Delayed Surgical Reversal of Optic Nerve Compression Leads to Exponential Degeneration of Optic Nerve Fibers and Selective Sparing of the Small Fibers.

Purpose: To evaluate the effectiveness of surgical reversal of experimental optic nerve compression in treating persistent compressive optic neuropathy and to explore the relationship between surgical outcomes and the timing of the procedure. Methods: Surgical reversal procedures (decompression surgery) were conducted at five time intervals: 1, 3, and 7 days and 2 and 3 weeks following optic nerve compression in a rabbit model. The groups were labeled as DC-1d, DC-3d, DC-7d, DC-2w, and DC-3w, respectively. The study investigated changes in ganglion cell complex (GCC) thickness using spectral-domain optical coherence tomography and the percentage of surviving retinal ganglion cells (RGCs) through immunofluorescence staining and optic nerve axons stained with p-phenylenediamine at 4 weeks after decompression. Additionally, the area distribution of surviving axons was analyzed. Results: The decline in GCC thickness was halted following decompression. The remaining thickness of the GCC in group DC-1d was found to be statistically significantly higher at 2, 3, and 4 weeks postonset compared to the no-decompression group. Similarly, GCC thickness in group DC-3d was significantly higher at 3 and 4 weeks postonset. The percentage of surviving RGCs and axons at 4 weeks postonset exhibited an exponential correlation with the onset time of decompression, with R2 values of 0.72 and 0.78, respectively. The surviving axon area declined following delayed decompression. Conclusions: Persistent substantial compression on the optic nerve leads to exponential degeneration of the optic nerve, initially affecting larger optic nerve fibers. Early intervention aimed at relieving the compression on the optic nerve may offer potential benefits in mitigating the degenerative effects and conserving visual function.

Peripheral nerve mucoid degeneration involving the sciatic nerve.

Peripheral nerve mucoid degeneration (PNMD) is a rare non-neoplastic degenerative condition characterized by endoneural deposit of mucoid matrix. Herein, we report a case of PNMD involving the sciatic nerve with preoperative features, surgical treatment and pathological findings.

A review of the role of epidural percutaneous neuroplasty.

Degeneration, whether from age or postsurgical, in the ventral and lateral epidural space can lead to irritation of both the nerve roots and of the nerves present in the epidural space, the peridural membrane and the posterior longitudinal ligament. This irritation is often accompanied by mild scarring. Neuroplasty is a specific procedure designed to relieve this irritation. The effectiveness of neuroplasty is not affected by the extent of spinal stenosis. Neuroplasty can be performed in the lumbar, thoracic and cervical spine, and using caudal, transforaminal and interlaminar approaches. Postprocedural home exercises are an integral part of the procedure. There are multiple high-grade studies positive for the effectiveness and safety of neuroplasty. Neuroplasty should be offered prior to surgery in patients with persistent back and/or extremity pain.

Neuro-regeneration therapy using human Muse cells is highly effective in a mouse intracerebral hemorrhage model.

A novel type of non-tumorigenic pluripotent stem cell, the Muse cell (multi-lineage, differentiating stress enduring cell), resides in the connective tissue and in cultured mesenchymal stem cells (MSCs) and is reported to differentiate into multiple cell types according to the microenvironment to repair tissue damage. We examined the efficiency of Muse cells in a mouse intracerebral hemorrhage (ICH) model. Seventy µl of cardiac blood was stereotactically injected into the left putamen of immunodeficient mice. Five days later, 2 × 105 of human bone marrow MSC-derived Muse cells (n = 6) or cells other than Muse cells in MSCs (non-Muse, n = 6) or the same volume of PBS (n = 11) was injected into the ICH cavity. Water maze and motor function tests were implemented for 68 days, and immunohistochemistry for NeuN, MAP2 and GFAP was done. The Muse group showed impressive recovery: Recovery was seen in the water maze after day 19, and motor functions after 5 days was compared with the other two groups, with a significant statistical difference (p < 0.05). The survival rate of the engrafted cells in the Muse group was significantly higher than in the non-Muse group (p < 0.05) at day 69, and those cells showed positivity for NeuN (~57%) and MAP-2 (~41.6%). Muse cells could remain in the ICH brain, differentiate into neural-lineage cells and restore functions without inducing them into neuronal cells by gene introduction and cytokine treatment prior to transplantation. A simple collection of Muse cells and their supply to the brain in naïve state facilitates regenerative therapy in ICH.

