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Results for “selective vulnerability”

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PubMed2000

The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer's disease-associated neurodegeneration and oxidative stress.

In Alzheimer's disease (AD) brains, selected populations of neurons degenerate heavily, whereas others are frequently spared from degeneration. To address the cellular basis for this selective vulnerability of neurons in distinct brain regions, we compared gene expression between the severely affected inferior temporal lobes and the mostly unaffected fronto-parietal cortices by using an mRNA differential display. We identified seladin-1, a novel gene, which was downregulated in large pyramidal neurons in vulnerable regions in AD but not control brains. Seladin-1 is a human homolog of the DIMINUTO/DWARF1 gene described in plants and Caenorhabditis elegans. Its sequence shares similarities with flavin-adenin-dinucleotide (FAD)-dependent oxidoreductases. In human control brain, seladin-1 was highly expressed in almost all neurons. In PC12 cell clones that were selected for resistance against AD-associated amyloid-beta peptide (Abeta)-induced toxicity, both mRNA and protein levels of seladin-1 were approximately threefold higher as compared with the non-resistant wild-type cells. Functional expression of seladin-1 in human neuroglioma H4 cells resulted in the inhibition of caspase 3 activation after either Abeta-mediated toxicity or oxidative stress and protected the cells from apoptotic cell death. In apoptotic cells, however, endogenous seladin-1 was cleaved to a 40 kDa derivative in a caspase-dependent manner. These results establish that seladin-1 is an important factor for the protection of cells against Abeta toxicity and oxidative stress, and they suggest that seladin-1 may be involved in the regulation of cell survival and death. Decreased expression of seladin-1 in specific neurons may be a cause for selective vulnerability in AD.

Aged↗

PubMed1988

The neuroprotective action of ketamine and MK-801 after transient cerebral ischemia in rats.

The neuroprotective activity of two systemically administered N-methyl-D-aspartate (NMDA) receptor antagonists, ketamine and MK-801, were investigated in a long-term recovery model of near-complete forebrain ischemia in the rat. Doses of each drug were chosen on the basis of the known degree and time course of NMDA antagonism seen in vivo after their systemic administration. Ketamine, administered at a dose of 20 mg.kg-1 iv, either immediately before or shortly after the 10-min ischemic period, failed to lessen neuronal damage in the selectively vulnerable hippocampal CA1 region. Increasing doses of ketamine administered over an increasing length of time in the postischemic period, however, did provide significant protection. MK-801 0.25 or 0.5 mg.kg-1 iv administered before ischemia also resulted in significant protection. The results support the proposal that NMDA receptor-mediated events may contribute to neuronal damage in selectively vulnerable regions of the central nervous system after ischemia.

Animals↗

PubMed1990

Regional neuroprotective effects of pentobarbital on ischemia-induced brain damage.

We investigated the neuroprotective effect of pentobarbital, a GABAA receptor-effector, on ischemic neuronal damage in the gerbils. The animals were allowed to survive for 7 days after 10-min ischemia induced by bilateral occlusion of the common carotid arteries. Morphological changes and abnormal calcium accumulation were evaluated in selectively vulnerable areas after ischemia. Pentobarbital (40 mg/kg, IP), administered 30 min prior to ischemia, significantly reduced neuronal cell loss in the neocortex, the striatum, and the hippocampal CA3 sector. However, pentobarbital failed to prevent the damage to the hippocampal CA1 sector and the thalamus. 45Ca autoradiographic study also revealed that a marked calcium accumulation was found in the selectively vulnerable regions after ischemia, which was consistent with the extent of histological neuronal damage. The abnormal calcium accumulation was reduced in the sites corresponding to most of the regions in which the protective effect of pentobarbital was found. The results suggest that ischemia-induced neuronal damage may be partly caused by an imbalance between excitatory and inhibitory input.

Animals↗

PubMed2003

Gene-environment interactions in wet beriberi: effects of thiamine depletion in CD36-defect rats.

