Carsten Wessig
Research interests
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InterestsNeurological Diseases, Neuromuscular Diseases, Neurophysiology
Publications
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7.39Impact points
Efficacy of enzyme replacement therapy in an aggravated mouse model of metachromatic leukodystrophy declines with age.
Human molecular genetics. 03/2012;
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a functional deficiency of arylsulfatase A (ASA). Previous studies in ASA-knockout mice suggested enzyme replacement therapy (ERT) to be a promising treatment option. The mild phenotype of ASA-knockout mice did, however, not... [more] Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a functional deficiency of arylsulfatase A (ASA). Previous studies in ASA-knockout mice suggested enzyme replacement therapy (ERT) to be a promising treatment option. The mild phenotype of ASA-knockout mice did, however, not allow to examine therapeutic responses of the severe neurological symptoms that dominate MLD. We, therefore, generated an aggravated MLD mouse model displaying progressive demyelination and reduced nerve conduction velocity (NCV) and treated it by weekly intravenous injections of 20 mg/kg recombinant human ASA for 16 weeks. To analyze the stage-dependent therapeutic effects, ERT was initiated in a presymptomatic, early and progressed disease stage, at age 4, 8 and 12 months, respectively. Brain sulfatide storage, NCV and behavioral alterations were improved only in early, but not in late, treated mice showing a clear age-dependent efficacy of treatment. Hematopoietic stem cell transplantation (HSCT) for late-onset variants is the only therapeutic option for MLD to date. ERT resembles a part of the HSCT rationale, which is based on ASA supply by donor cells. Beyond ERT, our results, therefore, corroborate the clinical observation that HSCT is only effective when performed in early stages of disease.
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3.91Impact points
In vivo imaging of inflammation in the peripheral nervous system by (19)F MRI.
Experimental neurology. 03/2011; 229(2):494-501.
Visualization of neuroinflammation is still a major task in neuroscience and neurology since inflammatory processes play a central pathophysiological role in many disorders of the nervous system but are not yet covered by conventional imaging techniques. Recently, (19)F magnetic resonance imaging (M... [more] Visualization of neuroinflammation is still a major task in neuroscience and neurology since inflammatory processes play a central pathophysiological role in many disorders of the nervous system but are not yet covered by conventional imaging techniques. Recently, (19)F magnetic resonance imaging (MRI) was introduced as a new cellular imaging technology. In the present study, we established (19)F high field MRI for cell tracking in the peripheral nervous system (PNS) of rats using dedicated MR coils. To mimic focal neuroinflammation, lysolecithin was locally injected into the left sciatic nerve inducing demyelination followed by severe infiltration of monocytes/macrophages from the circulation. Systemic administration of perfluorocarbons (PFC) led to a fluorine signal along the proximal stretch of the affected sciatic nerves in in vivo(19)F MRI which was not seen on the right healthy side. The preferential in vivo uptake of PFC by circulating mononuclear cells was confirmed by density gradient centrifugation of the blood. Removal of nerves with consecutive ex vivo(19)F MRI and additional (19)F spectroscopy for quantification corroborated the localization of the (19)F marker within the injured nerves (1.07×10(18)±1.00×10(18) mean detectable fluorine spins) while contralateral naive nerves did not exhibit any detectable fluorine signal. Histological assessment confirmed the presence of numerous ED1-positive macrophages within the nerve lesions. Control experiments showed that intraneural application of saline led to an inflammatory reaction restricted to the perineurium which could also be detected by (19)F MRI. In conclusion, we show that (19)F MRI is a promising new technology to visualize hematogenous macrophage responses in the nervous system.
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Detection of blood-nerve barrier permeability by magnetic resonance imaging.
Methods in molecular biology (Clifton, N.J.). 01/2011; 686:267-71.
