Axonal injury in the internal capsule correlates with motor impairment after stroke.
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Background and Purpose--Magnetic resonance spectroscopy (MRS) in ischemic stroke has shown a correlation between N-acetylaspartate (NAA) loss from the infarcted region and disability. We tested the hypothesis that NAA loss in the descending motor pathways, measured at the level of the posterior limb of the internal capsule, would determine motor deficit after a cortical, subcortical, or striatocapsular stroke. Methods--Eighteen patients with first ischemic stroke causing a motor deficit were examined between 1 month and 5 years after stroke. T2-weighted imaging of the brain and localized proton (voxel, 1.5x2x2 cm3) MRS from the posterior limb of each internal capsule were performed and correlated to a motor deficit score. Results--Mean internal capsule NAA was significantly lower in the patient group as a whole compared with the control group (P<0.001). Reductions in internal capsule NAA on the side of the lesion were seen in cases of cortical stroke in which there was no extension of the stroke into the voxel as well as in cases of striatocapsular stroke involving the voxel region. There was a strong relationship between reduction in capsule NAA and contralateral motor deficit (log curve, r2=0.9, P<0.001). Conclusions--Axonal injury in the descending motor pathways at the level of the internal capsule correlated with motor deficit in patients after stroke. This was the case for strokes directly involving the internal capsule and for strokes in the motor cortex and subcortex in which there was presumed anterograde axonal injury. (+info)
Temperature modulation reveals three distinct stages of Wallerian degeneration.
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After peripheral nerve transection, axons distal to the cut site rapidly degenerate, a process termed Wallerian degeneration. In wild-type mice the compound action potential (CAP) disappears by 3 d. Previous studies have demonstrated that cold temperatures and lower extracellular calcium ion (Ca2+) concentrations can slow the rate of Wallerian degeneration. We have incubated isolated sciatic nerve segments from wild-type and C57BL/Wld mice (which carry a gene slowing Wallerian degeneration) in vitro at 25 and 37 degrees C. At 25 degrees C we found that the degeneration rate of wild-type axons was slowed dramatically, with the CAP preserved up to 7 d post-transection. In contrast, at 37 degrees C the CAPs were minimal at 2 d. When the temperature of wild-type nerves was raised to 37 degrees C after 24-72 hr at 25 degrees C, degeneration occurred within the subsequent 24 hr. Wld nerves, too, were preserved longer at 25 degrees C but, on return to 37 degrees C, degenerated promptly. Cooling the nerve within 12 hr after axotomy enhanced axonal preservation. Neither wild-type nor Wld nerves showed different degeneration rates when they were incubated with 250 microM or 5 or 10 mM extracellular Ca2+ for 1-2 d, suggesting that an abrupt increase in intracellular Ca2+ occurs at the time of axonal destruction. Wallerian degeneration, thus, appears to progress through three distinct stages. Initiation occurs at the time of injury with subsequent temperature-dependent and -independent phases. Nerves appear to remain intact and are able to exclude Ca2+ from entering until an as yet unknown process finally increases axolemmal permeability. (+info)
Gangliosides are a family of sialic acid-containing glycosphingolipids highly enriched in the mammalian nervous system. Although they are the major sialoglycoconjugates in the brain, their neurobiological functions remain poorly defined. By disrupting the gene for a key enzyme in complex ganglioside biosynthesis (GM2/GD2 synthase; EC 2.4.1.92) we generated mice that express only simple gangliosides (GM3/GD3) and examined their central and peripheral nervous systems. The complex ganglioside knockout mice display decreased central myelination, axonal degeneration in both the central and peripheral nervous systems, and demyelination in peripheral nerves. The pathological features of their nervous system closely resemble those reported in mice with a disrupted gene for myelin-associated glycoprotein (MAG), a myelin receptor that binds to complex brain gangliosides in vitro. Furthermore, GM2/GD2 synthase knockout mice have reduced MAG expression in the central nervous system. These results indicate that complex gangliosides function in central myelination and maintaining the integrity of axons and myelin. They also support the theory that complex gangliosides are endogenous ligands for MAG. The data extend and clarify prior observations on a similar mouse model, which reported only subtle conduction defects in their nervous system [Takamiya, K., Yamamoto, A., Furukawa, K., Yamashiro, S., Shin, M., Okada, M., Fukumoto, S., Haraguchi, M., Takeda, N., Fujimura, K., et al. (1996) Proc. Natl. Acad. Sci. USA 93, 10662-10667]. (+info)
Peripheral nerve lesions in a case of equine motor neuron disease.
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A male 14-year-old Arab horse was pathologically diagnosed as equine motor neuron disease (EMND), which was kept as a breeding horse on a farm in Tokachi district of Hokkaido in Japan. On examination of the peripheral nerves, the most characteristic feature was Wallerian-type degeneration revealed by myelinoclasis associated with myelin ovoids which were sometimes infiltrated by macrophages. The other abnormalities were axonal swellings which were surrounded by thin myelin sheaths. Ultrastructurally, the axonal swelling was due to an accumulation of neurofilaments, and was accompanied by a thin and degenerating myelin sheaths. In teased nerve fiber preparations, the most conspicuous change was myelinoclasis represented by segmentation into myelin ovoids or balls. Occasionally, segmental demyelination and axonal degeneration characterized by multifocal axonal swelling were observed. (+info)
Evidence that Wallerian degeneration and localized axon degeneration induced by local neurotrophin deprivation do not involve caspases.
