Amyotrophic lateral sclerosis. An autoimmune disease?
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Amyotrophic Lateral Sclerosis↗
Biomedical subjects
P S Fishman
Publications and source records attributed to P S Fishman.
Fate of severed cortical projection axons.
Corticospinal neurons show a primarily degenerative response to axotomy in adult mammals. The long remaining proximal axon with its extensive synaptic contacts may contribute to the lack of initial regenerative response in this cell type. We examined a related group of cortical axons after lesions in the subcortical white matter close to their cell bodies of origin. With cholera B chain conjugated to horseradish peroxidase (CTB-HRP), transcallosal axons projecting into areas of a lesion were labeled. Animals surviving between 2 days and 4 months were examined with both light microscopic and ultrastructural techniques. During the first several days after injury, many of the axon terminals projecting into the lesion site had the appearance of axonal sprouts, although the majority of endings had the appearance of degenerating terminal swellings. By 2 weeks after injury some axonal sprouts had extended a short distance along the margins of the lesions, into overlying cortex. Four weeks after injury there is a reduction in the number of axons extending toward the lesion. This loss of axons appeared progressive and resulted in not only a loss of labeled axons, but also eventually in atrophy of the subcortical white matter near the lesion. In comparison to corticospinal axon lesions in the spinal cord or medullary pyramids, there is more extensive axonal sprouting and elongation after subcortical lesions. Degenerative morphological features still predominate after subcortical lesions and no successful trans-lesion axonal regeneration occurs. Axonal retraction and loss are both accelerated and more extensive after proximal subcortical axotomy than after corticospinal tract lesions.
Animals↗
A simplified method for the preparation of tetanus toxin binding fragment for neurobiology.
The non-toxic binding fragment of tetanus toxin (fragment C) binds avidly to neural tissue and has a growing number of neurobiological uses. Its current utility is limited by both its high commercial cost and the complex procedure for its preparation requiring highly purified tetanus toxin. We have developed a short procedure which prepares fragments of tetanus toxin from crude C. tetani extracts. The resultant proteins are atoxic with molecular sizes and immunological properties closely resembling fragment C. These proteins undergo retrograde axonal and apparent transneuronal transport in a fashion similar to fragment C.
Animals↗
Antibodies to the ganglioside GD1b in a patient with motor neuron disease and thyroid adenoma.
Patients with motor neuron disease with thyroid disorders have been described, although the relationship between the two conditions is unclear. We treated a patient with amyotrophic lateral sclerosis who also had a follicular adenoma of the thyroid gland. Because thyroid gland plasma membranes contain high concentrations of complex gangliosides, such as GD1b, and some patients with motor neuron disease have IgM antibodies to GD1b, we decided to assay serum from this patient for the presence of antiganglioside antibodies. IgM antibodies to GD1b were detectable at serum dilutions of 1:500 and 1:1000 by enzyme-linked immunosorbent assay. While these titers are less than those usually described in patients with plasma cell dyscrasia, they are well in excess of normal values. Antibody to GM1 was also detectable at a lower (1:100) dilution. We do not know the importance of the anti-GD1b antibodies in this patient, but it is possible that antibodies to GD1b are involved in this and other cases of motor neuron disease associated with thyroid disease.
Adenoma↗
Penetration and internalization of plasma proteins in the human spinal cord.
In animal studies, motoneurons take up plasma proteins including immunoglobulins at their terminals. These proteins are then transported back to cell bodies in the spinal cord. To determine if these processes also occur in humans, we localized several different plasma proteins in autopsied spinal cords from 13 patients without neurological disease. As in animals, plasma proteins are associated with vascular and pial structures. Motoneurons, particularly large cervical and lumbar motoneurons, frequently showed immunoreactivity within their cytoplasm to several plasma proteins. Motoneuron labeling was more consistent with antisera against plasma proteins of lower molecular weights such as IgG, IgA and transferrin, than with antisera against higher molecular weight proteins such as IgM and alpha-2-macroglobulin. Other large neurons without connections outside the blood-brain barrier such as those of Clarke's column also occasionally labeled with antisera against all plasma proteins tested. Our results are compatible with the concept that motoneurons take up and transport plasma proteins. These neurons can be distinguished from cells which internalized extravasated serum proteins before and after death. Uptake of pathogenic antibodies by motoneuron terminals may play a role in the pathogenesis of motoneuron disease.
