Experimental neurotoxic disorders of motor neurons: neurofibrillary pathology.
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Biomedical subjects
D L Price
Publications and source records attributed to D L Price.
Pathology of motor neurons in accelerated hereditary canine spinal muscular atrophy.
Hereditary canine spinal muscular atrophy is a dominantly inherited lower motor neuron disease with three phenotypic variants: accelerated, intermediate, and chronic. Pups with the accelerated disease develop weakness by 1.5 months and are quadriparetic by 3 months. The motor neurons of selected brainstem nuclei and ventral horn of the spinal cord are characterized by chromatolysis and by neurofibrillary abnormalities in perikarya, dendrites, and, most strikingly, proximal axons. Dendrites and axons are segmentally enlarged by accumulations of maloriented fascicles of neurofilaments; the axonal swelling usually involve internodes and are delimited by the initial segment or nodes of Ranvier. The disorganized neurofilaments appear to entrap mitochondria and other particular organelles. We have hypothesized that the neurofibrillary changes in this genetic disorder in dogs is associated with an abnormality of the cytoskeletal constituents of motor neurons. Hereditary canine spinal muscular atrophy shows features in common with human motor neuron disease.
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Pathology of the peripheral neuropathy induced by p-bromophenylacetylurea.
p-Bromophenylacetylurea (BPAU) is a neurotoxin known to cause intraaxonal accumulations of tubulovesicular materials and distal axonal degeneration. This study focused on two aspects of the pathology in the peripheral nerves in rats: (1) the comparative pathology of acute and chronic intoxication, and (2) the ability of intoxicated neurons to regenerate. The rats were divided into acute and chronic intoxication groups. Rats acutely intoxicated received one intraperitoneal injection (400 mg. per kg.) and developed paraparesis after 2 weeks. Rats chronically intoxicated were given daily intraperitoneal injections (10 mg. per kg.) for 2 to 7 months; paraparesis appeared after 8 weeks. Both groups showed degeneration of distal nerves. By 3 weeks, rats in the acute intoxication group showed an 18 to 50 per cent loss of axons in the distal phrenic nerve. Axons contained membranous trabeculae (tubules and vesicles); at later times, the tubulovesicular profiles increased and, subsequently, axons degenerated. In these animals, regenerating sprouts were first seen 3 weeks after stopping BPAU; these sprouts also contained tubulomembranous structures which persisted for 18 months. After 2 to 3 months, the chronic intoxication group showed a reduction in the number of axons in the distal phrenic nerve. Surviving axons showed tubulovesicular profiles similar to those observed in acutely intoxicated rats. In this group of rats, axonal regeneration was also characterized by the presence of membranous profiles in the axonal sprouts. Our observations indicate that the pathologic changes caused by BPAU are independent of the rate of administration of the drug. The long-standing abnormalities in the regenerating sprouts suggest a persistent toxic effect on axons. Since membranes are delivered and retrieved through fast anterograde and retrogade transport, the accumulation of membranes may be related to abnormalities in these systems. BPAU appears to be a useful agent to study the pathogenetic mechanisms causing tubulovesicular neuropathies.
Animals↗
Intoxication with beta, beta' -iminodipropionitrile: a model of optic disc swelling.
Human and experimental pathologic studies have suggested that optic disc swelling is due to enlargement of axons in the optic nerve head. Beta, beta' -Iminodipropionitrile (IDPN), a toxin known to produce neurofibrillary swellings in proximal portions of motor and sensory axons, was used to induce axonal lesions in the visual system of guinea pigs and dogs. Funduscopic examination showed progressive optic disc swelling. The axonal swellings, containing maloriented skeins of neurofilaments, appeared initially in the lateral portions of the optic disc; eventually, the majority of axons in the optic disc and in the retinal nerve fiber layer were enlarged. The swellings developed proximal to the level of Bruch's membrane. In addition, myelinated axons in the optic disc and retinal nerve fiber layer developed swellings proximal to the first heminode, demarcating the junction between the unmyelinated/myelinated segments. The retinal ganglion cells remained normal, and there was little axonal degeneration in the distal optic nerve. When beta, beta' -iminodipropionitrile was discontinued, the axonal swellings gradually disappeared.
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Clinical features of inherited cerebellar degeneration in Gordon setters.
