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Carsten Wessig

Publications and source records attributed to Carsten Wessig.

At least 19 recordsLinked to original sources
PubMed2006

In vivo visualization of focal demyelination in peripheral nerves by gadofluorine M-enhanced magnetic resonance imaging.

Magnetic resonance imaging (MRI) allows assessment of axonal nerve lesions, but detection of focal demyelination is still difficult. We have recently shown that the novel micellar magnetic resonance (MR) contrast agent gadofluorine M (Gf) accumulates in nerve fibers undergoing Wallerian degeneration. In the present study, we report on the in vivo visualization of focal demyelination induced by lysolecithin. Upon appropriate intraneural injection, lysolecithin focally dissolves myelin sheaths with sparing of axons. Conventional unenhanced and gadolinium-DTPA enhanced T1-w MRI did not show signal alterations or contrast enhancement. In contrast, application of Gf led to bright contrast enhancement on T1-w images at the site of focal demyelination, but spared distal nerve segments not affected by demyelination. Gf enhancement persisted until remyelination had occurred. Our study shows that areas of focal nerve demyelination can be detected in vivo by Gf-enhanced MRI. This finding opens up a broad spectrum of applications in experimental neurology, and, depending on further clinical development of Gf, may aid in the diagnostic work up of patients with patchy, multifocal demyelinative disorders in the future.

Animals↗
PubMed2006

Expression pattern and functional characterization of connexin29 in transgenic mice.

Using newly generated transgenic mice in which the coding region of the connexin29 (Cx29) gene was replaced by the lacZ reporter gene, we confirmed previous immunochemical results that Cx29 is expressed in Schwann cells, oligodendrocytes and Bergmann glia cells. In addition, we detected lacZ/Cx29 in Schwann cells of the sciatic nerve and in particular of the spiral ganglion in the inner ear, as well as at low abundance in the stria vascularis. Furthermore, we found lacZ/Cx29 expression in nonmyelinating Schwann cells of the adrenal gland, in chondrocytes of intervertebral discs and the epiphysis of developing bones. Electron microscopic analyses of myelin sheaths in the central and peripheral nervous system of Cx29-deficient mice detected no abnormalities. The nerve conduction in the sciatic nerve of adult Cx29-deficient mice and the auditory brain stem response as well as visually evoked potentials in 4- to 10-week-old Cx29-deficient mice were not different from wild-type littermate controls. Thus, in contrast to connexin32 and connexin47, which are also expressed in myelinating cells, Cx29 does not contribute to the function of myelin in adult mice.

Adrenal Medulla↗
PubMed2006

Attenuated demyelination in the absence of the macrophage-restricted adhesion molecule sialoadhesin (Siglec-1) in mice heterozygously deficient in P0.

Mouse mutants heterozygously deficient for the myelin component P0 mimic some forms of inherited neuropathies in humans. We have previously shown that both T lymphocytes and macrophages contribute to the demyelinating neuropathy. Both cell types appear to influence each other mutually, i.e., impaired T lymphocyte development in RAG-1-deficient P0 mutants leads to decreased macrophage numbers and retarded macrophage activation causes reduced T lymphocyte numbers in the peripheral nerves of P0(+/-) mice. In the present study, we investigated the possible role of the macrophage-restricted sialic acid-binding Ig-like lectin sialoadhesin (Sn, Siglec-1) in the pathogenesis of inherited demyelination in P0(+/-) mice. We found that most peripheral nerve macrophages express Sn in the mutants. Myelin mutants devoid of Sn show reduced numbers of CD8+ T lymphocytes and macrophages in peripheral nerves and less severe demyelination, resulting in improved nerve conduction properties. Our findings are potentially important in the development of future treatment strategies for inherited demyelinating neuropathies.

Animals↗
PubMed2006

Denervation hypertrophy may mimic local tumor spread on magnetic resonance imaging.

We report a patient with an extensive paranasal sinus carcinoma. One year after tumor resection, magnetic resonance imaging (MRI) showed swelling of the ipsilateral masticatory muscles with signal increase on T2-weighted images and gadolinium-DTPA uptake, suggestive of local tumor infiltration. However, electromyography, biopsy, and follow-up MRI confirmed denervation pseudohypertrophy of the muscles innervated by the mandibular nerve and excluded tumor recurrence. Muscle denervation and pseudohypertrophy should be considered in the differential diagnosis of appropriate patients with suspected tumor recurrence.

Adult↗
PubMed2005

An animal model for Charcot-Marie-Tooth disease type 4B1.