Adult↗
Relapsing transverse myelitis.
Acute transverse myelitis is a monophasic disorder, the recurrence of which raises the question of multiple sclerosis (MS) or other multifocal CNS disease. We now report three patients with a previously undescribed syndrome of relapsing isolated acute transverse myelitis. Each had two to five attacks over periods of 3 to 8 years, characterized by ascending paresthesias, urinary retention, sensory loss with a thoracic or cervical level, paraparesis, hyperreflexia, and bilateral Babinski signs. MRI demonstrated areas of increased signal intensity on T2- and proton density-weighted scans and decreased signal intensity on T1-weighed scans of the cervical or thoracic spinal cord consistent with an inflammatory or demyelinating process. All patients had normal complete myelograms, oligoclonal IgG bands were consistently absent from the cerebrospinal fluid, cranial MRIs were normal, and there was no other clinical or laboratory evidence of MS, collagen-vascular disease, or active viral infection. They were treated with high doses of intravenous corticosteroids, stabilized between episodes, and had partial or complete recovery. The recognition of these three patients at a single medical center in a 1-year period suggests that relapses of acute transverse myelitis may not be rare.
Adolescent↗
Internalization of plasma proteins by cerebellar Purkinje cells.
Animal studies suggest that Purkinje cells internalize proteins from the blood and CSF. This process may relate to the pathogenesis of paraneoplastic cerebellar degeneration in patients with anti-Purkinje cell antibodies. To determine if human Purkinje cells may also internalize plasma proteins, cerebellar tissue was taken from routine autopsies of eight patients without neurologic or neoplastic disease. Several plasma proteins including IgG, IgA, IgM, transferrin, albumin and alpha-2-macroglobulin were detected by immunohistochemistry within the cytoplasm of Purkinje cells. Internalized proteins frequently filled the entire soma and major dendrites, sparing the nucleus. Vascular structures were also immunolabeled, while glia internalized plasma proteins differentially, with oligodendrocytes selectively internalizing transferrin. Purkinje cells were the most numerous and heavily labeled neuronal cell type in spite of their small numerical representation in the cerebellar neuronal population. Our results are compatible with previous animal studies, and suggest that internalization of specific antibodies could contribute to the pathogenesis of Purkinje cell loss in paraneoplastic cerebellar degeneration.
Aged↗
Enhanced CNS uptake of systemically administered proteins through conjugation with tetanus C-fragment.
No other exogenous protein enters the central nervous system from the circulation as readily as tetanus toxin. We examined the capability of the non-toxic binding fragment of tetanus toxin (C-Fragment) so serve as a vehicle for transport of other proteins into the mouse CNS. Using periodate oxidation of the enzyme horseradish peroxidase (HRP), we synthesized two separate macromolecular complexes, one containing C-fragment and HRP, and the other C-fragment, HRP and a third "test" protein-human IgG. The distribution of C-fragment-HRP was typical of blood borne proteins including native C-fragment, with labeling of all neurons with known projections outside the blood-brain barrier, particularly large spinal motoneurons. C-fragment-HRP conjugates showed superior neuronal labeling to over 100-fold greater quantities of free HRP. Complexes containing C-fragment, HRP and human IgG were internalized by neurons from both intramuscular and intraperitoneal injections. The efficiency of neuronal uptake of IgG in the C-fragment conjugated form was enhanced over 40-fold compared to free IgG. Linkage of a large protein to C-fragment probably leads to enhanced endocytosis of that protein by neuronal terminals projecting outside the blood-brain barrier. C-fragment can serve as a vehicle to allow selected proteins to bypass the barrier and enter the CNS.