We evaluated a kindred of Gordon Setters affected with inherited ataxia. Six adults and 4 pups clinically affected by the disease were examined. Pathologic studies were performed on a 3-year-old affected female dog and on a 2-month-old pup born to affected parents. The dogs were normal at birth; the 1st signs of neurologic dysfunction (wide-based stance and hypermetria) appeared between 6 and 10 months of age. As the disease progressed, increased tone of the extensor musculature, truncal ataxia, and nystagmus were noted. The disease had a slowly progressive course. The pathologic abnormalities were limited to the cortex of the cerebellum. There was atrophy with loss of Purkinje cells and granule cells affecting predominantly the vermis and paravermian regions of lobules IV, V, and VI. The study of the pedigree and our observations of the progeny of 2 affected dogs indicated that the mode of inheritance of this ataxia is compatible with an autosomal recessive trait.
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Genetically determined deficiency of the third component of complement in the dog.
A genetically determined deficiency of the third component of complement (C3) has been identified in a colony of Brittany spaniels. Immunochemical methods show no detectable C3 in the serum of the affected dogs, and there is no evidence of an inhibitor of C3 in the serum. The C3 deficiency appears to be transmitted as an autosomal recessive trait.
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Immunocytochemical localization of tetanus toxin to synapses of spinal cord.
In this study, tetanus toxin was microinjected into the ventral horn of the spinal cord of rats, producing local tetanus. The toxin was localized by immunocytochemical methods. Reaction product was visualized within synaptic terminals, particularly those on the soma and dendrites of motor neurons. The distribution of staining terminals was similar to that of labeled synapses, visualized by autoradiography, after microinjection of either [125I]tetanus toxin or [3H]glycine, the latter a major inhibitor transmitter in the spinal cord.
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Model of Wernicke's encephalopathy.
After a week on a thiamine-free diet and daily injections of pyrithiamine hydrobromide, a group of rats began to lose weight; soon thereafter hypothermia, piloerection, and ataxia developed, followed by convulsions and death. Neuropathologic examination disclosed hemorrhagic necrotic lesions in the thalamus, hypothalamus, collicular plate, vestibular nuclei, and inferior olives. The control groups did not show neurologic signs or neuropathologic abnormalities. The lesions in thiamine-deficient rats were similar in character and distribution to those of human Wernicke's disease. Because this experimental regimen produces neuropathologic changes rapidly and consistently, this animal model should be useful in studies designed to examine the pathophysiologic aspects of experimental Wernicke's disease in particular and CNS thiamine deficiency in general.
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Canine inherited ataxia.
A previously unrecognized canine disorder consists of familial cortical cerebellar degeneration with many characteristics that are similar to inherited ataxias in humans. The disease occurs in Gordon setters and appears to be inherited as an autosomal recessive trait. The dogs appear normal during the first 6 months of life, but between 6 and 12 months of age they develop a broad-based gait and dysmetria, followed by truncal ataxia. Nystagmus occurs late. The disorder is slowly and insidiously progressive. Neuropathological examination shows atrophy of the cerebellar cortex, particularly the pars intermedia. There is loss of Purkinje and granule cells, more severe in older dogs. Other parts of the neuraxis appear normal. These pathological changes resemble those of the familial human cerebellar cortical atrophies.
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Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis.
The nucleus basalis of Meynert provides diffuse cholinergic input to the neocortex. When compared with an age- and sex-matched control, the nucleus basalis from a patient with Alzheimer disease demonstrated substantial reduction of neurons. Loss of this neuronal population may represent an anatomical correlate of the well-documented cholinergic derangement in Alzheimer disease.
Aged↗
Effects of spinal transection on presynaptic markers for glutamatergic neurons in the rat.