The blood-nerve barrier (BNB) separates the endoneurium from the endovascular space and the epineurial connective tissue. An intact BNB is very important for integrity and functions of the nerve fibers within the endoneurial space. Disruption of the BNB which leads to functional and structural impai... [more] The blood-nerve barrier (BNB) separates the endoneurium from the endovascular space and the epineurial connective tissue. An intact BNB is very important for integrity and functions of the nerve fibers within the endoneurial space. Disruption of the BNB which leads to functional and structural impairment of the peripheral nerve plays an important role in many disorders of the peripheral nerve like Wallerian degeneration, inflammatory nerve disorders, and demyelination. So far, this increased BNB permeability can only be assessed ex vivo. Assessing BNB disruption in vivo would be of great value for studying disorders of the peripheral nervous system. Gadofluorine M (Gf), a new amphiphilic contrast agent for MRI, accumulates in rat nerves with increased permeability of the BNB. After application of Gf, T1-weighted MR images show contrast enhancement of nerves with a disrupted BNB. This new tool of assessing BNB permeability in vivo is described.
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2.90Impact points
MR neurography of sciatic nerve injection injury.
Journal of neurology. 01/2011; 258(6):1120-5.
We report on magnetic resonance neurography (MRN) as a supplementary diagnostic tool in sciatic nerve injection injury. The object of the study was to test if T2-weighted (w) contrast within the sciatic nerve serves as an objective criterion for sciatic injection injury. Three patients presented wit... [more] We report on magnetic resonance neurography (MRN) as a supplementary diagnostic tool in sciatic nerve injection injury. The object of the study was to test if T2-weighted (w) contrast within the sciatic nerve serves as an objective criterion for sciatic injection injury. Three patients presented with acute sensory and/or motor complaints in the distribution of the sciatic nerve after dorsogluteal injection and underwent MRN covering gluteal, thigh and knee levels. Native and contrast-enhanced T1-w images were employed to identify the tibial and peroneal division of the sciatic nerve while T2-w images with fat suppression allowed visualization of the site and extent of the nerve lesion. MRN in the two patients with clinically severe sensory and motor impairment correctly depicted sciatic injury: continuity of the T2-w lesion within the nerve at the lesion site and distal to it corresponded well to severe injury confirmed by NCS/EMG as axonotmetic or neurotmetic. Topography of the T2-w lesion on cross-section corresponded to predominant peroneal involvement; moreover, associated denervation patterns of distal target muscles were revealed. One of these patients completely recovered with concomitant complete regression of MRN abnormalities on follow-up. The third patient experienced transient sensory and mild motor impairment with complete recovery after 2 weeks. In this patient, T2-w signal within the nerve and distal target muscles remained normal indicating only mild, non-axonal nerve affliction. Our case series shows that MRN can be very useful in precisely determining the site of sciatic injection injury and may provide diagnostic criteria for the assessment of lesion severity and recovery.
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0.78Impact points
[Amyotrophic lateral sclerosis: management of bulbar symptoms].
Der Nervenarzt. 10/2010; 81(10):1218-25.
Symptomatic treatment of amyotrophic lateral sclerosis (ALS) is relevant in preventing complications and improving quality of life as long as curative therapies are still out of sight. About one third of ALS patients show disabling problems associated with dysarthria, dysphagia, sialorrhea, and a ps... [more] Symptomatic treatment of amyotrophic lateral sclerosis (ALS) is relevant in preventing complications and improving quality of life as long as curative therapies are still out of sight. About one third of ALS patients show disabling problems associated with dysarthria, dysphagia, sialorrhea, and a pseudobulbar affective disorder already in the early stages of ALS. A multidisciplinary approach is the cornerstone of symptomatic treatment of bulbar and pseudobulbar ALS features. Except for riluzole randomized controlled trials are lacking. Here, we review the current views with regard to epidemiology, pathophysiology, diagnosis, and practical aspects of treating bulbar and pseudobulbar symptoms.
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7.39Impact points
Attenuation of MCP-1/CCL2 expression ameliorates neuropathy in a mouse model for Charcot-Marie-Tooth 1X.
Human molecular genetics. 09/2010; 19(18):3530-43.
The chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) has been previously shown to be an important mediator of macrophage-related neural damage in models of two distinct inherited neuropathies, Charcot-Marie-Tooth (CMT) 1A and 1B. In mice deficient in the gap junction protein connexin 32 (Cx... [more] The chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) has been previously shown to be an important mediator of macrophage-related neural damage in models of two distinct inherited neuropathies, Charcot-Marie-Tooth (CMT) 1A and 1B. In mice deficient in the gap junction protein connexin 32 (Cx32def), an established model for the X-chromosome-linked dominant form of CMT (CMT1X), we investigated the role of the chemokine in macrophage immigration and neural damage by crossbreeding the Cx32def mice with MCP-1 knockout mutants. In Cx32def mutants typically expressing increased levels of MCP-1, macrophage numbers were strongly elevated, caused by an MCP-1-mediated influx of haematogenous macrophages. Curiously, the complete genetic deletion of MCP-1 did not cause reduced macrophage numbers in the nerves due to compensatory proliferation of resident macrophages. In contrast, and as already seen in other CMT models, heterozygous deletion of MCP-1 led to reduced numbers of phagocytosing macrophages and an alleviation of demyelination. Whereas alleviated demyelination was transient, axonal damage was persistently improved and even robust axonal sprouting was detectable at 12 months. Other axon-related features were alleviated electrophysiological parameters, reduced muscle denervation and atrophy, and increased muscle strength. Similar to models for CMT1A and CMT1B, we identified MEK-ERK signalling as mediating MCP-1 expression in Cx32-deficient Schwann cells. Blocking this pathway by the inhibitor CI-1040 caused reduced MCP-1 expression, attenuation of macrophage increase and amelioration of myelin- and axon-related alterations. Thus, attenuation of MCP-1 upregulation by inhibiting ERK phosphorylation might be a promising approach to treat CMT1X and other so far untreatable inherited peripheral neuropathies in humans.
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9.49Impact points
Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition.
Brain : a journal of neurology. 09/2010; 133(11):3166-80.
Synaptic inhibition is a central factor in the fine tuning of neuronal activity in the central nervous system. Symptoms consistent with reduced inhibition such as stiffness, spasms and anxiety occur in paraneoplastic stiff person syndrome with autoantibodies against the intracellular synaptic protei... [more] Synaptic inhibition is a central factor in the fine tuning of neuronal activity in the central nervous system. Symptoms consistent with reduced inhibition such as stiffness, spasms and anxiety occur in paraneoplastic stiff person syndrome with autoantibodies against the intracellular synaptic protein amphiphysin. Here we show that intrathecal application of purified anti-amphiphysin immunoglobulin G antibodies induces stiff person syndrome-like symptoms in rats, including stiffness and muscle spasms. Using in vivo recordings of Hoffmann reflexes and dorsal root potentials, we identified reduced presynaptic GABAergic inhibition as an underlying mechanism. Anti-amphiphysin immunoglobulin G was internalized into neurons by an epitope-specific mechanism and colocalized in vivo with presynaptic vesicular proteins, as shown by stimulation emission depletion microscopy. Neurons from amphiphysin deficient mice that did not internalize the immunoglobulin provided additional evidence of the specificity in antibody uptake. GABAergic synapses appeared more vulnerable than glutamatergic synapses to defective endocytosis induced by anti-amphiphysin immunoglobulin G, as shown by increased clustering of the endocytic protein AP180 and by defective loading of FM 1-43, a styryl dye used to label cell membranes. Incubation of cultured neurons with anti-amphiphysin immunoglobulin G reduced basal and stimulated release of γ-aminobutyric acid substantially more than that of glutamate. By whole-cell patch-clamp analysis of GABAergic inhibitory transmission in hippocampus granule cells we showed a faster, activity-dependent decrease of the amplitude of evoked inhibitory postsynaptic currents in brain slices treated with antibodies against amphiphysin. We suggest that these findings may explain the pathophysiology of the core signs of stiff person syndrome at the molecular level and show that autoantibodies can alter the function of inhibitory synapses in vivo upon binding to an intraneuronal key protein by disturbing vesicular endocytosis.
