Wallerian Degeneration (wallerian + degeneration)

Distribution by Scientific Domains

Selected Abstracts

Wallerian Degeneration: A Major Component of Early Axonal Pathology in Multiple Sclerosis

Tomasz Dziedzic
Abstract Axonal loss is a major component of the pathology of multiple sclerosis (MS) and the morphological basis of permanent clinical disability. It occurs in demyelinating plaques but also in the so-called normal-appearing white matter (NAWM). However, the contribution of Wallerian degeneration to axonal pathology is not known. Here, we analyzed the extent of Wallerian degeneration and axonal pathology in periplaque white matter (PPWM) and lesions in early multiple sclerosis biopsy tissue from 63 MS patients. Wallerian degeneration was visualized using an antibody against the neuropeptide Y receptor Y1 (NPY-Y1R). The number of SMI-32-positive axons with non-phosphorylated neurofilaments was significantly higher in both PPWM and plaques compared to control white matter. APP-positive, acutely damaged axons were found in significantly higher numbers in plaques compared to PPWM. Strikingly, the number of NPY-Y1R-positive axons undergoing Wallerian degeneration was significantly higher in PPWM and plaques than in control WM. NPY-Y1R-positive axons in PPWM were strongly correlated to those in the lesions. Our results show that Wallerian degeneration is a major component of axonal pathology in the periplaque white matter in early MS. It may contribute to radiological changes observed in early MS and most likely plays a major role in the development of disability. [source]

Differences in grey and white matter atrophy in amnestic mild cognitive impairment and mild Alzheimer's disease

M. L. F. Balthazar
Background:, Grey matter (GM) atrophy has been demonstrated in amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD), but the role of white matter (WM) atrophy has not been well characterized. Despite these findings, the validity of aMCI concept as prodromal AD has been questioned. Methods:, We performed brain MRI with voxel-based morphometry analysis in 48 subjects, aiming to evaluate the patterns of GM and WM atrophy amongst mild AD, aMCI and age-matched normal controls. Results:, Amnestic mild cognitive impairment GM atrophy was similarly distributed but less intense than that of mild AD group, mainly in thalami and parahippocampal gyri. There were no difference between aMCI and controls concerning WM atrophy. In the mild AD group, we found WM atrophy in periventricular areas, corpus callosum and WM adjacent to associative cortices. Discussion:, We demonstrated that aMCI might be considered a valid concept to detect very early AD pathology, since we found a close proximity in the pattern of atrophy. Also, we showed the involvement of WM in mild AD, but not in aMCI, suggesting a combination of Wallerian degeneration and microvascular ischaemic disease as a plausible additional pathological mechanism for the discrimination between MCI and AD. [source]

Erythropoietin reduces Schwann cell TNF-,, Wallerian degeneration and pain-related behaviors after peripheral nerve injury

W. Marie Campana
Abstract Chronic sciatic nerve constriction injury (CCI) induces Wallerian degeneration and exaggerated pain-like behaviors. These effects are mediated in large part by pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-,). In this study, we demonstrate that systemically administered recombinant human erythropoietin (rhEpo) facilitates recovery from chronic neuropathic pain associated with CCI in rats. Because TNF-, has been implicated in the development of pain-related behaviors, we measured TNF-, mRNA at the nerve injury site. Systemically or locally administered rhEpo decreased TNF-, mRNA, compared with that observed in untreated animals. RhEpo also significantly (P < 0.05) decreased axonal degeneration. Immunohistochemistry of CCI nerve showed abundant TNF-, in Schwann cells, axoplasm and macrophages. In rhEpo-treated animals, TNF-, immunopositivity was decreased selectively in Schwann cells. These results suggest a model in which rhEpo counteracts the effects of TNF-, in CCI by blocking expression of TNF-, in Schwann cells. To further test this model, we studied primary Schwann cell cultures. RhEpo inhibited TNF-, expression in response to lipopolysaccharide, supporting the conclusions of our in vivo CCI experiments. In addition, rhEpo directly counteracted Schwann cell death induced by exogenously added TNF-,in vitro. These results indicated that rhEpo regulates TNF-, by multiple mechanisms; rhEpo regulates TNF-, mRNA expression by Schwann cells but also may directly counteract TNF-, signaling pathways that lead to injury, chronic pain and/or death. [source]