Charcot-Marie-Tooth disease (CMT) comprises a family of clinically and genetically very heterogeneous hereditary peripheral neuropathies and is one of the most common inherited neurological disorders. We have generated a mouse model for CMT type 4B1 using embryonic stem cell technology. To this end, we introduced a stop codon into the Mtmr2 locus within exon 9, at the position encoding amino acid 276 of the MTMR2 protein (E276X). Concomitantly, we have deleted the chromosomal region immediately downstream of the stop codon up to within exon 13. The resulting allele closely mimics the mutation found in a Saudi Arabian CMT4B1 patient. Animals homozygous for the mutation showed various degrees of complex myelin infoldings and outfoldings exclusively in peripheral nerves, in agreement with CMT4B1 genetics and pathology. Mainly, paranodal regions of the myelin sheath were affected, with a high degree of quantitative and qualitative variability between individuals. This pathology was progressive with age, and axonal damage was occasionally observed. Distal nerve regions were more affected than proximal parts, in line with the distribution in CMT. However, we found no significant electrophysiological changes, even in aged (16-month-old) mice, suggesting that myelin infoldings and outfoldings per se are not invariably associated with detectable electrophysiological abnormalities. Our animal model provides a basis for future detailed molecular and cellular studies on the underlying disease mechanisms in CMT4B1. Such an analysis will reveal how the disease develops, in particular, the enigmatic myelin infoldings and outfoldings as well as axonal damage, and provide mechanistic insights that may aid in the development of potential therapeutic approaches.

Alleles↗
PubMed2005

Assessment of lesion evolution in experimental autoimmune neuritis by gadofluorine M-enhanced MR neurography.

Experimental autoimmune neuritis (EAN) represents an animal model of acute inflammatory nerve injury mirroring pathophysiological aspects of the human Guillain-Barré syndrome. In the present study, we for the first time visualized the spatiotemporal evolution of autoimmune nerve injury and recovery by magnetic resonance imaging (MRI) by use of the novel micellar magnetic resonance (MR) contrast agent gadofluorine M (Gf). EAN was induced in Lewis rats by T-cell transfer (AT-EAN) leading to severe axonal damage, and Gf was applied intravenously at various disease stages mostly 24 h before MRI. In naive rats, Gf enhancement was present solely in the vascular compartment. In AT-EAN, clinically asymptomatic rats already showed consistent Gf uptake in spinal nerves on day 3, while sciatic nerves were spared. The cauda equina correspondingly exhibited massive T-cell infiltration. Gf enhancement further extended to the plexus lumbosacralis on day 4. On days 5 and 6, the entire peripheral neuraxis from the cauda equina, along the sciatic down to the tibial and peroneal nerves, showed strong Gf enhancement. Spinal and peripheral nerves now exhibited massive inflammation and axonal injury on parallel histological analysis. Gf enhancement persisted in the afflicted nerves until complete recovery and disappeared with a proximodistal gradient. In conclusion, Gf-enhanced MR neurography opens a new avenue for monitoring nerve damage in-vivo during an immune attack.

Animals↗
PubMed2005

Evidence for macrophage-mediated myelin disruption in an animal model for Charcot-Marie-Tooth neuropathy type 1A.

Charcot-Marie-Tooth neuropathy type 1A (CMT 1 A) is the most common inherited neuropathy in humans and is mostly caused by a 1.5-Mb tandem duplication of chromosome 17 comprising the gene for the peripheral myelin protein 22-kDa (PMP 22). Although there are numerous studies on the functional role of PMP 22, the mechanisms of myelin degeneration under PMP 22-overexpression conditions have not yet been fully understood. We have shown previously that in mouse mutants hetero- or homozygously deficient for two other myelin components, P0 and C x 32, respectively, immune cells contribute to the demyelinating neuropathy. To test this possibility for PMP 22 overexpression, we investigated a putative mouse model for CMT 1 A, i.e., the mouse strain C 6 1 mildly overexpressing human PMP 22 in peripheral nerves. Electron microscopic and electrophysiologic investigations revealed that this mouse strain develops pathologic features similar to those found in CMT 1 A patients. A novel finding, however, was the upregulation of CD8- and F4/80-positive lymphocytes and macrophages, respectively, in peripheral nerves. The observation that macrophages enter endoneurial tubes of the mutants and obviously phagocytose morphologically normal myelin strongly suggests that the myelin degeneration is mediated at least partially by these phagocytic cells. By gene array technology and quantitative RT-PCR of peripheral nerve homogenates from PMP 22 mutants, monocyte chemoattractant protein-1 (MCP-1; cc l2) could be identified as a putative factor to attract or activate macrophages that attack myelin sheaths in this model of CMT 1 A.

