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Background and Objectives: Cerebrovascular injury (CVI) after civilian gunshot wound to the head (GSWH) likely contributes to poor outcomes, but little supporting evidence exists. The purpose of this study was to determine whether intracranial CVI from GSWH and secondary vascular insult (stroke or rehemorrhage) were associated with poor outcomes in a large civilian population., Methods: This was a single-institution, retrospective cohort study on patients admitted between January 2014 and July 2022 at a large, metropolitan, level-1 trauma center. Multivariate regression models and propensity score matching were used., Results: A total of 512 civilian patients presented with GSWH, and a cohort of 172 (33.5%) met inclusion criteria, with 143 (83.1%) males and a mean (SD) age of 34.3 (±14.2) years. The incidence of intracranial CVI was 50.6% (87/172 patients), and that of secondary vascular insult was 32.2% (28/172 patients). Bifrontal trajectories (adjusted odds ratio [aOR] 13.11; 95% CI 2.45-70.25; P = .003) and the number of lobes traversed by the projectile (aOR 3.18; CI 1.77-5.71; P < .001) were associated with increased odds of resultant CVI. Patients with CVI suffered higher rate of mortality (34% vs 20%; odds ratio [OR] 2.1; CI 0.78-5.85; P = .015) and were less likely to achieve a good functional outcome with a Glasgow Outcome Score of 4-5 (34% vs 68%; OR 0.24; CI 0.1-0.6; P = .004) at follow-up. Furthermore, patients with CVI and resultant secondary vascular insult had even worse functional outcomes (Glasgow Outcome Score 4-5, 16.7% vs 39.0%; aOR 0.012; CI 0.001-0.169, P = .001)., Conclusion: Intracranial CVI from GSWH and associated secondary vascular insult are associated with poor outcomes. Given the high prevalence and potentially reversible nature of these secondary injuries, early screening with vascular imaging and treatment of underlying CVI may prove to be critical to improve outcomes by reducing stroke and rehemorrhage incidence., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Study Design: Ambispective study with propensity matching., Objective: To assess the impact of cervical spondylolisthesis (CS) on clinical presentation and surgical outcome in patients with degenerative cervical myelopathy (DCM)., Methods: A total of 458 magnetic resonance images (MRIs) from the AOSpine CSM-NA and CSM-I studies were reviewed and CS was identified. Patients with DCM were divided into 2 cohorts, those with CS and those without, and propensity matching was performed. Patient demographics, neurological and functional status at baseline and 2-year follow-up were compared., Results: Compared with nonspondylolisthesis (n = 404), CS patients (n = 54) were 8.8 years older ( P < .0001), presented with worse baseline neurological and functional status (mJOA [modified Japanese Orthopaedic Association Assessment Scale], P = .008; Nurick, P = .008; SF-36-PCS [Short Form-36 Physical Component Score], P = .01), more commonly presented with ligamentum flavum enlargement (81.5% vs 53.5%, P < .0001), and were less commonly from Asia ( P = .0002). Surgical approach varied between cohorts ( P = .0002), with posterior approaches favored in CS (61.1% vs 37.4%). CS patients had more operated levels (4.3 ± 1.4 vs 3.6 ± 1.2, P = .0002) and tended to undergo longer operations (196.6 ± 89.2 vs 177.2 ± 75.6 minutes, P = .087). Neurological functional recovery was lower with CS (mJOA [1.5 ± 3.6 vs 2.8 ± 2.7, P = .003]; Nurick [-0.8 ± 1.4 vs -1.5 ± 1.5, P = .002]), and CS was an independent predictor of worse mJOA recovery ratio at 2 years (B = -0.190, P < .0001). After propensity matching, improvement of neurological function was still lower in CS patients (mJOA [1.5 ± 3.6 vs 3.2 ± 2.8, P < .01]; Nurick [-0.8 ± 1.4 vs -1.4 ± 1.6, P = .02])., Conclusions: CS patients are older, present with worse neurological/functional impairment, and receive surgery on more levels and more commonly from the posterior. CS may indicate a more advanced state of DCM pathology and is more likely to result in a suboptimal surgical outcome., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Study Design: Narrative review., Objectives: To discuss the relationship between degenerative cervical myelopathy (DCM) and vitamin B 12 deficiency. Specifically, it is the aim to outline the rational for future research into assessment and therapeutic optimization of vitamin B 12 in the treatment of DCM., Methods: Literature review., Results: DCM is the commonest cause of spinal cord impairment, with an average age of presentation in the sixth decade. Patients at this age have also been reported to have a high prevalence of vitamin B 12 deficiency, with estimates of up to 20% in the elderly. Vitamin B 12 deficiency can result in subacute combined degeneration of the spinal cord (SACD), and several case reports have pointed to patients with both DCM and SACD. Both SACD and reversible compressive injury due to DCM necessitate remyelination in the spinal cord, a process that requires adequate vitamin B 12 levels. Basic science research on nerve crush injuries have shown that vitamin B 12 levels are altered after nerve injury and that vitamin B 12 along with dexamethasone or nonsteroidal anti-inflammatory drugs can reduce Wallerian degeneration. Furthermore, it has been suggested that a combination of B-vitamins can reduce glutamate-induced neurotoxicity., Conclusions: Given the high prevalence of clinical and subclinical vitamin B 12 deficiency in the elderly, the role of vitamin B 12 in myelination, and vitamin B 12 deficiency as a differential diagnosis of DCM, it is important to investigate what role vitamin B 12 levels play in patients with DCM in terms of baseline neurological function and whether optimization of vitamin B 12 levels can improve surgical outcome. Furthermore, the routine assessment of vitamin B 12 levels in patients considered for DCM surgery should be considered., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Sciubba is a consultant for Medtronic, Depuy-Synthes, Stryker, Nuvasive, and K2M. The other authors have no conflicts of interest to declare.