Proteasome inhibition suppresses Schwann cell dedifferentiation in vitro and in vivo

GLIA, Issue 16 2009
Hyun Kyoung Lee
Abstract The ubiquitin-proteasome system (UPS), lysosomes, and autophagy are essential protein degradation systems for the regulation of a variety of cellular physiological events including the cellular response to injury. It has recently been reported that the UPS and autophagy mediate the axonal degeneration caused by traumatic insults and the retrieval of nerve growth factors. In the peripheral nerves, axonal degeneration after injury is accompanied by myelin degradation, which is tightly related to the reactive changes of Schwann cells called dedifferentiation. In this study, we examined the role of the UPS, lysosomal proteases, and autophagy in the early phase of Wallerian degeneration of injured peripheral nerves. We found that nerve injury induced an increase in the ubiquitin conjugation and lysosomal-associated membrane protein-1 expression within 1 day without any biochemical evidence for autophagy activation. Using an ex vivo explant culture of the sciatic nerve, we observed that inhibiting proteasomes or lysosomal serine proteases prevented myelin degradation, whereas this was not observed when inhibiting autophagy. Interestingly, proteasome inhibition, but not leupeptin, prevented Schwann cells from inducing dedifferentiation markers such as p75 nerve growth factor receptor and glial fibrillary acidic protein in vitro and in vivo. In addition, proteasome inhibitors induced cell cycle arrest and cellular process formation in cultured Schwann cells. Taken together, these findings indicate that the UPS plays a role in the phenotype changes of Schwann cells in response to nerve injury. © 2009 Wiley-Liss, Inc. [source]

Schwann cells express erythropoietin receptor and represent a major target for Epo in peripheral nerve injury

GLIA, Issue 4 2005
Xiaoqing Li
Abstract Erythropoietin (Epo) expresses potent neuroprotective activity in the peripheral nervous system; however, the underlying mechanism remains incompletely understood. In this study, we demonstrate that Epo is upregulated in sciatic nerve after chronic constriction injury (CCI) and crush injury in rats, largely due to local Schwann cell production. In uninjured and injured nerves, Schwann cells also express Epo receptor (EpoR), and its expression is increased during Wallerian degeneration. CCI increased the number of Schwann cells at the injury site and the number was further increased by exogenously administered recombinant human Epo (rhEpo). To explore the activity of Epo in Schwann cells, primary cultures were established. These cells expressed cell-surface Epo receptors, with masses of 71 and 62 kDa, as determined by surface protein biotinylation and affinity precipitation. The 71-kDa species was rapidly but transiently tyrosine-phosphorylated in response to rhEpo. ERK/MAP kinase was also activated in rhEpo-treated Schwann cells; this response was blocked by pharmacologic antagonism of JAK-2. RhEpo promoted Schwann cell proliferation, as determined by BrdU incorporation. Cell proliferation was ERK/MAP kinase-dependent. These results support a model in which Schwann cells are a major target for Epo in injured peripheral nerves, perhaps within the context of an autocrine signaling pathway. EpoR-induced cell signaling and Schwann cell proliferation may protect injured peripheral nerves and promote regeneration. © 2005 Wiley-Liss, Inc. [source]

N-myc downstream-regulated gene 1 expression in injured sciatic nerves

GLIA, Issue 4 2004
Kazuho Hirata
Abstract N-myc downstream-regulated gene 1 (NDRG1)/RTP/Drg1/Cap43/rit42/TDD5/Ndr1 is expressed ubiquitously and has been proposed to play a role in growth arrest and cell differentiation. A recent study showed that mutation of this gene is responsible for hereditary motor and sensory neuropathy-Lom. However, the role of this gene in the peripheral nervous system is not fully understood. In our study, rabbit polyclonal antibodies were raised against this gene product and were used to examine changes in its expression over the time course of Wallerian degeneration and ensuing regeneration after crush injury of mouse sciatic nerves. Fluorescent immunohistochemistry showed that NDRG1 was expressed over the intact nerve fibers. Double labeling with a Schwann cell (SC) marker, S-100 protein (S-100), revealed that NDRG1 was localized in the cytoplasm of S-100-positive Schwann cells (SCs). NDRG1 expression was maintained in the early stage of myelin degradation but was then markedly depleted at the end stage of myelin degradation when frequent occurrence of BrdU-labeled SCs was observed (at 7,9 days). The depletion of NDRG1 at this time point was also confirmed by Western blotting analysis. NDRG1 expression finally recovered at the stage of remyelination, with immunoreactivity stronger than that in intact nerves. These findings suggest that NDRG1 may play an important role in the terminal differentiation of SCs during nerve regeneration. © 2004 Wiley-Liss, Inc. [source]