Mesenchymal stem cells attenuate peripheral neuronal degeneration in spinocerebellar ataxia type 1 knockin mice.

Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disorder in which an abnormally expanded polyglutamine tract is inserted into causative ataxin-1 proteins. We have previously shown that SCA1 knockin (SCA1-KI) mice over 6 months of age exhibit a degeneration of motor neuron axons and their encasing myelin sheaths, as reported in SCA1 patients. We examined whether axon degeneration precedes myelin degeneration or vice versa in SCA1-KI mice and then attempted to mitigate motor neuron degeneration by intrathecally administering mesenchymal stem cells (MSCs). Temporal examination of the diameters of motor neuron axons and their myelin sheaths revealed a decrease in diameter of the axon but not of the myelin sheaths in SCA1-KI mice as early as 1 month of age, which suggests secondary degeneration of the myelin sheaths. We injected MSCs into the intrathecal space of SCA1-KI mice at 1 month of age, which resulted in a significant suppression of degeneration of both motor neuron axons and myelin sheaths, even 6 months after the MSC injection. Thus, MSCs effectively suppressed peripheral nervous system degeneration in SCA1-KI mice. It has not yet been clarified how clinically administered MSCs exhibit significant therapeutic effects in patients with SCA1. The morphological evidence presented in this current mouse study might explain the mechanisms that underlie the therapeutic effects of MSCs that are observed in patients with SCA1.

Fluorescently labeled peptide increases identification of degenerated facial nerve branches during surgery and improves functional outcome.

Nerve degeneration after transection injury decreases intraoperative visibility under white light (WL), complicating surgical repair. We show here that the use of fluorescently labeled nerve binding probe (F-NP41) can improve intraoperative visualization of chronically (up to 9 months) denervated nerves. In a mouse model for the repair of chronically denervated facial nerves, the intraoperative use of fluorescent labeling decreased time to nerve identification by 40% compared to surgeries performed under WL alone. Cumulative functional post-operative recovery was also significantly improved in the fluorescence guided group as determined by quantitatively tracking of the recovery of whisker movement at time intervals for 6 weeks post-repair. To our knowledge, this is the first description of an injectable probe that increases visibility of chronically denervated nerves during surgical repair in live animals. Future translation of this probe may improve functional outcome for patients with chronic denervation undergoing surgical repair.

An analysis of spinopelvic sagittal alignment after lumbar lordosis reconstruction for degenerative spinal diseases: how much balance can be obtained?

STUDY DESIGN: A retrospective and radiological study of degenerative spinal diseases. OBJECTIVE: To explore the changes in spinopelvic sagittal alignment after lumbar instrumentation and fusion of degenerative spinal diseases. SUMMARY OF BACKGROUND DATA: Efforts have been paid to clarify the ideal postoperative sagittal profile for degenerative spinal diseases. However, little has been published about the actual changes of sagittal alignment after lumbar lordosis reconstruction. METHODS: Radiographical analysis of 83 patients with spinal degeneration was performed by measuring sagittal parameters before and after operations. Comparative studies of sagittal parameters between short (1 level) and long (≥ 2 level) instrumentation and fusion were performed. Different variances (Δ) of these sagittal parameters before and after operations were calculated and compared. Correlative study and linear regression were performed to establish the relationship between variances. RESULTS: No significant changes were shown in the short-fusion group postoperatively. In the long-fusion group, postoperative lumbar lordosis (LL) and sacral slope (SS) were significantly increased; pelvic tilt (PT), sagittal vertical axis (SVA), pelvic incidence minus lumbar lordosis, and PT/SS were significantly decreased. Different variances of ΔLL, ΔSS, ΔPT, ΔSVA, Δ(pelvic incidence - LL), and ΔPT/SS were significantly greater in the long-fusion group than the short-fusion group. Close correlations were mainly shown among ΔLL, ΔPT, and ΔSVA. Linear regression equations could be developed (ΔPT = -0.185 × ΔLL - 7.299 and ΔSVA = -0.152ΔLL - 1.145). CONCLUSION: In degenerative spinal diseases, long instrumentation and fusion (≥ 2 levels) provides more efficient LL reconstruction. PT, SS, and SVA improve corresponding to LL in a linear regression model. Linear regression equations could be developed and used to predict PT and SVA change after long instrumentation and fusion for LL reconstruction.

