To investigate differential item functioning or item bias of the Rivermead Mobility Index (RMI) and its impact on the drawing of valid comparisons with the RMI between subgroups of patients after stroke who differ with respect to age, sex, or side of lesion. DESIGN: Cross-sectional study. SETTING: A rehabilitation center in the Netherlands and 2 stroke rehabilitation units and the wider community in the United Kingdom. PARTICIPANTS: The RMI was completed for patients undergoing rehabilitation after stroke (N=620; mean age +/- SD, 69.2+/-12.5y; 297 [48%] men; 269 [43%] right hemisphere lesion, and 304 [49%] left hemisphere lesion). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Mokken scale analysis was used to investigate differential item functioning of the RMI between subgroups of patients who differed with respect to age (young vs older), sex (men vs women), and side of stroke lesion (right vs left hemisphere). RESULTS: No differential item functioning was found for any of the comparison subgroups. CONCLUSIONS: The RMI allows valid comparisons to be made between subgroups of patients undergoing rehabilitation after stroke who differ with respect to age, sex, or side of lesion.

To enable improved interpretation of the total score and faster scoring of the Rivermead Mobility Index (RMI) by studying item ordering or hierarchy and formulating start-and-stop rules in patients after stroke. DESIGN: Cohort study. SETTING: Rehabilitation center in the Netherlands; stroke rehabilitation units and the community in the United Kingdom. PARTICIPANTS: Item hierarchy of the RMI was studied in an initial group of patients (n=620; mean age +/- SD, 69.2+/-12.5y; 297 [48%] men; 304 [49%] left hemisphere lesion, and 269 [43%] right hemisphere lesion), and the adequacy of the item hierarchy-based start-and-stop rules was checked in a second group of patients (n=237; mean age +/- SD, 60.0+/-11.3y; 139 [59%] men; 103 [44%] left hemisphere lesion, and 93 [39%] right hemisphere lesion) undergoing rehabilitation after stroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Mokken scale analysis was used to investigate the fit of the double monotonicity model, indicating hierarchical item ordering. The percentages of patients with a difference between the RMI total score and the scores based on the start-and-stop rules were calculated to check the adequacy of these rules. RESULTS: The RMI had good fit of the double monotonicity model (coefficient H(T)=.87). The interpretation of the total score improved. Item hierarchy-based start-and-stop rules were formulated. The percentages of patients with a difference between the RMI total score and the score based on the recommended start-and-stop rules were 3% and 5%, respectively. Ten of the original 15 items had to be scored after applying the start-and-stop rules. CONCLUSIONS: Item hierarchy was established, enabling improved interpretation and faster scoring of the RMI.

Traumatic brain injury (TBI) is a leading cause of disability worldwide. Annually, 150 to 200/1,000,000 people become disabled as a result of brain trauma. Axonal degeneration is a critical, early event following TBI of all severities but whether axon degeneration is a driver of TBI remains unclear. Molecular pathways underlying the pathology of TBI have not been defined and there is no efficacious treatment for TBI. Despite this significant societal impact, surprisingly little is known about the molecular mechanisms that actively drive axon degeneration in any context and particularly following TBI. Although severe brain injury may cause immediate disruption of axons (primary axotomy), it is now recognized that the most frequent form of traumatic axonal injury (TAI) is mediated by a cascade of events that ultimately result in secondary axonal disconnection (secondary axotomy) within hours to days. Proposed mechanisms include immediate post-traumatic cytoskeletal destabilization as a direct result of mechanical breakage of microtubules, as well as catastrophic local calcium dysregulation resulting in microtubule depolymerization, impaired axonal transport, unmitigated accumulation of cargoes, local axonal swelling, and finally disconnection. The portion of the axon that is distal to the axotomy site remains initially morphologically intact. However, it undergoes sudden rapid fragmentation along its full distal length ~72 h after the original axotomy, a process termed Wallerian degeneration. Remarkably, mice mutant for the Wallerian degeneration slow (Wlds) protein exhibit ~tenfold (for 2–3 weeks) suppressed Wallerian degeneration. Yet, pharmacological replication of the Wlds mechanism has proven difficult. Further, no one has studied whether Wlds protects from TAI. Lastly, owing to Wlds presumed gain-of-function and its absence in wild-type animals, direct evidence in support of a putative endogenous axon death signaling pathway is lacking, which is critical to identify original treatment targets and the development of viable therapeutic approaches. Novel insight into the pathophysiology of Wallerian degeneration was gained by the discovery that mutant Drosophila flies lacking dSarm (sterile a/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously recapitulated the Wlds phenotype. The pro-degenerative function of the dSarm gene (and its mouse homolog Sarm1) is widespread in mammals as shown by in vitro protection of superior cervical ganglion, dorsal root ganglion, and cortical neuron axons, as well as remarkable in-vivo long-term survival (>2 weeks) of transected sciatic mouse Sarm1 null axons. Although the molecular mechanism of function remains to be clarified, its discovery provides direct evidence that Sarm1 is the first endogenous gene required for Wallerian degeneration, driving a highly conserved genetic axon death program. The central goals of this thesis were to determine (1) whether post-traumatic axonal integrity is preserved in mice lacking Sarm1, and (2) whether loss of Sarm1 is associated with improved functional outcome after TBI. I show that mice lacking the mouse Toll receptor adaptor Sarm1 gene demonstrate multiple improved TBI-associated phenotypes after injury in a closed-head mild TBI model. Sarm1-/- mice developed fewer beta amyloid precursor protein (βAPP) aggregates in axons of the corpus callosum after TBI as compared to Sarm1+/+ mice. Furthermore, mice lacking Sarm1 had reduced plasma concentrations of the phosphorylated axonal neurofilament subunit H, indicating that axonal integrity is maintained after TBI. Strikingly, whereas wild type mice exhibited a number of behavioral deficits after TBI, I observed a strong, early preservation of neurological function in Sarm1-/- animals. Finally, using in vivo proton magnetic resonance spectroscopy, I found tissue signatures consistent with substantially preserved neuronal energy metabolism in Sarm1-/- mice compared to controls immediately following TBI. My results indicate that the Sarm1-mediated prodegenerative pathway promotes pathogenesis in TBI and suggest that anti-Sarm1 therapeutics are a viable approach for preserving neurological function after TBI.