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Biomedical subjects

D L Price

Publications and source records attributed to D L Price.

At least 253 records · Page 14Linked to original sources
PubMed1987

Abnormalities in corticotropin-releasing hormone (CRH) in Alzheimer's disease and other human disorders.

CRH-IR is significantly reduced in the cerebral cortex of individuals with AD, PD and PSP. Furthermore, we report that the decreases in CRH-IR in AD are accompanied by reciprocal increases in CRH receptors in affected cortical areas. The changes in pre- and postsynaptic markers for CRH are significantly correlated with decrements in ChAT activity. The demonstration of an up regulation of CRH receptors following a decrease in CRH-IR indicates a physiological relevance of the receptor site and is consistent with the concept that CRH acts as a neurotransmitter in normal cortical functions and that disease of this peptidergic systems may be important in certain clinical manifestations of dementia. While the clinical consequences of the changes in CRH in these various disorders are unclear, future therapies directed at increasing CRH levels in brain may prove useful for treatment.

Acetylcholine↗
PubMed1987

Clinical study evaluating efficacy of praziquantel in clonorchiasis.

In 74 patients with clonorchiasis, the efficacy and safety of praziquantel was evaluated in a two-phase study: a double-blind, randomized controlled trial of praziquantel versus placebo (42 patients) and an open study (32 patients). All but one of the patients were Laotians. The intensity of clonorchiasis was light in 85% (63 of 74) and moderate in 15% (11 of 74) of the patients. Cure based on our established criteria was noted in 67 of 67 patients (100%) treated with praziquantel at a dose of 75 mg/kg per day. In contrast, four patients (20%) in the placebo group, each with light infection, ceased passing eggs and were, according to our established protocol, considered spontaneous cures (P less than 0.0001). Adverse effects of praziquantel were transient and included nausea and vomiting (15%), vertigo (12%), hepatomegaly (4.5%), headache (1.5%), rash (1.5%), and hypotension (1.5%). Of 20 patients who received placebo, 1 (5%) developed transient skin rash, fever, and chills. Clinically minor and transient, but statistically significant, changes in hemoglobin, total protein in serum, and levels of uric acid, cholesterol, and bilirubin in serum were noted. Results of this study showed that praziquantel is safe, well tolerated, and effective and should be considered as the drug of choice for treatment of clonorchiasis. In moderate infections, a second course of praziquantel therapy may be necessary to eliminate infection.

Adolescent↗
PubMed1987

Reductions in corticotropin releasing factor-like immunoreactivity in cerebral cortex in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy.

Dementias occurring in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy are associated with dysfunction and death of neurons in a variety of cell populations, including cholinergic, monoaminergic, and peptidergic systems. In the present investigation of these three disorders, we demonstrated decreased levels of corticotropin releasing factor (CRF)-like immunoreactivity in the frontal, temporal, and occipital poles of the neocortex. Moreover, reductions in peptidergic immunoreactivity correlated with reductions in the activity of choline acetyltransferase, the enzyme that catalyzes the formation of acetylcholine. The reduction in cortical CRF levels may be due to abnormalities of intrinsic cortical neurons or to dysfunction in neurons that contain CRF and innervate cortex.

Aged↗
PubMed1987

Animal models of degenerative neurological disease.

Amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD) are human neurological disorders which occur in middle and late life. These three diseases share certain features: they are slowly progressive; transmitter-specific groups of neurons are selectively affected by disease processes; and affected nerve cells exhibit cytoskeletal pathology. The causes and mechanisms of cell injury are unknown, and there are no treatments which directly affect the disease process. Dysfunction and death of these specific cell groups account for different clinical syndromes. In ALS, patients become paralyzed, at-risk cholinergic motor neurons in the spinal cord develop neurofilamentous swellings of proximal axons, and distal axons atrophy. In PD, affected individuals show slowed movements, tremor, and rigidity. These clinical findings are attributed to regeneration of dopaminergic neurons of the substantia nigra, a cell group showing abnormal accumulations of neurofilament antigens in the form of Lewy bodies. In AD, patients develop dementia (a syndrome of cognitive and memory impairment), and cholinergic neurons of the basal forebrain and certain other populations of nerve cells develop abnormalities of the cytoskeleton. These include perikaryal neurofibrillary tangles and enlarged distal axons which appear as neurites in senile plaques. Certain features of ALS, PD, and AD are recapitulated in three animal models described in this review. Hereditary Canine Spinal Muscular Atrophy (HCSMA), a dominantly inherited motor neuron disease, shows many clinical and pathological features in common with ALS. Affected dogs are clinically weak, have denervation atrophy of muscles, and develop neurofilamentous swellings of proximal axons, atrophy of distal axons, and degeneration of motor neurons. These abnormalities of axonal caliber are associated with impaired transport of the neurofilament triplet proteins and a maldistribution of phosphorylated neurofilaments. Intoxication of macaques with 1-methyl-4-]henyl-1,2,3,6,tetrahydropyridine (MPTP) produces a Parkinsonian syndrome due to selective injury of dopaminergic neurons in the substantia nigra and associated denervation of the striatum. Finally, aged rhesus monkeys (older than 23 years of age) show cognitive and memory deficits and exhibit senile plaques whose neurites are derived from cholinergic and other transmitter systems. Although these macaques do not have AD, they do provide a model for examining the relationships between age-associated cognitive deficits and pathological changes occurring in certain transmitter systems of primates.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1986

Sequestration of tubulin in neurons in Alzheimer's disease.

In Alzheimer's disease (AD), a variety of populations of neurons exhibits cytoskeletal abnormalities, including neurofibrillary tangles (NFT) in perikarya, Hirano bodies in dendrites and filament-distended axons/terminals/dendrites (neurites) in senile plaques. Some nerve cells, particularly pyramidal neurons of the hippocampus, also develop Hirano bodies (paracrystalline arrays of actin) and granulovacuolar degeneration (GVD; granular inclusions in cytoplasmic vacuoles). Since abnormalities of cytoskeletal elements have been implicated in the formation of NFT, neurites and Hirano bodies, the present study was designed to determine whether GVD also may represent a type of cytoskeletal pathology. Sections of hippocampus from controls and from individuals with AD were stained by immunocytochemical methods using monoclonal and polyclonal antibodies directed against a variety of cytoskeletal antigens. Granules of GVD contained tubulin-like immunoreactivity and absorption with purified tubulin abolished staining. Other antigens were not demonstrated in granules when antibodies directed against other cytoskeletal antigens were used. The observation of sequestration of tubulin in granules is consistent with the concept that abnormalities of the neuronal cytoskeleton are an important part of the cellular pathology of AD.

Adult↗
PubMed1986

Basal forebrain neurons provide major cholinergic innervation of primate neocortex.

In 3 monkeys, lesions were made in the basal forebrain by microinjections of ibotenic acid into the nucleus basalis. Bilateral samples of multiple neocortical gyri were assayed for the activity of choline acetyltransferase. Compared to control hemispheres, enzyme activity was reduced up to 69% in the neocortex ipsilateral to the lesion; in addition, acetylcholinesterase staining was decreased at the lesioned site and in the ipsilateral cortex. These results support the concept that the principal cholinergic innervation of the primate neocortex is derived from axons and nerve terminals of neurons whose perikarya are located in the basal forebrain, particularly the nucleus basalis.

Animals↗
PubMed1986

Nicotinic acetylcholine binding sites in Alzheimer's disease.

In Alzheimer's disease (AD), there is a loss of presynaptic cholinergic markers in the cerebral cortex, but the nature of cholinergic receptor changes is unclear. In this study, [3H]acetylcholine and [3H]nicotine were used to label nicotinic cholinergic binding sites in cerebral cortical tissues obtained at autopsy from patients with AD and from matched controls. A consistent and severe loss of nicotinic receptors was found in AD.

Acetylcholine↗
PubMed1986

Immunocytochemical studies of neurofilament antigens in the neurofibrillary pathology induced by aluminum.

