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Biomedical subjects

L C Walker

Publications and source records attributed to L C Walker.

At least 91 records · Page 5Linked to original sources
PubMed1988

Multiple transmitter systems contribute neurites to individual senile plaques.

Senile plaques (SP), which consist largely of abnormal neuronal processes in proximity to deposits of amyloid, are a characteristic neuropathological feature of Alzheimer's disease. In lesser numbers, SP also occur in the brains of nondemented aged humans and nonhuman primates. To date, it is not known whether neurites in individual SP derive from neurons of one or several neurotransmitter systems. In aged monkeys, two strategies were used to test the hypothesis that individual SP can contain abnormal neurites arising from multiple neuronal systems. First, immunocytochemical methods were used to identify somatostatin-immunoreactive neurites in plaques, and these sections were subsequently stained with silver to visualize other neurites. Numerous plaques contained both somatostatin-positive and somatostatin-negative (i.e. argyrophilic only) neurites, suggesting that more than one transmitter system contributed neurites to each of these plaques. Second, two-color immunocytochemical techniques showed, in a small percentage of plaques, that cholinergic neurites coexist with neuropeptide Y (NPY)-containing neurites or catecholaminergic neurites. These results suggest that the formation of SP may result from events that involve abnormalities of neuronal processes arising from multiple transmitter systems.

Alzheimer Disease↗
PubMed1987

Corticotropin-releasing factor as a transmitter in the human olivocerebellar pathway.

This study demonstrates that the neuropeptide, corticotropin-releasing factor (CRF), is present in neurons of the human inferior olivary complex (IOC). The medulla (including the inferior olive) and the anterior vermis of the cerebellum of 6 human controls obtained at autopsy were immunostained with an antibody directed against CRF. CRF receptors in cerebellum were localized with labeled CRF using in vitro receptor autoradiography. The great majority of neurons in all divisions of the IOC expressed CRF immunoreactivity, and CRF-immunoreactive fibers were demonstrated in the hilus of the olive and in the molecular layer of the cerebellum, where they closely resembled climbing fibers as visualized with other methods. CRF receptors were enriched in the cerebellum, with the highest density in inner portions of the molecular layer. These findings in human brain, consistent with studies in tissues from rat, cat, and monkey, demonstrate that CRF may be a peptidergic transmitter in the IOC climbing fiber system and that CRF receptors are expressed by cellular targets in the cerebellum.

Adult↗
PubMed1987

Dysfunction and death of neurons in human degenerative neurological diseases and in animal models.

The human neurological disorders--amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD)--share certain features: they occur in later stages of adult life; are slowly progressive; and involve specific groups of nerve cells. Different clinical syndromes result from dysfunction and death of these specific groups of neurons. In ALS, patients are weak due to disease of motor neurons in the spinal cord. The clinical features of PD, e.g. slow movements, tremor and rigidity, are attributed, in part, to degeneration of dopaminergic neurons of the substantia nigra. Impairments of cognition and memory in AD result from disease of neurons in a number of regions, including brainstem, basal forebrain, amygdala, hippocampus, and neocortex. In each of these diseases, affected neurons exhibit abnormalities of the neuronal cytoskeleton: in ALS, neurofilaments accumulate and distend proximal motor axons; in PD, nigral perikarya show Lewy bodies-intracytoplasmic inclusions containing neurofilament antigens; in AD, neurons develop neurofibrillary tangles, Hirano bodies, granulovacuolar degeneration and filament-filled neurites in plaques. Certain features of ALS, PD and AD are recapitulated in animal models, three of which are 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, including weakness, muscle atrophy, neurofilamentous swellings of proximal axons, impaired transport of neurofilament proteins, and degeneration of motor neurons. In primates, intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a parkinsonian syndrome due to injury of nigral dopaminergic neurons and associated denervation of the striatum. Finally, aged macaques exhibit memory deficits, and their cerebral cortices show senile plaques and filament-filled neurites derived from a variety of transmitter-specific populations of nerve cells. In human diseases, the causes and mechanisms leading to dysfunction and death of nerve cells are unknown. Investigators have begun using a variety of techniques derived from neurobiology to study animal models in an effort to clarify the mechanisms, evolutions, and consequences of structural-chemical abnormalities occurring in different neuronal systems implicated in human disease. Understanding such processes in these models should provide important new insights into the pathogeneses of similar processes occurring in ALS, PD and AD.

