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PubMed1988

Assessment of thoracic paraspinal muscles in the diagnosis of ALS.

The distribution of muscle involvement, assessed clinically and electromyographically, was analyzed prospectively in 55 consecutive amyotrophic lateral sclerosis (ALS) patients and in 54 patients with other predominantly motor syndromes, some of whom were referred with suspected ALS. In ALS patients, distal limb muscles and thoracic paraspinal muscles were affected most frequently, more so than proximal limb and cranial muscles. The incidence of bulbar symptoms in ALS was greater in women than in men. These patterns suggest selective vulnerability of specific neuronal populations. The vulnerability of truncal muscles, illustrated by thoracic paraspinal wasting or head and shoulder drooping, was a helpful differential sign in diagnosing ALS. Thoracic paraspinal electromyography was especially valuable in distinguishing ALS from other disorders, such as combined cervical and lumbar spondylotic amyotrophy or polymyositis, which may masquerade as ALS. The finding of denervation atrophy on biopsy of thoracic paraspinal muscles was diagnostic in difficult cases. Because the thoracic paraspinal muscles are frequently affected in ALS and spared in spondylotic amyotrophy, their assessment provides a practical strategy in differentiating ALS from other motor syndromes.

Aged↗

PubMed1990

Neuromuscular transmission in the mdx mouse.

In both disorders, the muscle fiber plasma membrane is rendered selectively vulnerable by dystrophin deficiency. In both disorders there are also ultrastructural abnormalities involving the postsynaptic membrane of the neuromuscular junction. The object of this electrophysiologic study was to determine whether the observed ultrastructural abnormalities at the mdx neuromuscular junction are associated with an abnormality of neuromuscular transmission. In comparison with age-matched control mice, the mdx mice show an abnormal, age-dependent decrease of the amplitude of the miniature end-plate potential and a concomitant increase in the quantal content of the end-plate potential. Consequently, the safety margin of neuromuscular transmission is not impaired.

Animals↗

PubMed1992

Insulin increases amino acid transport into rat soleus motor axons.

Hyperosmotic neurosecretion was used to measure basal and insulin-stimulated amino acid and myoinosital transport into rat motor nerve terminals. L-Alanine and alpha(methylamino)-isobutyric acid (a nonmetabolizable system A-specific analog) transport was rapid into motor nerve terminals innervating a fast-twitch muscle, the extensor digitorum longus, and slow into motor nerve terminals innervating the soleus, a slow-twitch muscle. A physiological concentration of insulin, 10 microU/mL, increased L-alanine and alpha(methylamino)-isobutyric acid transport into motor nerve terminals in the soleus. Large doses of insulin, 100 or 1000 microU/mL, had no effect on L-alanine or alpha(methylamino)-isobutyric acid transport into nerve terminals in the extensor digitorum longus. There was negligible basal or insulin-stimulated transport of D-alanine or myoinositol into nerve terminals of the soleus or extensor digitorum longus. These studies show that insulin regulates sterospecific amino acid transport into soleus motor axons, but has no effect on the rapid amino acid transport into extensor digitorum longus motor axons. Differences in basal and insulin-stimulated transport suggest that motor axons differ in their metabolism, and might be selectively vulnerable to disease processes.

Amino Acids↗

PubMed1995

Amyotrophic lateral sclerosis is a multifactorial disease.

Amyotrophic lateral sclerosis (ALS) is probably biphasic. An initial trigger(s) is followed by a terminal cascade coinciding with the onset of neurological deficits. The terminal cascade involves interactive multifactorial pathogenic mechanisms. Aging must play a crucial role leading to multiple defective or degraded gene products accumulating with progressing years. This in turn leads to failure of receptor integrity and resulting excitotoxicity, free radical accumulation, failure of neurotrophism, and possibly immunological disturbances. These events are predated by months or years by a trigger which is also likely to be multifactorial and cumulative. Evidence suggests that environmental factors may be important triggers. Failure of specific glutamate transporters and calcium binding proteins may account for selective vulnerability of the corticomotoneuronal system. It is postulated that in ALS the primary target cell is the corticomotoneuron or the local circuit interneurons which modulate its activity. Glia cells may play an important role in the demise of the corticomotoneuronal cell. The disordered corticomotoneuron induces excessive excitatory transmitter (glutamate?) release at the corticomotoneuronal-spinal-motoneuronal synapse resulting in the subsequent demise of this neuron.

