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Biomedical subjects

C Lubetzki

Publications and source records attributed to C Lubetzki.

At least 19 recordsLinked to original sources
PubMed2006

Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis.

Saltatory conduction in myelinated fibres depends on the specific molecular organization of highly specialized axonal domains at the node of Ranvier, the paranodal and the juxtaparanodal regions. Voltage-gated sodium channels (Na(v)) have been shown to be deployed along the naked demyelinated axon in experimental models of CNS demyelination and in multiple sclerosis lesions. Little is known about aggregation of nodal, paranodal and juxtaparanodal constituents during the repair process. We analysed by immunohistochemistry on free-floating sections from multiple sclerosis brains the expression and distribution of nodal (Na(v) channels), paranodal (paranodin/Caspr) and juxtaparanodal (K(v) channels and Caspr2) molecules in demyelinated and remyelinated lesions. Whereas in demyelinated lesions, paranodal and juxtaparanodal proteins are diffusely distributed on denuded axons, the distribution of Na(v) channels is heterogeneous, with a diffuse immunoreactivity but also few broad Na(v) channel aggregates in all demyelinated lesions. In contrast to the demyelinated plaques, all remyelinated lesions are characterized by the detection of aggregates of Na(v) channels, paranodin/Caspr, K(v) channels and Caspr2. Our data suggest that these aggregates precede remyelination, and that Na(v) channel aggregation is the initial event, followed by aggregation of paranodal and then juxtaparanodal axonal proteins. Remyelination takes place in multiple sclerosis tissue but myelin repair is often incomplete, and the reasons for this remyelination deficit are many. We suggest that a defect of Na(v) channel aggregation might be involved in the remyelination failure in demyelinated lesions with spared axons and oligodendroglial cells.

Adult↗
PubMed2005

Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study.

OBJECTIVE: To assess whether modafinil, a wakefulness-promoting agent, is useful for fatigue in patients with multiple sclerosis (MS). METHODS: Patients with MS with stable disability, and a baseline score of 45 or more on the Modified Fatigue Impact Scale (MFIS), were eligible for the 5-week randomized, double-blind, placebo-controlled, parallel group study. The initial daily dose of modafinil was 200 mg for 1 week. Depending on tolerance, the dose was increased by 100 mg every week up to 400 mg/day and remained unchanged between day 21 and day 35. The primary outcome variable was the change of MFIS score at day 35. RESULTS: A total of 115 patients with MS were enrolled in the study and in the intention to treat analysis. The mean MFIS score at baseline was 63 +/- 9 in the placebo group and 63 +/- 10 in the modafinil group. MFIS scores improved between day 0 and day 35 in both placebo-treated and modafinil-treated groups, but no significant difference was detected between the two groups. There was no major safety concern. CONCLUSIONS: There was no improvement of fatigue in patients with multiple sclerosis treated with modafinil vs placebo according to the Modified Fatigue Impact Scale.

Adult↗
PubMed2005

Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival.

Endothelial differentiation gene (Edg) proteins are G-protein-coupled receptors activated by lysophospholipid mediators: sphingosine-1-phosphate (S1P) or lysophosphatidic acid. We show that in the CNS, expression of Edg8/S1P5, a high-affinity S1P receptor, is restricted to oligodendrocytes and expressed throughout development from the immature stages to the mature myelin-forming cell. S1P activation of Edg8/S1P5 on O4-positive pre-oligodendrocytes induced process retraction via a Rho kinase/collapsin response-mediated protein signaling pathway, whereas no retraction was elicited by S1P on these cells derived from Edg8/S1P5-deficient mice. Edg8/S1P5-mediated process retraction was restricted to immature cells and was no longer observed at later developmental stages. In contrast, S1P activation promoted the survival of mature oligodendrocytes but not of pre-oligodendrocytes. The S1P-induced survival of mature oligodendrocytes was mediated through a pertussis toxin-sensitive, Akt-dependent pathway. Our data demonstrate that Edg8/S1P5 activation on oligodendroglial cells modulates two distinct functional pathways mediating either process retraction or cell survival and that these effects depend on the developmental stage of the cell.

Amino Acid Sequence↗
PubMed2005

[Adult onset hereditary leukoencephalopathies].

