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Results for “selective vulnerability”

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PubMed1986

Monoamine neurotransmitters in diffuse reversible forebrain ischemia and early recirculation: increased dopaminergic activity.

Regional levels of brain monoamines and their metabolites were examined in a rat model of reversible and diffuse forebrain ischemia with and without reperfusion. During ischemia, blood flow decreased by 87 to 95%, but recovered to control values during recirculation. Norepinephrine and serotonin decreased in the cerebral cortex and hippocampus during ischemia and diminished further during recirculation. On the other hand, dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, which were not much affected by ischemia, increased markedly in the cerebral cortex and striatum during recirculation, with a decrease in the ratio of dopamine to its metabolites. These results suggest central dopaminergic hyperactivity during recirculation, which may be related to the selective vulnerability of the striatum in similar models of reversible forebrain ischemia.

Animals↗

PubMed1987

Size-dependent myelinated fiber loss in the corticospinal tract in Shy-Drager syndrome and amyotrophic lateral sclerosis.

Morphometric evaluation was performed on myelinated fibers of the corticospinal tract at the seventh thoracic spinal cord segment from three patients with Shy-Drager syndrome (SDS), six patients with amyotrophic lateral sclerosis (ALS), and five patients with nonneurologic symptoms. In SDS, small-sized myelinated fibers were nearly completely depleted, while large-sized myelinated fibers were considerably well preserved. In ALS, on the contrary, large myelinated fibers were predominantly decreased. These results suggested that selective vulnerability of axonal loss depends on fiber size and should be considered in interpretation of pathology of corticospinal tracts.

Amyotrophic Lateral Sclerosis↗

PubMed1987

The potential beneficial effect of nicardipine in a rat model of transient forebrain ischemia.

In a rat 3-day survival model of 10-minute four-vessel occlusion, halothane anesthesia was used to attenuate the ictal blood pressure elevation of the cerebral ischemic response and thereby maintain an isoelectric EEG. Selectively vulnerable regions of the brain were protected by preischemia plus postischemia maintenance treatment with the calcium entry blocker nicardipine. Compared with untreated animals, repeated doses at 500 micrograms/kg IP were markedly more effective than doses of 50 micrograms/kg. Ongoing studies demonstrate a neurocytoprotective action of nicardipine when deferred treatment is given postischemia.

Animals↗

PubMed1987

Retrograde transport and differential accumulation of serum proteins in motor neurons: implications for motor neuron diseases.

We found immunocytochemical evidence of serum albumin and immunoglobulin G in motor neurons of rats under physiologic conditions, but not when axoplasmic flow was abolished. The amount of serum proteins was highest in somatic motor neurons of the spinal anterior horn, nucleus ambiguous, and trigeminal motor nucleus; less in hypoglossal and facial neurons; and sparse in preganglionic autonomic, oculomotor, and hypothalamic neurons. Toxic or trophic substances, bound to serum proteins, could also be incorporated into motor neurons. Quantitative differences in accumulation paralleled the selective vulnerability of somatic motor neurons in motor neuron diseases.

Animals↗

PubMed1991

Adult Reye's syndrome: a review with new evidence for a generalized defect in intramitochondrial enzyme processing.

A 42-year-old woman developed a flu-like illness and died 8 days later with Reye's syndrome (RS). There are 26 other cases of adult-onset RS reported. Biochemical, immunologic, and molecular studies of liver, brain, and skeletal muscle revealed a non-uniform decrease in several mitochondrial residual enzyme activities in liver and brain. Pyruvate carboxylase activity was negligible. Cross-reacting material was present in normal abundance in isolated liver mitochondria for several enzymes that had reduced catalytic activity including pyruvate carboxylase. Subunit II (encoded by mitochondrial DNA) and subunit IV (encoded by nuclear DNA) of cytochrome c oxidase also were present in normal abundance with normal electrophoretic mobility. These observations, combined with pertinent findings of other investigators, allow us to speculate that the intramitochondrial matrix chemical environment is disturbed by preceding pathophysiologic events resulting in a lowered ATP/ADP ratio. The lowered intramitochondrial energetic state interferes with the refolding and assembly of imported mitochondrial proteins, causing a loss of the catalytic efficiency of these enzymes. This explains the selective vulnerability of mitochondria in RS and the non-uniform, disproportionate loss of enzyme activity.

Adult↗

PubMed1991

Volumetric atrophy of the amygdala in Alzheimer's disease: quantitative serial reconstruction.