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4.52Impact points
Lack of evidence for a pathogenic role of T-lymphocytes in an animal model for Charcot-Marie-Tooth disease 1A.
Neurobiology of disease. 04/2010; 38(1):78-84.
We have previously shown that in two distinct models for inherited neuropathies of the Charcot-Marie-Tooth (CMT) type, T-lymphocytes are critically involved in demyelination. In the present study, we tested whether T-lymphocytes have a similar pathogenetic impact in another CMT model, i.e., in mice ... [more] We have previously shown that in two distinct models for inherited neuropathies of the Charcot-Marie-Tooth (CMT) type, T-lymphocytes are critically involved in demyelination. In the present study, we tested whether T-lymphocytes have a similar pathogenetic impact in another CMT model, i.e., in mice overexpressing the peripheral myelin protein (PMP)-22, representing the most prevalent form CMT1A. By cross breeding the myelin mutant mice with mutants lacking mature T- and B-lymphocytes (RAG-1-deficient mice), the pathological alterations were not changed in comparison to PMP22 mutants with a normal immune system. Reciprocal enhancement of lymphocyte activation, by inactivation of the lymphocytic co-inhibitor programmed death-1, also did not alter pathological changes, as opposed to models with approved lymphocytic involvement. These findings strongly suggest that lymphocytes are not pathogenetically relevant in this model for CMT1A. We suggest that - in contrast to myelin phagocytosing macrophages - T-lymphocytes are not a promising target for treatment of CMT1A.
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5.49Impact points
MCP-1/CCL2 modifies axon properties in a PMP22-overexpressing mouse model for Charcot-Marie-tooth 1A neuropathy.
The American journal of pathology. 03/2010; 176(3):1390-9.
Charcot-Marie-Tooth 1A (CMT1A) neuropathy, the most common inherited peripheral neuropathy, is primarily caused by a gene duplication for the peripheral myelin protein-22 (PMP22). In an accordant mouse model, we investigated the role of monocyte chemoattractant protein-1 (MCP-1/CCL2) as a regulator ... [more] Charcot-Marie-Tooth 1A (CMT1A) neuropathy, the most common inherited peripheral neuropathy, is primarily caused by a gene duplication for the peripheral myelin protein-22 (PMP22). In an accordant mouse model, we investigated the role of monocyte chemoattractant protein-1 (MCP-1/CCL2) as a regulator of nerve macrophages and neural damage including axonopathy and demyelination. By generating PMP22tg mice with reduced levels or lack of MCP-1/CCL2, we found that MCP-1/CCL2 is involved in the increase of macrophages in mutant nerves. PMP22tg mice with wild-type levels of MCP-1/CCL2 showed strong macrophage increase in the diseased nerves, whereas either 50% reduction or total absence of MCP-1/CCL2 led to a moderate or a strong reduction of nerve macrophages, respectively. Interestingly, MCP-1/CCL2 expression level and macrophage numbers were correlated with features indicative of axon damage, such as maldistribution of K+ channels, reduced compound muscle action potentials, and muscle weakness. Demyelinating features, however, were most highly reduced when MCP-1/CCL2 was diminished by 50%, whereas complete lack of MCP-1/CCL2 showed an intermediate demyelinating phenotype. We also identified the MEK1/2-ERK1/2-pathway as being involved in MCP-1/CCL2 expression in the Schwann cells of the CMT1A model. Our data show that, in a CMT1A model, MCP-1/CCL2 activates nerve macrophages, mediates both axon damage and demyelination, and may thus be a promising target for therapeutic approaches.
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14.35Impact points
Axonal prion protein is required for peripheral myelin maintenance.
Nature neuroscience. 03/2010; 13(3):310-8.
