The influence of lumbar vertebra and cage related factors on cage-endplate contact after lumbar interbody fusion: An in-vitro experimental study.

Lumbar interbody fusion (LIF) using interbody cages is an established treatment for lumbar degenerative disc disease, but fusion results are known to be affected by risk factors such as bone mineral density (BMD), endplate geometry and cage position. At present, direct measurement of endplate-cage contact variables that affect LIF have not been fully identified. The aim of this study was to use cadaveric experiments to investigate the dependency between BMD, endplate geometry, cage parameters like type, orientation, position, and contact variables like stress and area. One vertebral body specimen from each of the five lumbar positions was harvested from five male donors. The lower half of each vertebra was potted and placed in a material testing machine (Instron 8874). A spinal cage was clamped to the machine then lowered to bring it into contact against the superior endplate. A lockable ball-joint was used to rotate the cage such that its inferior surface was congruent with the local endplate surface. A pressure sensor (Tekscan) was placed between the cage and endplate to record contact area and the peak and average contact pressures. Axial compression of 400 N was performed for five positions using a straight cage, and in one anterior position using a curved cage. The linear mixed model was utilised to perform data analyses for experimental results with statistical significance set at p < 0.05. The results indicated two trends toward significance for contact area, one for volumetric BMD (vBMD) of the vertebra (p = 0.081), and another for predicted contact area (p = 0.057). Peak contact pressure correlated significantly with vBMD (p = 0.041), and there was a trend between average contact pressure and lateral position of cage (p = 0.051). In addition, predicted contact area correlated significantly with cage orientation (p < 0.001). These results indicated that high vBMD of vertebra and a medially positioned cage led to higher contact pressures. Logically, low vBMD of vertebra and transverse cage orientation increased the contact area between the cage and endplate. In conclusion, the study identified significant influence of vBMD of vertebra, cage position and orientation on cage-endplate contact which may help to inform cage selection and design for LIF.

Computed Tomographic Characterization for Basivertebral Nerve Ablation Utilizing a Radiofrequency Multitined Expandable Electrode.

Background: A growing body of clinical evidence has demonstrated that intraosseous minimally invasive basivertebral nerve (BVN) ablation results in significant and durable improvements in vertebrogenic back pain. Thus, it is important to develop, refine and validate new and additional devices to accomplish this procedure. Methods: Using reconstructions of 31 patient computed tomography (CT) scans of the lumbosacral spine (L1-S1), the primary objective was to simulate the intravertebral placement of a novel multitined expandable electrode in bipolar configuration at the targeted ablation site and determine if the proper trajectories could be achieved in order for the device tips to be in the correct position for lesion formation at the BVN plexus. Successful device deployment required that the distance between tips was between 10 mm and 20 mm. Results: The mean distances between device tips ranged from 11.35 mm (L5) to 11.87 mm (L3), and there were no statistically significance differences across the six vertebral levels (F = 0.72, p = 0.61). The percentage of successful intraosseous device placements within the tip distance acceptable range (≥ 10 mm to ≤ 20 mm) was 90% (162 of 180), with no tip-to-tip distances > 20 mm. There was a notable association between decreasing vertebral level and mean degree of angulation between contralateral devices ranging from 50.90° at L1 to 91.51° at S1, and the difference between across the six vertebral levels was significant (F = 89.5, p < 0.01). Conclusion: Feasibility evidence is provided from real world CT imaging data that validates using the multitined electrode for proper intraosseous placement within the vertebral body to effectively ablate the BVN plexus.

Finite element model reveals the involvement of cartilage endplate in quasi-static biomechanics of intervertebral disc degeneration.

Background and objective: The intrinsic link between the compositional and structural attributes and the biomechanical functionality is evident in intervertebral discs. However, it remains unclear from a biomechanical perspective whether cartilage endplate (CEP) degeneration exacerbates intervertebral disc degeneration. Methods: This study developed and quantitatively validated four biphasic swelling-based finite element models. We then applied four quasi-static tests and simulated daily loading scenarios to examine the effects of CEP degradation. Results: Under free-swelling conditions, short-term responses were prevalent, with CEP performance changes not significantly impacting response proportionality. The creep test results showed the more than 50 % of the strain was attributed to long-term responses. Stress-relaxation testing indicated that all responses increased with disc degeneration, yet CEP degeneration's impact was minimal. Daily load analyses revealed that disc degeneration significantly reduces nucleus pulposus pressure and disc height, whereas CEP degeneration marginally increases nucleus pressure and slightly decreases disc height. Conclusions: Glycosaminoglycan content and CEP permeability are critical to the fluid-dependent viscoelastic response of intervertebral discs. Our findings suggest that CEP contributes to disc degeneration under daily loading conditions.