In clinical practice, the term "genetic leukoencephalopathy" refers to a group of genetic diseases whose common point is to give an aspect of diffuse leukoencephalopathy on MRI. With progress in diagnostic techniques including radiology, biochemistry or genetics, a large number of hereditary diseases causing leukoencephalopathy have been identified. Although generally beginning in childhood, these diseases often have more insidious clinical forms which can begin in adulthood. These forms remain poorly known. Some are accessible to treatment so their diagnosis appears essential. The diagnostic steps must be guided by clinical examination (neurological, ophthalmological and systemic), electromyography and MRI. The purpose of this review is to propose a classification of the genetic leukoencephalopathies and to give a progress report applicable in neurological practice.

Age of Onset↗
PubMed2002

Oligodendroglial expression of Edg-2 receptor: developmental analysis and pharmacological responses to lysophosphatidic acid.

Edg-2 is a member of the G-protein-coupled seven-transmembrane receptor family recently identified in oligodendrocytes. Here we show that both in vitro and in vivo, Edg-2 transcripts are not detected during early stages of oligodendroglial development, but are expressed only in mature oligodendrocytes, shortly before the onset of myelination. Lysophosphatidic acid (LPA) has been reported to be a ligand of Edg-2 receptor in different cell types. However, in oligodendroglial cultures, LPA had no effect on survival, maturation, or cytoskeleton organization. In myelinating oligodendrocyte-neuron cocultures, LPA did not influence myelinogenesis. In addition, LPA failed to induce Ca2+ mobilization and had no effect on forskolin-induced cAMP accumulation. Phosphorylation of the ERK1/ERK2 MAP kinases was the only response elicited by LPA in oligodendrocytes. Therefore, in contrast to other cell types, in which LPA exerts pleiotropic effects, Edg-2-positive postmitotic oligodendrocytes display a restricted responsiveness to LPA.

Animals↗
PubMed2002

MR spectroscopic pulvinar sign in a case of variant Creutzfeldt-Jakob disease.

We report MR spectroscopic findings in a patient hospitalized with biopsy-proven variant Creutzfeldt-Jakob (vCJD) disease. N-acetyl aspartate was markedly decreased in the postero-medial part of the thalami (pulvinar) but was not diminished in the parieto-occipital white matter and cortical grey matter. These observations, which are in accordance with the pathological findings in this disease, suggest that MR spectroscopy, a highly sensitive method for the detection of subtle brain metabolic dysfunction, could be of interest for the diagnosis, prognosis and therapeutic follow-up of vCJD.

Adult↗
PubMed2001

Outcome of patients with HIV-1-related cognitive impairment on highly active antiretroviral therapy.

OBJECTIVE: To examine the impact of highly active antiretroviral therapy (HAART) on the outcome of HIV-1-related cognitive impairments using a neuropsychological (NP) battery to assess separately the psychomotor, executive function and memory fields. DESIGN: A longitudinal study of HIV-1-infected patients based on serial NP tests in a Paris University Hospital. METHODS: A group of 91 HIV-1-infected patients, of whom 47 were already taking HAART at their first NP examination, were initially categorized as cognitively impaired (n = 53) or non-impaired (n = 38) and underwent one to six serial NP batteries (mean follow-up 12.3+/-8.3 months). Generalized estimating equations (GEE) were used to evaluate performance in a given NP test according to the number of days on HAART. RESULTS: Despite a 25% mortality rate among patients who had cognitive impairment at their first NP examination, GEE showed a positive relationship between the duration of HAART and cognitive performance. Performance in psychomotor tests (e.g. Purdue Pegboard dominant hand) improved continuously during the study period, while memory test performance (e.g. Grober and Buschke free recall) tended to reach a plateau. CONCLUSIONS: HAART improves subcortical cognitive functions during the first year of treatment. Distinct neuropathological mechanisms appear to underlie psychomotor and memory dysfunctions in AIDS.

Adult↗
PubMed2001

Clinical and spectroscopic improvement in HIV-associated cognitive impairment.

To assess the impact of highly active antiretroviral therapy (HAART) on AIDS-associated cognitive impairment, 22 patients with AIDS with (n = 11) and without (n = 11) cognitive deficit were evaluated clinically and by MRS every 3 months for 9 months. Nineteen patients were on HAART at study entry, 21 after 2 months. Cognitively impaired patients presented with a subcorticofrontal deficit and decreased N-acetyl-aspartate in frontal white matter. These clinical and metabolic abnormalities reversed partially on HAART, whereas they remained within normal limits in cognitively unimpaired patients.

AIDS Dementia Complex↗
PubMed2001

[Idiopathic orbital myositis].

