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Biomedical subjects

D L Price

Publications and source records attributed to D L Price.

At least 199 records · Page 11Linked to original sources
PubMed1990

Mouse nerve growth factor prevents degeneration of axotomized basal forebrain cholinergic neurons in the monkey.

NGF, a trophic polypeptide, is necessary for the normal development and survival of certain populations of neurons in the CNS and PNS. In the CNS, cholinergic neurons of the basal forebrain magnocellular complex (BFMC) are prominent targets of NGF. During rat development, NGF increases the activity of ChAT in these neurons. In adult rats with experimental injury of axons in the fimbria-fornix, NGF prevents degenerative changes in axotomized cholinergic BFMC neurons in the medial septal nucleus (MSN). Because the amino acid sequences of NGF and its receptor (NGF-R) are highly conserved across species, we hypothesized that mouse NGF would also prevent degeneration of cholinergic BFMC neurons in nonhuman primates. Therefore, the present study was designed to test whether fimbria-fornix lesions result in retrograde degenerative changes in basal forebrain cholinergic neurons in macaques, whether these changes are prevented by mouse NGF, and whether the protective effect of NGF is selective for cholinergic neurons of the basal forebrain. Following unilateral complete transection of the fornix, animals were allowed to survive for 2 weeks, during which time half of the subjects received intraventricular NGF in vehicle and the other half received vehicle alone. In animals receiving vehicle alone, there was a 55% reduction in the number of ChAT-immunoreactive cell bodies within the MSN ipsilateral to the lesion; loss of immunoreactive somata was more severe in caudal planes of the MSN. Remaining immunoreactive neurons appeared smaller than those in control, unoperated animals. In Nissl stains, there was no apparent loss of basophilic profiles in the MSN, but cells showed reduced size and intensity of basophilia. Treatment with NGF almost completely prevented reductions in the number and size of cholinergic neurons and had a significant general effect in preventing atrophy in basophilic magnocellular neurons of the MSN, though some basophilic neurons in the MSN did not appear to respond to NGF. Adjacent 7-microns-thick sections stained with ChAT and NGF-R immunocytochemistry revealed that these markers are strictly colocalized in individual neurons in the MSN in controls and in both groups of experimental animals. Thus, mouse NGF profoundly influences the process of axotomy-induced retrograde degeneration in cholinergic BFMC neurons in primates. The in vivo effectiveness of mouse NGF on primate BFMC neurons suggests that mouse or human recombinant NGF may be useful in ameliorating the ACh-dependent, age-associated memory impairments that occur in nonhuman primates.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholinesterase↗
PubMed1990

Field orientation effects during 5.6-GHz radiofrequency irradiation of rats.

Ketamine-anesthetized Sprague-Dawley rats were exposed in E and H orientations (long axis parallel to electric and magnetic fields, respectively) to far-field 5.6-GHz continuous-wave radio-frequency radiation (RFR). Power densities were used that resulted in equivalent whole-body average specific absorption rates of 14 W/kg in both orientations (90 mW/cm2 for E and 66 mW/cm2 for H). Irradiation was conducted to increase colonic temperature by 1 degree C (from 38.5 to 39.5 degrees C). During experimentation, arterial blood pressure and respiratory rate and colonic, tympanic, left and right subcutaneous (sides toward and away from RFR source), and tail temperatures were continuously recorded. Results showed no significant difference in the times required to cause a 1 degree C increase or to recover to the initial temperature when irradiation was stopped. Significant differences between E- and H-orientation exposure were seen in the patterns of localized heating. The tail and left subcutaneous temperature increases were significantly greater during E-orientation exposure, the tympanic site showed no difference, and the right subcutaneous temperature increase was significantly greater during H-orientation exposure. Under both exposure conditions, heart rate and mean arterial blood pressure significantly increased during irradiation; however, there were no significant differences between E and H orientation responses. These findings at 5.6 GHz are in contrast to the significant cardiovascular response differences between E- and H-orientation exposure noted during a previous study of irradiation at 2.45 GHz.