Aging↗
PubMed2005

Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy.

A deficiency of arylsulfatase A (ASA) causes the lysosomal storage disease metachromatic leukodystrophy, which is characterized by accumulation of the sphingolipid 3-O-sulfogalactosylceramide (sulfatide). Sphingolipid storage results in progressive demyelination and severe neurologic symptoms. The disease is lethal, and curative therapy is not available. To assess the therapeutic potential of enzyme replacement therapy (ERT), ASA knockout mice were treated by intravenous injection of recombinant human ASA. Plasma levels of ASA declined with a half-time of approximately 40 min, and enzyme was detectable in tissues within minutes after injection. The uptake of injected enzyme was high into liver, moderate into peripheral nervous system (PNS) and kidney and very low into brain. The apparent half-life of endocytosed enzyme was approximately 4 days. A single injection led to a time- and dose-dependent decline of the excess sulfatide in PNS and kidney by up to 70%, but no reduction was seen in brain. Four weekly injections with 20 mg/kg body weight not only reduced storage in peripheral tissues progressively, but also were surprisingly effective in reducing sulfatide storage in brain and spinal cord. The histopathology of kidney and central nervous system was ameliorated. Improved neuromotor coordination capabilities and normalized peripheral compound motor action potential demonstrate the benefits of ERT on the nervous system function. Enzyme replacement may therefore be a promising therapeutic option in this devastating disease.

Animals↗
PubMed2005

Assessment of nerve degeneration by gadofluorine M-enhanced magnetic resonance imaging.

Nerve injury represents a major cause of disability. In the peripheral nervous system, nerves have the capacity to regrow but within weeks after injury, it is impossible to clarify whether proper regeneration is under way or is failing. In this experimental study, we report on a novel tool to assess nerve outgrowth in vivo. After systemic application, the novel gadolinium-based magnetic resonance (MR) contrast agent Gadofluorine M (Gf) selectively accumulated and persisted in nerve fibers undergoing Wallerian degeneration causing bright contrast on T1-weighted MR images. Gf enhancement on MR imaging was present already at 48 hours within the entire nerve segments undergoing Wallerian degeneration, and subsequently disappeared from proximal to distal parts in parallel to regrowth of nerve fibers. Most importantly, Gf enhancement persisted in nonregenerating, permanently transected nerves. Our novel Gf-based MR imaging methodology holds promise for clinical use to bridge the diagnostic gap between nerve injury and completed nerve regeneration, and to determine the necessity for neurolysis and engraftment if spontaneous regeneration is not successful.

Animals↗
PubMed2004

Characterization of Ighmbp2 in motor neurons and implications for the pathomechanism in a mouse model of human spinal muscular atrophy with respiratory distress type 1 (SMARD1).

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is caused by recessive mutations of the IGHMBP2 gene. The role of IGHMBP2 (immunoglobulin mu-binding protein 2) in the pathomechanism of motor neuron disease is unknown. We have generated antibodies against Ighmbp2 and showed that low levels of Ighmbp2 immunoreactivity are present in the nucleus of spinal motor neurons and high levels in cell bodies, axons and growth cones. Ighmbp2 protein levels are strongly reduced in neuromuscular degeneration (nmd) mice, the mouse model of SMARD1. Mutant mice show severe motor neuron degeneration before first clinical symptoms become apparent. The loss of motor neuron cell bodies in lumbar spinal cord is followed by axonal degeneration in corresponding nerves such as the femoral quadriceps and sciatic nerve and loss of axon terminals at motor endplates. Motor neuron degeneration and clinical symptoms then slowly progress until the mice die at the age of 3-4 months. In addition, myopathic changes seem to contribute to muscle weakness and especially to respiratory failure, which is characteristic of the disorder in humans. Cultured motor neurons from embryonic nmd mice did not show any abnormality with respect to survival, axonal growth or growth cone size, thus differing from motor neurons derived from, e.g. Smn (survival motor neuron) deficient mice, the model of spinal muscular atrophy (SMA). Our data suggest that the pathomechanism in SMARD1 is clearly distinct from other motor neuron diseases such as classic SMA.

Action Potentials↗
PubMed2004

Pathology of a mouse mutation in peripheral myelin protein P0 is characteristic of a severe and early onset form of human Charcot-Marie-Tooth type 1B disorder.