Amyotrophic Lateral Sclerosis↗

PubMed1991

Pathogenesis of ethanol-induced hydronephrosis and hydroureter as demonstrated following in vivo exposure of mouse embryos.

Urinary tract abnormalities have been noted to occur in 10-27% of individuals diagnosed as having Fetal Alcohol Syndrome. Among a wide range of functional and structural abnormalities, renal agenesis/hypoplasia, hydronephrosis, and ureteropelvic obstruction feature most prominently. This study was designed to examine the pathogenesis of ethanol-induced urinary tract abnormalities in a mouse model. C57Bl/6J mice were acutely exposed to two doses of ethanol (2.9 g/kg IP) administered 4 hours apart beginning on gestational day (GD) 9, hour 4. This resulted in an incidence of 40.7% urinary tract anomalies among GD18 fetuses. With the exception of duplicate ureter, urinary tract abnormalities consisted exclusively of hydroureter/hydronephrosis. Examination of GD13-17 fetuses revealed that the first grossly detectable differences in the urinary tracts of control vs. affected specimens occurred on GD16 and initially only involved ureteral changes. Hydronephrosis was first detected on GD17. A contributing factor to the development of hydronephrosis appears to be the abnormal location of the ureterovesicle junction which commonly involves duplicate ureteral lumens with resultant functional obstruction to urine flow at the distal end of the ureter. Study of the early pathogenetic changes which appear to result in the urinary tract malformations observed involved utilization of scanning electron microscopy, vital dye (Nile blue sulphate) staining of whole embryos, and analysis of histological sections. These studies revealed that 12 hours following initial maternal ethanol exposure, embryos have excessive amounts of cell death localized in the region of the developing mesonephric duct just proximal to the cloaca. Also affected were premigratory neural crest cells located just proximal to the posterior neuropore. We conclude that excessive amounts of ethanol-induced cell death in these selectively vulnerable populations could account for the subsequently observed urinary tract malformations.

Abnormalities, Drug-Induced↗

PubMed2001

TAG-1-deficient mice have marked elevation of adenosine A1 receptors in the hippocampus.

TAG-1 is a neural recognition molecule in the immunoglobulin superfamily that is predominantly expressed in the developing brain. Several lines of evidence suggest that TAG-1 is involved in the outgrowth, guidance, and fasciculation of neurites. To directly assess the function of TAG-1 in vivo, we have generated mice with a deletion in the gene encoding TAG-1 using homologous recombination in embryonic stem cells. Gross morphological analysis of the cerebellum, the spinal cord, and the hippocampus appeared normal in TAG-1-deficient mice. However, TAG-1 (-/-) mice showed the upregulation of the adenosine A1 receptors determined by [(3)H]cyclopentyl-1,3-dipropylxanthine in the hippocampus, and their greater sensitivity to convulsant stimuli than that in TAG-1 (+/+) mice. We suspect that the subtle changes in neural plasticity induced by TAG-1 deficiency during development cause the selective vulnerability of specific brain regions and the epileptogenicity in TAG-1 (-/-) mice.

Animals↗

PubMed1995

Asyntactic thematic role assignment: the use of a temporal-spatial strategy.