Animal Models of Internal Endplate Injury-Induced Intervertebral Disc Degeneration: A Systematic Review.

OBJECTIVE: To systematically review relevant animal models of disk degeneration induced through the endplate injury pathway and to provide suitable animal models for exploring the intrinsic mechanisms and treatment of disk degeneration. DESIGN: PubMed, Web of Science, Cochrane and other databases were searched for literature related to animal models of disk degeneration induced by the endplate injury pathway from establishment to August 2024, and key contents in the literature were screened and extracted to analyze and evaluate each type of animal model using the literature induction method. RESULTS: Fifteen animal experimental studies were finally included in the literature, which can be categorized into direct injury models and indirect injury models, of which direct injury models include transvertebral injury models and transpedicular approach injury models, and indirect injury models include endplate ischemia models and vertebral fracture-induced endplate injury models. The direct injury models have a minimum observation period of 2 months and a maximum of 32 wk. All direct injury models were successful in causing disk degeneration, and the greater the number of interventions, the greater the degree of disk degeneration caused. The observation period for the indirect injury models varied from 4 wk to 70 wk. Of the 9 studies, only one study was unsuccessful in inducing disk degeneration, and this was the first animal study in this research to attempt to intervene on the endplate to cause disk degeneration. CONCLUSION: The damage to the direct injury model is more immediate and controllable in extent and can effectively lead to disk degeneration. The indirect injury models do not directly damage the endplate structure, making it easier to observe the physiological and pathological condition of the endplate and associated structures of the disk. None of them can completely simulate the corresponding process of endplate injury-induced disk degeneration in humans, and there is no uniform clinical judgment standard for this type of model. The most appropriate animal model still needs further exploration and discovery.

[Effects of electroacupuncture at "Jiaji" (EX-B 2) on extracellular matrix of chondrocytes and inflammatory reaction in rabbits with Modic changes of cartilage endplate].

OBJECTIVE: To observe the effects of electroacupuncture (EA) at "Jiaji" (EX-B 2) on extracellular matrix (ECM) of chondrocytes and inflammatory reaction in rabbits with Modic changes (MC) of cartilage endplate, and to explore the mechanism of EA in treating MC of endplate cartilage. METHODS: Eighteen male New Zealand white rabbits were randomly divided into a sham operation group, a model group and an EA group, 6 rabbits in each group. Based on the autoimmune theory, MC model was established by embedding autogenous nucleus pulposus in the rabbits of the model group and the EA group, based on autoimmunity. After successful modeling, EA was applied at bilateral "Jiaji" (EX-B 2) of L5 and L6 in the EA group, with disperse-dense wave, 2 Hz/15 Hz in frequency and 1 mA in current intensity, 20 min a time, once a day, 1-day interval was taken after continuous 6-day intervention, for 4 weeks totally. Before and after modeling, as well as before and after intervention, the comprehensive response score was observed. After modeling and intervention, magnetic resonance imaging (MRI) was used to observe the signal intensity of intervertebral disc and cartilage endplate. After intervention, the morphology of chondrocytes of cartilage endplate was observed by HE staining; the positive expression of a disintegrin and metalloproteinase with thrombospondin motif-5 (ADAMTS5) and Aggrecan in the cartilage endplate was detected by immunohistochemistry; the levels of inflammatory factors i.e. interleukin-1ß (1L-1ß) and tumor necrosis factor-α (TNF-α) in the cartilage endplate were detected by ELISA; the protein expression of ADAMTS5, Aggrecan, matrix metalloproteinase-13 (MMP-13), IL-1ß and TNF-α in the cartilage endplate was detected by Western blot. RESULTS: Compared with the sham operation group, in the model group, the comprehensive response score was decreased (P<0.01); L5/L6 intervertebral disc and the cancellous bones of endplate vertebral body showed low signal and unclear boundary; the chondrocytes of the cartilage endplate increased significantly, the cells were enlarged and hypertrophic, and the nuclei were wrinkled and clustered; the positive expression of ADAMTS5 as well as the levels of IL-1ß and TNF-α were increased (P<0.01), while the positive expression of Aggrecan was decreased (P<0.01) in the cartilage endplate; the protein expression of ADAMTS5, MMP-13, IL-1ß and TNF-α was increased (P<0.01), while that of Aggrecan was decreased (P<0.01) in the cartilage endplate. Compared with the model group, in the EA group, the comprehensive response score was increased (P<0.01); the signal of L5/L6 intervertebral disc and the cancellous bones of endplate vertebral body was enhanced; the chondrocytes of the cartilage endplate were reduced, the nuclei were slightly crumpled and scattered; the positive expression of ADAMTS5 as well as the levels of IL-1ß and TNF-α were decreased (P<0.05, P<0.01), while the positive expression of Aggrecan was increased (P<0.01) in the cartilage endplate; the protein expression of ADAMTS5, MMP-13, IL-1ß and TNF-α was decreased (P<0.05, P<0.01), while that of Aggrecan was increased (P<0.05) in the cartilage endplate. CONCLUSION: EA at "Jiaji" (EX-B 2) can delay the MC of cartilage endplate. The mechanism may be related to inhibiting the degradation of ECM of chondrocytes and the secretion of inflammatory factors, and repairing the degeneration of endplate cartilage.

