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S K Ludwin

Publications and source records attributed to S K Ludwin.

At least 37 records · Page 2Linked to original sources
PubMed1989

Evolving concepts and issues in remyelination.

The ability of the central nervous system to undergo remyelination is now well established in both clinical and experimental situations. The focus of investigation has shifted from simple morphologic documentation to a detailed examination of the basic biologic processes controlling or limiting remyelination. Successful remyelination depends on an adequate number of oligodendrocytes, which may be provided either by proliferation of endogenous cells or by delivery of exogenous oligodendrocytes, which have been shown to be capable of remyelinating axons. It has recently been found that these transplanted cells are capable of significant migration to reach axons. The adhesion of myelinating cells to the demyelinated axon is probably another step in the process of remyelination and may require a form of cell adhesion molecule, although it is possible that the actual process of myelin wrapping depends on some other additional signal. Attempts to enhance remyelination will involve modulation of both the demyelinating event and these basic biological oligodendrocyte-axon interactions.

Animals↗
PubMed1988

The release of endogenous acetylcholine from the medial septum/diagonal band of rat brain.

This study sought to establish whether cholinergic neurons in the medial septum/vertical limb of the diagonal band (ms/vdB) release endogenous acetylcholine (ACh) locally, and whether the release was modulated by presynaptic feedback mechanisms. Release of ACh from slices of the ms/vdB was assessed by gas chromatography-mass spectrometry (GC-MS). Potassium depolarization resulted in a 20- to 25-fold increase in ACh release above spontaneous levels. Omission of Ca2+ from the incubation medium decreased this release by 91%. In the presence of 4 microM atropine, potassium-induced ACh release was enhanced by 48%. These results indicate that ACh is released in the ms/vdB by a Ca2+-dependent and atropine-sensitive process.

Acetylcholine↗
PubMed1988

Remyelination in the central nervous system and the peripheral nervous system.

Remyelination in the PNS is efficient, quick, and consistently found in all demyelinating diseases. Schwann cell proliferation in response to demyelination is rapid and prolific, and the numbers of Schwann cells generated are in excess of those required for adequate remyelination. This cell poses no limit to regenerative potential, and it can divide and remyelinate following numerous repetitive episodes. The Schwann cell generally has easy access to the denuded axons. The limiting factor to remyelination is the persistence of the demyelinating agent, be it directed at the myelin or secondarily through axonal disease. CNS remyelination differs in some respects. Although it has now become clear that it may occur in a variety of clinical and experimental situations, it is slower and often less complete than in the PNS. The limiting factors here include the nature of the demyelinating process, the regenerative potential of the oligodendrocyte, and the accessibility of the latter to the demyelinated axon. It is apparent that the oligodendrocyte is capable of some proliferation, but the time frame in which this can occur is more constrained than for the Schwann cell. Nevertheless the demonstration that the process occurs leads to increasing hope that clinically useful remyelination may be encouraged in the future either by more carefully controlling the extent of demyelination or by finding ways of stimulating oligodendrocyte proliferation and access to the axon.

Animals↗
PubMed1988

Can oligodendrocytes attached to myelin proliferate?

The uptake of thymidine by oligodendrocytes in the brains of adult mice was examined after the induction of cortical traumatic lesions in an attempt to determine whether mature oligodendrocytes actively attached to myelin sheaths were capable of proliferating. In view of the great difficulty in visualizing the connection between a given oligodendrocyte and a myelin sheath even in the normal adult animal, the neuropil was made edematous in the traumatized animals in order to separate out the components and to study the oligodendrocyte processes. Uptake of tritiated thymidine was found in oligodendrocytes, as well as in endothelial cells, astrocytes, and microglia. The percentage of labeled oligodendrocytes appeared low in relation to the total number of the oligodendrocytes. In addition, in a few labeled cells, cytoplasmic processes could be seen extending to and apparently forming the myelin sheath. The possibility that a differentiated cell still attached to myelin may at the same time be able to proliferate is of great significance in understanding the potential for remyelination and recovery, in the adult, because it would imply that any oligodendrocyte is a candidate for proliferation, rather than only uncommitted or immature glial cells, which may be limited in the mature brain.

Animals↗
PubMed1987

Neurotoxicity of quinolinate in the rat nucleus basalis magnocellularis.