We report syntactic comprehension performance of a left-handed man with a right-hemisphere infarct. He was unable to accurately map grammatical categories (subject, object) onto thematic roles (agent, patient), despite demonstrating intact conceptual knowledge of these thematic roles. He performed poorly on both active and passive reversible sentences. His asyntactic thematic role assignment cannot be accounted for by a short-term memory impairment or any hypothesis that predicts selective vulnerability to passive sentence constructions. Rather than performing randomly, our patient used a temporal or spatial strategy in assigning thematic roles. Because he also had a production-mapping deficit and used the same temporal-spatial strategy in production tasks, we hypothesize that the mapping of thematic roles onto grammatical categories and vice versa may be a specific aspect of sentence processing that is common to sentential production and comprehension. We also raise the possibility that thematic roles have underlying spatial representations prior to being elaborated by grammar.

Aged↗

PubMed1993

Insulin induces tyrosine phosphorylation of a 90-kDa protein during postischemic brain reperfusion.

Rat brain nuclear proteins were examined for tyrosine phosphorylation after resuscitation from a 10-min cardiac arrest. Insulin (1 unit/kg intravenously), given immediately after resuscitation, caused a marked increase in tyrosine phosphorylation of a 90-kDa brain protein. This effect occurred without hypoglycemia and was not observed after insulin administration in previously insulinopenic, diabetic, nonischemic animals. Insulin-responsive tyrosine phosphorylation of a specific 90-kDa protein during reperfusion may represent insulin stimulation of a neuroprotective brain response to an ischemic insult, consistent with recent observations that insulin administration during reperfusion protects selectively vulnerable neurons from postischemic death.

Analysis of Variance↗

PubMed1994

Selective loss of [3H]kainic acid and [3H]AMPA binding in layer VI of frontal cortex in Huntington's disease.

Excitatory amino acid neurotoxicity has been proposed to cause the neostriatal neuronal degeneration of Huntington's disease (HD); N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainate receptors have been hypothesized to play important roles in this process. We have recently reported a loss of neurons in layer VI of the cerebral cortex in HD. Using quantitative autoradiographic methods, we have now measured NMDA, AMPA, and kainate receptor binding in the frontal cerebral cortex of the brains of controls and individuals with HD. We find no change in NMDA receptor binding but a selective decrease in kainate and AMPA receptor binding in layer VI. These data suggest that cerebral cortical neurons possessing kainate or AMPA receptors may be selectively vulnerable in individuals with HD.

Autoradiography↗

PubMed1997

Huntingtin immunoreactivity in the rat neostriatum: differential accumulation in projection and interneurons.

Huntington's disease is caused by a mutation of the gene encoding the protein huntingtin. Features of the human disease, characterized by selective loss of neurons from the neostriatum, can be replicated in rodents by administration of excitotoxins. In both affected individuals and the rodent model, there is massive loss of striatal projection neurons with selective sparing of interneurons. Furthermore, in the human disease the earliest evidence of striatal injury is found in striosomal regions of the striatum. The mRNA encoding huntingtin is known to be expressed by neurons throughout the brain, a distribution which does not account for the selective patterns of neuronal death which are observed. Using fluorescence immunocytochemistry and confocal microscopy with an antibody to huntingtin, we have observed that in rats a subset of striatal projection neurons contains dense accumulations of huntingtin immunoreactivity (HT-ir), while most neurons in the striatum contain much smaller amounts. The intensely stained neurons are concentrated within the striatal striosomes, as defined by calbindin-D28K staining. In the matrix regions, relatively few neurons contain dense accumulations of HT-ir, and these cells always lack perikaryal staining for calbindin-D28K. Striatal interneurons, identified by the presence of immunoreactivity for choline acetyltransferase, parvalbumin, calretinin, or neuronal nitric oxide synthase, exhibit little or no HT-ir. The paucity of HT-ir in striatal interneurons, as well as the prominence of staining in a subset of striosomal neurons, mirrors the selective vulnerability of these different types of cells in early stages of human Huntington's disease and in rodent excitotoxic models of the disorder. Our observations suggest that mechanisms which modulate the accumulation of huntingtin may play a central role in the neuronal degeneration of Huntington's disease.

Animals↗

PubMed1998

Synaptic distribution of GluR2 in hippocampal GABAergic interneurons and pyramidal cells: a double-label immunogold analysis.