Mutations in the gene of the peripheral myelin protein zero (P0) give rise to the peripheral neuropathies Charcot-Marie-Tooth type 1B disease (CMT1B), Déjérine-Sottas syndrome, and congenital hypomyelinating neuropathy. To investigate the pathomechanisms of a specific point mutation in the P0 gene, we generated two independent transgenic mouse lines expressing the pathogenic CMT1B missense mutation Ile106Leu (P0sub) under the control of the P0 promoter on a wild-type background. Both P0sub-transgenic mouse lines showed shivering and ultrastructural abnormalities including retarded myelination, onion bulb formation, and dysmyelination seen as aberrantly folded myelin sheaths and tomacula in all nerve fibers. Functionally, the mutation leads to dispersed compound muscle action potentials and severely reduced conduction velocities. Our observations support the view that the Ile106Leu mutation acts by a dominant-negative gain of function and that the P0sub-transgenic mouse represents an animal model for a severe, tomaculous form of CMT1B.

Action Potentials↗
PubMed2004

Muscle magnetic resonance imaging of denervation and reinnervation: correlation with electrophysiology and histology.

A signal increase in denervated muscle on magnetic resonance imaging (MRI) has been described in several clinical and experimental studies. Here, we studied the time course of T2-relaxation time changes in denervation and subsequent reinnervation in a rat model and correlated the findings with electrophysiology and quantitative histology. A prolongation of the T2 relaxation time in muscles was present 48 h after denervation, which was paralleled by spontaneous activity on electromyography (EMG). Histologically, there was a marked enlargement of the capillaries at that time point, indicating increased blood volume. The relaxation time changes peaked 3 weeks after beginning of nerve regeneration identified by EMG. Subsequently, the T2 prolongation normalized until 10 weeks after beginning of regeneration which was associated with a histological regression of the capillary enlargement. MRI closely mirrors the electrophysiological changes following denervation and reinnervation and may thus be used as adjunct to electrophysiology. The pathophysiological basis for the MR relaxation time changes is predominantly the enlargement of the capillary bed.

Animals↗
PubMed2004

MRI of peripheral nerve degeneration and regeneration: correlation with electrophysiology and histology.

Acute axonal nerve lesions cause a hyperintense signal on T2-weighted (T2-w) magnetic resonance imaging (MRI) at the nerve lesion site and distal to it. The aim of this experimental study was to investigate the spatiotemporal evolution and resolution of MR nerve signal changes following denervation and reinnervation, and to relate these findings to electrophysiology and histology. The proximal sciatic nerve of adult rats was ligated by a tight suture that was removed 1 week later to induce complete axotomy and nerve regeneration upon release. Serial electromyography (EMG) and motor nerve conduction studies were performed parallel to MRI at multiple points of time. Moreover, sciatic nerves were taken for quantitative histological evaluation. Nerve hyperintensity on T2-w MRI was present distal to the lesion at thigh level 24 h after denervation preceding the occurrence of spontaneous activity on EMG by 24 h. After 48 h, the entire sciatic nerve and its branches showed an increased signal down to the level of the lower leg. The increased nerve signal regressed with a proximo-distal gradient beginning from week 2 after onset of nerve regeneration in the thigh. On EMG, the first reinnervation potentials were detected at that time at the respective level. Compound muscle action potential (CMAP) in the foot muscle fully recovered 12 weeks after onset of nerve regeneration, that is, 2 weeks after resolution of the hyperintensity along the entire nerve on MRI. Histology revealed axonal degeneration in the acute phase and later nerve oedema parallel to the increased nerve signal on MRI. MR signal alterations occur as early as 24 h after an axonal nerve lesion and correlate with nerve fiber degeneration and later with nerve oedema on histology. MR findings in denervation and reinnervation parallel the electrophysiological changes. Thus, MRI is a promising diagnostic tool for the early detection of acute axonal nerve lesions and monitoring of nerve regeneration.

Animals↗
PubMed2003

The Wlds mutation delays robust loss of motor and sensory axons in a genetic model for myelin-related axonopathy.