The Expression of Toll-like Receptors in Cartilage Endplate Cells: A Role of Toll-like Receptor 2 in Pro-Inflammatory and Pro-Catabolic Gene Expression.

INTRODUCTION: The vertebral cartilage endplate (CEP), crucial for intervertebral disc health, is prone to degeneration linked to chronic low back pain, disc degeneration, and Modic changes (MC). While it is known that disc cells express toll-like receptors (TLRs) that recognize pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), it is unclear if CEP cells (CEPCs) share this trait. The CEP has a higher cell density than the disc, making CEPCs an important contributor. This study aimed to identify TLRs on CEPCs and their role in pro-inflammatory and catabolic gene expression. METHODS: Gene expression of TLR1-10 was measured in human CEPs and expanded CEPCs using quantitative polymerase chain reaction. Additionally, surface TLR expression was measured in CEPs grouped into non-MC and MC. CEPCs were stimulated with tumor necrosis factor alpha, interleukin 1 beta, small-molecule TLR agonists, or the 30 kDa N-terminal fibronectin fragment. TLR2 signaling was inhibited with TL2-C29, and TLR2 protein expression was measured with flow cytometry. RESULTS: Ex vivo analysis found all 10 TLRs expressed, while cultured CEPCs lost TLR8 and TLR9 expression. TLR2 expression was significantly increased in MC1 CEPCs, and its expression increased significantly after pro-inflammatory stimulation. Stimulation of the TLR2/6 heterodimer upregulated TLR2 protein expression. The TLR2/1 and TLR2/6 ligands upregulated pro-inflammatory genes and matrix metalloproteases (MMP1, MMP3, and MMP13), and TLR2 inhibition inhibited their upregulation. Endplate resorptive capacity of TLR2 activation was confirmed in a CEP explant model. CONCLUSIONS: The expression of TLR1-10 in CEPCs suggests that the CEP is susceptible to PAMP and DAMP stimulation. Enhanced TLR2 expression in MC1, and generally in CEPCs under inflammatory conditions, has pro-inflammatory and pro-catabolic effects, suggesting a potential role in disc degeneration and MC.

Ultrashort-Echo-Time MRI of the Disco-Vertebral Junction: Modulation of Image Contrast via Echo Subtraction and Echo Times.

INTRODUCTION: The disco-vertebral junction (DVJ) of the lumbar spine contains thin structures with short T2 values, including the cartilaginous endplate (CEP) sandwiched between the bony vertebral endplate (VEP) and the nucleus pulposus (NP). We previously demonstrated that ultrashort-echo-time (UTE) MRI, compared to conventional MRI, is able to depict the tissues at the DVJ with improved contrast. In this study, we sought to further optimize UTE MRI by characterizing the contrast-to-noise ratio (CNR) of these tissues when either single echo or echo subtraction images are used and with varying echo times (TEs). METHODS: In four cadaveric lumbar spines, we acquired 3D Cones (a UTE sequence) images at varying TEs from 0.032 ms to 16 ms. Additionally, spin echo T1- and T2-weighted images were acquired. The CNRs of CEP-NP and CEP-VEP were measured in all source images and 3D Cones echo subtraction images. RESULTS: In the spin echo images, it was challenging to distinguish the CEP from the VEP, as both had low signal intensity. However, the 3D Cones source images at the shortest TE of 0.032 ms provided an excellent contrast between the CEP and the VEP. As the TE increased, the contrast decreased in the source images. In contrast, the 3D Cones echo subtraction images showed increasing CNR values as the second TE increased, reaching statistical significance when the second TE was above 10 ms (p < 0.05). CONCLUSIONS: Our study highlights the feasibility of incorporating UTE MRI for the evaluation of the DVJ and its advantages over conventional spin echo sequences for improving the contrast between the CEP and adjacent tissues. Additionally, modulation of the contrast for the target tissues can be achieved using either source images or subtraction images, as well as by varying the echo times.