Animals↗
PubMed1987

Loss of pedunculopontine neurons in progressive supranuclear palsy.

In the present study, the number of neurons (greater than 20 microns in diameter) within the lateral part of the pedunculopontine nucleus pars compacta (PPNc) was determined at six rostrocaudal levels in 3 subjects with progressive supranuclear palsy (PSP), in 9 subjects with Alzheimer's disease, and in 6 age-matched control subjects. At each level examined, significantly fewer neurons were present in patients with PSP than in control subjects (49 to 69% reduction). Significant differences in numbers of neurons were not demonstrated between control subjects and patients with Alzheimer's disease. The extent of pathological changes, particularly neurofibrillary tangles, was examined within the PPNc of subjects in these three groups. The average number of neurofibrillary tangles in a 12-microns-thick midlevel section of the lateral PPNc was 68.7 in subjects with PSP, 18.3 in those with Alzheimer's disease, and 3.0 in aged control subjects. These abnormalities of PPNc neurons in PSP may play important roles in some of the clinical features characteristic of this disease.

Aged↗
PubMed1987

Immunohistochemical study of neurons containing corticotropin-releasing factor in Alzheimer's disease.

In the brains of controls and individuals with Alzheimer's disease (AD), antisera to corticotropin-releasing factor (CRF) were used to immunostain neurons and their processes. In AD, we identified abnormal CRF-immunoreactive axons as well as neurites associated with deposits of amyloid in brain regions showing senile plaques. The number of immunoreactive fibers was decreased in individuals with AD. In contrast, CRF immunoreactivity was markedly increased in some neurons located within the paraventricular nucleus (PVN) of the hypothalamus. These findings support previous neurochemical studies indicating that certain CRF systems are affected in AD.

Adult↗
PubMed1987

An autoradiographic study of the development of [3H]hemicholinium-3 binding sites in human and baboon basal ganglia: a marker for the sodium-dependent high affinity choline uptake system.

The developmental distribution of the sodium-dependent high affinity choline uptake (SDHACU) system has been studied in the caudate and putamen of the baboon and of the human by in vitro autoradiography with the ligand, [3H]hemicholinium-3 [( 3H]HCh3). Our results show that [3H]HCh3 binding sites in the newborn baboon and fetal human neostriatum are localized to patches, and then adopt a 'striosome-like' distribution in the juvenile baboon brain. These findings indicate a reorganization of [3H]HCh3 binding site distribution during the ontogeny of the primate neostriatum.

Acetylcholinesterase↗
PubMed1987

Cross-reactive variable-region associated epitopes of human IgG1 lambda paraprotein detected by a monoclonal antibody panel.

This paper describes the production and characterization of a panel of 15 mouse monoclonal antibodies selected for putative activity against V-region related or allotypic determinants of a single IgG1 lambda paraprotein obtained from a patient with malignant lymphoplasmacytoid lymphoma. The specificity of each reagent for epitopes on the heavy (H) or light (L) chain or for conformational determinants (CD) of the immunogen was determined and the ability of one reagent to compete with another for these sites investigated. The fine specificity of the antibodies was assessed by screening on a large series of normal and paraprotein-containing sera. One monoclonal showed specificity for the Glm(f) allotype. The 14 other reagents identified a minimum of nine different epitopes in the V region of the immunogen, with four antibodies detecting private conformationally determined idiotypic specificities. Eight determinants were V-region markers also expressed on other paraproteins. A total of 30 out of 159 different paraproteins cross-reacted with one or more of the antibodies. Four of the shared epitopes were lambda-chain associated, three were H-chain associated and one was a conformational determinant. Homologies of lambda chain were identified more frequently among other paraproteins than those of H chain. The relationship between epitope expression and H-chain class of paraprotein was not random. The frequency of expression of cross-reactivities in association with IgG1 proteins was always exceeded by higher frequency of epitope expression in association with other classes of H-chain isotype. The potential therapeutic value of such panels of characterized monoclonal reagents is discussed.