The integrity of peripheral nerves relies on communication between axons and Schwann cells. The axonal signals that ensure myelin maintenance are distinct from those that direct myelination and are largely unknown. Here we show that ablation of the prion protein PrP(C) triggers a chronic demyelinati... [more] The integrity of peripheral nerves relies on communication between axons and Schwann cells. The axonal signals that ensure myelin maintenance are distinct from those that direct myelination and are largely unknown. Here we show that ablation of the prion protein PrP(C) triggers a chronic demyelinating polyneuropathy (CDP) in four independently targeted mouse strains. Ablation of the neighboring Prnd locus, or inbreeding to four distinct mouse strains, did not modulate the CDP. CDP was triggered by depletion of PrP(C) specifically in neurons, but not in Schwann cells, and was suppressed by PrP(C) expression restricted to neurons but not to Schwann cells. CDP was prevented by PrP(C) variants that undergo proteolytic amino-proximal cleavage, but not by variants that are nonpermissive for cleavage, including secreted PrP(C) lacking its glycolipid membrane anchor. These results indicate that neuronal expression and regulated proteolysis of PrP(C) are essential for myelin maintenance.
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3.97Impact points
Magnetic resonance neurography for the diagnosis of extrapelvic sciatic endometriosis.
Fertility and sterility. 02/2010; 94(1):351.e11-4.
To illustrate magnetic resonance neurography findings of severe sciatic injury and muscle denervation related to deep gluteal endometriosis at the sciatic notch. Case report. Academic teaching hospital. A 39-year-old woman with a 4-year history of sciatica related to the menstrual cycle. Surgical ex... [more] To illustrate magnetic resonance neurography findings of severe sciatic injury and muscle denervation related to deep gluteal endometriosis at the sciatic notch. Case report. Academic teaching hospital. A 39-year-old woman with a 4-year history of sciatica related to the menstrual cycle. Surgical exploration of the sciatic notch for diagnostic confirmation, external neurolysis of the sciatic nerve, and eventual pharmacologic treatment. Magnetic resonance neurography imaging revealed severe neuropathic injury and muscle denervation related to a deep infiltrative endometriotic focus at the sciatic notch, which was confirmed histologically on surgical exploration. Detailed electrodiagnostic and clinical neurologic examinations at initial presentation and during follow-up were obtained for further assessment of nerve degeneration, muscle denervation, and clinical recovery. Initial gynecologic and eventual laparoscopic evaluation on persisting complaints were without pathological findings. When a progressive weakness of the leg was noted, magnetic resonance neurography revealed a severe axonal damage to the sciatic nerve and denervation of distal target muscles related to a diffuse infiltrative lesion at the sciatic notch. On surgical exploration, extragenital endometriosis was confirmed histologically. Considerable improvement in pain and strength occurred after pharmacologic therapy with a GnRH analogue. This is the first report to describe imaging findings of magnetic resonance neurography in severe neuropathic injury of the sciatic nerve and subsequent muscle denervation related to a deep infiltrative gluteal endometriotic focus.
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5.94Impact points
C-terminal FUS/TLS mutations in familial and sporadic ALS in Germany.
Neurobiology of aging. 12/2009;
Amyotrophic lateral sclerosis (ALS), the major form of motor neuron disease in the adult occurs as a sporadic disease in more than 95% of all cases. Analysis of familial forms is considered as a key to understand the pathophysiology of the disease. It is expected that mutations responsible for famil... [more] Amyotrophic lateral sclerosis (ALS), the major form of motor neuron disease in the adult occurs as a sporadic disease in more than 95% of all cases. Analysis of familial forms is considered as a key to understand the pathophysiology of the disease. It is expected that mutations responsible for familial forms are also found in sporadic ALS. During the past years, several loci and genes have been identified in which disease associated mutations have been discovered. We report here on the screening of 596 sporadic ALS patients, 41 familial ALS cases and other motor neuron disease patients from Germany for mutations in the FUS/TLS gene. Sequencing of the last two exons in all patients revealed the C1561T transversion, which leads to the amino acid substitution at R521C, in one familial and one sporadic ALS patient. In addition three patients with a synonymous mutation at codon 522 were identified. None of these variants were present in the control population. Our results indicate that mutations in FUS/TLS are not a major cause of sporadic ALS in the German population.