To evaluate the hypothesis that glutamic acid may be the neurotransmitter of descending, excitatory supraspinal pathways, the uptake and release of L-[3H] glutamate and the levels of endogenous glutamate were measured in preparations from rat lumbar spinal cord following complete mid-thoracic transection. Following transection, the activity of the synaptosomal high-affinity glutamate uptake process was increased in both dorsal and ventral halves of lumbar cord between 1 and 14 days after transection and returned to control levels by 21 days posttransection. At 7 days, the increased activity of the uptake process for L-[3H]glutamate resulted in elevation of Vmax with no significant alteration in KT as compared to age-matched controls. Depolarization-induced release of L-[3H]glutamate from prelabeled slices did not differ significantly from control in the lesioned rat except at 21 days after lesion when the amount of tritium release was significantly greater in the transected preparations than in control. Amino acid analysis of the lumbar cord from control and transected rats indicated only a 10% decrease in the level of endogenous glutamate and no alterations in the concentration of GABA and glycine 7 days after lesion. These findings do not support the hypothesis that glutamate serves as a major excitatory neurotransmitter in supraspinal pathways innervating the lumbar cord of the rat.
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Schwann cell and glial responses in beta, beta'-iminodipropionitrile intoxication. I. Schwann cell and oligodendrocyte ingrowths.
In rats continuously exposed to beta, beta'-iminodipropionitrile (DPN) for long periods, numerous Schwann cell and oligodendrocyte ingrowths extending into giant axonal swellings were found. These ingrowths, cytoplasmic processes of the Schwann cells and oligodendrocytes which deeply indented the axon, regularly arose from Schmidt-Lanterman clefts in the internodes. They dissected along an intra-axonal 'cleavage plane' which separated the giant axonal swellings into two compartments: an inner central channel of relatively normal axoplasm and an outer 'axoplasmic pad' comprised of circularly or spirally-arranged masses of neurofilaments. Multiple ingrowths often arose within a single internode, resulting in nearly complete segregation of the axoplasmic pad from the central channel over long distances. At the interface between the two axoplasmic compartments, internal myelin sheaths were occasionally found. The distinctive ingrowths found in this study appear to represent unusual responses of the Schwann cells and oligodendrocytes to the primary neurofilamentous axonal pathology produced by IDPN.
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Incorporation of axonally transported glycoproteins into axolemma during nerve regeneration.
The insertion of axonally transported fucosyl glycoproteins into the axolemma of regenerating nerve sprouts was examined in rat sciatic motor axons at intervals after nerve crush. [(3)H]Fucose was injected into the lumbar ventral horns and the nerves were removed at intervals between 1 and 14 d after labeling. To follow the fate of the "pulse- labeled" glycoproteins, we examined the nerves by correlative radiometric and EM radioautographic approaches. The results showed, first, that rapidly transported [(3)H]fucosyl glycoproteins were inserted into the axolemma of regenerating sprouts as well as parent axons. At 1 d after delivery, in addition to the substantial mobile fraction of radioactivity still undergoing bidirectional transport within the axon, a fraction of label was already associated with the axolemma. Insertion of labeled glycoproteins into the sprout axolemma appeared to occur all along the length of the regenerating sprouts, not just in sprout terminals. Once inserted, labeled glycoproteins did not undergo extensive redistribution, nor did they appear in sprout regions that formed (as a result of continued outgrowth) after their insertion. The amount of radioactivity in the regenerating nerves decreased with time, in part as a result of removal of transported label by retrograde transport. By 7-14 d after labeling, radioautography showed that almost all the remaining radioactivity was associated with axolemma. The regenerating sprouts retained increased amounts of labeled glycoproteins; 7 or 14 d after labeling, the regenerating sprouts had over twice as much of radioactivity as comparable lengths of control nerves or parent axons. One role of fast axonal transport in nerve regeneration is the contribution to the regenerating sprout of glycoproteins inserted into the axolemma; these membrane elements are added both during longitudinal outgrowth and during lateral growth and maturation of the sprout.
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Cerebroside sulfotransferase: preparation of antibody and localization of antigen in kidney.
This immunohistochemical study describes the localization of the enzyme cerebroside sulfotransferase (phosphoadenosine phosphosulfate: galactosylceramide sulfotransferase, EC 2.8.2.11) in rat kidney. The enzyme was purified from kidney and the preparation was used to raise antibodies for immunocytochemical investigations. In the kidney, the antigen was present only on the brush border of the epithelial cells of the proximal tubules, suggesting that sulfation of glycolipids occurs in the cytoplasm and plasma membranes of these specific cells. Moreover, biochemical and immunocytochemical studies of cerebroside sulfotransferase during development indicate that catalytic activity is correlated with the appearance of enzyme protein.