Animals↗
PubMed1990

Hereditary canine spinal muscular atrophy: canine motor neuron disease.

Motor neuron diseases, manifest as weakness and atrophy of skeletal muscles, occur in infancy, childhood, and adult life. Some forms of this disease are inherited. Motor neurons are selectively affected and exhibit cytoskeletal pathology, primarily enlargements of proximal axons by accumulations of transported neurofilaments. A motor neuron disease, hereditary canine spinal muscular atrophy, has been discovered in Brittany spaniels. The disease is inherited as an autosomal dominant characteristic and shows striking clinical and pathological features in common with human motor neuron disease. The availability of this excellent animal model of the human condition has allowed neurobiological investigations of the dynamics of structural and chemical pathologies of vulnerable neurons.

Animals↗
PubMed1990

Laminar organization and age-related loss of cholinergic receptors in temporal neocortex of rhesus monkey.

Using in vitro receptor autoradiography, the distributions of cholinergic muscarinic [3H-N-methyl scopolamine (NMS), 3H-pirenzepine (PZ), and 3H-oxotremorine-M (OXO-M)] and nicotinic [3H-acetylcholine (ACh)] receptors were mapped in the temporal cortices of rhesus monkeys (Macaca mulatta) ranging from 2-22 years of age. Although high-affinity 3H-PZ, low-affinity 3H-NMS binding (M1 sites) and high-affinity 3H-OXO-M, high-affinity 3H-NMS binding (M2 sites) occurred across all layers of the temporal neocortex, the laminar distribution of M1 and M2 receptor binding sites was different. M1 muscarinic receptor binding was concentrated in layers II and III, whereas M2 muscarinic receptor binding was greatest in layers IV and V. The concentration of both muscarinic (M1 and M2) and nicotinic receptor binding sites declined with increasing age, and decrements were uniform across all cortical layers. This investigation provides evidence for a decrease in cholinergic receptor binding with age in temporal cortices of rhesus monkeys. Moreover, these changes appear to precede previously reported age-associated memory deficits and neuropathological changes that occur in this species.

Aging↗
PubMed1989

Compartment-specific changes in the density of choline and dopamine uptake sites and muscarinic and dopaminergic receptors during the development of the baboon striatum: a quantitative receptor autoradiographic study.

In the fetal and young primate neostriatum, cholinergic and dopaminergic markers show patches of high density surrounded by a lower-density matrix. In the adult, the same markers display the opposite pattern, a lower density in striosomes, surrounded by a higher-density matrix. In order to understand the developmental sequences leading to the adult compartmental organization of the primate neostriatum, a quantitative technique was used to study the ontogeny of pre- and postsynaptic components of cholinergic and dopaminergic neurons in baboon caudate nucleus and putamen. The development of specific uptake mechanisms for choline and dopamine and receptors was studied by means of quantitative autoradiography of the specific binding of [3H]-hemicholinium-3 [( 3H]-HC3) and [3H]-mazindol [( 3H]-MAZ) to the choline and dopamine uptake systems, respectively. [3H]-pirenzepine [( 3H]-PIR) was used to label M1 muscarinic receptors and [3H]-spiroperidol [( 3H]-SPI) was used to label striatal dopamine D2 receptors. Serial sections were used for each ligand to determine the precise anatomical relationships between the binding patterns of the different markers. Our aim was to determine whether the adult striosomal distribution of the binding sites studied was due to 1) a selective decrease in patch/striosomal binding density or 2) a selective increase in matrix binding density. Our studies show that a postnatal decrease in the density of [3H]-HC3 sites in the patch/striosomes and an increase in the matrix density of [3H]-MAZ sites are the primary, but not the sole, changes in the compartmental distribution of these sites leading to the adult striosomal organization of the striatal cholinergic and dopaminergic innervation. D2 receptors follow the general developmental pattern of [3H]-MAZ and [3H]-HC3, changing their density of distribution in both compartments during the developmental period examined. In addition, M1 muscarinic receptors already display their adult pattern in the newborn baboon striatum, and therefore represent one of the first neurochemical makers to adopt its mature organization.