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2.29Impact points
Distal-symmetric focal inflammatory myopathy distinct from focal myositis and polymyositis.
Muscle & nerve. 09/2009; 40(2):309-12.
We describe an inflammatory myopathy that was symmetrically restricted to both gastrocnemius muscles in a young man. Histopathological findings were typical for polymyositis, but there were neither signs of generalization nor muscle weakness and wasting. This condition was highly sensitive to steroi... [more] We describe an inflammatory myopathy that was symmetrically restricted to both gastrocnemius muscles in a young man. Histopathological findings were typical for polymyositis, but there were neither signs of generalization nor muscle weakness and wasting. This condition was highly sensitive to steroids and has been kept in remission for more than a year using azathioprine. Our findings add another entity to the spectrum of spatially restricted inflammatory myopathies. Muscle Nerve 40: 309-312, 2009.
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2.90Impact points
Enzyme replacement therapy with alglucosidase alfa in 44 patients with late-onset glycogen storage disease type 2: 12-month results of an observational clinical trial.
Journal of neurology. 09/2009;
Late-onset glycogen storage disease type 2 (GSD2)/Pompe disease is a progressive multi-system disease evoked by a deficiency of lysosomal acid alpha-glucosidase (GAA) activity. GSD2 is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduc... [more] Late-onset glycogen storage disease type 2 (GSD2)/Pompe disease is a progressive multi-system disease evoked by a deficiency of lysosomal acid alpha-glucosidase (GAA) activity. GSD2 is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduced life span. Since 2006 alglucosidase alfa has been licensed as a treatment in all types of GSD2/Pompe disease. We here present an open-label, investigator-initiated observational study of alglucosidase alfa enzyme replacement therapy (ERT) in 44 late-onset GSD2 patients with various stages of disease severity. Alglucosidase alfa was given i.v. at the standard dose of 20 mg/kg every other week. Assessments included serial arm function tests (AFT), Walton Gardner Medwin scale (WGMS), timed 10-m walk tests, four-stair climb tests, modified Gowers' maneuvers, 6-min walk tests, MRC sum score, forced vital capacities (FVC), creatine kinase (CK) levels and SF-36 self-reporting questionnaires. All tests were performed at baseline and every 3 months for 12 months of ERT. We found significant changes from baseline in the modified Gowers' test, the CK levels and the 6-min walk test (341 +/- 149.49 m, median 342.25 m at baseline; 393 +/- 156.98 m; median 411.50 m at endpoint; p = 0.026), while all other tests were unchanged. ERT over 12 months revealed minor allergic reactions in 10% of the patients. No serious adverse events occurred. None of the patients died or required de novo ventilation. Our clinical outcome data imply stabilization of neuromuscular deficits over 1 year with mild functional improvement.
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5.46Impact points
Transient widespread blood-brain barrier alterations after cerebral photothrombosis as revealed by gadofluorine M-enhanced magnetic resonance imaging.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 10/2008;
Magnetic resonance imaging (MRI) is a powerful tool to assess brain lesions, but currently available contrast agents are limited in the assessment of cellular and functional alterations. By use of the novel MRI contrast agent gadofluorine M (Gf) we report on imaging of transient and widespread chang... [more] Magnetic resonance imaging (MRI) is a powerful tool to assess brain lesions, but currently available contrast agents are limited in the assessment of cellular and functional alterations. By use of the novel MRI contrast agent gadofluorine M (Gf) we report on imaging of transient and widespread changes of blood-brain barrier (BBB) properties as a consequence of focal photothrombotic brain lesions in rats. After i.v. application, Gf led to bright contrast in the lesions, but also the entire ipsilateral cortex on T1-weighted MRI. In contrast, enhancement after application of gadolinium diethylenetriamine-pentaacetic acid (Gd-DTPA), a common clinical indicator of BBB leakage was restricted to the lesions. Remote Gf enhancement was restricted in time to the first 24 h after photothrombosis and corresponded to a transient breakdown of the BBB as revealed by extravasation of the dye Evans blue. In conclusion, our study shows that Gf can visualize subtle disturbances of the BBB in three dimensions not detectable by Gd-DTPA. Upon entry into the central nervous system Gf most likely is locally trapped by interactions with extracellular matrix proteins. The unique properties of Gf hold promise as a more sensitive contrast agent for monitoring BBB disturbances in neurologic disorders, which appear more widespread than anticipated previously.Journal of Cerebral Blood Flow & Metabolism advance online publication, 29 October 2008; doi:10.1038/jcbfm.2008.129.
