Validation of the National Institute of Neurological Disorders and Stroke Spinal Cord Injury MRI Common Data Elements Instrument

BACKGROUND AND PURPOSE:The National Institute of Neurological Disorders and Stroke common data elements initiative was created to provide a consistent method for recording and reporting observations related to neurologic diseases in clinical trials. The purpose of this study is to validate the subset of common data elements related to MR imaging evaluation of acute spinal cord injury.MATERIALS AND METHODS:Thirty-five cervical and thoracic MR imaging studies of patients with acute spinal cord injury were evaluated independently in 2 rounds by 5 expert reviewers. Intra- and interrater agreement were calculated for 17 distinct MR imaging observations related to spinal cord injury. These included ordinal, categoric, and continuous measures related to the length and location of spinal cord hemorrhage and edema as well as spinal canal and cord measurements. Level of agreement was calculated using the interclass correlation coefficient and kappa.RESULTS:The ordinal common data elements spinal cord injury elements for lesion center and rostral or caudal extent of edema or hemorrhage demonstrated agreement ranging from interclass correlation coefficient 0.68 to 0.99. Reproducibility ranged from 0.95 to 1.00. Moderate agreement was observed for absolute length of hemorrhage and edema (0.54 to 0.60) with good reproducibility (0.78 to 0.83). Agreement for the Brain and Spinal Injury Center score showed the lowest interrater agreement with an overall kappa of 0.27 (0.20, 0.34). For 7 of the 8 variables related to spinal cord injury, agreement improved between the first and second evaluation. Continuous diameter measures of the spinal cord and spinal canal using interclass correlation coefficient varied substantially (0.23 to 0.83).CONCLUSIONS:Agreement was more consistent for the ordinal measures of spinal cord injury than continuous measures. Good to excellent agreement on length and location of spinal cord hemorrhage and edema can be achieved with ordinal measures alone.

In 2006, the National Institute of Neurological Disorders and Stroke (NINDS) began a process to develop common data elements (CDEs) to provide a standardized method for the collection of clinical data related to neurologic diseases.^1-3 Recognizing that there is a lack of clear and consistent terminology for spine disorders, particularly spinal cord injury (SCI), in 2014, the NINDS convened a workgroup comprising expert stakeholders for the development of SCI CDE instruments that included clinical care assessments and imaging.^3-8 This new set of SCI CDE instruments aimed to increase the efficiency and value of clinical research studies and treatment, increase data quality, facilitate data sharing, and help educate new clinical investigators.³ Investigators are expected to incorporate the CDE modules in grant applications and National Institutes of Health–funded research.The MR imaging SCI CDE subset was created to be a comprehensive and standardized terminology for describing MR imaging findings in patients with SCI. This collection consists of a case report form (CRF) containing 35 discrete measures and responses divided into 4 main categories: general imaging characteristics, spinal injury features, canal and cord measurements, and chronic SCI features. The responses are of 3 types: Boolean, categoric, and an ordinal range representing specific anatomic locations. These measures were chosen to represent both objective and subjective assessment derived from routine clinical MR images. The workgroup codified these features using existing CDEs that have proved value in the published literature, and when ones did not exist, the workgroup developed the feature and the response parameters.As with the development of any CRF used for a clinical trial or research, the goal is to provide an instrument that provides useful data representations that are reproducible across trained observers and institutions, require minimal cognitive effort, minimize ambiguity, and are both accurate and precise. Reproducibility of the observations through rigorous testing by multiple observers is a needed step to validate the instrument before clinical or research use. However, the evaluation process may not entirely reproduce the clinical environment in which it is meant to be used such that datasets and observers are overly prepared or optimized. Therefore, the goal of this study is to determine the inter- and intrarater reliability of the NINDS MR imaging CDEs when assessed by MR imaging experts with familiarity with SCI. We hypothesize that there will be good to excellent agreement (kappa >0.4) among the expert raters after limited training.     

Emotional detachment,gait ataxia,and cerebellar dysconnectivity associated with compound heterozygous mutations in the SPG7 gene

ABSTRACT

We report a patient with autism-like deficits in emotional connectedness, executive dysfunction, and ataxia beginning at age 39. He had compound heterozygous variants in SPG7 (A510V and 1552+1 G>T substitutions), mutation of which is classically associated with spastic paraparesis. Diffusion MRI demonstrated abnormalities in the cerebellar outflow tracts. Transcranial magnetic stimulation showed a prolonged cortical silent period representing exaggerated cortical inhibition, as previously described with pure cerebellar degeneration. The acquired cerebellar cognitive affective syndrome in association with specific anatomic and neurophysiological abnormalities in the cerebellum expand the spectrum of SPG7-related neurodegeneration and support a role for cerebellar output in socio-emotional behavior.     