Animals↗
PubMed1989

GABAergic neurons in the primate basal forebrain magnocellular complex.

Hybridization histochemistry was used to detect messenger ribonucleic acid (mRNA) coding for glutamic acid decarboxylase, the synthesizing enzyme for gamma-aminobutyric acid (GABA), in neurons of the nucleus basalis of Meynert and nucleus of the diagonal band of Broca of one rhesus monkey and 4 baboons. GABAergic neurons were distributed among the unlabeled large, hyperchromic Nissl-stained neurons characteristic of this basal forebrain magnocellular complex, although they were infrequent within the dense islands of large cells. Most GABAergic cells were small to medium in size, but some were large and hyperchromic. These findings demonstrate a heterogeneous population of presumably inhibitory neurons in the basal forebrain magnocellular complex of primates.

Animals↗
PubMed1989

Mu opiate receptors are selectively labelled by [3H]carfentanil in human and rat brain.

[11C]Carfentanil is a potent opioid agonist currently in use as a specific PET (position emission tomography) scan radioligand for brain mu opioid receptors. In order to investigate the receptor interactions of carfentanil in detail [3H]carfentanil was used as a radioligand for labelling receptors in rat and human brain tissue homogenates. [3H]Carfentanil was found to bind saturably and with high affinity (KD = 0.08 +/- 0.01 nM) to membranes prepared from human cortical (Bmax = 42 +/- 3 fmol/mg) and thalamic (Bmax = 84 +/- 3 fmol/mg) tissues and rat cortex (Bmax = 82 +/- 4 fmol/mg) and diencephalon (Bmax = 105 +/- 5 fmol/mg). Association (1.23 +/- 0.19 X 10(10) Mol-1 X min-1 and dissociation rate (0.19 +/- 0.03 min-1) constants were determined in human cortical tissues; results from studies in rat cortical, and rat diencephalon tissue homogenates produced similar kinetic rate constants. Competition studies with a variety of drugs indicated that [3H]carfentanil interacts primarily with mu opioid receptors in the four tissues studied; the affinities of a series of non-radioactive opioid ligands were essentially identical in the four tissues (correlation coefficients = 0.88-0.93). Naloxone, morphine, DAGO [( D-Ala2-MePhe4-Gly-ol5]enkephalin), DADL [( D-Ala2-D-Leu5]enkephalin) and EKC (ehtylketazocine) potently displaced specific [3H]carfentanil binding with nM potency while the kappa agonist U-69593, the sigma agonists (+)-SKF 10047, (+)-3-PPP [3-hydroxyphenyl)-N-propylpiperidine) and haloperidol and PCP (phencyclidine) were less potent displacing agents. The higher affinities of DAGO and morphine versus DADL for the [3H]carfentanil binding sites indicates that delta opioid receptors are not being labelled.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Aberrant phosphorylation of neurofilaments accompanies transmitter-related changes in rat septal neurons following transection of the fimbria-fornix.