Loss of translation elongation factor (eEF1A2) expression in vivo differentiates between Wallerian degeneration and dying-back neuronal pathology

Lyndsay M. Murray
Abstract Wallerian degeneration and dying-back pathology are two well-known cellular pathways capable of regulating the breakdown and loss of axonal and synaptic compartments of neurons in vivo. However, the underlying mechanisms and molecular triggers of these pathways remain elusive. Here, we show that loss of translation elongation factor eEF1A2 expression in lower motor neurons and skeletal muscle fibres in homozygous Wasted mice triggered a dying-back neuropathy. Synaptic loss at the neuromuscular junction occurred in advance of axonal pathology and by a mechanism morphologically distinct from Wallerian degeneration. Dying-back pathology in Wasted mice was accompanied by reduced expression levels of the zinc finger protein ZPR1, as found in other dying-back neuropathies such as spinal muscular atrophy. Surprisingly, experimental nerve lesion revealed that Wallerian degeneration was significantly delayed in homozygous Wasted mice; morphological assessment revealed that ~80% of neuromuscular junctions in deep lumbrical muscles at 24 h and ~50% at 48 h had retained motor nerve terminals following tibial nerve lesion. This was in contrast to wild-type and heterozygous Wasted mice where < 5% of neuromuscular junctions had retained motor nerve terminals at 24 h post-lesion. These data show that eEF1A2 expression is required to prevent the initiation of dying-back pathology at the neuromuscular junction in vivo. In contrast, loss of eEF1A2 expression significantly inhibited the initiation and progression of Wallerian degeneration in vivo. We conclude that loss of eEF1A2 expression distinguishes mechanisms underlying dying-back pathology from those responsible for Wallerian degeneration in vivo and suggest that eEF1A2 -dependent cascades may provide novel molecular targets to manipulate neurodegenerative pathways in lower motor neurons. [source]

Rapid loss of motor nerve terminals following hypoxia,reperfusion injury occurs via mechanisms distinct from classic Wallerian degeneration

Becki Baxter
Abstract Motor nerve terminals are known to be vulnerable to a wide range of pathological stimuli. To further characterize this vulnerability, we have developed a novel model system to examine the response of mouse motor nerve terminals in ex vivo nerve/muscle preparations to 2 h hypoxia followed by 2 h reperfusion. This insult induced a rapid loss of neurofilament and synaptic vesicle protein immunoreactivity at pre-synaptic motor nerve terminals but did not appear to affect post-synaptic endplates or muscle fibres. The severity of nerve terminal loss was dependent on the age of the mouse and muscle type: in 8,12-week-old mice the predominantly fast-twitch lumbrical muscles showed an 82.5% loss, whereas the predominantly slow-twitch muscles transversus abdominis and triangularis sterni showed a 57.8% and 27.2% loss, respectively. This was contrasted with a > 97% loss in the predominantly slow-twitch muscles from 5,6-week-old mice. We have also demonstrated that nerve terminal loss occurs by a mechanism distinct from Wallerian degeneration, as the slow Wallerian degeneration (Wlds) gene did not modify the extent of nerve terminal pathology. Together, these data show that our new model of hypoxia,reperfusion injury is robust and repeatable, that it induces rapid, quantitative changes in motor nerve terminals and that it can be used to further examine the mechanisms regulating nerve terminal vulnerability in response to hypoxia,reperfusion injury. [source]

Ultrastructural correlates of synapse withdrawal at axotomized neuromuscular junctions in mutant and transgenic mice expressing the Wld gene