Single-cell RNA sequencing reveals the differentiation and regulation of endplate cells in human intervertebral disc degeneration.

Low back pain (LBP) is largely attributed to intervertebral disc degeneration (IVDD), of which the endplate changes are an important component. However, the alterations in cell fate and properties within the endplates during degeneration remain unknown. Here, we firstly performed the single-cell RNA-sequencing analysis (scRNA-seq) of the cells focusing on degenerative human endplates. By unsupervised clustering of the 8,534 single-cell based on the gene expression, we identified nine distinct cell types. We employed Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, and the single-cell regulatory network inference and clustering (SCENIC) to determine the enriched pathways and transcriptional activities across seven chondrocyte subpopulations. Furthermore, two cell fates of chondrocyte differentiation were found by trajectory analysis, one was enriched in inflammation-related genes, and the other was related to extracellular matrix (ECM). Additionally, the intercellular interactions of macrophages (MA) and chondrocytes, T cells/natural killer cells (T/NK) and chondrocytes were examined by ligand-receptor pairs analysis, showing the important regulative function of FN1 from MA and CD74 from T/NK during endplate degeneration. Overall, our findings provide novel perspectives on the endplate degeneration at the single-cell level and a whole-transcriptome size.

Research Progress on the Role of Cartilage Endplate in Intervertebral Disc Degeneration.

Low back pain significantly impacts individuals' quality of life, with intervertebral disc degeneration (IDD) being a primary contributor to this condition. Currently, IDD treatment primarily focuses on symptom management and does not achieve a definitive cure. The cartilage endplate (CEP), a crucial nutrient-supplying tissue of the intervertebral disc, plays a pivotal role in disc degeneration. This review examines the mechanisms underlying CEP degeneration, summarizing recent advancements in understanding the structure and function of CEP, the involvement of various signaling pathways, and the roles of cartilage endplate stem cells (CESCs) and exosomes (Exos) in this process. The aim of this review is to provide a comprehensive reference for future research on CEP. Despite progress in understanding the role of CEP in IDD, the mechanisms underlying CEP degeneration remain incompletely elucidated. Future research poses significant challenges, necessitating further investigations to elucidate the complexities of CEP.

Insufficient endplate-bone graft contact is a risk factor for high-grade cage subsidence occurring after lateral lumbar interbody fusion supplemented with lateral plate: An analysis of 121 cases.

BACKGROUND: Lateral lumbar interbody fusion (LLIF) is a minimally invasive fusion technique that can be performed with lateral plate. Insufficient contact between the endplate and bone graft may result in cage subsidence. This study aimed to investigate the potential risk factor for high-grade cage subsidence (HCS) occurring after LLIF supplemented with lateral plate. METHODS: Between June 2017 and February 2023, 121 patients (48 males, 73 females; mean age 63.0 years; minimum follow-up period 12 months) undergoing LLIF supplemented with lateral plate were retrospectively reviewed. The incidence of HCS was assessed, and patients were categorized into HCS group or non-HCS group based on the occurrence of HCS. A revision surgery of posterior pedicle screw fixation was performed in patients with cage subsidence and complained with intolerable back pain or radicular symptoms. Comparative analyses were performed on demographic characteristics, surgical variables, and parameters related to endplate-bone graft contact between the two groups. Multivariable logistic regression analysis was employed to identify the potential risk factors associated with HCS. The receiver operating characteristic (ROC) analysis was used to calculate the cutoff values for the risk factors. Clinical outcomes were evaluated using Oswestry Disability Index (ODI), and radiographic fusion at the final follow-up was assessed based on the Bridwell grading system. RESULTS: The HCS group comprised 12 patients, while the non-HCS group included 109 patients. The incidence of HCS occurring after LLIF supplemented with lateral plate was 9.9 %. Compared to non-HCS group, patients in HCS group had lower sagittal and coronal endplate-bone graft contact rates and larger cage-endplate angles. Low sagittal (OR, 1.099; 95 % CI, 1.033-1.169; P=0.003) and low coronal (OR, 1.149, 95 % CI, 1.061-1.243, P=0.001) endplate-bone graft contact rates were determined to be correlated with HCS. The cutoff value of the sagittal and coronal endplate-bone graft contact rate was 63.5 % and 60.9 %. Eleven (91.7 %) patients in HCS group underwent revision posterior pedicle screw fixation. Both HCS and non-HCS groups experienced significant improvements in ODI at the final follow-up, while there were no differences between groups. Ninety-five (87.2 %) patients in non-HCS group, and nine (81.8 %) of the 11 patients who underwent revision surgery in HCS group achieved radiographic fusion at the final follow-up. CONCLUSIONS: The incidence of HCS occurring after LLIF supplemented with lateral plate was 9.9%. Insufficient endplate-bone graft contact is an important risk factor of HCS, and sagittal and coronal endplate-bone graft contact rates can be used as effective predictors for HCS.