Functional recovery is markedly restricted following traumatic brain injury (TBI), partly due to myelin-associated inhibitors including Nogo-A, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp), that all bind to the Nogo-66 receptor-1 (NgR1). In previous studies, pharmacological neutralization of both Nogo-A and MAG improved outcome following TBI in the rat, and neutralization of NgR1 improved outcome following spinal cord injury and stroke in rodent models. However, the behavioral and histological effects of NgR1 inhibition have not previously been evaluated in TBI. We hypothesized that NgR1 negatively influences behavioral recovery following TBI, and evaluated NgR1(-/-) mice (NgR1(-/-) study) and, in a separate study, soluble NgR1 infused intracerebroventricularly immediately post-injury to neutralize NgR1 (sNgR1 study) following TBI in mice using a controlled cortical impact (CCI) injury model. In both studies, motor function, TBI-induced loss of tissue, and hippocampal beta-amyloid immunohistochemistry were not altered up to 5 weeks post-injury. Surprisingly, cognitive function (as evaluated with the Morris water maze at 4 weeks post-injury) was significantly impaired both in NgR1(-/-) mice and in mice treated with soluble NgR1. In the sNgR1 study, we evaluated hippocampal mossy fiber sprouting using the Timm stain and found it to be increased at 5 weeks following TBI. Neutralization of NgR1 significantly increased mossy fiber sprouting in sham-injured animals, but not in brain-injured animals. Our data suggest a complex role for myelin-associated inhibitors in the behavioral recovery process following TBI, and urge caution when inhibiting NgR1 in the early post-injury period.

Soluble oligomers of the amyloid-beta (Abeta) peptide are thought to play a key role in the pathophysiology of Alzheimer's disease (AD). Recently, we reported that synthetic Abeta oligomers bind to cellular prion protein (PrP(C)) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Abeta peptide. We hypothesized that PrP(C) is essential for the ability of brain-derived Abeta to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1DeltaE9 into Prnp-/- mice to examine the necessity of PrP(C) for AD-related phenotypes. Neither APP expression nor Abeta level is altered by PrP(C) absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrP(C) expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1DeltaE9 transgenic mice. The AD transgenic mice with intact PrP(C) expression exhibit deficits in spatial learning and memory. Mice lacking PrP(C), but containing Abeta plaque derived from APPswe/PSen1DeltaE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrP(C) expression dissociates Abeta accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrP(C).