GluR2 is the regulatory subunit in the AMPA family of glutamate receptors (GluRs) in that its presence inhibits calcium flux and dominates the current/ voltage characteristics of AMPA receptors. Studies from other laboratories have shown that GABAergic interneurons have a lower ratio of GluR2/GluR1 mRNA than pyramidal cells as well as possessing AMPA receptors that have a higher relative permeability to calcium. We hypothesized that such differences might be related to differences in the subunit stoichiometry at the AMPA synapses in each cell class, and used a GluR2-specific monoclonal antibody in a double-label immunogold protocol with anti-GABA and anti-CaM kinase II to compare the GluR2 representation at asymmetric synapses in GABA neurons to that of pyramidal cells in rat CA1. Virtually all CA1 pyramidal cells as well as the majority of GABAergic interneurons were GluR2 positive. EM immunogold labeling also showed that GABAergic interneurons had distinctive ultrastructural features and contained GluR2 in both their soma and their dendrites, as did the spines and shafts of pyramidal cells. GluR2 immunoreactivity was frequently preferentially located at asymmetric synapses on both pyramidal cell spines and shafts as well as the dendritic processes and soma of GABAergic interneurons. However, the labeled synapses on GABAergic neurons had a significantly lower number of immunogold particles than those on pyramidal cells. In fact, 90% of the labeled asymmetric synapses on GABAergic cells had one to three gold particles, whereas greater than 70% of the labeled asymmetric synapses on pyramidal cells had four or more gold particles associated with the synapse. These data suggest that while both cell classes contain GluR2, they differ in the relative representation of GluR2 at their AMPA synapses, such that GABAergic neurons might possess AMPA receptors with higher calcium permeability on average than pyramidal cells. Such differences in subunit representation at AMPA-receptor-mediated synapses would not only lead to differences in calcium permeability and functional characteristics across these two cell classes, but might also be relevant to the hippocampal patterns of selective vulnerability with respect to excitotoxicity and neurodegeneration.

Animals↗

PubMed1998

Distinct roles for sodium, chloride, and calcium in excitotoxic dendritic injury and recovery.

The postsynaptic neuronal dendrite is selectively vulnerable to hypoxic-ischemic brain injury and glutamate receptor overactivation. We explored the glutamate receptor pharmacology and ionic basis of rapid, reversible alterations in dendritic shape which occur in cultured neurons exposed to glutamate. Dendrite morphology was assessed with the fluorescent membrane tracer, DiI, or immunofluorescence labeling of the somatodendritic protein, MAP2. Cortical cultures derived from 15-day-old mouse embryos underwent segmental dendritic beading when exposed to NMDA, AMPA, or kainate, but not to metabotropic glutamate receptor agonists. Varicosity formation in response to NMDA or kainate application was substantially attenuated in reduced sodium buffer (substituted with N-methyl-D-glucamine). Furthermore, veratridine-induced sodium entry mimicked excitotoxic alterations in dendrites and additionally caused varicosity formation in axons. Solutions deficient in chloride (substituted with Na methylsulfate) and antagonists of chloride-permeable GABA/glycine receptors reduced NMDA- or kainate-induced varicosity formation. An increase in dendrite volume was observed as varicosities formed, and varicosity formation was attenuated in sucrose-supplemented hypertonic media. Despite marked structural changes affecting virtually all neurons, dendrite shape returned to normal within 2 h of terminating glutamate receptor agonist application. Neurons exposed to kainate recovered more rapidly than those exposed to NMDA, and neurons exposed to NMDA in calcium-free buffer recovered more rapidly than cells treated with NMDA in normal buffer. While sodium, chloride, and water entry contribute to excitotoxic dendritic injury acutely, calcium entry through NMDA receptors results in lasting structural changes in damaged dendrites.

Animals↗

PubMed1999

MPTP-Induced pallidal lesions in rhesus monkeys.