Biomechanical effects of endplate sagittal coverage change on cervical disc replacement: a finite element analysis.

Background: In recent years, the number of artificial cervical disc replacements has increased, and paravertebral ectopic ossification is a common complication. Although the exact mechanism is not clear, some studies suggest that it is related to the concentration of tissue stress caused by incomplete coverage of the trailing edge of the endplate. Therefore, this study performed a quantitative analysis to compare the biomechanical effects of different sagittal distances at the posterior edge of the endplate of the upper and lower prosthesis on the cervical spine and to explore the mechanical response of incomplete coverage of the posterior edge of the endplate on the paravertebral tissues. Methods: A C2-C7 nonlinear finite element model of the cervical spine was established and validated. Based on the cervical spine model, cervical disc replacement surgery models were constructed with different distances of sagittal distance at the posterior edge of the upper prosthetic endplate (0, 1, 2, 3 mm, respectively) and sagittal distance at the posterior edge of the lower prosthetic endplate (1, 2, 3 mm, respectively). Each model was subjected to the same 1Nm torque and 73.6N driven compressive load. Range of motion (ROM), intervertebral disc pressure (IDP), facet joint force (FJF), and endplate stress were measured at the cervical surgical and other segments. Results: Compared to the intact cervical spine model, the sagittal distance of the posterior edge of the prosthesis endplate at different distances increased the stress on the intervertebral disc and the capsular joint in the adjacent vertebral body segments to different degrees, especially in extension. In different directions of motion, the posterior margin sagittal distance of the posterior edge of the endplate of the lower prosthesis has a greater mechanical influence on the cervical spine compared to the posterior margin sagittal distance of the posterior edge of the endplate of the upper prosthesis. Compared with the intact model, the biomechanical parameters (ROM, FJF, endplate stress) of the C5-C6 segment increased the most when the sagittal distance of the posterior edge of the endplate of the upper prosthesis was 3 mm. Compared with the intact model, the maximum intervertebral disc stress of C4-C5 and C6-C7 was 0.57 MPa and 0.53 MPa, respectively, when the sagittal distance of the posterior edge of the upper prosthetic endplate was 3 mm. Conclusion: After the sagittal distance of the posterior edge of the prosthetic endplate was completely covered, the mechanical influence of the entire cervical spine was low. The sagittal distance at the posterior edge of the endplate of different sizes changed the motion pattern and load distribution of the implanted segment to some extent. When the sagittal distance between the prosthesis and the upper endplate was greater than or equal to 3 mm, the mechanical indices of the implanted segment increased significantly, increasing the risk of local tissue injury, especially during extension motion. Compared to the sagittal distance at the posterior edge of the endplate of the lower prosthesis, increasing the sagittal distance at the posterior edge of the endplate of the upper prosthesis has a greater effect on the mechanics of the cervical spine.

Oblique lumbar interbody fusion combined with anterolateral screw fixation and stress endplate augmentation for treating degenerative lumbar spondylolisthesis with osteoporosis.

