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Biomedical subjects

D L Price

Publications and source records attributed to D L Price.

At least 397 records · Page 22Linked to original sources
PubMedDate not supplied

Senile plaques in aged squirrel monkeys.

Aged squirrel monkeys develop senile plaques in the brain that are similar to those occurring in aged rhesus monkeys and aged humans. These plaques consist of abnormal, swollen neurites around an amyloid core. In whole-hemisphere coronal sections through the level of the rostral temporal lobe, plaques are present in temporal cortex, amygdala, hippocampal formation and, occasionally, in other cortical regions. In more rostral sections through the frontal lobe, plaques are most common in orbitofrontal and frontal opercular cortical regions. In immunocytochemical preparations, some neurites show immunoreactivity with antibodies directed against phosphorylated neurofilaments and neuropeptide Y. Thus, plaques in these New World primates are similar in distribution and composition to those occurring in aged Old World primates.

Aging↗
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Loss of NMDA, but not GABA-A, binding in the brains of aged rats and monkeys.

In this quantitative neurochemical study we investigated age-related changes in the GABAergic, glutamatergic, and cholinergic neurotransmitter systems in rats and rhesus monkeys. Sixteen young (5 months) and 20 aged (24 months) rats and seven "young" (4-9 years), six "adult" (20-25 years), and five "aged" (29-34 years) monkeys were studied. NMDA-displaceable 1-[3H]glutamate binding was significantly decreased in many neocortical and subcortical regions examined in aged rats and monkeys. The level of choline acetyltransferase (ChAT) activity and [3H]muscimol binding were unchanged in aged animals.

Aging↗
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Aged monkeys exhibit behavioral deficits indicative of widespread cerebral dysfunction.

To determine whether the decline of behavioral abilities with aging in monkeys is selective or widespread, we examined 18 monkeys ranging from 3 to 34 years of age on a wide variety of tests with the ultimate goal of correlating behavioral deficits with age-related changes in the brain. In our initial study we found impaired visual recognition ability in the aged monkeys (43). In the present study, we assessed the same animals on tests of spatial memory, visual habit formation, visuospatial orientation, visually guided reaching, motor skill learning, and reaction time, these categories having been chosen to test the integrity of different cerebral systems. There were three major findings. First, age-related impairments were observed in nearly all test categories, though often not on easy versions of the tests, suggesting that the deficits observed were in the specific abilities measured and not an artifact of lowered motivation or other general disability. Second, the behavioral decline began in the late teens for certain spatial abilities but did not affect other abilities until the late 20's, suggesting that although the cerebral dysfunction eventually becomes widespread, the cerebral systems underlying spatial abilities are compromised by aging earlier than others. Finally, the finding of correlations between scores of aged animals primarily within test categories as opposed to across categories suggests that different animals have different patterns of cerebral involvement.

Aging↗
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Neurotransmitters in neocortex of aged rhesus monkeys.

The effects of aging on levels of neurotransmitters were determined in two regions of the cerebral cortex in rhesus monkeys (Macaca mulatta). Choline acetyltransferase (ChAT) activity as well as somatostatin, neuropeptide Y, and substance P immunoreactivities were analyzed in the right caudal cingulate gyrus and in the left and right inferior occipital poles in five age groups: 4-6 years; 8-11 years; 20-25 years; 26-29 years; and 31-34 years. Neuroactive amino acids and markers for monoamine transmitters were analyzed only in the youngest (4-6 years) and oldest (31-34 years) animals. Across the five age groups studied. ChAT activity as well as somatostatin and neuropeptide Y immunoreactivities were significantly decreased bilaterally in occipital poles of the 31- to 34-year-old group. There were no significant age-related differences in substance P immunoreactivity. In 4-6-year-old vs. 31-34-year-old monkeys, levels of amino acid neurotransmitters were unchanged. However, there were significant reductions in norepinephrine, serotonin and its metabolites, kynurenine, and 4-hydroxyphenyllactic acid in occipital poles of the 31- to 34-year-old monkeys. No significant neurochemical changes were detected in the cingulate cortex. These findings demonstrate that aged nonhuman primates show reductions in cortical markers for a variety of neurotransmitters, including acetylcholine, somatostatin, neuropeptide Y, norepinephrine, and serotonin but that these changes do not occur uniformly in the neocortex.

Aging↗
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Developmental expression of alpha 1-antichymotrypsin in brain may be related to astrogliosis.

