Complement-dependent neuroinflammation in spinal cord injury: from pathology to therapeutic implications.

ABSTRACT: Spinal cord injury remains a major cause of disability in young adults, and beyond acute decompression and rehabilitation, there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population. Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation, a similar role for complement in spinal neuroinflammation is a focus of ongoing research. In this work, we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins, triggers of complement activation, and role of effector functions in the pathology. We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris, and or activation via antibody binding to damage-associated molecular patterns. Several effector functions of complement have been implicated in spinal cord injury, and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury. Following this pathophysiological review, we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects. This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury, to evaluate the phases of involvement of opsonins and anaphylatoxins, and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

Association of Cerebrovascular Injury and Secondary Vascular Insult With Poor Outcomes After Gunshot Wound to the Head in a Large Civilian Population.

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.

The Influence of Cervical Spondylolisthesis on Clinical Presentation and Surgical Outcome in Patients With DCM: Analysis of a Multicenter Global Cohort of 458 Patients.

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.

The Role of Vitamin B12 in the Management and Optimization of Treatment in Patients With Degenerative Cervical Myelopathy.

STUDY DESIGN: Narrative review. OBJECTIVES: To discuss the relationship between degenerative cervical myelopathy (DCM) and vitamin B12 deficiency. Specifically, it is the aim to outline the rational for future research into assessment and therapeutic optimization of vitamin B12 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 B12 deficiency, with estimates of up to 20% in the elderly. Vitamin B12 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 B12 levels. Basic science research on nerve crush injuries have shown that vitamin B12 levels are altered after nerve injury and that vitamin B12 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 B12 deficiency in the elderly, the role of vitamin B12 in myelination, and vitamin B12 deficiency as a differential diagnosis of DCM, it is important to investigate what role vitamin B12 levels play in patients with DCM in terms of baseline neurological function and whether optimization of vitamin B12 levels can improve surgical outcome. Furthermore, the routine assessment of vitamin B12 levels in patients considered for DCM surgery should be considered.

Subacute combined degeneration of the spinal cord following nitrous oxide anesthesia: A systematic review of cases.

OBJECTIVE: Vitamin B12 deficiency can lead to subacute combined degeneration (SCD). Nitrous oxide (N2O) is an anesthetic which oxidizes the cobalt ion of vitamin B12, interfering with its function as a coenzyme. In this study, we conduct a systematic review of reported cases of SCD following nitrous oxide anesthesia. PATIENTS AND METHODS: A comprehensive search of multiple databases was conducted, and information about patient characteristics, symptomatology, clinical work-up, and treatment was extracted from eligible articles. Univariate analyses were performed to identify predictors of poor neurological recovery following SCD. RESULTS: 32 studies, reporting 37 cases of nitrous oxide-induced SCD, were included through the screening process. These cases included 21 male patients and 16 female patients, with an average age of 50.4 years (SD 17.6). An etiology for subclinical B12 deficiency was determined in 30 reports; of these, 25 were due to vitamin malabsorption secondary to a gastrointestinal disorder. Duration of nitrous oxide exposure was described in 19 reports, and ranged from 30 min to 11 h. Univariate analysis failed to find an association between post-operative recovery and age (p = 0.60), sex (p = 0.46), positive MRI findings (p = 0.47), post-operative serum B12 (p = 1.00), post-operative hemoglobin (p = 0.18), type of surgery (p = 0.58), or post-operative high mean corpuscular volume (p = 0.13). CONCLUSION: In patients with postsurgical myelopathy, surgeons should evaluate B12 status and consider the possibility that nitrous oxide could cause a subclinical B12 deficiency to become overt, particularly in patients with malabsorptive GI comorbidities. Treatment with B12 in this population can result in significant improvement of neurological function.

Degenerative Cervical Myelopathy: A Clinical Review.

Degenerative Cervical Myelopathy (DCM) is the most common form of spinal cord impairment in adults and results in disability and reduced quality of life. DCM can present with a wide set of clinical and imaging findings, including: 1) pain and reduced range of motion of the neck, and motor and sensory deficits on clinical exam, and 2) cord compression due to static and dynamic injury mechanisms resulting from degenerative changes of the bone, ligaments, and intervertebral discs on MRI. The incidence and prevalence of DCM has been estimated at a minimum of 4.1 and 60.5 per 100,000, respectively, but surgical trends and an aging population suggest these numbers will rise in the future. The diagnosis of DCM is based on clinical examination, with a positive Hoffmann's sign and hand numbness typically appearing in the upper limbs, and gait abnormalities such as difficulty with tandem gait serving as sensitive diagnostic findings. Loss of bladder function may also occur in patients with severe DCM. The degree of neurological impairment can be measured using the modified Japanese Association Scale (mJOA) or Nurick grade. Non-operative management has a limited role in the treatment, while surgical management has been shown to both be safe and effective for halting disease progression and improving neurological function. Predictors of surgical outcome include age and baseline severity, indicating that early recognition of DCM is important for ensuring an optimal surgical outcome.

Memory impairment in transgenic Alzheimer mice requires cellular prion protein.

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).

Genetic deletion and pharmacological inhibition of Nogo-66 receptor impairs cognitive outcome after traumatic brain injury in mice.

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.

Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers.

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.

Subcutaneous Nogo receptor removes brain amyloid-beta and improves spatial memory in Alzheimer's transgenic mice.

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.

Alzheimer precursor protein interaction with the Nogo-66 receptor reduces amyloid-beta plaque deposition.

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.