Selective vulnerability to thiamine deficiency is known to occur between individuals and within different tissues. However, no comprehensive explanation for this has been found, and there are no reports that reproduce the cardiovascular manifestations of human wet beriberi in animals. We hypothesized that the distinction of substrate reliance, namely, the primary dependency on glucose as substrate, could be an underlying factor in the selective vulnerability of thiamine deficiency. In the setting of impaired fatty acid entry, which occurs in CD36-defect rats, substrate reliance shifts from fatty acid to glucose, which would be expected to lead to a susceptibility to thiamine deficiency. Genomic DNA was analyzed for CD36 defects in three cognate strains of rats [spontaneously hypertensive rats (SHR)/NCrj, SHR/Izm, and Wistar-Kyoto (WKY)/NCrj], which identified the presence of a CD36 defect in SHR/NCrj rats but not in SHR/Izm and WKY/NCrj rats. Treatment with 2 wk of thiamine-depleted chow on 4-wk-old rats of each of these strains resulted in increased body and lung weight in the SHR/NCrj rats but not in the SHR/Izm and WKY/NCrj rats. The increased lung weight in the SHR/NCrj rats was accompanied with histological changes of congestive vasculopathy, which were not observed in either the SHR/Izm or the WKY/NCrj rats. Thiamine-deficient 12-wk-old SHR/NCrj rats demonstrated increased body weight (305.6 +/- 6.2 g in thiamine-deficient rats vs. 280.8 +/- 9.1 g in control; P < 0.0001), lactic acidemia (pH, 7.322 +/- 0.026 in thiamine-deficient rats vs. 7.443 +/- 0.016 in control; P < 0.0001; lactate, 2.42 +/- 0.28 mM in thiamine-deficient rats vs. 1.20 +/- 0.11 mM in control; P < 0.0001) and reduced systemic vascular resistance (4.61 +/- 0.42 x 104 dyn.s.cm-5 in thiamine-deficient rats vs. 6.55 +/- 1.36 x 104 dyn.s.cm-5 in control; P < 0.0001) with high cardiac output (186.0 +/- 24.7 ml in thiamine-deficient rats vs. 135.4 +/- 27.2 ml in control; P < 0.0019). In conclusion, SHR/NCrj rats harboring a genetic defect of long-chain fatty acid uptake present the relevant clinical cardiovascular signs of human wet beriberi, strongly indicating a close gene-environment interaction in wet beriberi.

Animal Feed↗

PubMed1990

Densitometric analysis of cytochrome oxidase in ischemic rat brain.

Elevated brain lactate during incomplete ischemia is thought to contribute to the irreversibility of cell damage by interference with mitochondrial respiratory function, that should be evident in reduced cytochrome oxidase (CO) activity. In this study changes in the density of CO staining in a stroke model in the rat were assessed. Brains were analyzed subsequent to 30 min of ischemia followed by 30 min of reperfusion. The effects of postischemic treatment with sodium dichloroacetate (DCA)--a compound used to decrease lactate, were also evaluated. Examination of lateral cortex, hippocampus, and corpus striatum showed different intensities of CO in a distribution consistent with known regional variations in metabolic activity of the forebrain. Known laminar staining patterns in lateral cortex and areal patterns in the hippocampus were also confirmed. Comparable regions in ischemic forebrain were stained less densely for CO than controls. Image analysis demonstrated that the density of CO: (a) was greater in lateral cortex than hippocampus in control; (b) in ischemics was reduced by an equal degree in cortex and hippocampus; (c) lacked regional uniformity in ischemic rats; and (d) was not changed by DCA treatment in the majority of cases of ischemia. Our results suggest that lactate may not be the major determinant of 'selective vulnerability'. Despite elevated lactate levels in lateral cortex when compared to hippocampus in a previous study, the proportionate decrease in CO activity in lateral cortex and hippocampus was equal. However, there was a considerable decrease in CO activity subsequent to high brain lactate and some ischemic hemispheres appeared to respond to DCA treatment. Therefore, the role of excessive lactate in the exacerbation of 'selective vulnerability' warrants further evaluation. CO histochemistry can be used successfully to determine the distribution of pathology and the quality of fixation of ischemic forebrain. Densitometric measurements allowed comparative assessment of degrees of injury and the effects of treatment in discrete anatomical regions. This kind of analysis may allow localization of pathology within specific cellular circuits.

Acetates↗

PubMed1995

Trauma, axonal injury, and amyotrophic lateral sclerosis: a clinical correlate of a neuropharmacologic model.

Axonal injury induces cell death in selectively vulnerable motor neurons of immature animals. This extensively studied animal model of trauma-induced motor neuron death is being used to develop the theoretical basis for the therapeutic use of neurotrophic factors to "rescue" dying neurons in amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Antecedent trauma has been implicated as a precipitating factor for amyotrophic lateral sclerosis in susceptible individuals. The animal model of trauma-induced motor neuron death provides support for the concept that motor neurons in individuals susceptible to amyotrophic lateral sclerosis may be selectively vulnerable to trauma producing axonal injury. The case histories of six young adult men who developed amyotrophic lateral sclerosis after trauma with axonal injury are presented.