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3.91Impact points
Gadofluorine M-enhanced magnetic resonance nerve imaging: comparison between acute inflammatory and chronic degenerative demyelination in rats.
Experimental neurology. 04/2008; 210(1):137-43.
Nerve imaging by magnetic resonance imaging (MRI) is an emerging tool for the diagnostic work-up of patients with PNS disorders. We have recently shown that the experimental MR contrast agent gadofluorine M (Gf, Bayer Schering Pharma AG, Berlin) accumulates in nerves undergoing Wallerian degeneratio... [more] Nerve imaging by magnetic resonance imaging (MRI) is an emerging tool for the diagnostic work-up of patients with PNS disorders. We have recently shown that the experimental MR contrast agent gadofluorine M (Gf, Bayer Schering Pharma AG, Berlin) accumulates in nerves undergoing Wallerian degeneration and in areas of acute focal demyelination allowing in-vivo assessment of nerve pathology. The exact pathomechanism underlying Gf accumulation in peripheral nerve disorders is unknown so far. In the present study we compared nerve signal alterations on T2-w and Gf-enhanced T1-w MRI in two different models of acute inflammatory and chronic degenerative demyelination: experimental autoimmune neuritis (EAN) induced by immunization with PNS myelin and experimental Charcot-Marie-Tooth (CMT) disease in rats overexpressing the myelin protein PMP22. During the acute stage of inflammation and demyelination, strong Gf enhancement on T1-w MRI was seen in nerve roots and peripheral nerves in EAN, which resolved with completed remyelination. Similarly, Gf accumulation was seen in CMT rats during early stages with active demyelination at 6 weeks while at chronic stages (9 months) Gf enhancement decreased despite numerous demyelinated axons and onion bulb formation. At all disease stages no signal alterations were seen on T2-w MRI. In conclusion, our data show that the novel MR contrast agent Gf, but not Gadolinium (Gd)-DTPA, facilitates detection of ongoing demyelination by MR neurography independent from the underlying pathology. It appears that the extent of Gf enhancement depends on the acuity of demyelination and is probably related to a transient disturbance of the blood-nerve barrier. Clinical development of Gf may help to further improve the sensitivity of nerve lesion assessment by MRI in patients with peripheral neuropathies.
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7.39Impact points
Mtmr13/Sbf2-deficient mice: an animal model for CMT4B2.
Human molecular genetics. 01/2008; 16(24):2991-3001.