Injections of quinolinic acid (QUIN) alone or combinations of QUIN with dipicolinic acid, Mg2+ or 3,4-diaminopyridine were made into the nucleus basalis magnocellularis of the rat. Choline acetyltransferase activity in the cortex decreased following injections of QUIN and this was antagonized by co-injections of QUIN with dipicolinic acid or Mg2+. Co-injections of QUIN with 3,4-diaminopyridine increased the neurotoxicity of quinolinic acid, while diaminopyridine alone was not toxic.

4-Aminopyridine↗
PubMed1987

Blood-brain barrier permeability during Cuprizone-induced demyelination. Implications for the pathogenesis of immune-mediated demyelinating diseases.

Blood vessels in the superior cerebellar peduncles were studied in Cuprizone-fed mice for leakage of proteins into the parenchyma. The status of the blood-brain barrier was determined at various stages of demyelination both by tracer methods using horseradish peroxidase and immunochemically using antisera to extravasated serum proteins and was compared to three positive and negative control conditions. The results showed no evidence of significant protein leakage into the subendothelial basement membrane or extravascular space in Cuprizone mice, during the development of demyelination. The apparent lack of damage to the blood-brain barrier found in Cuprizone animals as compared to the blood-brain barrier alterations previously reported for immune-mediated demyelinating diseases, confirms the theory that these alterations are not a non-specific association of any demyelinating process, but are of primary pathogenetic importance in immune-mediated demyelination.

Animals↗
PubMed1987

Effect of quinolinic acid in the nucleus basalis magnocellularis on cortical high-affinity choline uptake.

A transient 45% increase in cortical high-affinity choline uptake (HACU) was observed after an injection of quinolinic acid (QUIN) into the nucleus basalis magnocellularis (nbM) of the rat. This was followed by a steady decline in choline uptake, which resulted in a 46% decrease by day 7. Specific [3H]hemicholinium-3 binding to coronal brain sections showed a similar pattern following injections of QUIN into the nbM. The increase in cortical HACU elicited by QUIN appeared to be dose dependent.

Animals↗
PubMed1987

Remyelination in demyelinating diseases of the central nervous system.

It is well accepted that a thorough understanding of pathogenetic mechanisms involved in demyelination and remyelination of the central nervous system (CNS) is fundamental to a better understanding of the etiology and pathogenesis of clinical demyelinating disease. In this review, experimental and clinical models of demyelination are discussed in an attempt to elucidate the mechanism by which they cause breakdown of the myelin sheath and/or damage to the oligodendrocyte. An attempt is made to determine whether mechanisms operating during experimental diseases may be applicable to the human situation. In a similar fashion, the occurrence of remyelination within the CNS in experimental animals and its relationship to the potential for remyelination following not only demyelinating disease but also remyelination following trauma and other destructive lesions are explored. The evidence for meaningful remyelination in the clinical situation is assessed, and the importance of such theoretical factors as the ability of oligodendrocytes to proliferate and migrate is evaluated.

Animals↗
PubMed1986

Gliogenesis in organotypic tissue culture of the spinal cord of the embryonic mouse. I. Immunocytochemical and ultrastructural studies.

The technique of organotypic tissue culture offers an opportunity to observe in vitro complex interactions among glial cells and neurons, leading to the formation of myelin. In the present and accompanying work a combined ultrastructural, immunocytochemical and autoradiographic approach was used in a detailed study of the process of gliogenesis. Using immunocytochemical and ultrastructural criteria, differentiation along the oligodendroglia cell line is seen to be initiated a few days later than along the astroglial line. The sequence and timing of oligodendroglial differentiation both ultrastructurally and chemically follow those described in vivo. Formation of myelin has been demonstrated only by oligodendrocytes in which there is continuity between the perikaryal plasmalemma and myelin membranes. Oligodendroglial maturation culminated with the formation of light, medium and dark oligodendrocytes. The periodic acid Schiff-positive, glial fibrillary acidic protein (GFAP)-negative process of radial glial cells at explantation become GFAP-positive within 3 days, as described in vivo. Many of the astrocytes appear to have been derived from radial glial cells. Large numbers of dark glial cells, similar to the so-called 'intermediate glial cells', were seen. These were found to be astrocytes whose appearance probably reflected reaction to explantation-induced injury.