The present study quantitatively assessed volumes of the amygdala and its subnuclei in autopsied cases of advanced Alzheimer's disease (AD) for comparison with age-matched controls. Amygdalar nuclei showed significant atrophy in AD with the exception of the paralaminar portion of the basal nucleus. The magnocellular regions of the amygdala showed proportionately greater size reductions as a fraction of total amygdala volume than did other areas. Computerized reconstruction of the amygdala provided three-dimensional views of a variety of structural alterations accompanying the volumetric declines with AD. The apparent selective vulnerability of the magnocellular amygdalar areas coincides with the loss of large nerve cells in AD.

Alzheimer Disease↗

PubMed1991

New pathologic observations in juvenile onset parkinsonism with dystonia.

A patient with hereditary juvenile onset parkinsonism with dystonia died at age 39. There were Lewy bodies and regionally selective neuronal damage in the substantia nigra pars compacta. These changes closely resemble those seen in Parkinson's disease, and emphasize the selective vulnerability of the ventral tier of the pars compacta in these degenerations.

Adult↗

PubMed1998

Vigabatrin-associated retinal cone system dysfunction: electroretinogram and ophthalmologic findings.

OBJECTIVE: To determine the sources of vigabatrin-associated visual disturbances in patients treated for epilepsy. BACKGROUND: Vigabatrin is an extremely effective antiepileptic drug that selectively increases brain gamma-aminobutyric acid (GABA). Several patients recently developed constricted visual fields during vigabatrin treatment in the United Kingdom, indicating the possibility of GABA-associated retinal dysfunction. METHODS: Patients with visual symptoms treated chronically with vigabatrin at our center underwent visual evoked potentials (VEP), electroretinograms (ERG), and visual field and ophthalmologic examinations. RESULTS: Four of 38 patients treated with vigabatrin developed visual symptoms 2 to 40 months after starting the drug. Two patients complained of constricted visual fields and two had blurred vision. ERG demonstrated evidence of bilateral retinal dysfunction consistent with reduced inner retinal cone response in all four patients. Oscillatory potential responses were lost, suggesting impairment of the highly GABAergic amacrine cells. Two of the patients had normal VEPs and minimal findings on clinical ophthalmology examinations despite abnormal ERGs. Abnormal examination findings were narrowed retinal arteries, surface wrinkling retinopathy, and abnormal macular reflexes. One patient also had reduced rod photoreceptor function in the more symptomatic left eye. CONCLUSIONS: Visual field constriction and blurring during vigabatrin therapy is associated with retinal cone system dysfunction. Visual symptoms may represent selective vulnerability of retinas of affected patients to GABAergic effects of vigabatrin. The prevalence and course of retinal changes associated with vigabatrin therapy are important to determine in a larger group of patients.

Adult↗

PubMed2001

Transgenic mouse models of tauopathies: prospects for animal models of Pick's disease.

Because filamentous neuronal tau inclusions are neuropathologic hallmarks of Pick's disease and a number of other neurodegenerative disorders known as tauopathies, the authors generated lines of transgenic (Tg) mice that overexpress the shortest human tau isoform in the CNS. These Tg mice accumulated argyrophilic and filamentous tau immunoreactive neuronal inclusions with age in cortex and brainstem as well as in spinal cord, where these inclusions were most abundant and associated with gliosis. The ventral roots of affected spinal cord segments showed axonal degeneration, whereas residual axons exhibited reduced microtubules and reduced fast axonal transport. The inclusions were composed of 10 to 20 nm tau immunopositive straight filaments. In addition, the Tg mice developed age-related motor weakness as well as progressive hyperphosphorylation and decreased solubility of brain and spinal cord tau proteins. Thus, these Tg mice recapitulate phenotypic features of human tauopathies. In this article the authors review the phenotype of these Tg mice and discuss how the availability of relevant animal model of tauopathies will facilitate discovery of more effective therapies to treat Pick's disease and related disorders characterized by filamentous tau pathology in selectively vulnerable regions of the CNS.

Animals↗

PubMed2002

FADD: A link between TNF family receptors and caspases in Parkinson's disease.

Fas-associating protein with a death domain (FADD) is a proximal adaptor protein of the tumor necrosis factor (TNF) receptor family death pathway. This human postmortem study showed a significant decrease in the percentage of FADD-immunoreactive dopaminergic (DA) neurons in the substantia nigra pars compacta of patients with PD compared with controls (-24.8%). This decrease correlated with the known selective vulnerability of nigral DA neurons in PD, suggesting that this pathway contributes to the susceptibility of DA neurons in PD to TNF-mediated apoptosis.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Genetically engineered models relevant to neurodegenerative disorders: their value for understanding disease mechanisms and designing/testing experimental therapeutics.