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Comparison of three collection-preservation methods for detection of intestinal parasites.
A study was designed to compare the effectiveness and time efficiency of three collection-preservation methods individually and grouped to form systems. Employees and members of their families of an agricultural grower in Hillsborough County, Fla., provided all fecal specimens used in the study. The 160 individuals participating were members of 64 families and represented a cross section of all job activity levels including management. Specimens were collected in Merthiolate/iodine/Formalin, Formalin (10% neutral buffered solution), and polyvinyl alcohol fixative. Parasites were found in the specimens from 39 (24.4%) of the 160 individuals participating, which represented 29.7% of the 64 families. No single method was effective in recovering all of the parasites found. When the methods were grouped to form diagnostic systems, the Merthiolate/iodine/Formalin system appeared to be more effective for parasite recovery as well as more time efficient than the Formalin/polyvinyl alcohol fixation system.
Agriculture↗
Demyelination in experimental beta, beta'-iminodipropionitrile and hexacarbon neuropathies. Evidence for an axonal influence.
beta, beta'-Iminodipropionitrile and 2,5-hexanediol are best known for their ability to induce axonal pathology, including formation of giant axonal swellings. During studies of the pathology of rats exposed to these agents for long periods, we found extensive recurrent demyelination in the spinal roots. To determine whether the demyelination occurred in response to the axonal disease or whether it represented a direct toxic effect on Schwann cells, we examined the time course and distribution of axonal changes and demyelination, asking whether demyelination correlated with, or was independent of, axonal pathology. Experimental animals were continuously intoxicated with one of these agents, and groups were taken for pathologic examination at intervals of up to 2 years; in both models, the relationship between axonal pathology and demyelination was systematically studied in multiple regions of the L5 spinal roots. In control rats, mild demyelination was present by 14 months and increased with age. By 24 months, untreated animals showed widespread demyelination in the spinal roots; in these animals, there was no predilection for proximal or distal regions of the roots, nor was their evidence of recurrent demyelination. Administration of beta, beta'-iminodipropionitrile produced giant axonal swellings located primarily in the proximal 10 mm. of the ventral root and the distal 10 mm. of the dorsal root. By 12 months of exposure, intramyelinic vacuoles (myelin bubbles) and demyelinated segments were numerous in the same regions. By 24 months, the affected regions contained elaborate onion bulbs. The regions without axonal swellings showed only mild demyelination. In contrast, in the 2,5-hexanediol group, giant axonal swellings and axonal degeneration began distally and progressed more proximally with time. By 15 months, when axonal swellings were present primarily in the distal ventral root, there were numerous myelin bubbles. By 24 months, onion bulbs, predominantly involving the distal ventral roots, had developed. Semiquantitative analysis of the time course and distribution of demyelination in these toxic models showed a relationship between axonal abnormalities and subsequent development of demyelination. We concluded that changes in the axons contribute to the development of demyelination in these models and determine the distribution of the lesions. These experimental neuropathies provide models for studies of the stimulus and mechanisms of secondary demyelination.
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The development of catecholaminergic innervation in chick spinal cord.
This combined biochemical and histofluorescent study of the embryonic chick was designed to investigate the temporal and spatial development of noradrenergic pathways in the spinal cord. The sequence of catecholaminergic innervation was analyzed by measuring the specific uptake of [3H]norepinephrine, the levels of endogenous norepinephrine, and the distribution of catecholamine histofluorescence. Uptake studies showed early axons present in all levels of spinal cord by 10 days incubation with subsequent increases of uptake activity appearing in a rostrocaudal fashion. Endogenous norepinephrine values were low until day 14, at which time transmitter levels began to increase, approaching hatched values on incubation day 17. Morphologic studies demonstrated catecholaminergic terminals first in the intermediate gray matter and later concentrated in the ventral and dorsal horns. These observations were interpreted to indicate that: (1) noradrenergic axons are an early descending supraspinal pathway; (2) arborization of this system occurs in a rostral-caudal sequence; and (3) monoaminergic uptake mechanisms develop prior to and independent of neurotransmitter synthesis and storage. The development of this noradrenergic system parallels alteration in spinal cord physiology and refinements in the motility of the embryo.
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Cholinergic transmission regulates extrajunctional acetylcholine receptors.
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Acetylcholine↗