Lesions of the fimbria-fornix (FF) have been reported to cause retrograde changes in neurons of the medial septal nucleus (MSN). To analyze the nature and time course of these events, we investigated changes in cytoskeletal elements (phosphorylated and non-phosphorylated neurofilament (NF) proteins) and transmitter-related enzymes (choline acetyltransferase (ChAT) in MSN neurons following FF transection. During the first week postlesion, ChAT immunoreactivity and size of many perikarya were reduced. Irregular, swollen cholinergic fibers appeared first at postlesion day 2 in caudal septum and soon spread rostrally, reaching rostral septum by day 7. A few perikarya developed abnormal accumulations of phosphorylated NFs. At postlesion days 7-10, many neurons did not stain for ChAT. Phosphorylated NFs were present in many perikarya. At this time, cell loss was apparent in Nissl-stained material. Cholinergic cell loss continued through postlesion weeks 6-8 but at a much slower rate than during the first week. Phosphorylated NF accumulations in MSN perikarya persisted until postlesion week 6, disappearing thereafter. Double-immunostaining procedures showed that MSN neurons expressed both ChAT and phosphorylated NF immunoreactivity at postlesion day 3; however, at days 7 and 14, cells that accumulated phosphorylated NFs did not stain for ChAT. The results of this study indicate that FF transection leads to perikaryal shrinkage with loss of ChAT immunoreactivity, perikaryal phosphorylation of NFs, cholinergic fiber abnormalities, and cell loss. Recent evidence suggests that reduction of transmitter markers and aberrant phosphorylation of NFs may be involved in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease. Therefore, FF transection provides a useful animal model for further investigations of complex disorders of the central nervous system that involve degeneration of transmitter-specific pathways.

Animals↗
PubMed1989

Noradrenergic innervation of human pineal gland: abnormalities in aging and Alzheimer's disease.

Using previously characterized polyclonal antibody directed against dopamine beta-hydroxylase (DBH), immunoreactive fibers were demonstrable in pineals of 6 controls of various ages and of 3 individuals with Alzheimer's disease (AD). Abnormal, swollen axons were present in pineals from aged individuals and from individuals with AD. The pathology of noradrenergic axons in a structure innervated by the superior cervical ganglion suggests that peripheral noradrenergic systems may be affected in aging and in AD.

Adrenergic Fibers↗
PubMed1989

Noradrenergic systems in human cerebellum.

Thin, beaded axons, immunostained with antisera to human dopamine beta-hydroxylase (DBH), were present in all layers of the anterior vermis of human cerebellum. This plexus appears similar to that described in rodents and provides information complementary to receptor autoradiographic studies that show significant noradrenergic innervation of mammalian cerebellum. Moreover, in two aged controls, we demonstrated abnormal, swollen, tortuous axons not visualized in young controls.

Adult↗
PubMed1989

Peptidergic neurons in the basal forebrain magnocellular complex of the rhesus monkey.

The basal forebrain magnocellular complex of primates is defined by the presence of large, hyperchromic, usually cholinergic neurons in the nucleus basalis of Meynert and nucleus of the diagonal band of Broca. Because there is growing evidence for noncholinergic neuronal elements in the basal forebrain complex, five neuropeptides and the enzyme choline acetyltransferase were studied immunocytochemically in this region of rhesus monkeys. Galaninlike immunoreactivity coexists with choline-acetyl-transferase-like immunoreactivity in most large neurons and in some smaller neurons of the primate nucleus basalis and nucleus of the diagnonal band. Four other peptides show immunoreactivity in more limited regions of the basal forebrain complex, usually in separate smaller, noncholinergic neurons. Numerous small, somatostatinlike-immunoreactive neurons occupy primarily anterior and intermediate segments of the nucleus basalis, especially laterally and ventrally. Somewhat fewer, small neuropeptide Y-like-immunoreactive somata are found in the same regions. Neurons that show neurotensinlike immunoreactivity are slightly larger than cells that contain immunoreactivity for somatostatin or neuropeptide Y, but these neurons also occur mainly in anterior and intermediate parts of the nucleus basalis. Overall, the usually small, leucine-enkephalin-like-immunoreactive neurons are infrequent in the basal forebrain complex and are most abundant in the rostral intermediate nucleus basalis. Thus, neurons that appear to contain somatostatin, neuropeptide Y, neurotensin, or enkephalin mingle with cholinergic/galaninergic neurons only in some subdivisions of the nucleus basalis/nucleus of the diagonal band, and their distributions suggest that some of these small neurons could be associated with structures that overlap with cholinergic neurons of the labyrinthine basal forebrain magnocellular complex. We also have found light microscopic evidence for innervation of basal forebrain cholinergic neurons by boutons that contain galanin-, somatostatin-, neuropeptide Y-, neurotensin-, or enkephalinlike immunoreactivity. The origins and functions of these putative synapses remain to be determined.