Significant progress in the identification of disease-specific genes for a variety of neurodegenerative diseases have provided opportunities to understand molecular mechanisms and to test experimental therapeutic for these disorders. Recent works on clarifying the selective vulnerability of neurons and pathogenic mechanisms using genetically engineered mouse models of familial forms of Alzheimer's disease and motor neuron disease will be reviewed.

Alzheimer Disease↗

PubMed2004

Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease.

The mechanism that controls the selective vulnerability of striatal neurons in Huntington's disease is unclear. Brain-derived neurotrophic factor (BDNF) protects striatal neurons and is regulated by Huntingtin through the interaction with the neuron-restrictive silencer factor. Here, we demonstrate that the downregulation of BDNF by mutant Huntingtin depends on the length and levels of expression of the CAG repeats in cell cultures. To analyze the functional effects of these changes in BDNF in Huntington's disease, we disrupted the expression of bdnf in a transgenic mouse model by cross-mating bdnf(+/ -) mice with R6/1 mice. Thus, we compared transgenic mice for mutant Huntingtin with different levels of BDNF. Using this double mutant mouse line, we show that the deficit of endogenous BDNF modulates the pathology of Huntington's disease. The decreased levels of this neurotrophin advance the onset of motor dysfunctions and produce more severe uncoordinated movements. This behavioral pathology correlates with the loss of striatal dopamine and cAMP-regulated phosphoprotein-32-positive projection neurons. In particular, the insufficient levels of BDNF cause specific degeneration of the enkephalinergic striatal projection neurons, which are the most affected cells in Huntington's disease. This neuronal dysfunction can specifically be restored by administration of exogenous BDNF. Therefore, the decrease in BDNF levels plays a key role in the specific pathology observed in Huntington's disease by inducing dysfunction of striatal enkephalinergic neurons that produce severe motor dysfunctions. Hence, administration of exogenous BDNF may delay or stop illness progression.

Age of Onset↗

PubMed2004

Neuron-specific mRNA complexity responses during hippocampal apoptosis after traumatic brain injury.

In an effort to understand the complexity of genomic responses within selectively vulnerable regions after experimental brain injury, we examined whether single apoptotic neurons from both the CA3 and dentate differed from those in an uninjured brain. The mRNA from individual active caspase 3(+)/terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling [TUNEL(-)] and active caspase 3(+)/TUNEL(+) pyramidal and granule neurons in brain-injured mice were amplified and compared with those from nonlabeled neurons in uninjured brains. Gene analysis revealed that overall expression of mRNAs increased with activation of caspase 3 and decreased to below uninjured levels with TUNEL reactivity. Cell type specificity of the apoptotic response was observed with both regionally distinct expression of mRNAs and differences in those mRNAs that were maximally regulated. Immunohistochemical analysis for two of the most highly differentially expressed genes (prion and Sos2) demonstrated a correlation between the observed differential gene expression after traumatic brain injury and corresponding protein translation.

Animals↗

PubMed1988

Verbal and nonverbal abstracting--problem-solving abilities and familial alcoholism in female alcoholics.

Women alcoholics (N = 54) had significantly worse performance on clusters of verbal and nonverbal abstracting - problem-solving tasks than peer nonalcoholic controls (N = 48). On the nonverbal cluster, alcoholic women with an alcoholic parent or sibling (FH+) performed significantly poorer than peer alcoholics without such a family history (FH-) and nonalcoholic FH+ and FH- groups. On the verbal cluster, FH+ alcoholics performed significantly worse than the nonalcoholic groups. FH- alcoholics did not differ significantly from the nonalcoholic groups on either of the clusters. There were no differences between FH+ and FH- nonalcoholics on the two types of tasks. The results suggest that female alcoholics have a generalized deficit on cognitive tasks involving abstracting and problem-solving, and that these deficits tend to be more pronounced in alcoholic women with a positive family history of alcohol abuse. Whether these deficits are due to a premorbid lowering of abstracting - problem-solving abilities in the FH+ individuals who subsequently become alcoholics, or are the result of a selective vulnerability of these cognitive processes to the effects of alcohol abuse in such subjects, or some combination of these factors, remains to be investigated.

Adult↗

PubMed2005

Alpha-synuclein targets the plasma membrane via the secretory pathway and induces toxicity in yeast.