Mice deficient in the peripheral myelin component P0 mimic severe forms of inherited peripheral neuropathies in humans, with defective myelin formation and consequent axonal loss. We cross-bred these mice with the spontaneous mutant C57BL/Wld(s) typically showing protection from Wallerian degeneration because of fusion of the ubiquitination factor E4B (Ube4b) and nicotinamide mononucleotide adenylyltransferase (Nmnat) genes. We found that in the double mutants, the robust myelin-related axonal loss is reduced at 6 weeks and 3 months of age. Moreover, retrograde labeling from plantar nerves revealed an increased survival of motor axons. These motor axons appeared functionally active because both the amplitude of compound muscle action potentials and muscle strength were less reduced in the double mutants. At 6 months of age, reduction of axonal loss was no longer detectable in the double mutants when compared with littermates carrying the P0 null mutation only, although the Wld(s) gene was not reduced in its expression at this age. We conclude that myelin-related axonal loss is a process having some features in common with Wallerian degeneration. Introducing the Wld(s) gene would be a promising approach to delaying detrimental axonal loss in myelin disorders.

Action Potentials↗
PubMed2003

MR imaging in the differential diagnosis of neurogenic foot drop.

BACKGROUND AND PURPOSE: Prolonged T2 relaxation time of denervated muscle has been described in several clinical and experimental studies. The purpose of this study was to evaluate the utility of MR imaging in the diagnosis of neurogenic muscle disorders compared with that of clinical and electrophysiologic examination. METHODS: In a prospective study, 40 consecutive patients clinically presenting with a foot drop were included. MR imaging of the lower leg included axial T1-weighted and axial turbo inversion recovery magnitude (TIRM) sequences. Two readers blinded to clinical data evaluated T1-weighted images for anatomic localization of affected muscles and TIRM images for patterns of signal intensity increase. After MR imaging, a detailed neurophysiologic examination was performed. Cause of foot drop was independently determined on the basis of MR and electrophysiologic data. RESULTS: Clinical examination and electromyography (EMG) disclosed 20 peroneal nerve lesions, nine cases of L5 radiculopathy, and 11 nerve lesions extending beyond neural structures. MR imaging revealed three distinct patterns of signal intensity increase on TIRM images: peroneal nerve pattern, L5 pattern, and unspecific pattern. MR imaging and EMG findings were in agreement in 37 (92%) of 40 patients. In three patients, MR imaging revealed a more widespread involvement than did EMG. In one of these patients, denervation in the corresponding muscle was validated by follow-up EMG. No false-negative diagnoses were made by use of MR imaging as compared with use of EMG. CONCLUSION: MR imaging improves accuracy in the differential diagnosis of peripheral nerve lesions compared with that of EMG and can supplement EMG in the diagnosis of denervated muscles.

Action Potentials↗
PubMed2002

Sequential MR imaging of denervated muscle: experimental study.

BACKGROUND AND PURPOSE: MR changes in denervated muscles have been reported to occur within days up to several weeks after peripheral nerve damage. The purpose of this experimental study was to investigate the longitudinal changes in denervated muscles by using MR imaging. METHODS: In 12 Lewis rats, the left sciatic nerve was transected at the level of the proximal thigh. MR imaging of both legs was performed before and 1 hour, 24 hours, 48 hours, 7 days, 14 days, 28 days, and 2 months after the procedure. The MR protocol included T1-weighted spin-echo, T2-weighted double turbo spin-echo, and turbo inversion recovery magnitude (TIRM) sequences obtained in the axial plane. Signal intensities (T2-weighted double turbo spin-echo and TIRM sequences) and the T2 TR (T2-weighted double turbo spin-echo sequence) were recorded for the soleus, peroneal, and gracilis muscles of both sides. Moreover, the circumferences of both lower legs were determined on the basis of T1-weighted images. RESULTS: Twenty-four hours after denervation, a signal intensity increase in the denervated peroneal and soleus muscles was present on TIRM images. On T2-weighted images, only the peroneal muscle exhibited slightly increased signal intensities and T2 TR. Forty-eight hours after nerve transection, the denervated soleus and peroneal muscles revealed prolonged T2 TR and marked increased signal intensities on T2-weighted and TIRM images when compared with the contralateral side, which further increased at or less than 2 months after denervation. Muscle atrophy of the denervated muscles was present as early as 7 days after denervation and was also increased at follow-up examinations. CONCLUSION: The TIRM sequence is more sensitive than is T2-weighted imaging in the detection of signal intensity changes in denervated muscle. These changes occur as early as 24 (TIRM sequence) and 48 (T2-weighted sequence) hours, respectively, after complete transection of the sciatic nerve in rats and precede muscle atrophy. The sensitivity to early signal intensity changes in denervated muscles may support the use of MR imaging in the diagnosis of peripheral nerve lesions.

Animals↗