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The selective degeneration of an axon, without the death of the parent neuron, can occur in response to injury, in a variety of metabolic, toxic, and inflammatory disorders, and during normal development. Recent evidence suggests that some forms of axon degeneration involve an active and regulated program of self-destruction rather than a passive "wasting away" and in this respect and others resemble apoptosis. Here we investigate whether selective axon degeneration depends on some of the molecular machinery that mediates apoptosis, namely, the caspase family of cysteine proteases. We focus on two models of selective axon degeneration: Wallerian degeneration of transected axons and localized axon degeneration induced by local deprivation of neurotrophin. We show that caspase-3 is not activated in the axon during either form of degeneration, although it is activated in the dying cell body of the same neurons. Moreover, caspase inhibitors do not inhibit or retard either form of axon degeneration, although they inhibit apoptosis of the same neurons. Finally, we cannot detect cleaved substrates of caspase-3 and its close relatives immunocytochemically or caspase activity biochemically in axons undergoing Wallerian degeneration. Our results suggest that a neuron contains at least two molecularly distinct self-destruction programs, one for caspase-dependent apoptosis and another for selective axon degeneration. (+info)
The macrophage in acute neural injury: changes in cell numbers over time and levels of cytokine production in mammalian central and peripheral nervous systems.
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We evaluated the timing and density of ED-1-positive macrophage accumulation (ED 1 is the primary antibody for the macrophage) and measured cytokine production by macrophages in standardized compression injuries to the spinal cord and sciatic nerves of individual rats 3, 5, 10 and 21 days post-injury. The actual site of mechanical damage to the nervous tissue, and a more distant site where Wallerian degeneration had occurred, were evaluated in both the peripheral nervous system (PNS) and the central nervous system (CNS) at these time points. The initial accumulation of activated macrophages was similar at both the central and peripheral sites of damage. Subsequently, macrophage densities at all locations studied were statistically significantly higher in the spinal cord than in the sciatic nerve at every time point but one. The peak concentrations of three cytokines, tumor necrosis factor &agr; (TNF &agr; ), interleukin-1 (IL-1) and interleukin-6 (IL-6), appeared earlier and were statistically significantly higher in injured spinal cord than in injured sciatic nerve. We discuss the meaning of these data relative to the known differences in the reparative responses of the PNS and CNS to injury. (+info)
Improved functional outcome in patients with hemorrhagic stroke in putamen and thalamus compared with those with stroke restricted to the putamen or thalamus.
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BACKGROUND AND PURPOSE: We analyzed the effect of late intensive inpatient rehabilitation on the functional outcome of patients with subcortical hemorrhagic stroke. METHODS: Patients who were nonambulatory with hemorrhagic stroke in the internal capsule and putamen (n=55), the thalamus (n=24), or all 3 regions (n=15) underwent intensive inpatient rehabilitation. Patients with surgical intervention or an episode of ventricular hemorrhage were excluded. Lesion location was evaluated by MRI 4 months after the ictus. RESULTS: Demographic data, initial disability, and impairment measures were comparable in the 3 groups. Functional outcome demonstrated significant differences in mobility subscores (P<0.05) of the Functional Independence Measure such that patients with injury in the 3 regions were more likely to ambulate independently than were patients in the other groups. Lesion location data demonstrated that the ventral anterior nucleus of the thalamus was always spared; the ventral posterior (lateral and medial) nucleus was always damaged, and the ventral lateral nucleus was frequently damaged. Putaminal damage always included the postcommissural area. In addition, the entire posterior half limb of the internal capsule was always damaged. CONCLUSIONS: Subcortical lesions to multiple structures in the basal ganglia-thalamocortical motor circuits permitted enhanced motor recovery. Lesion location predicted the level of independent ambulation and the rate of recovery in patients with stroke who were nonambulatory before neurorehabilitation therapy. (+info)
A developmentally regulated switch directs regenerative growth of Schwann cells through cyclin D1.
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Sciatic nerve axons in cyclin D1 knockout mice develop normally, become properly ensheathed by Schwann cells, and appear to function normally. However, in the Wallerian degeneration model of nerve injury, the mitotic response of Schwann cells is completely inhibited. The mitotic block is Schwann cell autonomous and developmentally regulated. Rescue analysis (by "knockin" of cyclin E) indicates that D1 protein, rather than regulatory elements of the D1 gene, provides the essential Schwann cell function. Genetic inhibition of the Schwann cell cycle shows that neuronal responses to nerve injury are surprisingly independent of Schwann cell mitotic responses. Even axonal regrowth into the distal zone of a nerve crush injury is not markedly impaired in cyclin D1-/- mice. (+info)