Animals↗
PubMed1986

Gliogenesis in organotypic tissue culture of the spinal cord of the embryonic mouse. II. Autoradiographic studies.

Organotypic cultures of the spinal cord of the embryonic mouse were subjected to pulses of tritiated thymidine at various times between explanation and 42 days in vitro (DIV). Autoradiography was performed both on cultures fixed immediately at the end of the pulse and on cultures maintained in radioactive-free medium for various periods after the pulse. Quantitative light autoradiographic studies showed a single peak of glial cell proliferation at 9 DIV equivalent to that demonstrated in vivo. The growth rate of glial cells (related to time in culture) decreased along an exponential decay type curve. All these observations were statistically significant when tested against the corresponding null hypothesis. Ultrastructural autoradiography shows that at early stages of the culture, radial glial cells and immature glial cells divided and eventually gave rise to astrocytes and oligodendrocytes. During the period of maximal cell proliferation, tritiated thymidine was incorporated by differentiated astrocytes and ultrastructurally recognizable immature oligodendrocytes. Oligodendrocytes did not divide beyond the stage of active oligodendrocytes (the cells initiating myelination). They were capable of producing dark oligodendrocytes within a week following the last division. These observations emphasize the similarity of the proliferation during development in organotypic culture to that in vivo, modified by the trauma of explantation and the culture conditions.

Animals↗
PubMed1986

Clinicopathological studies of some non-Alzheimer dementing diseases.

The brains of most demented patients show at autopsy the lesions of Alzheimer's disease (AD). However, the brains of other demented patients show either no morphological changes or lesions distinct from those of AD. We report clinicopathological studies on two diseases in this latter group. The study of these diseases can improve our understanding of AD. Pick's disease is characterized by dementia, lobar cerebral atrophy, and neuronal cytoplasmic inclusions. Most cases, which we have called "classical", show inclusions made up of straight fibrils that are immunologically cross-reactive with the paired helical filaments of AD. In other "generalized" cases, similar fibrils are coated by granular material and are less reactive with anticytoskeletal antibodies. In contrast to the cytoplasmic localization of the lesions in Pick's disease, it is the cell nucleus that shows abnormalities in neuronal intranuclear hyaline inclusion disease. This disease can present clinically as dementia of adult onset. Thus, either nuclear or cytoplasmic lesions can produce a pattern of neuronal dysfunction resulting in dementia.

Cell Nucleus↗
PubMed1986

Adult-onset neuronal intranuclear hyaline inclusion disease.

We studied the clinical and pathologic features of two cases of neuronal intranuclear hyaline inclusion disease. The cases were unique in late onset, presentation with dementia, possible autosomal dominant pattern of inheritance (in one patient), predominance of inclusions in glial cells, and mineral deposits within some inclusions. Differences from other reported cases indicate that this is probably not a homogeneous entity.

Atrophy↗
PubMed1985

Quinolinic acid neurotoxicity in the nucleus basalis antagonized by kynurenic acid.

Quinolinic acid, a metabolite of tryptophan, behaves as an excitotoxic amino acid. It has been proposed that quinolinic acid might be implicated in neurodegenerative diseases. The related metabolite, kynurenic acid, has been found to be a powerful antagonist of quinolinic acid. The ability of quinolinic acid, alone or in combination with kynurenic acid, to destroy cholinergic neurons projecting to the cortex was examined by morphological and biochemical criteria. The compounds were injected unilaterally into the nbm of the rat. Neuronal destruction of the basal forebrain occurred with quinolinic acid alone; however, no cell loss was observed when kynurenic and quinolinic acid were co-injected. Quinolinic acid lesions of the nucleus basalis caused significant decreases in cortical choline acetyltransferase, acetylcholinesterase, high affinity choline uptake and 3H-acetylcholine release. These reductions in cortical cholinergic markers were prevented by co-injecting kynurenic with quinolinic acid. A significant decrease in cortical choline acetyltransferase activity was observed three months following quinolinic acid lesions of the nucleus basalis. The results indicate that quinolinic acid can be used as an endogenous neurotoxin to produce lesions of the nbm resulting in impaired cortical cholinergic function similar to that seen in Alzheimer's disease.

Acetylcholinesterase↗
PubMed1985

Intermediate glial cells and reactive astrocytes revisited. A study in organotypic tissue culture.