Gamma Knife rhizotomy-induced histopathology in multiple sclerosis-related trigeminal neuralgia.

OBJECT: In this report, the authors describe the pathological changes in the human trigeminal nerve after Gamma Knife radiosurgery. METHODS: Three trigeminal nerves of patients with multiple sclerosis (MS)-related trigeminal neuralgia (MSTN) after Gamma Knife radiosurgery and other ablative procedures were examined by a neuropathologist. These cases were compared with 3 patients with typical TN who underwent partial surgical rhizotomy following recurrent symptoms after gasserian injury procedures, as well as with autopsy specimens from patients with and without MSTN. RESULTS: The three irradiated MS-TN specimens exhibited axon loss, demyelination, myelin debris, and fibrosis. Mild lymphocytic infiltrate was present in all 3 samples from MS-TN patients. The nonirradiated trigeminal nerve samples were generally well myelinated with rare degenerating axons. The microscopic findings in trigeminal nerve autopsy specimens were normal in patients without TN, with MS but not TN, and MS-TN. CONCLUSIONS: The inflammation observed in MS-TN specimens collected following Gamma Knife radiosurgery has not previously been described in the literature. These data provide new insight into the changes that occur in trigeminal nerve following stereotactic radiosurgery.

Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats.

Traumatic brain injury (TBI) survivors exhibit motor and cognitive symptoms from the primary injury that can become aggravated over time because of secondary cell death. In the present in vivo study, we examined the beneficial effects of human adipose-derived stem cells (hADSCs) in a controlled cortical impact model of mild TBI using young (6 months) and aged (20 months) F344 rats. Animals were transplanted intravenously with 4 × 10(6) hADSCs (Tx), conditioned media (CM), or vehicle (unconditioned media) at 3 h after TBI. Significant amelioration of motor and cognitive functions was revealed in young, but not aged, Tx and CM groups. Fluorescent imaging in vivo and ex vivo revealed 1,1' dioactadecyl-3-3-3',3'-tetramethylindotricarbocyanine iodide-labeled hADSCs in peripheral organs and brain after TBI. Spatiotemporal deposition of hADSCs differed between young and aged rats, most notably reduced migration to the aged spleen. Significant reduction in cortical damage and hippocampal cell loss was observed in both Tx and CM groups in young rats, whereas less neuroprotection was detected in the aged rats and mainly in the Tx group but not the CM group. CM harvested from hADSCs with silencing of either NEAT1 (nuclear enriched abundant transcript 1) or MALAT1 (metastasis associated lung adenocarcinoma transcript 1), long noncoding RNAs (lncRNAs) known to play a role in gene expression, lost the efficacy in our model. Altogether, hADSCs are promising therapeutic cells for TBI, and lncRNAs in the secretome is an important mechanism of cell therapy. Furthermore, hADSCs showed reduced efficacy in aged rats, which may in part result from decreased homing of the cells to the spleen.

Proteoglycan-mediated axon degeneration corrects pretarget topographic sorting errors.