Intrathecal administration of aluminum salts induces accumulation of neurofilaments in axons and perikarya of motor neurons and is associated with impaired axonal transport of neurofilament proteins. Because phosphorylation of the 200-kilodalton (kd) neurofilament protein, thought to be a major component of the sidearms, seems to be important in interactions of neurofilaments with other cytoskeletal elements, we have postulated that aluminum may produce neurofibrillary pathology by altering patterns of neurofilament phosphorylation. To test this hypothesis, antibodies against phosphorylated and non-phosphorylated neurofilament epitopes were used for immunocytochemical analysis of spinal cord sections from aluminum-injected rabbits. In control animals, phosphorylated 200-kd neurofilament proteins were not demonstrable in perikarya of motor neurons. In experimental rabbits, perikarya and proximal axons of affected motor neurons showed striking accumulations of immunoreactivity of one phosphorylated epitope. The presence of phosphorylated 200-kd neurofilament proteins in these regions may have important consequences for the organization of the cytoskeleton and for the transport of neurofilaments. A similar, but not identical, pattern of accumulation of phosphorylated neurofilament immunoreactivity has recently been observed in neurofibrillary tangles in Alzheimer's disease.

Aluminum↗
PubMed1986

Structural correlates of physiological abnormalities in beta, beta'-iminodipropionitrile.

beta, beta'-Iminodipropionitrile (IDPN) produces neurofilamentous giant axonal swellings in proximal internodes of large myelinated axons. Secondary demyelinative changes result from the production of these axonal enlargements. Electrophysiological studies have demonstrated profound alterations in the electrical properties of motor neurons (MN) within the spinal cord. On the basis of intracellular recordings, it has been suggested that electrical contacts may exist between swollen axons and neighboring MN. In addition, the possibility remained that synaptic contacts develop on demyelinated axonal swellings. In the present study, we report the lack of either synapses on demyelinated axonal swellings or direct electrical contacts between neighboring MN. Axonal swellings are surrounded by attenuated processes of glial cells (probably fibrillary astrocytes), a finding discussed in terms of its possible role in the production of ephaptic transmission. There was considerable variation in the degree of axonal enlargements and in the extent of secondary (passive and active) demyelination. It is suggested that these morphological changes may represent structural correlates of some electrophysiological alterations observed in IDPN neuropathy.

Animals↗
PubMed1986

Injury of nigral neurons exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: a tyrosine hydroxylase immunocytochemical study in monkey.

Six monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine developed a Parkinsonian syndrome (rigidity, akinesia, flexed posture and tremor). In both high and low dose groups, neurons in the substantia nigra were selectively damaged. At high dose levels, nigral neurons were severely damaged, but because the monkeys died, the evolution of the pathology could not be studied. At low dose levels, some nigral neurons survived, and a significant number of these nerve cells showed reductions in the immunoreactivity of tyrosine hydroxylase. Axonal pathology was conspicuous in the nigrostriatal pathway. Loss of the immunoreactivity of tyrosine hydroxylase in perikarya may represent a retrograde axonal reaction, a potentially reversible response. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model should prove useful for investigating abnormalities occurring as a consequence of dysfunction of the nigrostriatal system, for examining processes associated with repair of damaged neuronal systems, and for developing and testing therapeutic approaches designed to prevent or ameliorate the Parkinsonian syndrome.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Phosphorylated neurofilament antigens in neurofibrillary tangles in Alzheimer's disease.