Thomas H. Gillingwater
Abstract We carried out an ultrastructural analysis of axotomized synaptic terminals in Wlds and Ube4b/Nmnat (Wld) transgenic mice, in which severed distal axons are protected from Wallerian degeneration. Previous studies have suggested that axotomy in juvenile (< 2 months) Wld mice induced a progressive nerve terminal withdrawal from motor endplates. In this study we confirm that axotomy-induced terminal withdrawal occurs in the absence of all major ultrastructural characteristics of Wallerian degeneration. Pre- and post-synaptic membranes showed no signs of disruption or fragmentation, synaptic vesicle densities remained at pre-axotomy levels, the numbers of synaptic vesicles clustered towards presynaptic active zones did not diminish, and mitochondria retained their membranes and cristae. However, motor nerve terminal ultrastructure was measurably different following axotomy in Wld transgenic 4836 line mice, which strongly express Wld protein: axotomized presynaptic terminals were retained, but many were significantly depleted of synaptic vesicles. These findings suggest that the Wld gene interacts with the mechanisms regulating transmitter release and vesicle recycling. [source]

Pathogenesis of Brain and Spinal Cord Atrophy in Multiple Sclerosis

Alireza Minagar MD
ABSTRACT For more than a century, multiple sclerosis was viewed as a disease process characterized by oligodendrocyte and myelin loss, and research into the pathogenesis of multiple sclerosis was mainly focused on the mechanisms of inflammation. However, with development of more sophisticated neuroimaging and molecular biology techniques, attention has shifted to new aspects of pathogenesis of multiple sclerosis: axonal loss and neurodegeneration. Evidence is increasing that tissue destruction, primarily axonal loss and neurodegeneration, is a key element in the pathogenesis of multiple sclerosis. In addition, it is now known that brain and spinal cord atrophy begins early in the disease process of multiple sclerosis and advances relentlessly throughout the course of the disease. Cumulative data suggest that axonal loss is the major determinant of progressive neuro logic disability in patients with multiple sclerosis. Magnetic resonance imaging and magnetic resonance spectroscopy in patients with multiple sclerosis for < 5 years indicate brain atrophy and loss of axonal integrity. Neurodegeneration and axonal loss in patients with multiple sclerosis are initially accompanied by a local response from oligodendrocyte progenitor cells and some remyelination. However, these repair mechanisms eventually fail, and patients typically develop generalized brain atrophy, cognitive decline, and permanent disability. Although the exact mechanisms underlying central nervous system atrophy in patients with multiple sclerosis are largely unknown, evidence exists that atrophy may represent an epiphenomenon related to the effects of dynamic inflammation within the central nervous system, including demyelination, axonal injury, neuronal loss, Wallerian degeneration, and possibly iron deposition. This article summarizes the potential mechanisms involved in central nervous system atrophy in patients with multiple sclerosis. [source]

Involvement of nerve injury and activation of peripheral glial cells in tetanic sciatic stimulation-induced persistent pain in rats

Lingli Liang
Abstract Tetanic stimulation of the sciatic nerve (TSS) produces long-lasting pain hypersensitivity in rats. Long-term potentiation (LTP) of C- and A-fiber-evoked field potentials in the spinal cord has been explored as contributing to central sensitization in pain pathways. However, the peripheral mechanism underlying TSS-induced pain hypersensitivity remains largely unknown. We investigated the effect of TSS on peripheral nerve and the expression of activating transcription factor 3 (ATF3) in dorsal root ganglion (DRG) as a marker of neuronal injury. TSS induced a mechanical allodynia for at least 35 days and induced ATF3 expression in the ipsilateral DRG. ATF3 is colocalized with NF200-labeled myelinated DRG neurons or CGRP- and IB4-labeled unmyelinated ones. Furthermore, we found that TSS induced Wallerian degeneration of sciatic nerve at the level of myelinisation by S100 protein (to label Schwann cells) immunohistochemistry, luxol fast blue staining, and electron microscopy. TSS also elicited the activation of satellite glial cells (SGCs) and enhanced the colocalization of GFAP and P2X7 receptors. Repeated local treatment with tetrodotoxin decreased GFAP expression in SGCs and behavioral allodynia induced by TSS. Furthermore, reactive microglia and astrocytes were found in the spinal dorsal horn after TSS. These results suggest that TSS-induced nerve injury and glial activation in the DRG and spinal dorsal horn may be involved in cellular mechanisms underlying the development of persistent pain after TSS and that TSS-induced nerve injury may be used as a novel neuropathic pain model. © 2010 Wiley-Liss, Inc. [source]

Local isoform-specific NOS inhibition: A promising approach to promote motor function recovery after nerve injury