PURPOSE: To evaluate the outcomes of Oblique lumbar interbody fusion (OLIF)combined with anterolateral screw fixation (AF) and Stress Endplate Augmentation(SEA) versus OLIF-AF in the treatment of degenerative lumbar spondylolisthesis (DLS)with osteoporosis (OP). METHODS: 30 patients underwent OLIF-AF-SEA (SEA group) were matched with 30 patients received OLIF-AF (control group), in terms of sex, age, body mass index (BMI) and bone mineral density (BMD). Clinical outcomes including visual analog scale (VAS) score of the lower back pain (VAS-LBP), leg pain (VAS-LP), and Oswestry Disability Index (ODI) were evaluated at different postoperative intervals and comparedwith their preoperative counterparts. Radiographic outcomes such as disk height (DH), slip distance (SD), lumbar lordosis (LL), segmental lordosis (SL), cage subsidence (CS) rate and fusion rate were evaluated at different postoperative intervals and compared with their preoperative counterparts. RESULTS: SEA group presented to be better at 3-month and 12-month follow-up, the VAS-LBP, VAS-LP and ODI scores of the SEA group were significantly lower than the control group (3-month SEA vs control: 2.30±0.70 vs 3.30±0.75, 2.03±0.72 vs 2.90±0.76,15.60±2.36 vs 23.23±3.07, respectively, all p<0.05. VAS-LBP and ODI 12-month SEA vs control: 1.27±0.74 vs 1.93±0.58, 12.20±1.88 vs 14.43±1.89,respectively, all p<0.05). At 24-month follow-up, both groups showed no difference in fusion rate (83.33% vs 90.00%, p=0.45), while SEA group showed a lower CS rate (13.33% vs 53.33%, p<0.05). CONCLUSION: OLIF-AF-SEA was safe with no adverse effects and resulted in lower CS rate and better sagittal balance. OLIF-AF-SEA is a promising surgical method for treating patients with DLS-OP.

Naringin safeguards vertebral endplate chondrocytes from apoptosis and NLRP3 inflammasome activation through SIRT3-mediated mitophagy.

AIM: The degradation of the cartilage endplate (CEP) plays a critical role in the initiation and progression of intervertebral disc degeneration (IVDD), a disease closely associated with inflammation and oxidative stress. Naringin (NGN), a flavonoid compound derived from citrus fruits, has been shown to exhibit significant anti-inflammatory and antioxidant properties. This suggests a promising avenue for NGN's application in IVDD therapy. This study aims to elucidate the therapeutic effects and underlying mechanisms of NGN on CEP degeneration, contributing to the formulation of evidence-based treatment strategies for IVDD. METHODS: In vivo, we developed an intervertebral disc degeneration (IVDD) model in mice by excising the bilateral facet joints and surrounding ligaments, and evaluated the effects of naringin using HE staining and Micro-CT analysis. In vitro, endplate chondrocytes were isolated and subjected to TBHP to replicate the IVDD pathological condition. The protective effects of NGN on these cells were confirmed through immunofluorescence, Western Blot, and flow cytometry. RESULTS: In vivo, NGN effectively mitigated IVDD progression and CEP calcification in mice. In vitro, NGN enhanced mitophagy and suppressed NLRP3 inflammasome activation through the SIRT3/FOXO3a/Parkin pathway. Furthermore, NGN safeguarded chondrocytes against apoptosis and calcification triggered by oxidative stress, in addition to mitigating the degradation of the extracellular matrix. However, silencing SIRT3 negated NGN's protective influence on chondrocytes. CONCLUSION: Our study demonstrated that NGN effectively shields chondrocytes from apoptosis and NLRP3 inflammasome activation by facilitating SIRT3-mediated mitophagy. These insights could pave the way for innovative approaches in the prevention and management of IVDD.

Functional and Structural Changes in Diaphragm Neuromuscular Junctions in Early Aging.

Age-related impairment of the diaphragm causes respiratory complications. Neuromuscular junction (NMJ) dysfunction can be one of the triggering events in diaphragm weaknesses in old age. Prominent structural and functional alterations in diaphragm NMJs were described in elderly rodents, but NMJ changes in middle age remain unclear. Here, we compared diaphragm muscles from young adult (3 months) and middle-aged (12 months) BALB/c mice. Microelectrode recordings, immunofluorescent staining, electron microscopy, myography, and whole-body plethysmography were used. We revealed presynaptic (i) and postsynaptic (ii) changes. The former (i) included an increase in both action potential propagation velocity and neurotransmitter release evoked by low-, moderate-, and high-frequency activity but a decrease in immunoexpression of synapsin 1 and synaptic vesicle clustering. The latter (ii) consisted of a decrease in currents via nicotinic acetylcholine receptors and the area of their distribution. These NMJ changes correlated with increased contractile responses to moderate- to high-frequency nerve activation. Additionally, we found alterations in the pattern of respiration (an increase in peak inspiratory flow and a tendency of elevation of the tidal volume), which imply increased diaphragm activity in middle-aged mice. We conclude that enhancement of neuromuscular communication (due to presynaptic mechanism) accompanied by improved contractile responses occurs in the diaphragm in early aging.

The effect of increasing motor end-plate innervation on smile activation in acute and early facial palsy.