Animals↗
Transsynaptic transfer of retrogradely transported tetanus protein-peroxidase conjugates.
Tetanus toxin and its atoxic binding fragment, C-fragment (CF), are the only known proteins which undergo extensive transfer from motoneurons to presynaptic terminals in the spinal cord. Intramuscular injection of CF conjugated to horseradish peroxidase (HRP) was used to elucidate the ultrastructural basis for this unique property. Motoneurons labeled by retrograde axonal transport contained enzymatic reaction product within cytoplasmic vesicles and were surrounded by presynaptic terminals with label in the synaptic cleft and synaptic vesicles. Membranous structures on both sides of the synapse remained labeled for several days after the injection. Nonsynaptic regions were virtually free of CF-HRP. Transport of CF may reflect the movement of the tetanus toxin receptor in a unique synaptic compartment.
Animals↗
Selective localization by neuroglia of immunoglobulin G in normal mice.
Plasma proteins including immunoglobulins have been previously localized in neurons with processes extending outside the blood-brain barrier, but not within glia under normal conditions. Immune modulating functions have been proposed for both microglia and astrocytes in several pathological states. Using immunocytochemistry, we have found that large numbers of neuroglial cells contain immunoglobulin G (IgG) in normal mice of the C57 BL/6 strain. Most IgG-positive cells had both the morphology and distribution of microglia, including a higher density in grey matter, and were frequently found in perivascular or perineuronal locations. The accumulation of IgG does not appear to be by nonselective phagocytosis of extracellular fluid, since serum albumin could not be detected within microglia. There was little overlap in the distribution of cellular processes positive for IgG and those which showed astrocytic markers. Neuronal accumulation of plasma proteins was also seen in a distribution described by previous investigators. The function of this selective accumulation of IgG by normal microglia is unknown, but may reflect a role in the immune response within the central nervous system.
Animals↗
Posttraumatic narcolepsy: the complete syndrome with tissue typing. Case report.
Although sleep disturbances following head injury are common, well-documented posttraumatic narcolepsy has rarely been reported. A patient with all four major features of narcolepsy following significant head injury is presented. Tissue typing revealed the presence of the human lymphocyte antigen DR2, which is strongly associated with idiopathic narcolepsy. Interaction between the brain injury and a genetic predisposition appears to be involved in the development of posttraumatic narcolepsy.
Adult↗
Motoneuron uptake from the circulation of the binding fragment of tetanus toxin.
Tetanus toxin enters the central nervous system from the systemic circulation after it is internalized by motoneuron terminals at the neuromuscular junction. We have demonstrated that the atoxic binding fragment (C-fragment) of tetanus toxin is internalized preferentially by motoneurons. We examined the distribution of C-fragment after intravenous injection in the nervous systems of mice by immunohistochemical methods. All animals remained asymptomatic until killed one to two days after injection. C-fragment was found only within neurons with processes outside the blood-brain barrier. Large motoneurons of the spinal cord showed the greatest accumulation of C-fragment. Motoneurons of brain-stem nuclei (particularly facial and trigeminal), also showed substantial label of C-fragment. Small amounts of C-fragment were detected in dorsal root ganglion cells. Affinity of a systemically distributed substance for synaptic components, as well as an inability to cross the blood-brain barrier, may lead to its preferential localization in motoneurons.
Animals↗
Limbic encephalitis after inhalation of a murine coronavirus.
The spread of a neurotropic coronavirus, mouse hepatitis virus strain A59, in the mouse central nervous system was studied after intranasal inoculation. Mouse hepatitis virus strain A59 spread during the 3- to 5-day postinoculation period, through the olfactory pathway into the limbic system. Coronavirus particles were detected in the limbic system by electron microscopy. The combination of temporal propagation through an anatomical-physiological central nervous system pathway and anatomical restriction of viral infection suggests that specific interneuronal transport is important in spread of the virus. This experimental system may represent a model for diseases associated with human coronaviruses (common cold viruses) and/or the human limbic system.