Bernardo Moreno-López
Abstract Physical injury to a nerve is the most frequent cause of acquired peripheral neuropathy, which is responsible for loss of motor, sensory and/or autonomic functions. Injured axons in the peripheral nervous system maintain the capacity to regenerate in adult mammals. However, after nerve transection, stumps of damaged nerves must be surgically joined to guide regenerating axons into the distal nerve stump. Even so, severe functional limitations persist after restorative surgery. Therefore, the identification of molecules that regulate degenerative and regenerative processes is indispensable in developing therapeutic tools to accelerate and improve functional recovery. Here, I consider the role of nitric oxide (NO) synthesized by the three major isoforms of NO synthases (NOS) in motor neuropathy. Neuronal NOS (nNOS) seems to be the primary source of NO that is detrimental to the survival of injured motoneurons. Endothelial NOS (eNOS) appears to be the major source of NO that interferes with axonal regrowth, at least soon after injury. Finally, NO derived from inducible NOS (iNOS) or nNOS is critical to the process of lipid breakdown for Wallerian degeneration and thereby benefits axonal regrowth. Specific inhibitors of these isoforms can be used to protect injured neurons from degeneration and promote axonal regeneration. A cautious proposal for the treatment of acquired motor neuropathy using therapeutic tools that locally interfere with eNOS/nNOS activities seems to merit consideration. © 2010 Wiley-Liss, Inc. [source]

Retrograde Wallerian degeneration of cranial corticospinal tracts in cervical spinal cord injury patients using diffusion tensor imaging

Saurabh Guleria
Abstract Diffusion tensor imaging (DTI) has the potential to reveal disruption of white matter microstructure in chronically injured spinal cords. We quantified fractional anisotropy (FA) and mean diffusivity (MD) to demonstrate retrograde Wallerian degeneration (WD) of cranial corticospinal tract (CST) in cervical spinal cord injury (SCI). Twenty-two patients with complete cervical SCI in the chronic stage were studied with DTI along with 13 healthy controls. Mean FA and MD values were computed for midbrain, pons, medulla, posterior limb of internal capsule, and corona radiata. Significant reduction in the mean FA and increase in MD was observed in the cranial CST in patients with SCI compared with controls, suggesting retrograde WD. Statistically significant inverse FA and MD changes were noted in corona radiata, indicating some restoration of spared white matter tracts. Temporal changes in the DTI metrics suggest progressing degeneration in different regions of CST. These spatiotemporal changes in DTI metrics suggest continued WD in injured fibers along with simultaneous reorganization of spared white matter fibers, which may contribute to changing neurological status in chronic SCI patients. © 2008 Wiley-Liss, Inc. [source]

Axon-Schwann cell interactions regulate the expression of fibroblast growth factor-5 (FGF-5)

Marina Scarlato
Abstract We screened for genes whose expression is significantly up- or downregulated during Wallerian degeneration in adult rat sciatic nerve with cDNA arrays. Fibroblast growth factor-5 (FGF-5) mRNA seemed to be induced. This was confirmed by northern blotting and in situ hybridization, as well as Western blotting for FGF-5 in axotomized nerve. Axon-Schwann cell interactions decreased the steady-state level of FGF-5 mRNA in regenerating sciatic nerves, and forskolin diminished its expression in cultured Schwann cells. We conclude that denervated Schwann cells synthesize FGF-5, which is a secreted, neuronotrophic member of the FGF family. J. Neurosci. Res. 66:16,22, 2001. © 2001 Wiley-Liss, Inc. [source]

Pathology of lumbar nerve root compression Part 1: Intraradicular inflammatory changes induced by mechanical compression