Adult↗

PubMed1991

Peripheral pain fiber function is relatively insensitive to the neurotoxic actions of acrylamide in the rat.

Acrylamide causes degeneration of sensory nerve axons in a range of experimental animals and in humans. Evidence of selective vulnerability of large diameter fibers has been derived largely from histological and electrophysiological measurements. We have examined the effect of repeated doses of acrylamide on the function of small diameter peripheral pain fibers in rats by measuring the intensity of neurogenic edema initiated by chemosensitive nerve endings and assessing the sensitivity of the hind paws to a noxious stimulus. These effects have been compared to the impaired sensorimotor performance (landing foot spread) resulting from acrylamide treatment and the change in functional integrity of the pain fibers following surgical lesioning of the sciatic nerves. Our results show that the selective vulnerability of large over small diameter sensory fibers previously reported in the literature is reflected in the differential impairment of proprioceptive and pain-related functions in the rat.

Acrylamide↗

PubMed1992

Barbiturate promotes post-ischemic reaggregation of polyribosomes in gerbil hippocampus.

A brief period of cerebral ischemia is followed by severe inhibition of protein synthesis which is slowly reversed in the resistant but not in the selectively vulnerable regions of the brain. Inhibition occurs at the translational level, as evidenced by the disaggregation of ribosomes into monosomes. In order to evaluate the importance of this disturbance for the evolution of ischemic injury, the effect of the neuroprotective drug, pentobarbital, on ribosomal aggregation was studied in gerbils subjected to 5 min bilateral carotid artery occlusion. Pentobarbital (50 mg/kg, i.p.) was applied shortly after the ischemia, and the aggregational state of ribosomes was investigated by electron microscopy after recirculation times ranging from 15 min to 1 day. Pentobarbital treatment did not prevent the initial post-ischemic disaggregation but promoted the subsequent reaggregation in the selectively vulnerable neurons. This suggests that post-ischemic application of barbiturates exerts its beneficial effect by reversing the post-ischemic block of ribosomal reaggregation in vulnerable regions.

Animals↗

PubMed1991

Long-term observations on calcium accumulation in postischemic gerbil brain.

We studied delayed postischemic calcium accumulation and neuronal damage in the gerbil brain, using 45Ca autoradiography as a marker for detection of injured tissue and light microscopy. Transient cerebral ischemia was induced for 15 min. Sham-operated gerbils showed no abnormal calcium accumulation and neuronal damage throughout the brain. At 2 and 7 days following 15 min of ischemia, marked calcium accumulation and mild to severe neuronal damage were found in the selectively vulnerable areas such as neocortex, striatum, hippocampus and thalamus, and brainstem such as medial geniculate body, substantia nigra and inferior colliculus. After 1-2 months of recirculation, the calcium accumulation was not recognized in the brainstem. But, the accumulation was still detectable in the striatum, the hippocampus and the thalamus. Morphological study showed that marked proliferation of glia cells was rapid in the inferior colliculus and was relatively slow in the striatum and the hippocampus, although these structures were severely damaged after ischemia. The result suggests that the speed of restoration of injured tissue and the mechanisms for the damage after cerebral ischemia may be different between the selectively vulnerable areas and the brainstem. Furthermore, they suggest that 45Ca autoradiographic technique may provide a useful approach for diagnosis of the restoration of injured tissue at chronic stage following cerebral ischemia.

Animals↗

PubMedDate not supplied

Brain PGD2 and PGE2 changes during posthaemorrhagic hypovolemia in rats.

This study examined the changes of prostaglandins (PGs) E2 and D2 in brain structures of conscious rats during one hour period following acute bleeding. The analyses were performed in brain structures which are important for cardiovascular homeostasis (medulla oblongata, hypothalamus) and these which are not directly involved in central homeostatic mechanisms but are selectively vulnerable to low-flow states (hippocampus, cortex). Haemorrhage was induced by gradual withdrawal of blood from the cannulated right femoral artery (18 ml/kg, LD30) during a 3-min interval. The brain prostanoid contents were measured by radioimmunoassays. The bleeding induced significant changes in brain prostanoid content which were expressed to the highest extent in medulla oblongata and hypothalamus. The time course of the alterations in PGD2 and PGE2 contents was different in m. oblongata and hypothalamus from that in cortex and hippocampus. It was observed that PGE2 and PGD2 levels rose significantly in brain structures which are important for cardiovascular homeostasis and that their alterations were less expressed with different time course in structures which are selectively vulnerable to ischemia. Therefore, the authors suppose that the prostanoid changes in m. oblongata and hypothalamus are induced by the activation of central homeostatic mechanisms rather than by cerebral ischemia produced by haemorrhagic hypotension.