While it has been over half a century since primary cross-facial nerve grafting was first described for facial reanimation, the outcome of this procedure, remains inconsistent and provide lesser smile excursion when compared to the likes of the masseteric nerve. However, the latter itself has limitations in terms of the lack of spontaneity and resting tone. While combinations have been attempted more proximally, we ask the question as to whether more distal nerve transfers with vascularized nerve grafts are a better option. In a retrospective review of clinical practice at our institute, 16 consecutive patients had single, double, and finally triple distal nerve transfers, close to the target facial muscle to reinnervate the motor endplates directly, over a 6-year period (2018-23). All patients had the onset of facial palsy within 18 months. Statistical analysis of the comparison between three sub-cohorts was performed using student's t-test and one-way ANOVA, respectively. Qualitatively, masseteric neurotization of a single facial nerve branch translated into smile improvement in 50% of cases, as opposed to all cases of double- and triple-neurotization of the smile muscles. In terms of upper lip elevation, single neurotization showed improvement in 25% of cases, double-neurotization in 40% of cases and triple-neurotization in 100% of cases. Upper lip elevation was also significantly better in those who had a vascularized cross-facial nerve graft (Student's t-test <0.05). In summary, increasing neural input to the motor endplates of smile muscles can significantly improve smile activation, in acute flaccid facial palsies.

Molecular Adaptations of BDNF/NT-4 Neurotrophic and Muscarinic Pathways in Ageing Neuromuscular Synapses.

Age-related conditions, such as sarcopenia, cause physical disabilities for an increasing section of society. At the neuromuscular junction, the postsynaptic-derived neurotrophic factors brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NT-4) have neuroprotective functions and contribute to the correct regulation of the exocytotic machinery. Similarly, presynaptic muscarinic signalling plays a fundamental modulatory function in this synapse. However, whether or not these signalling pathways are compromised in ageing neuromuscular system has not yet been analysed. The present study analyses, through Western blotting, the differences in expression and activation of the main key proteins of the BDNF/NT-4 and muscarinic pathways related to neurotransmission in young versus ageing Extensor digitorum longus (EDL) rat muscles. The main results show an imbalance in several sections of these pathways: (i) a change in the stoichiometry of BDNF/NT-4, (ii) an imbalance of Tropomyosin-related kinase B receptor (TrkB)-FL/TrkB-T1 and neurotrophic receptor p 75 (p75NTR), (iii) no changes in the cytosol/membrane distribution of phosphorylated downstream protein kinase C (PKC)ßI and PKCε, (iv) a reduction in the M2-subtype muscarinic receptor and P/Q-subtype voltage-gated calcium channel, (v) an imbalance of phosphorylated mammalian uncoordinated-18-1 (Munc18-1) (S313) and synaptosomal-associated protein 25 (SNAP-25) (S187), and (vi) normal levels of molecules related to the management of acetylcholine (Ach). Based on this descriptive analysis, we hypothesise that these pathways can be adjusted to ensure neurotransmission rather than undergoing negative alterations caused by ageing. However, further studies are needed to assess this hypothetical suggestion. Our results contribute to the understanding of some previously described neuromuscular functional age-related impairments. Strategies to promote these signalling pathways could improve the neuromuscular physiology and quality of life of older people.

CT-based surrogate parameters for MRI-based disc height and endplate degeneration in the lumbar spine.

PURPOSE: This study investigated potential use of computed tomography (CT)-based parameters in the lumbar spine as a surrogate for magnetic resonance imaging (MRI)-based findings. METHODS: In this retrospective study, all individuals, who had a lumbar spine CT scan and MRI between 2006 and 2012 were reviewed (n = 198). Disc height (DH) and endplate degeneration (ED) were evaluated between Th12/L1-L5/S1. Statistics consisted of Spearman correlation and univariate/multivariable regression (adjusting for age and gender). RESULTS: The mean CT-DH increased kranio-caudally (8.04 millimeters (mm) at T12/L1, 9.17 mm at L1/2, 10.59 mm at L2/3, 11.34 mm at L3/4, 11.42 mm at L4/5 and 10.47 mm at L5/S1). MRI-ED was observed in 58 (29%) individuals. CT-DH and MRI-DH had strong to very strong correlations (rho 0.781-0.904, p < .001). MRI-DH showed higher absolute values than CT-DH (mean of 1.76 mm). There was a significant association between CT-DH and MRI-ED at L2/3 (p = .006), L3/4 (p = .002), L4/5 (p < .001) and L5/S1 (p < .001). A calculated cut-off point was set at 11 mm. CONCLUSIONS: In the lumbar spine, there is a correlation between disc height on CT and MRI. This can be useful in trauma and emergency cases, where CT is readily available in the lack of an MRI. In addition, in the middle and lower part of the lumbar spine, loss of disc height on CT scans is associated with more pronounced endplate degeneration on MRIs. If the disc height on CT scans is lower than 11 mm, endplate degeneration on MRIs is likely more pronounced. LEVEL AND DESIGN: Level III, a retrospective study.