Proper arrangement of axonal projections into topographic maps is crucial for brain function, especially in sensory systems. An important mechanism for map formation is pretarget axon sorting, in which topographic ordering of axons appears in tracts before axons reach their target, but this process remains poorly understood. Here, we show that selective axon degeneration is used as a correction mechanism to eliminate missorted axons in the optic tract during retinotectal development in zebrafish. Retinal axons are not precisely ordered during initial pathfinding but become corrected later, with missorted axons selectively fragmenting and degenerating. We further show that heparan sulfate is required non-cell-autonomously to correct missorted axons and that restoring its synthesis at late stages in a deficient mutant is sufficient to restore topographic sorting. These findings uncover a function for developmental axon degeneration in ordering axonal projections and identify heparan sulfate as a key regulator of that process.

Patterns of target tissue reinnervation and trophic factor expression after nerve grafting.

BACKGROUND: Reinnervation of target tissues determines functional outcomes after nerve grafting, which is important in traumatic injury caused by accidents or consequences resulting from surgical removal of tumors. Previous studies documented the influences of nerve repair mainly based on nerve morphometry but rarely compared the final outcomes according to target reinnervation patterns by nerve fibers of different categories. METHODS: In a mouse model of nerve grafting, the authors analyzed the innervation indexes of different target tissues after transection-reimplantation on the sciatic nerve, which were defined as a parameter on the operated side normalized to that on the control side. RESULTS: Muscle reinnervation appeared to be the best compared with skin reinnervation (p < 0.0001) and sweat gland reinnervation (p < 0.0001) at postoperative month 3. The sudomotor reinnervation was relatively higher than the cutaneous reinnervation (p = 0.014). The abundance of trophin transcripts for brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and neurotrophin 3 (NT3) was higher in plantar muscles on the operated side than those on the control side. In contrast, transcripts of BDNF, GDNF, nerve growth factor, and NT3 were all similar in the footpad skin between the operated and control sides. CONCLUSIONS: The results suggested that, compared with the skin, muscles achieved the best reinnervation after nerve grafting, which was related to higher expression of BDNF, GDNF, and NT3 in muscles than in the skin.

Bone marrow cell transplantation restores olfaction in the degenerated olfactory bulb.

Bone marrow contains heterogeneous cell types including end-lineage cells, committed tissue progenitors, and multipotent stem/progenitor cells. The immense plasticity of bone marrow cells allows them to populate diverse tissues such as the encephalon, and give rise to a variety of cell types. This unique plasticity makes bone marrow-derived cells good candidates for cell therapy aiming at restoring impaired brain circuits. In the present study, bone marrow cells were transplanted into P20 mice that exhibit selective olfactory degeneration in adulthood between P60 and P150. These animals, the so-called Purkinje Cell Degeneration (PCD) mutant mice, suffer from a progressive and specific loss of a subpopulation of principal neurons of the olfactory bulb, the mitral cells (MCs), sparing the other principal neurons, the tufted cells. As such, PCD mice constitute an interesting model to evaluate the specific role of MCs in olfaction and to test the restorative function of transplanted bone marrow-derived cells. Using precision olfactometry, we revealed that mutant mice lacking MCs exhibited a deficit in odorant detection and discrimination. Remarkably, the transplantation of wild-type bone marrow-derived cells into irradiated PCD mutant mice generated a large population of microglial cells in the olfactory bulb and reduced the degenerative process. The alleviation of MC loss in transplanted mice was accompanied by functional recovery witnessed by significantly improved olfactory detection and enhanced odor discrimination. Together, these data suggest that: (1) bone marrow-derived cells represent an effective neuroprotective tool to restore degenerative brain circuits, and (2) MCs are necessary to encode odor concentration and odor identity in the mouse olfactory bulb.

An alteration in the lateral geniculate nucleus of experimental glaucoma monkeys: in vivo positron emission tomography imaging of glial activation.