Orbital myositis is a rare disorder considered as a subgroup of inflammatory orbital pseudotumors. The pathophysiology is still unknown. Patients typically present with orbital pain exacerbated by eye movement and diplopia. Response to steroids is dramatic. We report a case of idiopathic myositis of the right inferior muscle, which recovered after steroid therapy.

Adult↗
PubMed2001

[Treatment of remitting forms of multiple sclerosis].

Disease-modifying treatments in multiple sclerosis emerged during the last few years, concerning mainly relapsing-remitting forms of the disease. They are essentially represented by beta-interferons. beta-interferons reduce relapse rate, achieving about 30 p. cent, and have an effect on brain lesions detected on MRI. They are indicated for use in ambulatory patients with relapsing-remitting multiple sclerosis characterized by at least 2 attacks of neurological dysfunction over the preceding 2 (or 3)-year period. Questions and controversies still remain concerning dose-response effect, early initiation and duration of treatment. Copolymer, which has a different mechanism of action, also decreases frequency of relapses, and the magnitude of the clinical effect is similar to beta-interferon. Copolymer is indicated for use in patients with relapsing-remitting multiple sclerosis, having either an intolerance or a contra-indication to beta-interferon.

Clinical Trials as Topic↗
PubMed2000

An oligodendrocyte cell adhesion molecule at the site of assembly of the paranodal axo-glial junction.

Two major isoforms of the cell adhesion molecule neurofascin NF186 and NF155 are expressed in the central nervous system (CNS). We have investigated their roles in the assembly of the node of Ranvier and show that they are targeted to distinct domains at the node. At the onset of myelination, NF186 is restricted to neurons, whereas NF155 localizes to oligodendrocytes, the myelin-forming glia of the CNS. Coincident with axon ensheathment, NF155 clusters at the paranodal regions of the myelin sheath where it localizes in apposition to the axonal adhesion molecule paranodin/contactin-associated protein (Caspr1), which is a constituent of the septate junction-like axo-glial adhesion zone. Immunoelectron microscopy confirmed that neurofascin is a glial component of the paranodal axo-glial junction. Concentration of NF155 with Caspr1 at the paranodal junctions of peripheral nerves is also a feature of Schwann cells. In Shiverer mutant mice, which assemble neither compact CNS myelin nor normal paranodes, NF155 (though largely retained at the cell body) is also distributed at ectopic sites along axons, where it colocalizes with Caspr1. Hence, NF155 is the first glial cell adhesion molecule to be identified in the paranodal axo-glial junction, where it likely interacts with axonal proteins in close association with Caspr1.

Animals↗
PubMed2000

Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule.

Many factors have been shown to promote myelination, but few have been shown to be inhibitory. Here, we show that polysialylated-neural cell adhesion molecule (PSA-NCAM) can negatively regulate myelin formation. During development, PSA-NCAM is first expressed on all growing fibers; then, axonal expression is down-regulated and myelin deposition occurs only on PSA-NCAM-negative axons. Similarly, in cocultures of oligodendrocytes and neurons, PSA-NCAM expression on axons is initially high, but decreases as myelination proceeds. Importantly, if expression of PSA-NCAM is prematurely decreased in cultures, by either antibody-mediated internalization or enzymatic removal of the PSA moieties with endoneuraminidase N (endo-N), myelination increases 4- to 5-fold. In the optic nerve, premature cleavage of PSA moieties by intravitreous injection of endo-N also induces a transient increase in the number of myelinated internodes, but does not interfere with the onset of myelination. Previously, we showed that axonal electrical activity strongly induced myelination, which could be prevented by tetrodotoxin (TTX), an action potential blocker. Interestingly, removal of PSA moieties does not reverse the inhibition of myelination by TTX. Together, this suggests that myelination is tightly controlled by both positive (electrical activity) and negative (PSA-NCAM expression) regulatory signals.

Animals↗
PubMed2000

Differential expression of collapsin response mediator proteins (CRMP/ULIP) in subsets of oligodendrocytes in the postnatal rodent brain.