Animals↗

PubMed1981

The role of postischemic recirculation in the development of ischemic neuronal injury following complete cerebral ischemia.

The neuronal response to complete cerebral ischemia (CCI) of 5-15 min duration was evaluated at the light and electron microscopic level subsequent to postischemic recirculation periods of up to 60 min. Following postischemic reperfusion, the homogeneous neuronal changes characteristic of permanent CCI were modified into a heterogeneous pattern of selectively vulnerable neuronal responses. Four basic types of neuronal injury were represented within this heterogeneous neuronal population. The Type I neuronal response was most numerous and consisted of chromatin clumping, nucleolar condensation and a breakdown of polysomes. This response may represent a reversal of some of the neuronal changes observed after permanent CCI. In addition to the above changes, Type II neurons contained swollen mitochondria and Golgi saccules which appeared as microvacuoles under the light microscope. Type III neurons displayed varying degrees of neuronal shrinkage and numerous swollen mitochondria. Type IV neurons were markedly shrunken and electron-dense with few identifiable subcellular structures. The distribution of Type I neurons was random but the other neuronal responses occurred in "selectively vulnerable" brain regions. The number of Type II, III, and IV neurons increased with extended insult durations but were unaffected by the length of recirculation. Ten minutes of CCI represented the threshold for a significant increase in the number of severely altered neurons. These findings suggest that considerable neuronal injury may be present after 10-15 min of CCI, and the lack of a recirculation period following CCI appears to afford the brain parenchyma an extensive degree of structural protection.

Animals↗

PubMed1997

Histopathologic clues to the pathways of neuronal death following ischemia/hypoxia.

This review describes histopathologic observations made with both light and electron microscopy using both conventional staining techniques and histochemistry. Several conditions are analyzed: Ischemic cell change; delayed neuronal death; selective vulnerability. The histopathologic support for the calcium hypothesis and for the excitotoxic hypothesis explaining neuronal death is also reviewed. The findings lead to several suggestions relevant to attempts at developing interventional therapies administered after the onset of ischemia/hypoxia. (1) Except in gerbils, delayed neuronal death and more rapid neuronal death appear to be on the same continuum of cellular events. The lag between ischemia and either onset or termination of these shared events depends upon the severity and/or duration of ischemia/hypoxia. We still do not know whether the "delay," when it occurs, is a delay between ischemia and initiation of the lethal sequence or is, instead, a delay between an immediate initiation of the sequence and its lethal termination. (2) Selective vulnerability (e.g., of CA1 sector in hippocampus) is only relative. The changes are again those of ischemic cell change and are identical to the changes seen elsewhere in more severe ischemia. (3) There is histopathologic support for both the calcium hypothesis and for the cytotoxic hypothesis. Indeed, there is histopathologic support linking the two hypotheses and linking these mechanisms to the appearance of ischemic cell change. However, the histopathologic data are surprisingly sparse. The role of either hypothesis in explaining neuronal death in all areas of brain, in all types of ischemic insult, and at all times following such an insult remains to be established. (3) Apoptosis may be an important mode of neuronal death following ischemia. It differs from acute ischemic cell change; nevertheless, both calcium overload and/or excitotoxic neurotransmitters may trigger apoptosis. (4) Third cell change has been described: Eosinophilic neurons that are not shrunken and whose nuclei are not pyknotic but contain clumped chromatin. The pathogenesis and fate of these neurons remains uncertain. It is possible that they represent early apoptotic neurons. Adequate assessment of apoptosis and its relationship (to both these neurons and to neurons displaying classical ischemic cell change) may depend upon dual staining with conventional aniline dyes and with histochemical techniques designed to detect intranuclear fragments of DNA.

Animals↗

PubMed2004

Continuous remodeling of adult extraocular muscles as an explanation for selective craniofacial vulnerability in oculopharyngeal muscular dystrophy.