Increasing age is associated with a poor prognosis following traumatic brain injury (TBI). CNS axons may recover poorly following TBI due to expression of myelin-derived inhibitors to axonal outgrowth such as Nogo-A. To study the role of Nogo-A/B in the pathophysiological response of the elderly to TBI, 1-year-old mice deficient in Nogo-A/B (Nogo-A/B homozygous(-/-) mice), Nogo-A/B heterozygous(-/+) mice, and age-matched wild-type (WT) littermate controls were subjected to a controlled cortical impact (CCI) TBI. Sham-injured WT mice (7 months old) and 12 month old naïve Nogo-A/B(-/-) and Nogo-A/B(-/+) served as controls. Neurological motor function was evaluated up to 3 weeks, and cognitive function, hemispheric tissue loss, myelin staining and hippocampal beta-amyloid (A beta) immunohistochemistry were evaluated at 4 weeks post-injury. In WT littermates, TBI significantly impaired learning ability at 4 weeks and neurological motor function up to 2 weeks post-injury and caused a significant loss of hemispheric tissue. Following TBI, Nogo-A/B(-/-) mice showed significantly less recovery from neurological motor and cognitive deficits compared to brain-injured WT mice. Naïve Nogo-A/B(-/-) and Nogo-A/B(-/+) mice quickly learned the MWM task in contrast to brain-injured Nogo-A/B(-/-) mice who failed to learn the MWM task at 4 weeks post-injury. Hemispheric tissue loss and cortical lesion volume were similar among the brain-injured genotypes. Neither TBI nor the absence of NogoA/B caused an increased A beta expression. Myelin staining showed a reduced area and density in the corpus callosum in brain-injured Nogo-A/B(-/-) animals compared to their littermate controls. These novel and unexpected behavioral results demonstrate that the absence of Nogo-A/B may negatively influence outcome, possibly related to hypomyelination, following TBI in mice and suggest a complex role for this myelin-associated axonal growth inhibitor following TBI.

A pathological hallmark of Alzheimer's disease is an accumulation of insoluble plaque containing the amyloid-beta peptide of 40-42 amino acid residues. Prefibrillar, soluble oligomers of amyloid-beta have been recognized to be early and key intermediates in Alzheimer's-disease-related synaptic dysfunction. At nanomolar concentrations, soluble amyloid-beta oligomers block hippocampal long-term potentiation, cause dendritic spine retraction from pyramidal cells and impair rodent spatial memory. Soluble amyloid-beta oligomers have been prepared from chemical syntheses, transfected cell culture supernatants, transgenic mouse brain and human Alzheimer's disease brain. Together, these data imply a high-affinity cell-surface receptor for soluble amyloid-beta oligomers on neurons-one that is central to the pathophysiological process in Alzheimer's disease. Here we identify the cellular prion protein (PrP(C)) as an amyloid-beta-oligomer receptor by expression cloning. Amyloid-beta oligomers bind with nanomolar affinity to PrP(C), but the interaction does not require the infectious PrP(Sc) conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-beta oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-beta-oligomer binding to PrP(C) and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-beta. Thus, PrP(C) is a mediator of amyloid-beta-oligomer-induced synaptic dysfunction, and PrP(C)-specific pharmaceuticals may have therapeutic potential for Alzheimer's disease.

The production and aggregation of cerebral amyloid-beta (Abeta) peptide are thought to play a causal role in Alzheimer's disease (AD). Previously, we found that the Nogo-66 receptor (NgR) interacts physically with both Abeta and the amyloid precursor protein (APP). The inverse correlation of Abeta levels with NgR levels within the brain may reflect regulation of Abeta production and/or Abeta clearance. Here, we assess the potential therapeutic benefit of peripheral NgR-mediated Abeta clearance in APPswe/PSEN-1deltaE9 transgenic mice. Through site-directed mutagenesis, we demonstrate that the central 15-28 aa of Abeta associate with specific surface-accessible patches on the leucine-rich repeat concave side of the solenoid structure of NgR. In transgenic mice, subcutaneous NgR(310)ecto-Fc treatment reduces brain Abeta plaque load while increasing the relative levels of serum Abeta. These changes in Abeta are correlated with improved spatial memory in the radial arm water maze. The benefits of peripheral NgR administration are evident when therapy is initiated after disease onset. Thus, the peripheral association of NgR(310)ecto-Fc with central Abeta residues provides an effective therapeutic approach for AD.

Pathophysiologic hypotheses for Alzheimer's disease (AD) are centered on the role of the amyloid plaque Abeta peptide and the mechanism of its derivation from the amyloid precursor protein (APP). As part of the disease process, an aberrant axonal sprouting response is known to occur near Abeta deposits. A Nogo to Nogo-66 receptor (NgR) pathway contributes to determining the ability of adult CNS axons to extend after traumatic injuries. Here, we consider the potential role of NgR mechanisms in AD. Both Nogo and NgR are mislocalized in AD brain samples. APP physically associates with the NgR. Overexpression of NgR decreases Abeta production in neuroblastoma culture, and targeted disruption of NgR expression increases transgenic mouse brain Abeta levels, Abeta plaque deposition, and dystrophic neurites. Infusion of a soluble NgR fragment reduces Abeta levels, amyloid plaque deposits, and dystrophic neurites in a mouse transgenic AD model. Changes in NgR level produce parallel changes in secreted APPalpha and Abeta, implicating NgR as a blocker of secretase processing of APP. The NgR provides a novel site for modifying the course of AD and highlights the role of axonal dysfunction in the disease.