In the brains of individuals with Alzheimer's disease (AD) and aged monkeys, the serine protease inhibitor alpha 1-antichymotrypsin (ACT) is selectively associated with deposits of amyloid found in senile plaques and in the walls of blood vessels. The origin of ACT in the brains of these aged subjects is unclear. In this study, ribonucleic acid (RNA) blots of human brains show that ACT messenger RNA (mRNA) increases during development. Levels of mRNA were negligible in fetuses and young adults but were increased slightly in normal aged individuals and highest in individuals with AD. In situ hybridization detected ACT transcripts in astrocytes of the cortex, subependymal region, and superficial white matter. The expression of ACT mRNA was highest in subjects with AD, in an adult with Down's syndrome, in an individual with Pick's disease, and in cases of Huntington's disease. In the brains of adult monkeys, ACT expression was detected primarily in astrocytes of the subependyma and white matter. Thus the presence of ACT appears to be related to the response of astrocytes to the brain abnormalities seen in these conditions.

Adolescent↗
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Age-related spatial reference and working memory deficits assessed in the water maze.

Aged rats have spatial memory deficits relative to young rats. The extent of these deficits in intermediate-aged rats is not well established. The present study examined the pattern of age-related changes in spatial reference and working memory in four ages of Fischer-344 rats. Place discrimination (PD) in the Morris water maze measured spatial reference memory. Repeated acquisition (RA), a discrimination in which the escape platform location varied from session to session, measured spatial working memory. Fischer-344 rats, 4 months, 11 months, 17 months, and 24 months of age, were tested. Compared to 4-month-olds, 24-month-olds were significantly impaired on all six PD measures of performance, 17 months were significantly impaired on five PD measures, and 11 months were significantly impaired on only one PD measure. Only 24-month-olds had a significant working memory impairment in RA relative to 4 months. Reference and working memory measures were distinct as assessed by a principal components analysis. The results indicate a nonlinear age-related spatial memory decline in Fischer-344 rats from 4 to 24 months of age.

Aging↗
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A review of the current use of magnetic resonance imaging in pregnancy and safety implications for the fetus.

This paper presents an overview of the application of and risks of exposure to Magnetic Resonance Imaging (MRI) in pregnancy. It reviews the risks to the fetus by considering the hazards in terms of the three main components of an MRI system. These are the static magnetic field, the time-varying magnetic gradient fields and the pulsed radio frequency fields. The hazards discussed are biological effects, miscarriage, heating effects and acoustic noise exposure. This paper also presents a survey of MRI sites within the United Kingdom to ascertain the extent of MRI usage in pregnancy. To validate the situation of MRI in pregnancy a survey was sent to 352 MR units throughout the United Kingdom. The questions were grouped to assess (a) maternal MRI diagnosis (b) fetal MRI and (c) work practices for pregnant MRI staff. The results showed that 91% of sites were imaging pregnant women in need of diagnosis in the second and third trimester. This paper highlights that MRI can add information for fetal central nervous system abnormalities identified by ultrasound screening, however within the UK direct fetal imaging was only performed in 8% of sites. This paper indicates the need for research to be undertaken for specific MRI clinical conditions. It also advises that risk assessment for pregnant staff working in MRI is performed, and that there is a clear need for further research into the effects of MRI in pregnancy as there is a need for clear authoritive advice.

Central Nervous System↗
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The neural basis of memory decline in aged monkeys.

Nonhuman primates experience changes in behavior as they progress into old age. Visual recognition, spatial learning, habit formation, and visuospatial manipulation are impaired in aged rhesus monkeys relative to young controls. We have begun to study the possible neural substrate for these changes, focusing on brain areas that are known, from lesion studies, to be essential for the successful performance of specific tasks. Aged nonhuman primates develop senile plaques, most commonly in amygdala, hippocampus, and neocortex. Our preliminary data suggest that the density of plaques may be related to poor behavioral performance in some aged monkeys. However, behavioral decline begins before the appearance of significant numbers of senile plaques, suggesting that other factors may interfere with cognition. Numerous studies of several genera have shown that receptors for neurotransmitters decline in number between the adolescent years and old age. Our autoradiographic analyses of primate temporal neocortex demonstrate loss of muscarinic, nicotinic, dopaminergic and serotoninergic receptor binding sites between the ages of 2 and 22 years. Preliminary data indicate that markers for adenyl cyclase and phosphatidyl inositol second-messenger systems also are reduced in temporal cortex. Although these declines represent a potential substrate for behavioral changes, no studies have directly related a decrease in receptor number to deficits in learning and memory in aged primates. Other changes in the aging brain include loss of neurons, reduced neurochemical markers, and decreased content of neuronal ribonucleic acid (RNA). All of these decrements may be interrelated to some extent in that decreased RNA could result in changes in neurochemical markers and receptors and, eventually, in dysfunction and death of neurons. These observations underscore the importance of establishing a time course for age-associated neural abnormalities, examining regions of brain in which changes are most likely to occur, and studying their relationship to the progression of behavioral dysfunction. Detailed anatomical analyses of the distribution of in situ uptake/receptor binding sites and messenger RNA (mRNA) in aged nonhuman primates may clarify some of the factors that most likely contribute to behavioral changes in elderly humans.