Charcot-Marie-Tooth (CMT) disease denotes a large group of genetically heterogeneous hereditary motor and sensory neuropathies and ranks among the most common inherited neurological disorders. Mutations in the Myotubularin-Related Protein-2 (MTMR2) or MTMR13/Set-Binding Factor-2 (SBF2) genes are ass... [more] Charcot-Marie-Tooth (CMT) disease denotes a large group of genetically heterogeneous hereditary motor and sensory neuropathies and ranks among the most common inherited neurological disorders. Mutations in the Myotubularin-Related Protein-2 (MTMR2) or MTMR13/Set-Binding Factor-2 (SBF2) genes are associated with the autosomal recessive disease subtypes CMT4B1 or CMT4B2. Both forms of CMT share similar features including a demyelinating neuropathy associated with reduced nerve conduction velocity (NCV) and focally folded myelin. Consistent with a common disease mechanism, the homodimeric MTMR2 acts as a phosphoinositide D3-phosphatase with phosphatidylinositol (PtdIns) 3-phosphate and PtdIns 3,5-bisphosphate as substrates while MTMR13/SBF2 is catalytically inactive but can form a tetrameric complex with MTMR2, resulting in a strong increase of the enzymatic activity of complexed MTMR2. To prove that MTMR13/SBF2 is the disease-causing gene in CMT4B2 and to provide a suitable animal model, we have generated Mtmr13/Sbf2-deficient mice. These animals reproduced myelin outfoldings and infoldings in motor and sensory peripheral nerves as the pathological hallmarks of CMT4B2, concomitant with decreased motor performance. The number and complexity of myelin misfoldings increased with age, associated with axonal degeneration, and decreased compound motor action potential amplitude. Prolonged F-wave latency indicated a mild NCV impairment. Loss of Mtmr13/Sbf2 did not affect the levels of its binding partner Mtmr2 and the Mtmr2-binding Dlg1/Sap97 in peripheral nerves. Mice deficient in Mtmr13/Sbf2 together with known Mtmr2-deficient animals will be of major value to unravel the disease mechanism in CMT4B and to elucidate the critical functions of protein complexes that are involved in phosphoinositide-controlled processes in peripheral nerves.
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7.18Impact points
Increasing sulfatide synthesis in myelin-forming cells of arylsulfatase A-deficient mice causes demyelination and neurological symptoms reminiscent of human metachromatic leukodystrophy.
The Journal of neuroscience : the official journal of the Society for Neuroscience. 09/2007; 27(35):9482-90.
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ASA). This results in accumulation of sulfated glycosphingolipids, mainly 3-O-sulfogalactosylceramide (sulfatide), in the nervous system and various other organs. In patients, lipid storag... [more] Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ASA). This results in accumulation of sulfated glycosphingolipids, mainly 3-O-sulfogalactosylceramide (sulfatide), in the nervous system and various other organs. In patients, lipid storage causes a progressive loss of myelin leading to various neurological symptoms. The sulfatide storage pattern in ASA-deficient [ASA(-/-)] mice is comparable to humans, but regrettably, the mice do not mimic the myelin pathology. We reasoned that increasing sulfatide storage in this animal model might provoke demyelination. Therefore, we generated transgenic ASA(-/-) [tg/ASA(-/-)] mice overexpressing the sulfatide-synthesizing enzyme galactose-3-O-sulfotransferase-1 in myelinating cells. Indeed, these tg/ASA(-/-) mice displayed a significant increase in sulfatide storage in brain and peripheral nerves. Mice older than 1 year developed severe neurological symptoms. Nerve conduction velocity was significantly reduced in tg/ASA(-/-) mice because of a peripheral neuropathy characterized by hypomyelinated and demyelinated axons. Inhomogeneous myelin thickness in the corpus callosum, increased frequency of hypomyelinated and demyelinated axons in corpus callosum and optic nerve, and substantially reduced myelin basic protein levels are in accordance with loss of myelin in the CNS. Thus, increasing sulfatide storage in ASA(-/-) mice leads to neurological symptoms and morphological alterations that are reminiscent of human MLD. The approach described here may also be applicable to improve other mouse models of lysosomal as well as nonlysosomal disorders.
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3.91Impact points
In vivo visualization of focal demyelination in peripheral nerves by gadofluorine M-enhanced magnetic resonance imaging.
Experimental neurology. 04/2007; 204(1):14-9.
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... [more] 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.
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2.90Impact points
Pregnancy and delivery of a healthy baby in autoimmune Lambert-Eaton myasthenic syndrome.
Journal of neurology. 10/2006; 253(9):1236-7.
Following (3)
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Annette E Rünker
Technische Universität Dresden -
Suzana Atanasoski
Universität Basel -
Mirko Pham
Heidelberg University Hospital, Germany
Topics (3)