Shigeru Kobayashi
Study design: This study is to investigate the intraradicular inflammation induced by mechanical compression using in vivo model. Objectives: The relationship between the intraradicular edema and nerve fiber degeneration induced by mechanical compression was determined in the nerve root. Summary of background data: Recently some studies reported that mechanical compression increased microvascular permeability of the endoneurial capillaries and resulted in an intraradicular inflammation. These changes may be an important factor of the pathogenesis of radiculopathy. However, the natural courses of the intraradicular inflammation after mechanical compression are still poorly understood. Methods: In dogs, laminectomy was performed at L7 and the seventh nerve root was exposed to compression at 7.5 gram force (gf) clipping power. The animals were evaluated at 1 and 3 weeks after clipping. After the appropriate period of nerve root compression, Evans blue albumin (EBA) was injected intravenously. The nerve root sections were divided into two groups. The sections were used to investigate the status of the blood,nerve barrier function under the fluorescence microscope. The other sections were used for light and transmission electron microscopic study. Results: After 1 and 3 weeks, intraradicular edema was observed not only at the site of compression but also in the peripheral zone of a compressed anterior root and in the central zone of a compressed posterior root. The evidence of active Wallerian degeneration was also seen in the area of intraradicular edema. In addition, the nerve roots showing Wallerian degeneration were infiltrated by inflammatory cells, such as macrophages and mast cells. Conclusions: Inflammatory reaction, such as Wallerian degeneration, breakdown of blood,nerve barrier and appearance of macrophage, may be deeply involved in radiculitis arising from mechanical compression, and these factors seem to be important in the manifestation of radiculopathy. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. [source]


Article first published online: 11 MAR 200
Conti G.1, Pasquale C.1, Rostami A.3, De Pol A.2, Galimberti D.1, Scarpini E.1, Baron P.L.1, Scarlato G.1 1 Milano Italy, 2 Modena, Italy, 3Philadelphia USA. Nitric oxide (NO), during CNS demyelination, is synthesised in inflammatory cells from L-arginine by the nitric oxide synthases (NOS). NO can subserve different functions, from cytotoxicity to neuroprotection and trigger either necrotic or apoptotic cell death. In this study we detected inducible form of NOS (iNOS) gene expression in experimental allergic neuritis (EAN), induced in Lewis rats by injection of "SP26," emulsified in complete Freund's adjuvant, which clinical, electrical, and pathological features resemble those of "Guillain-Barré" syndrome. Northern blot, single nerve fiber immmunostaining, and immuno-electron microscope showed that both iNOS mRNA and protein were induced in the PNS of EAN rats by day 14 after immunization, at the beginning of EAN clinical signs. However, with the same experimental procedures, we failed to find iNOS expression during Wallerian degeneration following nerve cut. These data support the hypothesis that iNOS regulation has an active role in cell-mediated demyelination. [source]

C-Peptide Deficiency: An Important Pathogenetic Factor In Type 1 Diabetic Neuropathy

Aaf Sima
Background: C-peptide has insulin-like effects and ameliorates the acute nerve conduction defect (NCD) in experimental and human type 1 diabetic neuropathy (DN). Methods: In this study, diabetic BB/Wor-rats were treated with rat C-peptide (75 ng/kg) from onset of diabetes for 8 months (prevention-group, PG). In a separate experiment, 5-mo untreated diabetic BB/Wor-rats were started on the same C-peptide treatment continued to 8 mo of diabetes (intervention group, IG). Results: In the PG, the NCD was significantly decreased (p < 0.001) compared to untreated BB/Wor-rats and was similar to that of normo-C-peptidemic and isohyperglycemic type 2 BBZ rats. This effect was associated with significant preventions of nodal changes (p < 0.001) including axo-glial dysjunction (p < 0.001), which was not different from non-diabetic control rats. Axonal atrophy and Wallerian degeneration were significantly prevented (both p < 0.05). In the IG, the NCD decreased significantly (p < 0.01) during the 3 mo treatment period. Associated with the functional improvement, nodal changes improved significantly (p < 0.001) as did axonal degenerative changes (p < 0.01). C-peptide treatment in the IG resulted in a significant increase in the frequency of regenerating fibers (p < 0.001) compared with untreated 5 mo diabetic rats. Conclusion: These studies demonstrate that C-peptide replacement in type 1 diabetes prevents the chronic NCD and structural changes. Furthermore, C-peptide treatment significantly improves the already established functional and structural abnormalities of DN. This is the first demonstration of a therapeutic improvement of established neuropathy in experimental diabetes. We conclude that C-peptide deficiency in type 1 diabetes is an important pathogenetic component of DN and that its replacement may provide a valuable adjunct to intensive insulin treatment. [source]

Electrophysiological studies in a mouse model of Schwartz,Jampel syndrome demonstrate muscle fiber hyperactivity of peripheral nerve origin

