Diffusion tensor imaging as a tool to detect presymptomatic axonal degeneration in a preclinical spinal cord model of amyotrophic lateral sclerosis

The G93A-SOD1 mice model and MRI diffusion as a preclinical tool to study amyotrophic lateral sclerosis （ALS）： ALS is a progressive neurological disease characterized primarily by the development of limb paralysis, which eventually leads to lack of control on muscles under voluntary control and death within 3–5 years. Genetic heterogeneity and environmental factors play a critical role in the rate of disease progression and patients display faster declines once the symptoms have manifested. Since its original discovery, ALS has been associated with pathological alterations in motor neurons located in the spinal cord （SC）, where neuronal loss by a mutation in the protein superoxide dismutase in parenthesis （mSOD1） and impairment in axonal connectivity, have been linked to early functional impairments. In addition,mechanisms of neuroinflammation, apoptosis, necroptosis and autophagy have been also implicated in the development of this disease. Among different animal models developed to study ALS, the transgenic G93A-SOD1 mouse has become recognized as a benchmark model for preclinical screening of ALS therapies. Furthermore, the progressive alterations in the locomotor phenotype expressed in this model closely resemble the progressive lower limb dysfunction of ALS patients. Among other imaging tools, MR diffusion tensor imaging （DTI） has emerged as a crucial, noninvasive and real time neuroimaging tool to gather information in ALS. One of the current concerns with the use of DTI is the lack of biological validation of the microstructural information given by this technique. Although clinical studies using DTI can provide a remarkable insight on the targets of neurodegeneration and disease course,they lack histological correlations. To address these shortcomings, preclinical models can be designed to validate the microstructural information unveiled by this particular MRI technique. Thus, the scope of this review is to describe how MRI diffusion and optical microscopy evaluate axonal structural changes at early stages of the disease in a preclinical model of ALS.

Rho A/Rho kinase in spinal cord injury

A spinal cord injury refers to an injury to the spinal cord that is caused by a trauma instead of diseases. Spinal cord injury includes a primary mechanical injury and a much more complex secondary injury process involving inflammation, oxidation, excitotoxicity, and cell death. During the secondary injury, many signal pathways are activated and play important roles in mediating the pathogenesis of spinal cord injury. Among them, the Rho A/Rho kinase pathway plays a particular role in mediating spinal degeneration and regeneration. In this review, we will discuss the role and mechanism of Rho A/Rho kinase-mediated spinal cord pathogenesis, as well as the potential of targeting Rho A/Rho kinase as a strategy for promoting both neuroprotection and axonal regeneration.

Autophagy in degenerating axons following spinal cord injury: evidence for autophagosome biogenesis in retraction bulbs

Macroautophagy （here autophagy） is a catabolic mechanism responsible for the degradation of bulk cytoplasm, long-lived proteins and organeUes. During autophagy, the cargos are engulfed by double-membrane structures named phagophores, which expand to form the autophagosomes. Subsequently, these autophagosomes fuse with lysosomes, in which the cytoplasmic cargos are degraded. Autophagy is a constitutive pro- cess, which plays an important role in cellular homeostasis. In primary neurons autophagosome formation occurs continuously and preferentially at the distal end of axons. On the other hand, autophagy is increased by different stresses, and its dysregulation or excessive induction may lead to detrimental effects. Many neurological disorders have been associated with alterations in the autophagic pathway and an increase in autophagy during axonal degeneration was described.