Comparing contribution of bony and cartilaginous endplate changes to intervertebral disc degeneration.

Objective: To compare the degenerative features of cartilaginous endplate with bony endplate in association with intervertebral degeneration in local population at radiographic, macroscopic and microscopic level in human motion segments. Methods: This cross-sectional descriptive study examined 59 lumbar spine motion segments from adult male cadavers at the Department of Anatomy, University of Health Sciences, Lahore, between May and September, 2022. Radiographic assessment observed bony endplate (BEP) for the presence of sclerosis & osteophytes and degeneration scores from 1-8 were assigned. Macroscopic assessment was done to evaluate BEP, cartilaginous endplate (CEP) and IVD, and scores ranged from 1to 28 for BEP, 1-4 for CEP and 1-64 for IVD were assigned. Microscopic assessment revealed degeneration scores of CEP ranged from 1-42 and 1-30 for IVD. Segments with BEP defects were also identified on radiographs & macroscopy. Results: Significant correlations were observed between the total degeneration scores of BEP with IVD and CEP scores (r=0.88 and r=0.909, respectively, p<0.001). Similarly, the total degeneration scores of the CEP is also significantly correlated with total IVD (r=0.86, p<0.001). Additionally, the samples with BEP defects were having higher IVD degeneration scores (p<0.001). Conclusion: This study, for the first time identifies that there exists a critical association of bony and cartilaginous endplate with intervertebral disc degeneration individually in the same tissue sections using multi-dimension assessment methods. Degeneration in any of the components of VEP is consonantly associated with IVD degeneration. The BEP & CEP, though, they are unique structures but are interlinked with each other structurally and functionally.

From Modic to Disc Endplate Bone Marrow Complex - The Natural Course and Clinical Implication of Vertebral Endplate Changes.

STUDY DESIGN: Review article. OBJECTIVES: A review of literature on the epidemiology, natural course, pathobiology and clinical implications of vertebral endplate changes. METHODS: A literature search was performed using the Cochrane Database of Systematic Reviews, EMBASE, and PubMed. Studies published over the last 10 years were analysed. The searches were performed using Medical Subject Headings terms, and the subheadings used were "Vertebral endplate changes", "Modic changes", "Disc Endplate Bone Marrow complex". RESULTS: The disc, endplate (EP), and bone marrow region of the spine constitute a unified morphological and functional unit, with isolated degeneration of any one structure being uncommon. Disc degeneration causes endplate defects, which result in direct communication and a constant cross-talk between the disc and the vertebral body. This may result in a persistent inflammatory state of the vertebral bone marrow, serving as a major pain generator. This review article focuses on vertebral endplate changes and how the current understanding has progressed from the Modic classification to the Disc Endplate Bone Marrow complex classification. It provides a clear portrayal of the natural course of these alterations and their clinical implications in low back pain. CONCLUSIONS: In light of the heightened interest and current prominence of vertebral endplate changes within the spine community, we must progress beyond the Modic changes to achieve a comprehensive understanding. The DEBM complex classification will play a major part in disc degeneration research and clinical care, representing a considerable advancement in our understanding of the vertebral endplate changes over the classical Modic changes.

Qualitative and Quantitative MR Imaging of the Cartilaginous Endplate: A Review.

The cartilaginous endplate (CEP) plays a pivotal role in facilitating the supply of nutrients and, transport of metabolic waste, as well as providing mechanical support for the intervertebral disc (IVD). Recent technological advances have led to a surge in MR imaging studies focused on the CEP. This article describes the anatomy and functions of the CEP as well as MRI techniques for both qualitative and quantitative assessment of the CEP. Effective CEP MR imaging sequences require two key features: high spatial resolution and relatively short echo time. High spatial resolution spoiled gradient echo (SPGR) and ultrashort echo time (UTE) sequences, fulfilling these requirements, are the basis for most of the sequences employed in CEP imaging. This article reviews existing sequences for qualitative CEP imaging, such as the fat-suppressed SPGR and UTE, dual-echo subtraction UTE, inversion recovery prepared and fat-suppressed UTE, and dual inversion recovery prepared UTE sequences. These sequences are employed together with other techniques for quantitative CEP imaging, including measurements of T2*, T2, T1, T1ρ, magnetization transfer, perfusion, and diffusion tensor parameters. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.