We examined lateral geniculate nucleus (LGN) degeneration as an indicator for possible diagnosis of glaucoma in experimental glaucoma monkeys using positron emission tomography (PET). Chronic intraocular pressure (IOP) elevation was induced by laser trabeculoplasty in the left eyes of 5 cynomolgus monkeys. Glial cell activation was detected by PET imaging with [(11)C]PK11195, a PET ligand for peripheral-type benzodiazepine receptor (PBR), before and at 4 weeks after laser treatment (moderate glaucoma stage). At mild, moderate, and advanced experimental glaucoma stages (classified by histological changes based on the extent of axonal loss), brains were stained with cresyl violet, or antibodies against PBR, Iba-1 (a microglial marker), and GFAP (an activated astrocyte marker). In laser-treated eyes, IOP was persistently elevated throughout all observation periods. PET imaging showed increased [(11)C]PK11195 binding potential in the bilateral LGN at 4 weeks after laser treatment; the increase in the ipsilateral LGN was statistically significant (P<0.05, n = 4). Immunostaining showed bilateral activations of microglia and astrocytes in LGN layers receiving input from the laser-treated eye. PBR-positive cells were observed in LGN layers receiving input from laser-treated eye at all experimental glaucoma stages including the mild glaucoma stage and their localization coincided with Iba-1 positive microglia and GFAP-positive astrocytes. These data suggest that glial activation occurs in the LGN at a mild glaucoma stage, and that the LGN degeneration could be detected by a PET imaging with [(11)C]PK11195 during the moderate experimental glaucoma stage after unilateral ocular hypertension. Therefore, activated glial markers such as PBR in the LGN may be useful in noninvasive molecular imaging for diagnosis of glaucoma.

Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer's disease mouse model through modulation of neuroinflammation.

Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) have a potential therapeutic role in the treatment of neurological disorders, but their current clinical usage and mechanism of action has yet to be ascertained in Alzheimer's disease (AD). Here we report that hUCB-MSC transplantation into amyloid precursor protein (APP) and presenilin1 (PS1) double-transgenic mice significantly improved spatial learning and memory decline. Furthermore, amyloid-ß peptide (Aß) deposition, ß-secretase 1 (BACE-1) levels, and tau hyperphosphorylation were dramatically reduced in hUCB-MSC transplanted APP/PS1 mice. Interestingly, these effects were associated with reversal of disease-associated microglial neuroinflammation, as evidenced by decreased microglia-induced proinflammatory cytokines, elevated alternatively activated microglia, and increased anti-inflammatory cytokines. These findings lead us to suggest that hUCB-MSC produced their sustained neuroprotective effect by inducing a feed-forward loop involving alternative activation of microglial neuroinflammation, thereby ameliorating disease pathophysiology and reversing the cognitive decline associated with Aß deposition in AD mice.

Watching worms whither: modeling neurodegeneration in C. elegans.

Caenorhabditis elegans is increasingly being used to study neurodegenerative diseases. Nematodes are translucent, which facilitates study of particular neurons in the living animal, and easy to manipulate genetically. Despite vast evolutionary divergence, human proteins are functionally active when expressed in C. elegans, and disease-linked mutations in these proteins also cause phenotypic changes in the nematode. In this chapter, we review use of C. elegans to investigate the pathophysiology of Alzheimer's disease, Parkinson's disease, and axonal degeneration. Studies of presenilin, ß-amyloid, tau, α-synuclein, and LRRK2 all produce strong phenotypic effects in C. elegans, and in many cases reproduce selective neuronal vulnerability observed in humans. Disease-linked mutations enhance degeneration in the C. elegans models. These studies are increasingly leading to high-throughput screens that identify novel genes and novel pharmaceuticals that modify the disease course.

Synergism of human amnion-derived multipotent progenitor (AMP) cells and a collagen scaffold in promoting brain wound recovery: pre-clinical studies in an experimental model of penetrating ballistic-like brain injury.