Antibodies, Monoclonal↗
PubMed1985

Glutamic acid decarboxylase-like immunoreactive neurites in senile plaques.

In the neocortex of an aged (26-year-old) rhesus monkey, a small percentage of abnormal neurites within some senile plaques (defined by the presence of amyloid) were immunoreactive for glutamic acid decarboxylase. This suggests that gamma-aminobutyric acid-synthesizing neurons may contribute to plaque formation in the aged brain.

Aging↗
PubMed1985

Abnormalities of the nucleus basalis in Down's syndrome.

One of the most striking manifestations of Down's syndrome is profound mental retardation. Furthermore, after 35 years of age, many patients with Down's syndrome develop clinical and pathological features of Alzheimer's disease. Since brains of patients with Alzheimer's disease show significant loss of neurons in the nucleus basalis of Meynert (nbM), we sought to establish normal standards of nbM neurons in persons with Down's syndrome and to determine whether reductions in the number of neurons occur with increasing age. The number and size of neurons in the nbM were measured in selected sagittal sections from 5 patients with Down's syndrome and 5 age-matched controls. The patients (age range, 16 to 56 years) had 29% fewer nbM neurons than controls, and the oldest patient had the lowest cell count of all subjects. The size of nbM neurons did not differ significantly between the two groups. Our results show that the nbM contains fewer neurons in young persons with Down's syndrome than in normal controls and suggest that the number of these nerve cells may be further reduced in older persons with Down's syndrome.

Adolescent↗
PubMed1985

Catecholaminergic neurites in senile plaques in prefrontal cortex of aged nonhuman primates.

Immunocytochemical studies, using a polyclonal antibody directed against tyrosine hydroxylase, identified catecholaminergic axons in prefrontal cortex of young and aged nonhuman primates. Aged monkeys, who showed cortical senile plaques in silver stains, had swollen tyrosine hydroxylase-immunoreactive axons in neocortex. Some of these abnormal processes were associated with deposits of amyloid (visualized by thioflavin-T fluorescence) and were similar in appearance to neurites demonstrated by silver impregnation methods. This study provides evidence for structural abnormalities in catecholaminergic axons/nerve terminals in the neocortices of aged primates.

Adrenergic Fibers↗
PubMed1985

Noncollateral projections of basal forebrain neurons to frontal and parietal neocortex in primates.

To test the hypothesis that axons of the basal forebrain cholinergic system collateralize to innervate widely separated areas of cortex, two distinct, retrogradely transported fluorescent dyes were injected into discrete neocortical regions of three macaques. In two monkeys, True Blue was injected into parietal cortex and Nuclear Yellow into frontal cortex; in a third monkey, placement of the dyes was reversed. Following these large (3-10 microliters total) injections, neurons single labeled with either Nuclear Yellow or True Blue were seen throughout most of the ipsilateral nucleus basalis of Meynert and nucleus of the diagonal band of Broca. Neurons projecting to either frontal or parietal cortex were most heavily concentrated in the anteromedial aspect of the basal forebrain. A small number of labeled neurons was also seen in the contralateral basal forebrain. Cells single labeled with either True Blue or Nuclear Yellow were frequently adjacent to one another, but in no case was a neuron labeled with both dyes. Thus, individual neurons of the basal forebrain complex do not appear to innervate both frontal and parietal lobes of monkeys. This finding is consistent with recent studies in rodents which suggest that basal forebrain neurons innervate relatively small, restricted cortical fields.

Animals↗
PubMed1985

Neurobiological studies of transmitter systems in aging and in Alzheimer-type dementia.