The family of collapsin response mediator protein/Unc-33-like protein (CRMP/Ulip), composed of four homologous members, is specifically and highly expressed in the nervous system during embryonic neuronal development and dramatically down-regulated in the adult. Members of this family have been proposed to be part of the semaphorins signal transduction pathway involved in axonal outgrowth. Here, we show by in situ hybridization and immunohistochemistry that CRMP2/Ulip2, and to a lesser extent CRMP3/Ulip4, are expressed in immature and mature oligodendrocytes, but not in astrocytes. Transcripts encoding the other CRMP/Ulip members are also detectable by RT-PCR in highly purified mature oligodendrocytes. Interestingly, in the adult, the protein CRMP2/Ulip2 is mainly detectable in subsets of oligodendrocytes distributed according to an increasing rostrocaudal gradient, with the largest number of positive cells being present in the brain stem and spinal cord. In cultures of highly purified oligodendrocytes, however, CRMP2/Ulip2 was detectable in all the cells. Addition of Sema3A in the culture medium completely inhibited the emergence of oligodendrocyte processes suggesting that, as in neurons, a Sema3A signaling pathway mediated via CRMP2/Ulip2 may be involved in the regulation of oligodendroglial process outgrowth.

Animals↗
PubMed2000

Similar subcortical pattern of cognitive impairment in AIDS patients with and without dementia.

The aim of this study was to develop a series of neuropsychological tests that define the cortical and subcortical features of cognitive impairment and the characteristics of memory in demented and mildly cognitively impaired AIDS patients. We attempted to establish a usable method to assess and determine the type and degree of cognitive impairment in individual AIDS patients. We examined 53 patients without central nervous system opportunistic infections. A short battery included two scales of global efficiency (the Mattis dementia rating scale and the Mini Mental State Examination), a psychomotor speed test, an executive control assessment and explicit memory evaluation. Patients were categorized into four groups based on their score on both the Mattis dementia rating scale and the DSM-IV criteria: (1) asymptomatic; (2) having AIDS without cognitive impairment; (3) having AIDS with mild cognitive impairment; and (4) having AIDS dementia. Patients with mildly impaired cognition demonstrated slowed thinking, abnormal initiation and conceptualization, and memory impairment. AIDS dementia patients had slower motor activity and memory recall was more severely affected. The short neuropsychological battery was able to characterize modified cognitive performances in both severely and mildly cognitively impaired AIDS patients. The subcortical pattern of the memory disorder was obvious, regardless of the degree of cognitive impairment.

AIDS Dementia Complex↗
PubMed2000

[Role of axonal signals in myelination of the central nervous system].

The myelination of the axons of the central nervous system (CNS) is assumed by the oligodendrocytes, which depend at least in part on signals of axonal origin. The axonal influence on myelination seems to consist of the sum of positive and negative factors, which can either act on the axon or on the oligodendrocyte, allowing the neuron to decide when and where myelinization is initiated. The induction factors appear to be mediated, in some cases, by electrical activity. Among the negative factors, certain factors such as the adhesion molecule PSA-NCAM seem to act by inhibiting the adhesion between the axon and the oligodendrocytic extension. Others, such as the inhibitory signalling pathway, jagged1/Notch1, appear to trigger an inhibitory oligodendroglial signalling, therapy preventing maturation and myelination. The recent determination of the role of these axonal signals has provided a new approach to the mechanisms of normal myelination. These results could be extrapolated to the process of remyelination in human demyelinating pathologies such as multiple sclerosis, and open up new therapeutic research possibilities aimed at neuronal protection.

Animals↗
PubMed2000

[Pivotal role of axonal adhesion molecules in central nervous system myelination].

Close relationship between neurons and oligodendrocytes seems to be of the greatest importance during oligodendrocyte maturation and myelin formation within central nervous system. Two major factors are likely to play the decisive role in CNS myelination--adhesion molecules and electrical activity. It has been shown, both in vitro and in vivo, that blocking or stimulating electrical activity may inhibit or induce myelination respectively. The fact that even in culture oligodendrocytes myelinate solely axons and not other cellular processes present within CNS as well as the finding that normal myelin sheath compaction is encountered only around axons suggest that close interaction between oligodendrocytes and neurons is required for normal myelin formation. Adhesion molecules are most likely involved in this interaction by not only bringing the axon and the glial cell close to each other but also by transducing signals to initiate myelination. The neural cell adhesion molecule (NCAM) is a candidate molecule that could regulate axon/glial cell interaction. It is abundantly present in all growing fiber tracts of the developing CNS. Since its polysialylated from (PSA-NCAM) has been shown to disappear from axonal surface as myelination progresses and that its removal increases 4 to 5 fold myelination, it is thought to be a negative factor for myelin formation. These observations may have important implications in therapeutic strategies in demyelinating disorders like multiple sclerosis.

Axonal Transport↗