One of the histopathological consequences of a penetrating ballistic brain injury is the formation of a permanent cavity. In a previous study using the penetrating ballistic-like brain injury (PBBI) model, engrafted human amnion-derived multipotent progenitor (AMP) cells failed to survive when injected directly in the injury tract, suggesting that the cell survival requires a supportive matrix. In this study, we seated AMP cells in a collagen-based scaffold, injected into the injury core, and investigated cell survival and neuroprotection following PBBI. AMP cells suspended in AMP cell conditioned medium (ACCS) or in a liquefied collagen matrix were injected immediately after a PBBI along the penetrating injury tract. Injured control rats received only liquefied collagen matrix. All animals were allowed to survive two weeks. Consistent with our previous results, AMP cells suspended in ACCS failed to survive; likewise, no collagen was identified at the injury site when injected alone. In contrast, both AMP cells and the collagen were preserved in the injury cavity when injected together. In addition, AMP cells/collagen treatment preserved some apparent brain tissue in the injury cavity, and there was measurable infiltration of endogenous neural progenitor cells and astrocytes into the preserved brain tissue. AMP cells were also found to have migrated into the subventricular zone and the corpus callosum. Moreover, the AMP cell/collagen treatment significantly attenuated the PBBI-induced axonal degeneration in the corpus callosum and ipsilateral thalamus and improved motor impairment on rotarod performance. Overall, collagen-based scaffold provided a supportive matrix for AMP cell survival, migration, and neuroprotection.

Impact of cordectomy as a treatment option for posttraumatic and non-posttraumatic syringomyelia with tethered cord syndrome and myelopathy.

OBJECT: Spinal cordectomy has recently become more important in the treatment of end-stage posttraumatic or postoperative syringomyelia and arachnopathy as a last resort to manage ascending neurological dysfunction, spasticity, and pain in paraplegic patients. The aim in this study was to confirm a clinical benefit in strict indications for cordectomy. METHODS: Between February 2000 and September 2007, 15 spinal cordectomies were performed at the Department of Neurosurgery, Cantonal Hospital, St. Gallen. Indications for treatment were end-stage myelopathies caused by syringomyelia, tethered cord syndrome, and arachnopathy with progressive spasticity and pain or progressive upper-level neurological deficits related to the tethered cord syndrome. All patients had severe motor and sensory deficits with no residual voluntary function below the affected level. RESULTS: Fourteen of 15 patients showed stabilization or even an improvement in motor and sensory function. Four patients suffered from progressive spasticity and 3 from deterioration due to pain. There were no other adverse surgical events. CONCLUSIONS: Cordectomy can be a useful instrument to preserve functions of the upper extremities and to improve spasticity and pain in patients with severe myelopathy and tethered cord, syringomyelia, or arachnopathy of various etiologies.

Hippocampal stem cell grafting-mediated recovery of injured hippocampus in the rat model of temporal lobe epilepsy.

Hippocampal stem cells (HSCs) are considered promising donor cells to promote reorganization of degenerated regions of the injured hippocampus in the epileptic brain. However, the efficacy of HSC grafting for repairing injured hippocampus remains unclear. To address this issue, we transplanted neonatal rat HSCs into the right hippocampus in rats with kainite acid (KA)-induced epilepsy. The activity of the hippocampus and amygdala nucleus was monitored with electroencephalogram (EEG) throughout 24 weeks posttransplantation. Rats with grafted HSCs exhibited reduced frequency of epileptic wave discharge and a 50% decrease in the amplitude of discharge. At 1, 4, 8, and 24 weeks posttransplantation, the aberrant mossy fiber sprouting (MFS) was evaluated with Timm's stain and the number of CA3 pyramidal neurons was analyzed with Nissl staining. Aberrant MFS induced by KA-lesion was notably suppressed by HSC grafts beginning 4 weeks posttransplantation, and was most effective by 8 weeks. In addition, the loss of CA3 pyramidal neurons was partially restored and reached the most recovery at 8 weeks. Taken together, these results suggest that HSCs derived from the postnatal hippocampus offer a promising reparative effect on KA-induced epileptic brain.