A pathological feature of Parkinson's disease is the presence of Lewy bodies within selectively vulnerable neurons. These are ubiquitinated cytoplasmic inclusions containing alpha-synuclein, an abundant protein normally associated with presynaptic terminals. Point mutations in the alpha-synuclein gene (A30P and A53T), as well as triplication of the wild-type (WT) locus, have been linked to autosomal dominant Parkinson's. How these alterations might contribute to disease progression is unclear. Using the genetically tractable yeast Saccharomyces cerevisiae as a model system, we find that both the WT and the A53T isoforms of alpha-synuclein initially localize to the plasma membrane, to which they are delivered via the classical secretory pathway. In contrast, the A30P mutant protein disperses within the cytoplasm and does not associate with the plasma membrane, and its intracellular distribution is unaffected by mutations in the secretory pathway. When their expression is elevated, WT and A53T, but not A30P, are toxic to cells. At moderate levels of expression, WT and A53T induce the cellular stress (heat-shock) response and are toxic to cells bearing mutations in the 20S proteasome. Our results reveal a link between plasma membrane targeting of alpha-synuclein and its toxicity in yeast and suggest a role for the quality control (QC) system in the cell's effort to deal with this natively unfolded protein.

Amino Acid Substitution↗

PubMed1995

Amyotrophic lateral sclerosis.

The final cascade of amyotrophic lateral sclerosis (ALS) coincides with the onset of clinical neurological deficits and involves multifactorial interactive mechanisms. These terminal events include excitotoxicity, free radical accumulation and possibly immunological disturbances. They are probably predated by months or years by thus far unidentified triggers. Selective vulnerability of the corticomotneuronal system in ALS is likely due to degradation of several gene products essential to transmitter, receptor and nerve growth factor maintenance specific to this functional system. Therapeutic strategies involve neuroprotection, symptomatic and combination neuronal therapy targeted to the final cascade of ALS.

Amyotrophic Lateral Sclerosis↗

PubMed1997

Evoked potentials in patients with chronic respiratory insufficiency.

P300, somatosensory evoked potential (SEP) and brainstem auditory evoked potential (BAEP) are widely used neurophysiological methods for objectively evaluating cognitive, somatosensory and brainstem auditory functions. We studied the P300, SEP and BAEP in 17 patients with chronic respiratory insufficiency (PaO2:58.2 +/- 7.0 mmHg; mean +/- SD) and 15 age-matched healthy subjects (PaO2: 84.4 +/- 11.3 mmHg). The latency and amplitude of P300, the N9 latency, N9-N13 and N13-N20 interpeak latencies (IPL) in SEP, wave I latency and I-V IPL in BAEP were compared between the patients and controls. The P300 latency, N9-N13 and N13-N20 IPLs in SEP in the patients were significantly prolonged compared to the controls. In contrast, the amplitude of P300, N9 latency in SEP, wave I latency and I-V IPL in BAEP were not significantly different between the patients and controls. These results suggest that chronic respiratory insufficiency influences the cognitive and somatosensory functions, and indicate that there is a selective vulnerability of evoked potentials to this condition.

Aged↗

PubMed1999

Effect of cerebrospinal fluid shunting on experimental syringomyelia: magnetic resonance imaging and histological findings.

The histological changes associated with syringomyelia after reduction of the syrinx size were investigated after cerebrospinal fluid shunting in experimental syringomyelia in the rabbit. Five weeks after syringomyelia was induced by the injection of kaolin into the cisterna magna in Japanese white rabbits, ventriculosubgaleal shunting or syringoepidural shunting were performed. After 1 week magnetic resonance (MR) imaging and histological examination were then carried out. Five of 11 shunted animals showed postoperative reduction of syrinx size on MR imaging. Grossly, some specimens showed cavity collapse and parenchymal healing, and others showed a small residual syrinx in the dorsal horn. The most dramatic histological changes occurred in the gray matter. Specimens with syrinx collapse showed rarefaction and tearing of the gray matter, with mild glial reaction. The edematous gray matter showed both degeneration and regeneration, with neuronal processes surrounded by edema fluid. Reactive astrocytes were observed mainly at the margin of the residual syrinx. Some astrocytic processes invested the extraaxonal space and gray matter lacked supportive tissue. Greater reduction of the syrinx after shunting operation was correlated with more regeneration and less degeneration, and the white matter was edematous and histological changes were milder. Syrinx shrinkage occurred after shunting in this experimental model of syringomyelia. The selective vulnerability of gray matter even after shunting may explain discrepancies between imaging findings and clinical features in this disease. The study supports the potential benefit from early treatment, considering the associated morphological findings of regeneration.

Animals↗