MUSCLE AND NERVE, Issue 1 2009
Andoni Echaniz-Laguna MD
Abstract Schwartz,Jampel syndrome (SJS) is an autosomal-recessive condition characterized by muscle stiffness and chondrodysplasia. It is due to loss-of-function hypomorphic mutations in the HSPG2 gene that encodes for perlecan, a proteoglycan secreted into the basement membrane. The origin of muscle stiffness in SJS is debated. To resolve this issue, we performed an electrophysiological investigation of an SJS mouse model with a missense mutation in the HSPG2 gene. Compound muscle action potential amplitudes, distal motor latencies, repetitive nerve stimulation tests, and sensory nerve conduction velocities of SJS mice were normal. On electromyography (EMG), neuromyotonic discharges, that is, bursts of motor unit action potentials firing at high rates (120,300 HZ), were constantly observed in SJS mice in all muscles, except in the diaphragm. Neuromyotonic discharges were not influenced by general anesthesia and disappeared with curare administration. They persisted after complete motor nerve section, terminating only with Wallerian degeneration. These results demonstrate that perlecan deficiency in SJS provokes a neuromyotonic syndrome. The findings further suggest a distal axonal localization of the generator of neuromyotonic discharges. SJS should now be considered as an inherited disorder with peripheral nerve hyperexcitability. Muscle Nerve, 2009 [source]

Assessing optic nerve pathology with diffusion MRI: from mouse to human

Junqian Xu
Abstract The optic nerve is often affected in patients with glaucoma and multiple sclerosis. Conventional MRI can detect nerve damage, but it does not accurately assess the underlying pathologies. Mean diffusivity and diffusion anisotropy indices derived from diffusion tensor imaging have been shown to be sensitive to a variety of central nervous system white matter pathologies. Despite being sensitive, the lack of specificity limits the ability of these measures to differentiate the underlying pathology. Directional (axial and radial) diffusivities, measuring water diffusion parallel and perpendicular to the axonal tracts, have been shown to be specific to axonal and myelin damage in mouse models of optic nerve injury, including retinal ischemia and experimental autoimmune encephalomyelitis. The progression of Wallerian degeneration has also been detected using directional diffusivities after retinal ischemia. However, translating these findings to human optic nerve is technically challenging. The current status of diffusion MRI of human optic nerve, including imaging sequences and protocols, is summarized herein. Despite the lack of a consensus among different groups on the optimal sequence or protocol, increased mean diffusivity and decreased diffusion anisotropy have been observed in injured optic nerve from patients with chronic optic neuritis. From different mouse models of optic nerve injuries to the emerging studies on patients with optic neuritis, directional diffusivities show great potential to be specific biomarkers for axonal and myelin injury. Copyright © 2008 John Wiley & Sons, Ltd. [source]

Multimodal microglia imaging of fiber tracts in acute subcortical stroke,

Basia A. Radlinska BSc
Objective Case series with 11C-PK11195 and positron emission tomography (PET) in stroke patients suggest that activated microglia may be detected in remote brain regions with fiber tract connections to the lesion site as an indicator of poststroke neuroinflammation. However, the specificity of these imaging findings remains to be demonstrated. Methods In a prospective controlled study, we measured microglia activity using 11C-PK11195-PET along the pyramidal tract, as defined by diffusion tensor imaging, in 21 patients with first-time acute subcortical ischemia within 2 weeks of stroke. Uptake ratios (affected vs unaffected side) were determined for a set of standardized volumes of interest along the pyramidal tracts (PT). Uptake ratios from patients in whom the PT was affected were compared with those in whom the PT was not affected. Uptake ratios were related to motor deficit and lesion size according to correlation analyses. Results Increased uptake ratios were only found in patients in whom the PT was affected by stroke. In the affected hemisphere, uptake was increased at the level of pons, midbrain, and internal capsule, but not in the oval center. The extent of remote microglia activation was independent of infarct size or clinical measures of stroke severity. Interpretation A specific activation of microglia was only found in patients in whom the PT was affected by the stroke and only caudal (anterograde) to the lesion; no activation was found in the retrograde direction or in those patients in whom the PT was not affected. These findings were independent of infarct size and may represent changes secondary to early Wallerian degeneration. Ann Neurol 2009;66:825,832 [source]

Clinical and pathological findings associated with congenital hypovitaminosis A in extensively grazed beef cattle