Administration, Intranasal↗
Retrograde transneuronal transfer of the C-fragment of tetanus toxin.
The transport of the C-fragment of tetanus toxin after intramuscular injection was studied with immunohistochemical techniques. Brainstems and spinal cords of mice were examined after injections of C-fragment into the tongue or forearm. Labelled motorneurons were observed within 6 h. By two days after injection, the bulk of detectable C-fragment had passed out of motorneurons into the surrounding neuropil. C-fragment, like native tetanus toxin, appears to be transferred from motorneurons to presynaptic structures to an extent not observed with other proteins. It is useful in the study of retrograde transneuronal transfer since it lacks the toxicity of tetanus toxin.
Animals↗
Late-convalescent poliomyelitis. Corticospinal tract integrity.
Since both poliomyelitis and amyotrophic lateral sclerosis affect spinal motor neurons, a relationship between these two diseases has been suggested. Corticospinal tract (CST) degeneration, a prominent aspect of amyotrophic lateral sclerosis, is rarely observed in acute poliomyelitis. Autopsy material from seven patients who had survived long periods after severe paralytic poliomyelitis was examined for evidence of CST degeneration. Although there was severe motor neuron loss and destruction of ventral horn cytoarchitecture, none of the spinal cords showed significant demyelination, fiber loss, or gliosis in the region of the CST. The structural integrity of the CST is maintained for many years after severe motor neuron loss due to poliomyelitis.
Adult↗
Retrograde changes in the corticospinal tract of posttraumatic paraplegics.
Autopsy material from patients with posttraumatic paraplegia of long duration was examined to determine the extent of survival of corticospinal axons proximal to the injury. Spinal cord sections from sites above a functionally complete spinal cord injury were examined for the presence of axons, myelin, and gliosis. There was a marked depletion of axons from the corticospinal tract close to the region of injury. There appeared to be a gradual increase in the density of axons within the tract at increasing distance from the injury in all patients. Corticospinal axons appear to retract from the spinal cord injury site, but do not show progressive degeneration even years after a spinal cord injury.
Adult↗
Systemic recombinant alpha-2 interferon therapy in relapsing multiple sclerosis.
This report describes the first use of recombinant-DNA-produced human interferon in patients with multiple sclerosis (MS). Ninety-eight patients who were clinically definite for MS with two or more documented exacerbations during the preceding two years were admitted to this placebo-controlled double-blind randomized trial. Although both groups were similar, placebo patients had later MS onset. Patients injected themselves with 2 X 10(6) IU of alpha-2 interferon or placebo three times each week for up to 52 weeks. This dose of interferon was well tolerated in that side effects were minimal. During the trial, the exacerbation rate was sharply reduced in both groups. In the three-month follow-up period after stopping treatment, more patients who were receiving interferon than placebo became worse neurologically. More patients who were receiving interferon than placebo changed from exacerbating MS to progressive MS during the trial. Thus, no clear therapeutic benefit of alpha-2 interferon for MS was detected.
Adult↗
Neural transplantation: scientific gains and clinical perspectives.
Neural transplantation, once deemed impossible, is being studied in many laboratories. Embryonic CNS from a variety of sites can be grafted into an adult host. The foreign cells differentiate and then produce neurotransmitters or neurohormones. Physical connection can be seen between graft and host. Grafting of fetal tissue may be followed by improved function of animals with experimental forms of neurologic disease or physical injury. Grafted segments of peripheral nerve become innervated by central axons that can conduct physiologic impulses. Grafted glial cells can form myelin within the CNS. Therapeutic grafting into the human nervous system may be feasible, but many scientific and ethical questions remain to be addressed.
Animals↗