Dra. Vidal-Vera, Pía

Degenerative cervical myelopathy (DCM) is caused by age-related degeneration of the cervical spine, causing chronic spinal cord compression and inflammation. The aim of this study was to assess whether the natural progression of DCM is accompanied by hematological changes in the white blood cell composition. If so, these changes can be used for diagnosis complementing established imaging approaches and for the development of treatment strategies, since peripheral immunity affects the progression of DCM. Gradual compression of the spinal cord was induced in C57B/L mice at the C5-6 level. The composition of circulating white blood cells was analyzed longitudinally at four time points after induction of DCM using flow cytometry. At 12 weeks, serum cytokine levels were measured using a Luminex x-MAP assay. Neurological impairment in the mouse model was also assessed using the ladder walk test and CatWalk. Stepping function (* p < 0.05) and overground locomotion (*** p < 0.001) were impaired in the DCM group. Importantly, circulating monocytes and T cells were affected primarily at 3 weeks following DCM. T cells were two-fold lower in the DCM group (*** p < 0.0006), whereas monocytes were four-fold increased (*** p < 0.0006) in the DCM compared with the sham group. Our data suggest that changes in white blood cell populations are modest, which is unique to other spinal cord pathologies, and precede the development of neurobehavioral symptoms.

Background: Degenerative cervical myelopathy (DCM) is the most common cause of non-traumatic spinal cord injury worldwide. Surgical decompression is recommended as the preferred treatment strategy for DCM as it halts disease progression and improves neurologic symptoms. We previously demonstrated that neuroinflammation, including monocytes, plays a critical role in the pathobiology of DCM and in ischemic-reperfusion injury (IRI) following surgical decompression. Monocytes are able to enter the spinal cord and brain tissues due to damage to the blood spinal cord and blood brain barrier following injury. Studies have demonstrated that stroke patients and individuals undergoing hip replacement surgery have increased systemic levels of monocytes. Additionally, changes in the signalling responses of monocytes are associated with post-surgical recovery or with ischemic neural tissue damage. Herein, we investigated the role of systemic monocytes as a predictive biomarker for clinical recovery following decompressive surgery for DCM. Findings: There was a 2-fold increase in the number of monocytes in DCM patients at 24 h following decompression as compared to baseline levels, which was associated with a significant improvement in the modified Japanese Orthopedic Association scale (mJOA) at 6-months after surgery (p < .0001). In a mouse model of DCM, depleting acute monocytes reduced the non-classical (Ly6Clow) subset from circulation (p < .05) and resulted in a 1.8-fold increase in CD11b expression in the spinal cord at 5 weeks following decompression. Acute monocyte depletion was accompanied by a modest decline in long-term overground locomotion, as evidenced by significantly reduced hindlimb swing speed. Conclusions: This work demonstrated that decompressive surgery leads to an acute increase in peripheral monocytes in human DCM patients, which is modestly associated with clinical recovery. We anticipate that this work could contribute to the implementation of routine measurements of blood monocyte subsets, their activation state, and production of cytokines following decompressive surgery. This information could help to select perioperative anti-inflammatory treatments that can enhance the beneficial effects of decompressive surgery and reduce the incidence of post-operative complications, while avoiding a reduction in systemic monocytes.

Spinal cord injury (SCI) results in the development of detrimental autoantibodies against the lesioned spinal cord. IgM immunoglobulin maintains homeostasis against IgG-autoantibody responses, but its effect on SCI recovery remains unknown. In the present study we investigated the role of IgM immunoglobulin in influencing recovery after SCI. To this end, we induced cervical SCI at the C6/C7 level in mice that lacked secreted IgM immunoglobulin [IgM-knock-out (KO)] and their wild-type (WT) littermate controls. Overall, the absence of secretory IgM resulted in worse outcomes as compared with WT mice with SCI. At two weeks after injury, IgM-KO mice had significantly more IgG antibodies, which fixed the complement system, in the injured spinal cord parenchyma. In addition to these findings, IgM-KO mice had more parenchymal T-lymphocytes as well as CD11b+ microglia/macrophages, which co-localized with myelin. At 10 weeks after injury, IgM-KO mice showed significant impairment in neurobehavioral recovery, such as deteriorated coordination, reduced hindlimb swing speed and print area. These neurobehavioral detriments were coupled with increased lesional tissue and myelin loss. Taken together, this study provides the first evidence for the importance of IgM immunoglobulin in modulating recovery after SCI and suggests that modulating IgM could be a novel therapeutic approach to enhance recovery after SCI.

Degenerative cervical myelopathy (DCM) describes a spectrum of disorders that cause progressive and chronic cervical spinal cord compression. The clinical presentation can be complex and can include locomotor impairment, hand and upper extremity dysfunction, pain, loss of bladder and bowel function, as well as gastrointestinal dysfunction. Once diagnosed, surgical decompression is the recommended treatment for DCM patients with moderate to severe impairment. Our body is composed of a large community of microorganisms, known as the microbiota. Traumatic and nontraumatic spinal cord injuries (SCIs) can induce changes in the gut microbiota and gut microbiota derived metabolites. These changes have been reported as important disease-modifying factors after injury. However, whether gut dysbiosis is associated with functional neurological recovery after surgical decompression has not been examined to date. Here, DCM was induced in C57BL/6 mice by implanting an aromatic polyether material underneath the C5–6 laminae. The extent of gut dysbiosis was assessed by gas chromatography and 16S rRNA sequencing from fecal samples before and after decompression. Neuromotor activity was assessed using the Catwalk test. Our results show that DCM pre- and post- surgical decompression is associated with gut dysbiosis, without altering short chain fatty acids (SCFAs) levels. Significant differences in Clostridia, Verrumicrobiae, Lachnospiracea, Firmicutes, Bacteroidales, and Clostridiaceae were observed between the DCM group (before decompression) and after surgical decompression (2 and 5 weeks). The changes in gut microbiota composition correlated with locomotor features of the Catwalk. For example, a longer duration of ground contact and dysfunctional swing in the forelimbs, were positively correlated with gut dysbiosis. These results show for the first time an association between gut dysbiosis and locomotor deterioration after delayed surgical decompression. Thus, providing a better understanding of the extent of changes in microbiota composition in the setting of DCM pre- and postsurgical decompression.