BD Hill
Objective To determine the cause of exceptionally high mortality (41.4%) in perinatal calves on a beef cattle property 50 km south-west of Julia Creek in north-western Queensland. Design Investigations were based on clinical assessment of affected calves and laboratory analysis of pre- and postmortem specimens taken from 12 calves aged from 6 to 36 h of age. Methods Associations between gross and histopathological findings and biochemical analyses conducted on serum and tissue samples were examined in relation to clinical observations. Results Clinical signs varied, but commonly included mild to severe ataxia, difficulty finding a teat and sucking, blindness (partial or complete, as judged by avoidance of obstacles) and depression with prominent drooping of the head. Gross and histopathological findings included herniation of the cerebellar vermis through the foramen magnum, squamous metaplasia of interlobular ducts in the parotid salivary glands and Wallerian degeneration of the optic nerves. Biochemical analysis of serum and liver samples available from four of the calves revealed low or undetectable levels of both vitamin A and vitamin E. Conclusion Although vitamin E is known to have a sparing effect on vitamin A, the role (if any) played by deficiency of this vitamin was uncertain. The combination of clinical signs, postmortem findings, histopathological features and biochemical findings indicate that gestational vitamin A deficiency was highly likely to have been an important contributor to perinatal calf mortalities in this herd. [source]

Wallerian Degeneration: A Major Component of Early Axonal Pathology in Multiple Sclerosis

Tomasz Dziedzic
Abstract Axonal loss is a major component of the pathology of multiple sclerosis (MS) and the morphological basis of permanent clinical disability. It occurs in demyelinating plaques but also in the so-called normal-appearing white matter (NAWM). However, the contribution of Wallerian degeneration to axonal pathology is not known. Here, we analyzed the extent of Wallerian degeneration and axonal pathology in periplaque white matter (PPWM) and lesions in early multiple sclerosis biopsy tissue from 63 MS patients. Wallerian degeneration was visualized using an antibody against the neuropeptide Y receptor Y1 (NPY-Y1R). The number of SMI-32-positive axons with non-phosphorylated neurofilaments was significantly higher in both PPWM and plaques compared to control white matter. APP-positive, acutely damaged axons were found in significantly higher numbers in plaques compared to PPWM. Strikingly, the number of NPY-Y1R-positive axons undergoing Wallerian degeneration was significantly higher in PPWM and plaques than in control WM. NPY-Y1R-positive axons in PPWM were strongly correlated to those in the lesions. Our results show that Wallerian degeneration is a major component of axonal pathology in the periplaque white matter in early MS. It may contribute to radiological changes observed in early MS and most likely plays a major role in the development of disability. [source]

An autopsy case of Fabry disease with neuropathological investigation of the pathogenesis of associated dementia

Riki Okeda
The pathogenesis of dementia associated with Fabry disease was examined neuropathologically in an autopsy case. The patient was a 47-year-old computer programmer who developed renal failure at the age of 36, necessitating peritoneal dialysis, and thereafter suffered in succession episodic pulmonary congestion, bradyacusia, heart failure, and dementia, before dying of acute myocardial infarction. MRI of the brain demonstrated leuko-araiosis. The CNS parenchyma showed widespread segmental hydropic swelling of axons in the bilateral cerebral and cerebellar deep white matter in addition to neuronal ballooning due to glycolipid storage in a few restricted nuclei and multiple tiny lacunae. Hydropic axonal swelling was also sparsely distributed in the pyramidal tract, pedunculus cerebellaris superior and brachium colliculi inferioris, but wallerian degeneration of these tracts was absent. Additional features included angiopathy of the subarachnoidal arteries due to Fabry disease, such as medial thickening resulting from glycolipid deposition in smooth muscle cells (SMCs) and adventitial fibrosis with lymphocytic infiltration, together with widespread subtotal or total replacement of medial SMCs by fibrosis, associated with prominent intimal fibrous thickening and undulation of the internal elastic membrane of medium-sized (1000,100 ,m diameter) arteries. The findings in this case suggest that axonopathic leukoencephalopathy due to multisegmental hydropic swelling of axons in the bilateral cerebral deep white matter is responsible for the dementia associated with Fabry disease, and may be caused by ischemia resulting from widespread narrowing and stiffening of medium-sized subarachnoidal arteries and progressive heart failure. [source]