Dopamine neurons in the substantia nigra of the midbrain are the primary neuronal population affected by 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) toxicity, which produces the pathological and behavioral features of Parkinson's disease in nonhuman primates and man. We have identified another injury site in magnetic resonance imaging (MRI) brain scans in 13 of 37 rhesus monkeys taken 10-12 months after administration of this neurotoxin via the right carotid artery. Focal lesions, ranging in volume from 6.75 to 60 mm3 in the rostral globus pallidus region, were seen on the right side of the brain in these 13 animals in addition to the midbrain effects. While no significant differences were seen between globus pallidus lesioned and nonlesioned animals in the severity of MPTP-induced parkinsonian symptoms, the response to levodopa was muted in pallidal-lesioned animals. To confirm the role of neurotoxicity in producing the lesions, brain scans from an additional 12 monkeys were evaluated during the acute period following exposure to either MPTP (n = 6) or saline (n = 6). Focal lesions in the rostral globus pallidus were seen as early as 2-4 h following a carotid artery infusion in two of six MPTP recipients, but no evidence of injury was seen in saline recipients. The globus pallidus includes important components of the neural circuitry regulating motor functions. The present results indicate that in addition to midbrain dopamine neurons, a focal region of the rostral globus pallidus is selectively vulnerable to MPTP toxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2000

Cyclosporin A enhances survival, ameliorates brain damage, and prevents secondary mitochondrial dysfunction after a 30-minute period of transient cerebral ischemia.

Cyclosporin A (CsA) has been shown to be efficacious in protecting against ischemic injury after short periods (5 to 10 min) of forebrain ischemia. The present experiments were undertaken to study if a long period of forebrain ischemia (30 min), induced at a brain temperature of 37 degrees C, is compatible with survival and if the brain damage incurred can be ameliorated by CsA. The results showed that animals subjected to 30 min of forebrain ischemia at a brain temperature of 37 degrees C failed to survive after the first 24 h of recovery and showed extensive neuronal necrosis in all selectively vulnerable regions after 1 day of survival. CsA, when injected in combination with an intracerebral lesion to open the blood-brain barrier, markedly prolonged the survival time. CsA-injected animals also showed amelioration of histological lesions, an effect that was sustained for at least 4 days. Experiments with mitochondria isolated from the neocortex and hippocampus showed that state 3 respiratory rates decreased during ischemia, recovered after 1 and 3 h of recirculation, and then showed a secondary decline at 6 h. Administration of CsA prevented this secondary decline. Measurements of neocortical cerebral blood flow showed that there was no secondary hypoperfusion prior to secondary mitochondrial dysfunction, implying that changes in blood flow may not be responsible for the rapidly developing, secondary brain damage. The results thus demonstrate that if brain temperature is upheld at 37 degrees C, a 30-min period of ischemia is not compatible with survival after the first day of recovery, and gross histopathological damage develops within that period. CsA was efficacious in prolonging animal survival, ameliorating brain damage, and preventing the secondary mitochondrial dysfunction. Since CsA blocks the mitochondrial permeability transition pore its action may, at least in part, be on mitochondrial integrity and function.

Animals↗

PubMed2001

Delayed increase in neuronal nitric oxide synthase immunoreactivity in thalamus and other brain regions after hypoxic-ischemic injury in neonatal rats.

We examined the response of neuronal nitric oxide synthase (nNOS)-containing CNS neurons in rats exposed to a unilateral hypoxic-ischemic insult at 7 days of age. Animals were sacrificed at several time points after the injury, up to and including 7 days (Postnatal Day 14). Brain regions ipsilateral to the injury (including cerebral cortex, caudate-putamen, and thalamus) exhibited delayed, focal increases in nNOS immunoreactivity. The increase in nNOS immunoreactive fiber staining was prominent in areas adjacent to severe neuronal damage, especially in the cortex and the thalamus, regions that are also heavily and focally injured in term human neonates with hypoxic-ischemic encephalopathy. In cerebral cortex, these increases occurred despite modest declines in nNOS catalytic activity and protein levels. Proliferation of surviving nNOS immunoreactive fibers highlights regions of selective vulnerability to hypoxic-ischemic insult in the neonatal brain and may also contribute to plasticity of neuronal circuitry during recovery.