Neurofibrillary tangles (NFT) are a hallmark of Alzheimer's disease (AD), and their presence correlates with the presence of dementia. A major constituent of NFT is the insoluble paired helical filament which shares some antigenic relationships with normal cytoskeletal elements, particularly neurofilaments. If neurofilament proteins (200, 145-160, and 68 kilodaltons [kd]) participate in the formation of NFT, the distribution of these constituents might be expected to be abnormal. To examine this issue, we used immunocytochemical methods to localize phosphorylated and nonphosphorylated epitopes of neurofilament proteins in hippocampal neurons of controls and patients with AD. Normally, the 200-kd neurofilament protein is not phosphorylated in the perikarya of neurons. However, in AD, many pyramidal neurons contained immunoreactive phosphorylated neurofilaments. Patterns of immunoreactivity (linear, flame-shaped, or skein-like within perikarya) greatly resembled the appearance of silver-stained NFT. This pattern of immunoreactivity was not present in hippocampal pyramidal neurons in controls, except in one aged patient in whom adjacent silver-stained sections revealed a few NFT. Patterns of immunoreactivity with antibodies for nonphosphorylated neurofilament proteins were similar in control and AD neurons. Our results indicate that some NFT are associated with abnormal distributions of high molecular weight phosphorylated neurofilament proteins. One domain of the 200-kd protein is believed to be a component of the side arms which link neurofilaments and interact with microtubules. Abnormal interactions of perikaryal neurofilaments could play a role in the genesis of NFT, and this abnormality of the cytoskeleton could contribute to the dysfunction of neurons at risk in AD.

Aged↗
PubMed1986

New perspectives on Alzheimer's disease.

Significant progress has been made in refining diagnostic criteria for AD and in developing imaging approaches to exclude treatable disease and to assess some of the metabolic processes occurring in vivo in the brains of individuals with AD. However, as yet, no reliable diagnostic test is available. Although risk factors have been identified, the etiology of AD remains an enigma. The roles of familial, chromosomal, and genetic factors, toxins, and transmissible agents in the pathogenesis of this disease deserve intensive study. A variety of neurotransmitter systems are affected in the disease, and it seems likely that new approaches may identify additional systems at risk. Of particular importance will be studies on surviving neurons, since these cells will be targets for treatment. Neurons in certain parts of the brainstem, basal forebrain, amygdala, hippocampus, and neocortex show several types of cytoskeletal abnormalities, but mechanisms of cytoskeletal disorganization are not well understood, e.g. we do not have a clear idea of the sequence of cytoskeletal pathology, the time course of dysfunction of individual neurons, and consequences of these processes on cell function. In situ hybridization with radiolabeled nucleic acid probes and immunocytochemical approaches should provide information about levels of gene expression, protein compositions, and posttranslational modifications of normal and abnormal proteins in these cells. The relationships and sources of some of the abnormal proteins (e.g. those associated with PHF, 15-nm straight filaments, plaque amyloid, and vascular amyloid) can be clarified by new approaches of protein chemistry (purification and sequencing) and molecular biology (recombinant DNA techniques). Finally, investigations of animal models that recapitulate certain features of AD should provide new insights into the nature, mechanisms, and consequences of cellular pathology of specific systems. These models may be useful for imaging studies similar to those used in human patients and for developing and testing new therapeutic approaches that eventually may be useful for treating this all-too-common disorder of the central nervous system.

Acetylcholine↗
PubMed1986

Hematogenous origin of brain macrophages: a case report.

Del Río-Hortega believed that phagocytic cells in the CNS arise from microglia; however, recent autoradiographic studies have suggested a hematogenous origin for brain macrophages. To clarify this issue, we studied a young man with acute lymphoblastic leukemia and a peripheral white blood cell count of 22/mm3 who had an embolic brain infarct 2 weeks before he died. Macrophages were scarce within the lesion, suggesting that the principal phagocytic cell is hematogenous.

Adolescent↗
PubMed1985

Senile plaques in cortex of aged normal monkeys.

The density, type, and distributions of cortical senile plaques were determined in 6 aged rhesus monkeys. Plaque densities were highest in prefrontal and temporal cortices and lowest in occipital cortex. Neurite plaques contained many argentophilic neurites and little amyloid, mixed plaques had both neurites and amyloid, and amyloid plaques showed significant amounts of amyloid and fewer numbers of neurites. As total plaque density increased, there was a linear increase in the density of amyloid plaques, suggesting that plaques evolve from neurite, to mixed, to amyloid types.

Aging↗