The existence of cells sharing features of oligodendrocytes and astrocytes has been repeatedly proposed. We have studied this problem ultrastructurally in organotypic tissue culture together with light-microscopic immunocytochemistry for the astrocyte marker glial fibrillary acidic protein (GFAP) and for 2 oligodendrocyte markers, myelin basic protein (MBP) and myelin-associated glycoprotein (MAG). Large numbers of GFAP+ cells (astrocytes) were seen, invariably giving rise to a wealth of tapering processes. In contrast, oligodendrocytes were found far less frequently either immunocytochemically or ultrastructurally, and showed smooth contours and scarcity of processes. Ultrastructurally, the cells corresponding to the intermediate glial cells in the literature which were far more numerous in culture than MBP-stained cells, were identified as reactive astrocytes by their numbers, location and morphological similarity with the GFAP-stained cells. Other characteristics were the presence of bundles of intermediate filaments and the covering of the plasmalemma adjacent to the collagen substrate by a basal lamina, in spite of the content of microtubules and the density of the cells. It was possible to demonstrate the difference between the wrapping of axons by astrocytic digitiform processes, and true myelination by processes identifiable as oligodendrocytes. We conclude that in this model the astrocytic and oligodendrocytic cell lines appear separate from the time of initial differentiation; in other systems such as dissociated cell culture, this may not be so. The cells with 'intermediate' features are in fact a reactive form of astrocyte.

Animals↗
PubMed1985

Reaction of oligodendrocytes and astrocytes to trauma and implantation. A combined autoradiographic and immunohistochemical study.

Small excision wounds were made in the parietooccipital cortex of adult mice, and in some of the animals a variety of fetal and adult tissues were implanted into the defect. The response of the oligodendrocytes to trauma and implantation was studied autoradiographically and immunohistochemically and compared to that seen in other glia. The results following trauma alone resembled those seen following implantation. Within 3 days of the surgery a marked proliferative response was seen in mature oligodendrocytes, as judged by uptake of tritiated thymidine in the nuclei, both around the wound and at distant sites extending even into the opposite hemisphere. Labeled astrocytes, microglia (macrophages), and endothelial cells were also found in the same distribution. Immunohistochemical examination using the myelin proteins, myelin basic protein and myelin-associated glycoprotein, failed to show any difference in staining characteristics from normal, in contrast to the marked increase in glial fibrillary acidic protein accompanying the division of astrocytes. The results of this experiment demonstrate that mature oligodendrocytes can proliferate and undergo mitosis in response to nonspecific damage to the central nervous system, in a manner similar to that seen with other glia. This response is, however, not linked to a nonspecific production of myelin proteins, which obviously require some other stimulus for their production.

Animals↗
PubMed1984

Aicardi's syndrome. A clinicopathologic study.

A 9-week-old female infant was seen with typical clinical features of Aicardi's syndrome. At autopsy (at 21 months of age), examination of the brain disclosed polymicrogyria and agenesis of the corpus callosum. Histopathologic studies of the posterior segments showed areas of intact but attenuated and depigmented retinal pigment epithelium, and atypical colobomatous defect of both posterior segments, and ectatic scleral channels lined by a retinal pigment epithelial choriocapillarislike complex in the left eye. The pathogenesis of the ocular defects is discussed.

Abnormalities, Multiple↗
PubMed1984

Classic and generalized variants of Pick's disease: a clinicopathological, ultrastructural, and immunocytochemical comparative study.

Six sporadic cases of dementia with lobar atrophy and neuronal cytoplasmic inclusions (Pick's disease) could be separated into two groups on the basis of the involvement of subcortical structures, the distribution and the histochemical, immunochemical, and ultrastructural characteristics of the inclusions, and possibly the age at onset. The first group (classic) was characterized by predominantly cortical atrophy and the presence in the hippocampus and neocortex of argyrophilic cytoplasmic inclusion bodies that reacted with a monoclonal antibody against neurofilament proteins and antitubulin antisera. Ultrastructurally the bodies were composed of straight fibrils of variable diameter, averaging 15 nm, and long-period constricted fibrils. The second group (generalized) showed subcortical as well as antibodies against neurofilaments and microtubules. Ultrastructurally the straight fibrils composing the bodies were coated with granular material, presumed to be derived from ribosomes. The generalized cases occurred in younger patients than did the classic cases in this series.

Adult↗