Animals↗
PubMed1989

The pedunculopontine nucleus in Parkinson's disease.

This study demonstrated a significant loss of neurons within the lateral part of the pedunculopontine nucleus pars compacta in individuals with idiopathic Parkinson's disease and in individuals with combined Parkinson's and Alzheimer's disease. We also examined the extent of neuronal loss within the substantia nigra pars compacta, locus ceruleus, dorsal raphe nucleus, and nucleus basalis of Meynert. The number of pedunculopontine nucleus pars compacta neurons in the patients with Parkinson's or Parkinson's and Alzheimer's disease was reduced (average, 40%) in comparison with the number in control subjects or patients with Alzheimer's disease (p less than 0.01). This finding correlated significantly with the extent of loss of substantia nigra pars compacta neurons (p less than 0.01).

Aged↗
PubMed1989

Serotoninergic neurites in senile plaques in cingulate cortex of aged nonhuman primate.

In immunocytochemical studies, a polyclonal antiserotonin antibody was used to visualize fibers within the cingulate cortex of young and aged rhesus monkeys. Intricate and distinct patterns of serotoninergic processes were seen in anterior and posterior segments of cingulate cortex (Brodmann areas 24 and 23). In these regions of cortex, many multivaricose serotonin-immunoreactive axonal swellings were identified, and some of these immunostained neurites were associated with deposits of amyloid. These observations suggest that serotoninergic processes are involved in the formation of senile plaques in neocortex of aged macaques.

Aging↗
PubMed1989

Normal pattern of labeling of cerebral cortical corticotropin-releasing factor (CRF) receptors in Alzheimer's disease: evidence from chemical cross-linking studies.

Recent data have demonstrated that in Alzheimer's disease, the concentrations of corticotropin-releasing factor (CRF) were reduced and that there were reciprocal increases in CRF receptors in affected cerebrocortical areas. In order to determine whether the increases in CRF receptors in Alzheimer's disease were due to altered molecular composition of the binding protein, we compared the labeling pattern of 125I-Tyr0-ovine CRF in temporal neocortex of Alzheimer's patients and age-matched controls using chemical cross-linking techniques. A similar pattern of 125I-Tyr0-ovine CRF labeling was seen in Alzheimer's and control brains, with the major CRF binding protein corresponding to an apparent molecular weight of 58,000 Da. These data indicate that the increased CRF receptor population in cerebral cortex in Alzheimer's disease comprises bona fide CRF receptor binding subunits with no apparent change in the molecular structure.

Aged↗
PubMed1989

Alpha 1-antichymotrypsin is present together with the beta-protein in monkey brain amyloid deposits.

The recent finding that the serine protease inhibitor, alpha 1-antichymotrypsin, is tightly associated with the amyloid deposits in brains of normal aged individuals and patients with Alzheimer's disease [Abraham C. R., Selkoe D. J. and Potter H. (1988) Cell 52, 487-501], suggests a role for this inhibitor in the progressive deposition of brain amyloid in humans. We have used immunocytochemistry to detect alpha 1-antichymotrypsin in the amyloid that accumulates in brains of aged monkeys, a naturally occurring animal model of Alzheimer-like neuropathology. In monkeys of increasing age, the earliest alpha 1-antichymotrypsin immunoreactivity was found in cortical perivascular cells, before the appearance of either Thioflavin S-detectable amyloid deposits or beta-protein reactivity in the vessel walls. Subsequently, amyloid deposits appeared in small meningeal blood vessels and cortical neuritic plaques. The oldest monkeys also showed microvascular amyloid in the cortical gray matter. Amyloid was never seen in white matter. The amyloid deposits in meningeal vessels were always positive for both beta-protein and alpha 1-antichymotrypsin, whereas in the cortex, alpha 1-antichymotrypsin immunoreactivity seemed to appear somewhat later than that of beta-protein. These findings demonstrate that two of the brain amyloid components of human senescence and Alzheimer's disease--the beta-protein and the protease inhibitor alpha 1-antichymotrypsin--are also present in the amyloid deposits of normal aged monkey brain. The extended molecular parallels between normal brain aging and Alzheimer's disease suggest that similar biochemical mechanisms may underlie progressive amyloid deposition in both situations.