Oculopharyngeal muscular mystrophy (OPMD) is an inherited disorder caused by mutations of the polyadenylate binding protein nuclear 1 (PABPN1) gene. While a pathogenic hypothesis has been formulated that links the genetic and molecular abnormalities to cellular abnormalities, there is no proven explanation for the targeting of the craniofacial muscles. We propose a hypothesis that bridges this gap. It is based on the phenomenon of continuous remodeling of normal adult extraocular muscles (EOMs). Unlike the EOMs, the myonuclei of other skeletal muscles are postmitotic in the adult unless the muscles are injured. Continuous myofiber remodeling most likely requires upregulation of genes involved in cell cycling, and in protein degradation and synthesis. PABPN1 is a nuclear protein that performs the essential function of controlling polyadenylation of mRNA and the fidelity of protein synthesis. In OPMD, the ongoing production of mutant PABPN1 in muscles undergoing continuous remodeling could result in a failure of accurate production of mRNA required for the maintenance of the myocytes. Over many years, this would lead to cumulative myonuclear loss and finally to myofiber loss. This hypothesis offers an explanation for the selective involvement of extraocular muscles affected in OPMD and the onset of symptoms in adulthood.

Facial Muscles↗

PubMed1999

A fiber-reinforced composite model of the viscoelastic behavior of the brainstem in shear.

Brainstem trauma occurs frequently in severe head injury, often resulting in fatal lesions due to importance of brainstem in crucial neural functions. Structurally, the brainstem is composed of bundles of axonal fibers distinctly oriented in a longitudinal direction surrounded by an extracellular matrix. We hypothesize that the oriented structure and architecture of the brainstem dictates this mechanical response and results in its selective vulnerability in rotational loading. In order to understand the relationship between the biologic architecture and the mechanical response and provide further insight into the high vulnerability of this region, a structural and mathematical model was created. A fiber-reinforced composite model composed of viscoelastic fibers surrounded by a viscoelastic matrix was used to relate the biological architecture of the brainstem to its anisotropic mechanical response. Relevant model parameters measured include the brainstem's composite complex moduli and relative fraction of matrix and fiber. The model predicted that the fiber component is three times stiffer and more viscous than the matrix. The fiber modulus predictions were compared with experimental tissue measurements. The optic nerve, a bundle of tightly packed longitudinally arranged myelinated fibers with little matrix, served as a surrogate for the brainstem fiber component. Model predictions agreed with experimental measures, offering a validation of the model. This approach provided an understanding of the relationship between the specific biologic architecture of the brainstem and the anisotropic mechanical response and allowed insight into reasons for the selective vulnerability of this region in rotational head injury.

Animals↗

PubMed1997

Effect of brain ischemia and reperfusion on the localization of phosphorylated eukaryotic initiation factor 2 alpha.

Postischemic brain reperfusion is associated with a substantial and long-lasting reduction of protein synthesis in selectively vulnerable neurons. Because the overall translation initiation rate is typically regulated by altering the phosphorylation of serine 51 on the alpha-subunit of eukaryotic initiation factor 2 (eIF-2 alpha), we used an antibody specific to phosphorylated eIF-2 alpha [eIF-2(alpha P)] to study the regional and cellular distribution of eIF-2(alpha P) in normal, ischemic, and reperfused rat brains. Western blots of brain postmitochondrial supernatants revealed that approximately 1% of all eIF-2 alpha is phosphorylated in controls, eIF-2(alpha P) is not reduced by up to 30 minutes of ischemia, and eIF-2(alpha P) is increased approximately 20-fold after 10 and 90 minutes of reperfusion. Immunohistochemistry shows localization of eIF-2(alpha P) to astrocytes in normal brains, a massive increase in eIF-2(alpha P) in the cytoplasm of neurons within the first 10 minutes of reperfusion, accumulation of eIF-2(alpha P) in the nuclei of selectively vulnerable neurons after 1 hour of reperfusion, and morphology suggesting pyknosis or apoptosis in neuronal nuclei that continue to display eIF-2(alpha P) after 4 hours of reperfusion. These observations, together with the fact that eIF-2(alpha P) inhibits translation initiation, make a compelling case that eIF-2(alpha P) is responsible for reperfusion-induced inhibition of protein synthesis in vulnerable neurons.

Animals↗

PubMed1996

Local injection of kainic acid causes widespread degeneration of NADPH-d neurons and induction of NADPH-d in neurons, endothelial cells and reactive astrocytes.

