While axonal regeneration after CNS injury is limited, partial injury is frequently accompanied by extensive functional recovery. To investigate mechanisms underlying spontaneous recovery after incomplete spinal cord injury, adult rhesus monkeys underwent C7 spinal cord hemisections, with subsequent analysis of behavioral, electrophysiological and anatomical adaptations. We found remarkable spontaneous plasticity of corticospinal projections, with reconstitution of fully 60% of pre-lesion axon density arising from sprouting of spinal cord midline-crossing axons. This extensive anatomical recovery was associated with improvement in coordinated muscle recruitment, hand function and locomotion. These findings identify what may be the most extensive natural recovery of mammalian axonal projections after nervous system injury observed to date, highlighting an important role for primate models in translational disease research.

Traumatic brain injury (TBI) is a major risk factor for the development of multiple neurodegenerative diseases. With respect to the increasing prevalence of TBI, new therapeutic strategies are urgently needed that will prevent secondary damage to primarily unaffected tissue. Consistently, neuroinflammation has been implicated as a key mediator of secondary damage following the initial mechanical insult. Following injury, there is uncertainty regarding the role that accumulating CCR2 ϩ macrophages play in the injury-induced neuroinflammatory sequelae and cognitive dysfunction. Using CX3CR1 GFP/ϩ CCR2 RFP/ϩ reporter mice, we show that TBI initiated a temporally restricted accumulation of peripherally derived CCR2 ϩ macrophages, which were concentrated in the hippocampal formation, a region necessary for learning and memory. Multivariate analysis delineated CCR2 ϩ macrophages' neuroinflammatory response while identifying a novel therapeutic treatment window. As a proof of concept, targeting CCR2 ϩ macrophages with CCX872, a novel Phase I CCR2 selective antagonist, significantly reduced TBI-induced inflammatory macrophage accumulation. Concomitantly, there was a significant reduction in multiple proinflammatory and neurotoxic mediators with this treatment paradigm. Importantly, CCR2 antagonism resulted in a sparing of TBI-induced hippocampal-dependent cognitive dysfunction and reduced proinflammatory activation profile 1 month after injury. Thus, therapeutically targeting the CCR2 ϩ subset of monocytes/macrophages may provide a new avenue of clinical intervention following TBI.

OBJECTIVE To determine the clinical relevance, if any, of traumatic intracranial findings on early head CT and brain MRI to 3-month outcome in mild traumatic brain injury (MTBI) METHODS 135 MTBI patients evaluated for acute head injury in emergency departments of three Level I Trauma Centers were enrolled prospectively. In addition to admission head CT, early brain MRI was performed 12+/-3.9 days after injury. Univariate and multivariate logistic regression were used to assess for demographic, clinical, socioeconomic, CT, and MRI features that were predictive of Extended Glasgow Outcome Scale (GOS-E) at 3 months post-injury. RESULTS Twenty-seven percent of MTBI patients with normal admission head CT had abnormal early brain MRI. CT evidence of subarachnoid hemorrhage was associated with a multivariate odds ratio of 3.5 (p=0.01) for poorer 3-month outcome, after adjusting for demographic, clinical, and socioeconomic factors. One or more brain contusions on MRI, and ≥4 foci of hemorrhagic axonal injury on MRI, were each independently associated with poorer 3-month outcome, with multivariate odds ratios of 4.5 (p=0.01) and 3.2 (p=0.03), respectively, after adjusting for head CT findings and demographic, clinical, and socioeconomic factors. INTERPRETATION In this prospective multicenter observational study, the clinical relevance of abnormal findings on early brain imaging after MTBI is demonstrated. The addition of early CT and MRI markers to a prognostic model based on previously known demographic, clinical, and socioeconomic predictors resulted in a greater than two-fold increase in the explained variance in 3-month GOS-E.