrocyte differentiation.

TPPP/p25, a recently identified tubulin polymerization-promoting protein (TPPP), is expressed mainly in myelinating oligodendrocytes of the CNS. Here, we show that TPPP/p25 is strongly upregulated during the differentiation of primary oligodendrocyte cells as well as the CG-4 cell line. The microRNA expression profile of CG-4 cells before and after induction of differentiation was established and revealed differential regulation of a limited subset of microRNAs. miR-206, a microRNA predicted to target TPPP/p25, was not detected in oligodendrocytes. Overexpression of miR-206 led to downregulation of TPPP/p25 resulting in inhibition of differentiation. Transfection of siRNAs against TPPP/p25 also inhibited cell differentiation and promoted cell proliferation, providing evidence for an important role of TPPP/p25 during oligodendrogenesis. These results support an essential role for TPPP/p25 in oligodendrocyte differentiation likely via rearrangement of the microtubule system during the process elongation prior to the onset of myelination.

Advancing Therapeutic Development for Pulmonary Morbidities Associated with Preterm Birth.

Chronic pulmonary and respiratory conditions associated with preterm birth are incompletely characterized, complicating long-term treatment and development of more effective therapies. Stakeholders face challenges in the development of validated, clinically meaningful endpoints that adequately measure morbidities and predict or represent health outcomes for preterm neonates. We propose in this paper a research agenda, informed by the input of experts from a 2018 workshop we convened on this topic, to advance endpoint and treatment development. We discuss the necessity of further evaluation of existing endpoints and the improved characterization of disease endotypes. We also discuss key steps to the development of optimized short- and long-term endpoints that can be linked to meaningful health outcomes. Finally, we discuss the importance of limiting variability in data collection and the application of new clinical trial endpoints as well as the critical nature of multi-stakeholder collaboration to advancing therapeutic development for this vulnerable patient population.

Identification of dynamically regulated microRNA and mRNA networks in developing oligodendrocytes.

MicroRNAs (miRNAs) play important roles in modulating gene expression at the posttranscriptional level. In postnatal oligodendrocyte lineage cells, the miRNA expression profile ("microRNAome") contains 43 miRNAs whose expression dynamically changes during the transition from A2B5(+) oligodendrocyte progenitor cells to premyelinating GalC(+) cells. The combination of microRNAome profiling with analyses of the oligodendrocyte transcriptome reveals a target bias for a class of miRNAs which includes miR-9. We show that miR-9 is downregulated during oligodendrocyte differentiation. In addition, miR-9 expression level inversely correlates with the expression of its predicted targets, among which is the peripheral myelin protein PMP22. We found that PMP22 mRNA but not protein is detectable in oligodendrocytes, whereas Schwann cells producing PMP22 protein lack miR-9. We demonstrate that miR-9 interacts with the 3' untranslated region of PMP22 and downregulates its expression. Our results support models in which miRNAs can act as guardians of the transcriptome.