Nitric oxide (NO), a diffusible gas, is a messenger molecule that mediates vascular dilatation and neural transmission. The enzyme nitric oxide synthase (NOS) present in neurons is activated by Ca2+ influx associated with activation of glutamate receptors. Cultured cortical neurons containing NOS are selectively vulnerable to injury by kainic acid (KA). However, the relationship between NOS neurons and excitotoxicity under in vivo conditions is not entirely clear. In the present study, we examined the time course and spatial distribution of changes in NOS neurons caused by an intracortical microinjection of KA in adult rats. NADPH-diaphorase (NADPH-d) histochemistry was used as a marker for NOS and the neuronal changes were correlated with changes in glial cells and endothelial cells. We demonstrated a rapid loss of NADPH-d neurons in the lesion center and degeneration of NADPH-d neurons and nerve terminals throughout ipsilateral cortex and hippocampus; the striatal neurons appeared to be unaffected. Subsequent to cortical neuronal degeneration, new NADPH-d activity appeared in proliferative reactive astrocytes and in endothelial cells at lesion periphery, and in neuronal groups at lesion periphery, in ipsilateral entorhinal cortex and bilateral hippocampus. These findings indicate that neurons expressing NADPH-d in cerebral cortex and hippocampus are selectively vulnerable to KA toxicity in vivo. The subsequent induction of NOS in neural and non-neural cells may be regarded as an adaptive response to the kainate-induced brain lesion.

Animals↗

PubMed1997

Distribution of parvalbumin-immunoreactive neurons in brain correlates with hippocampal and temporal cortical pathology in Creutzfeldt-Jakob disease.

There is a distinctive pattern of hippocampal involvement in Creutzfeldt-Jakob disease (CJD) and evidence for selective vulnerability of GABAergic neurons in experimental and human prion disease. We studied hippocampus and temporal cortex from human CJD and control autopsy brains and surgical cryptogenic temporal lobe epilepsy specimens for distribution and density of parvalbumin (PV) and calbindin-D28K (Cal) -positive neurons that are subpopulations of GABAergic neurons. Pathology was evaluated semiquantitatively in 8 regions in 23 CJD brains for severity of spongiform change, astrogliosis and pathological prion protein deposition. In CJD, pathology was severe in pre-parasubiculum and temporal cortex, and little or absent in CA1-4; PV+ neurons were severely reduced or absent in all cases, whereas Cal+ neurons were largely preserved. In controls, the density of PV+ neurons was highest in pre-parasubiculum and temporal cortex, and lowest in CA1-4. In cTLE, loss of PV+ neurons was seen only in CA1-4. The diffuse and severe loss of PV+ neurons in CJD, and the topographical correlation of tissue lesioning in CJD with density of PV+ neurons in controls suggest selective vulnerability and early loss of this subset of inhibitory neurons in CJD. This might relate to characteristic CJD symptoms such as myoclonus and the distinctive EEG pattern.

Adult↗

PubMed1993

Parvalbumin and calbindin D-28k in the human motor system and in motor neuron disease.

Calbindin D-28k and parvalbumin are neuronal calcium binding proteins of interest in relation to neurodegenerative diseases. Expression of calbindin and parvalbumin may be one of the determinants of selective vulnerability in these disorders. The distribution of these proteins was surveyed in the normal human motor system and in motor neuron disease (MND) using immunocytochemistry in formalin fixed post-mortem tissues. CNS tissues from 14 MND patients (mean age 61.2 years, mean post-mortem delay 24.6 h) and seven controls (mean age 62.6 years, mean post-mortem delay 25.3 h) were studied. Preliminary studies on the effects of fixation were performed. In normal cases upper and lower motor neurons showed absent expression of both proteins. Several neuronal groups characteristically spared in MND showed varying patterns of immunoreactivity: oculomotor neurons showed parvalbumin staining of the perikaryon; the thoracic preganglionic sympathetic neurons showed calbindin staining in perikarya. Onuf's nucleus showed calbindin staining in the neuropil only. In motor neuron disease a loss of ventral horn interneurons and calbindin immunoreactive processes was observed with no other disease related changes in the spinal cord, brain-stem, or motor cortex. These findings are consistent with the hypothesis that the distribution of these proteins is one determinant of selective vulnerability to the neurodegenerative processes in MND acting via disturbance of neuronal calcium homeostasis.

Amyotrophic Lateral Sclerosis↗