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

Regulator of G protein signaling (RGS) proteins are gatekeepers regulating the cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. Specifically, RGS proteins determine the magnitude and duration of GPCR signaling by acting as a GTPase-activating protein for Gα subunits, an activity facilitated by their semiconserved RGS domain. The R7 subfamily of RGS proteins is distinguished by two unique domains, DEP/DHEX and GGL, which mediate membrane targeting and stability of these proteins. RGS6, a member of the R7 subfamily, has been shown to specifically modulate Gα_i/o protein activity which is critically important in the central nervous system (CNS) for neuronal responses to a wide array of neurotransmitters. As such, RGS6 has been implicated in several CNS pathologies associated with altered neurotransmission, including the following: alcoholism, anxiety/depression, and Parkinson’s disease. In addition, unlike other members of the R7 subfamily, RGS6 has been shown to regulate G protein-independent signaling mechanisms which appear to promote both apoptotic and growth-suppressive pathways that are important in its tumor suppressor function in breast and possibly other tissues. Further highlighting the importance of RGS6 as a target in cancer, RGS6 mediates the chemotherapeutic actions of doxorubicin and blocks reticular activating system (Ras)-induced cellular transformation by promoting degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) to prevent its silencing of pro-apoptotic and tumor suppressor genes. Together, these findings demonstrate the critical role of RGS6 in regulating both G protein-dependent CNS pathology and G protein-independent cancer pathology implicating RGS6 as a novel therapeutic target.     

Sex-Specificity in the Reward Value of Facial Attractiveness

Studies of the sex-specificity of sexual arousal in adults (i.e., the tendency to respond more strongly to preferred-sex individuals than non-preferred sex individuals) have suggested that heterosexual men, homosexual men, and homosexual women show stronger sex-specific responses than do heterosexual women. Evidence for a similar pattern of results in studies investigating the reward value of faces is equivocal. Consequently, we investigated the effects of (1) sexual orientation (homosexual vs. heterosexual), (2) sex (male vs. female), (3) image sex (preferred-sex vs. non-preferred-sex), and (4) the physical attractiveness of the individual shown in the image on the reward value of faces. Participants were 130 heterosexual men, 130 homosexual men, 130 heterosexual women, and 130 homosexual women. The reward value of faces was assessed using a standard key-press task. Multilevel modeling of responses indicated that images of preferred-sex individuals were more rewarding than images of non-preferred-sex individuals and that this preferred-sex bias was particularly pronounced when more physically attractive faces were presented. These effects were not qualified by interactions involving either the sexual orientation or the sex of our participants, however, suggesting that the preferred-sex bias in the reward value of faces is similar in heterosexual men, homosexual men, heterosexual women, and homosexual women.     

A Pragmatic Observational Feasibility Study on Integrated Treatment for Musculoskeletal Disorders: Design and Protocol

Background:Musculoskeletal disorders(MSD) comprise a wide range of conditions,associated with an enormous pain and impaired mobility,and are affecting people's lives and work.Management of musculoskeletal disorders typically involves a multidisciplinary team approach.Positive findings have been found in previous studies evaluating the effectiveness of complementary therapies,though little attention has been paid to evaluating of the effectiveness of integrated packages of care combining conventional and complementary approaches for musculoskeletal conditions in a National Health Service(NHS) setting.Objective:To determine the feasibility of all aspects of a pragmatic observational study designed:(1) to evaluate the effectiveness and cost effectiveness of integrated treatments for MSDs in an integrated NHS hospital in the UK;(2) to determine the acceptability of the study design and research process to patients;(3) to explore patients' expectation and experience of receiving integrated treatments.Methods:This is an observational feasibility study,with 1-year recruitment and 1-year follow-up,conducted in Royal London Hospital for Integrated Medicine,University College London Hospital Trust,UK.All eligible patients with MSDs newly referred to the hospital were included in the study.Interventions are integrated packages of care(conventional and complementary) as currently provided in the hospital.SF-36 Health Survey,short form Brief Pain Inventory,Visual Analogue Scale,and modified Client Service Receipt Inventory will be assessed at 4/5 time points.Semi-structured interview/focus group will be carried out before treatment,and 1 year after commence of treatment.Discussion:We intend to conduct a pragmatic observational study of integrated medical treatment of MSDs at a public sector hospital.It will inform the design of a future trial including recruitment,retention,suitability of the outcome measures and patients experiences.