Animals↗

PubMed2001

Calpain activity in the rat brain after transient forebrain ischemia.

Activity of the Ca(2+)-dependent protease calpain is increased in neurons after global and focal brain ischemia, and may contribute to postischemic injury cascades. Understanding the time course and location of calpain activity in the post-ischemic brain is essential to establishing causality and optimizing therapeutic interventions. This study examined the temporal and spatial characteristics of brain calpain activity after transient forebrain ischemia (TFI) in rats. Male Long Evans rats underwent 10 min of normothermic TFI induced by bilateral carotid occlusion with hypovolemic hypotension (MABP 30 mm Hg). Brain calpain activity was examined between 1 and 72 h after reperfusion. Western blot analysis of regional brain homogenates demonstrated a bimodal pattern of calpain-mediated alpha-spectrin degradation in the hippocampus, cortex, and striatum with an initial increase at 1 h followed by a more prominent secondary increase at 36 h after reperfusion. Immunohistochemical analysis revealed that calpain activity was primarily localized to dendritic fields of selectively vulnerable neurons at one hour after reperfusion. Between 24 and 48 h after reperfusion neuronal calpain activity progressed from the dorsal to ventral striatum, medial to lateral CA1 hippocampus, and centripetally expanded from watershed foci in the cerebral cortex. This progression was associated with fragmentation of dendritic processes, calpain activation in the neuronal soma and subsequent neuronal degeneration. These observations demonstrate a clear association between calpain activation and subsequent delayed neuronal death and suggest broad therapeutic window for interventions aimed at preventing delayed intracellular Ca(2+) overload and pathologic calpain activation.

Animals↗

PubMed2002

Olfactory bulbectomy protects hippocampal pyramidal neurons against excitotoxic death.

The olfactory system is functionally linked to the hippocampus, and odors can modify the activity of hippocampal neurons. Because hippocampal neurons are selectively vulnerable to death in several prominent neurodegenerative conditions, we tested the hypothesis that activity in olfactory pathways can modify the sensitivity of hippocampal neurons to excitotoxic damage. We report that rats subjected to olfactory bulbectomy exhibit a decrease in the vulnerability of hippocampal pyramidal neurons to excitotoxic injury. Four-month-old male Sprague-Dawley rats were subjected to bilateral olfactory bulbectomy or a sham operation. Three months later the rats were given a unilateral infusion of kainic acid in the dorsal hippocampus and were euthanized 24 h later. There was a threefold increase in the number of CA3 neurons that survived kainic acid administration in the bulbectomized rats compared to sham-operated rats. These findings provide the first evidence that olfactory input affects the vulnerability of neurons to excitotoxic death.

Animals↗

PubMed2000

p53 is abnormally elevated and active in the CNS of patients with amyotrophic lateral sclerosis.

Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is a form of apoptosis, but the mechanisms for this neuronal cell death are not known. We evaluated whether motor neuron degeneration in ALS is associated with changes in the levels and function of the apoptosis regulating protein p53. The protein levels and localizations of p53 are abnormal in ALS. By immunoblotting, p53 is elevated in the nuclear compartment of selectively vulnerable CNS regions in individuals with ALS compared to age-matched controls. The levels of a carboxyl-terminal degradation fragment of p53 were decreased in cases of ALS. DNA binding assay demonstrated that the increased p53 in individuals with ALS had competent DNA binding activity. Immunocytochemistry revealed that in normal human CNS p53 is expressed in subsets of nonneuronal cells, but it is found only rarely in neurons; in contrast, in individuals with ALS, p53 is frequently found in motor neurons of spinal cord and motor cortex and is upregulated in astroglia. It is concluded that p53 may participate in the mechanisms for motor neuron apoptosis in ALS.

Adult↗