Decrease with aging of the microcirculatory function of the lumbar vertebral marrow preceding the loss of bone material density and the onset of intervertebral discal degeneration:A study about the potential cause

Objective: Using a dynamic computed tomographic perfusion (CTP) imaging method to explore the age-related distribution of the microcirculation perfusion function in the vertebral marrow, the bone material density (BMD), and the intervertebral discal degeneration (IDD). Further, to discuss a possible causation relationship between them. Methods: One hundred and eighty-six people were randomly enrolled by stratified sampling and grouped by age:?15, 16e25, 26e35, 36e45, 46e55, 56e65, 66e75, and ?76 years old. The average CTP and BMD of the third and fourth lumbar vertebrae marrow were measured and the IDD incidence of the third-fourth vertebrae was assessed. The temporalespatial distribution patterns of the age-related changes of the CTP, BMD, and IDD were described, and the correlations between them were calculated. Results: The microcirculatory perfusion function of the vertebral marrow develops to maturity by 25 years and is maintained until age 35, then declines with aging. The BMD grew to a peak from 26 to 45 years old, then decreased yearly. The IDD showed a sudden increase after 45 years of age. The CTP [BF (r ? 0.806, P ? 0.000), BV (r ? 0.685, P ? 0.005) and PMB (r ? 0.619, P ? 0.001)] showed strong positive correlations and CTP [TTP (r ? ?0.211, P ? 0.322) and MTT (r ? ?0.598, P ? 0.002)] showed negative correlations with BMD. The CTP [BF (r ? ?0.815, P ? 0.000), BV (r ? ?0.753, P ? 0.000) and PMB (r ? ?0.690, P ? 0.000)] had strong negative correlations, and CTP [TTP (r ? 0.323, P ? 0.126) and MTT (r ? 0.628, P ? 0.001)] had positive correlations with the incidence of IDD. Conclusion: The decrease with aging of the microcirculatory perfusion in the lumbar vertebral marrow preceded, and is a potential causative factor for the loss of BMD and the onset of IDD. Copyright ? 2015, Chinese Medical Association Production. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Comparison of Topping-off and posterior lumbar interbody fusion surgery in lumbar degenerative disease： a retrospective study

Background Topping-off surgery is a newly-developed surgical technique which combines rigid fusion with an interspinous process device in the adjacent segment to prevent adjacent segment degeneration. There are few reports on Topping-off surgery and its rationality and indications remains highly controversial. Our study aims to investigate the short-term and mid-term clinical results of Topping-off surgery in preventing adjacent segment degeneration when mild or moderate adjacent segment degeneration existed before surgery. Methods The 25 cases that underwent L5-$1 posterior lumbar interbody fusion （PLIF） ＋ L4-L5 interspinous process surgeries between April 2008 and March 2010 formed Topping-off group. The 42 cases undergoing L5-$1 PLIF surgery formed PLIF group. Both groups matched in gender, age, body mass index and Pfirrmann grading （4 to 6）. The patients were evaluated with visual analogue scale （VAS） and Japanese orthopaedic association （JOA） scores before surgery and in the last follow-up. Modic changes of endplates were recorded. Results The follow-up averaged 24.8 and 23.7 months. No symptomatic or radiological adjacent segment degeneration was observed. There was no significant difference in intraoperative blood loss or postoperative drainage. VAS and lumbar JOA scores improved significantly in both groups （t=-12.1 and 13.5, P 〈0.05）. Neither anterior nor posterior disc height was significantly changed. Segmental lordosis of L4-L5 and total lordosis were all increased significantly （Topping-off group： t=-2.30 and -2.24, P 〈0.05; PLIF group： t=--2.76 and -1.83, P 〈0.01）. In the hyperextension and hyperflexion view, Topping-off group＇s range of motion （ROM） and olisthesis in the L4-L5 segment did not significantly change in flexion, but decreased in extension. In PLIF group, ROM （t=--7.82 and -4.90, P 〈0.01） and olisthesis （t=--15.67 and -18.58, P 〈0.01） both significantly increased in extension and flexion. Conclusions Compared with single segment PLIF surgery, Topping-off surgery can achieve similar symptomatic improvement in cases with pre-existing mild or moderate adjacent segment degeneration, restrict the adjacent segment＇s ROM in extension and prevent excessive olisthesis of adiacent seament in both extension and flexion