Aging↗
PubMed1989

Changes in neuronal size and neurotransmitter marker in hereditary canine spinal muscular atrophy.

Hereditary canine spinal muscular atrophy (HCSMA) is a dominantly inherited motor neuron disease that produces muscle weakness and atrophy. Immunocytochemical and computer-imaging morphometric methods were used to compare early changes that occurred in dogs with HCSMA (n = 4) versus controls (n = 2). The size and number of neurons in the ventral horn and the number of motor neurons expressing choline acetyltransferase were quantitated. The density of all ventral horn neurons per micrometer squared in dogs with HCSMA was greater than controls, and there were more small neurons than in controls. Immunocytochemical methods revealed more small cholinergic neurons and fewer large cholinergic neurons in HCSMA than in controls, suggesting growth arrest in HCSMA or a shift in size class from large cholinergic neurons to small ones. The density of cholinergic neurons per micrometer squared was not significantly different between the two groups. Analysis of predicted distributions of cholinergic and noncholinergic neurons revealed that HCSMA cholinergic neurons were smaller and that, in some size classes, fewer neurons expressed choline acetyltransferase. These observations indicate that in HCSMA the motor neuron fails to achieve normal size and/or undergoes atrophy.

Animals↗
PubMed1989

Neuropathology of aminergic nuclei in Alzheimer's disease.

In order to comprehensively evaluate pathological involvement of the locus coeruleus (LC) and cortically projecting raphe nuclei in Alzheimer's disease (AD), we have recently completed a study (Zweig, et al., 1988) in which numbers of neurons containing neuromelanin within the LC and large nucleolus-containing neurons within the dorsal raphe nucleus (DR) and the central superior (raphe) nucleus (CSN) were determined in 25 cases of AD and 12 age-matched controls. Numbers of neurofibrillary tangles (NFTs) within these regions were also counted. Pathological results were compared with clinical data, including psychiatric evaluations, available for 21 of the AD cases. Neuronal loss in AD cases was most severe within LC at mid level (p less than .01) and within DR, caudally (p less than .05). Counts of NFTs within LC were also highest at mid level (p less than .05) in comparison with caudal level). Neuronal loss was not demonstrated within CSN, although NFTs were abundant within this nucleus. At individual levels, neuronal and NFT counts did not correlate. Relative severity of neuronal loss or NFTs was usually consistent from level to level within nuclei; internuclear correlations were weaker. Cases of AD complicated by depression had significantly fewer neurons at mid LC and rostral CSN levels than nondepressed cases (p less than .05). There was also a trend (nonsignificant) suggesting increased neuronal loss at all levels of LC and DR in depressed cases. Neuronal loss correlated negatively with age, particularly within LC. NFT counts correlated negatively with duration of illness, particularly within DR. As all but 3 individuals had severe dementia, NFT counts may reflect rate of progression of disease. Neuronal loss and NFTs frequently occur in the LC and cortically projecting raphe nuclei in AD (Curcio and Kemper, 1984, Hirano and Zimmermann, 1962, Ishii, 1966, Marcynuik et al., 1986, Yamamoto and Hirano, 1985, Bondareff and Mountjoy, 1986, Iverson et al., 1983, Mann et al., 1985, Tabaton et al., 1986). We have recently completed a comprehensive evaluation of pathological involvement of the LC, the DR, and the CSN in a series of aged controls and AD patients for whom detailed clinical information, including psychiatric evaluations, were available (Zweig et al., 1988). This report summarizes the findings of that study.

Aged↗