Dysfunction and death of specific neuronal systems are important processes occurring in aging and in Alzheimer's and in Parkinson's disease. The neuropathology and neurochemistry of some of the neuronal systems at risk in these settings are subjects of active research; the nature and consequences of these cellular pathologies have begun to be clarified. The availability of animal models (including aged monkeys, macaques with cholinergic deficiencies, and monkeys with MPTP-induced nigrostriatal pathology, all of which recapitulate certain features of human aging or disease) allow the opportunity to assess the efficacies of new pharmacotherapies, neural grafts, and trophic factors. These approaches can be monitored by behavioral testing and, in some instances, by in vivo imaging methods, which can in turn be correlated with morphologic and chemical analyses of brain. Demonstration of the efficacy of these procedures in nonhuman primates would have profound implications on the development of new therapies designed to alleviate the effects of aging and disease on the human brain.

Acetylcholinesterase↗
PubMed1985

Two monoclonal antibodies raised against a Burkitt lymphoma cell line recognise different cell types within lymphoid follicles.

Monoclonal antibodies were raised against a laboratory derived variant of the Raji Burkitt lymphoma cell line. We have characterized two of these antibodies by screening on haematopoietic cell lines, and frozen sections of both reactive and neoplastic lymphoid tissue, and found reactivity with separate cellular components of lymphoid follicles. Monoclonal FW37.4.D5 reacts in section specifically with follicular dendritic reticular cells. Monoclonal 35.1C5 reacts with a subpopulation of splenic marginal zone, and lymph node mantle zone, B lymphocytes, but stains only rare cells within germinal centres. This monoclonal is operationally B lymphocyte specific, distinguishing an 'intermediate' B cell subset, represented in lymphoma by B chronic lymphocytic leukaemia, B hairy cell leukaemia and centrocytic lymphoma.

Animals↗
PubMed1984

Somatostatinergic neurites in senile plaques of aged non-human primates.

Using a polyclonal antibody directed against somatostatin, normal somatostatin-positive neurons and fibers were seen in the amygdala and periamygdaloid cortex of both young and aged macaques. In addition, immunoreactive structures, identical in appearance to neurites demonstrated by silver impregnation methods, were seen in the amygdala of one aged monkey that exhibited numerous senile plaques. Some of these immunoreactive neurites were associated with deposits of amyloid, as seen with thioflavin-T stains, suggesting that these were neurites of senile plaques. This study provides direct evidence for abnormalities in peptidergic neurons in brains of aged non-human primates.

Aging↗
PubMed1983

Subcortical projections to the occipital and parietal lobes of the chimpanzee brain.

The subcortical sources of afferents to occipital and parietal cortex were studied in two chimpanzees with the aid of retrogradely transported horseradish peroxidase (HRP). In chimpanzee 1, HRP was injected into right cortical areas 17 and 18; chimpanzee 2 received HRP into right areas 17, 18, 19, and 39. The following subcortical structures were found to project to area 17 and/or area 18: locus coeruleus, dorsal raphe nucleus, nucleus annularis, nucleus centralis superior, pontine reticular formation, mesencephalic reticular formation, dorsal hypothalamus, lateral hypothalamus, nucleus basalis of Meynert, nucleus of the diagonal band of Broca, claustrum, nucleus basalis lateralis amygdalae, lateral geniculate nucleus, inferior pulvinar, lateral pulvinar, nucleus limitans, medial magnocellular part of the nucleus ventralis anterior, nucleus paracentralis, and nucleus centralis medialis thalami. Some of these structures may also project to area 19 and/or area 39. The following thalamic nuclei were found to project to area 19 and/or area 39 but not to areas 17 and 18: nucleus lateralis posterior, nucleus centralis lateralis, nucleus medialis dorsalis, nucleus ventralis lateralis, nucleus ventralis anterior nucleus lateralis dorsalis, and nucleus anterior ventralis. In several Instances, the HRP-labeled cells traversed specific nuclear borders, extending uninterruptedly from one classically defined nucleus into another. These results in the chimpanzee largely confirm data from a number of other mammalian taxa on the subcortical sources of afferents to the posterior cortex. Because of the close biological relationship between chimpanzee and man, we feel confident that such projections are also features of the human brain.

Amygdala↗