Aging↗
PubMedDate not supplied

Age-related changes in multiple neurotransmitter systems in the monkey brain.

Age-associated changes in cholinergic, monoaminergic and amino acid neurotransmitter systems were analyzed in 14 brain regions of 23 rhesus monkeys that ranged in age from 2 to 37 years. In the frontal pole, the levels of choline acetyltransferase (ChAT) activity, the density of [3H]ketanserin (serotonin type-2) binding sites and endogenous levels of dopamine, homovanillic acid and serotonin, all expressed per milligram of protein, decreased significantly with aging. In precentral motor cortex, ChAT activity decreased; in parietal and occipital cortex, the number of [3H]ketanserin binding sites decreased while the number of Na+-independent [3H]glutamate binding sites increased with age. In the caudate nucleus, endogenous levels of norepinephrine decreased. This descriptive study indicates that the aging monkey may be a very useful model for future investigations of age-associated transmitter abnormalities similar to those that occur in humans.

Age Factors↗
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Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice.

Amyloid precursor protein (APP) is a member of a larger gene family including amyloid precursor-like proteins (APLP), APLP2 and APLP1. To examine the function of APLP2 in vivo, we generated APLP2 knockout (KO) mice. They are of normal size, fertile, and appear healthy up to 22 months of age. We observed no impaired axonal outgrowth of olfactory sensory neurons following bulbectomy, suggesting against an important role for APLP2 alone in this process. Because APLP2 and APP are highly homologous and may serve similar functions in vivo, we generated mice with targeted APLP2 and APP alleles. Approximately 80% of double KO mice die within the first week after birth, suggesting that APLP2 and APP are required for early postnatal development. The surviving approximately 20% of double KO mice are 20-30% reduced in weight and show difficulty in righting, ataxia, spinning behavior, and a head tilt, suggesting a deficit in balance and/or strength. Adult double KO mice mate poorly, despite apparent normal ovarian and testicular development. Otherwise, double KO mice appear healthy up to 13 months of age. We conclude, that APLP2 and APP can substitute for each other functionally.

Amyloid beta-Protein Precursor↗
PubMedDate not supplied

Cognitive decline strongly correlates with cortical atrophy in Alzheimer's dementia.

Alzheimer's disease (AD) is characterized by progressive dementia and distinct neuropathology at autopsy. In order to test the relationship between dementia severity and loss of brain volumes, we prospectively documented the neurological/medical health of 26 male and 26 female controls and AD cases, and evaluated a subset of controls and AD cases using the Mini Mental State Examination (MMSE). At autopsy, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria confirmed diagnoses in 33 AD cases and 19 controls, and using unbiased stereology we quantified total volumes of cortical gray matter, subcortical grey matter including white matter, and forebrain. For ages of death between 50 to 100 years, controls showed minor cortical atrophy in the absence of cognitive decline. Cortical atrophy in AD cases was 20 to 25% greater than that in controls; AD patients dying at older ages showed less severe cortical atrophy than those dying at younger ages. Across all AD cases there was a strong correlation between cognitive performance on the Mini Mental State Examination and cortical volume loss. These findings confirm fundamental differences in the temporal patterns of cortical volume loss in aging and AD, and support cortical degeneration as the primary basis for cognitive decline in AD.

Aged↗
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Reciprocal changes in corticotropin-releasing factor (CRF)-like immunoreactivity and CRF receptors in cerebral cortex of Alzheimer's disease.

Alzheimer's disease is a progressive degenerative disease of the nervous system characterized neuropathologically by the presence of senile plaques and neurofibrillary tangles in amygdala, hippocampus and neocortex. Dysfunction and death of basal forebrain cholinergic neurones projecting to forebrain targets are associated with marked decreases in cholinergic markers, including the activity of choline acetyltransferase (ChAT). Although cortical levels of somatostatin and somatostatin receptors are reduced in Alzheimer's, no consistent changes have been reported in other neuropeptide systems. We have now examined in control and Alzheimer's brain tissues pre- and postsynaptic markers of corticotropin-releasing factor (CRF), a hypothalamic peptide regulating pituitary-adrenocortical secretion which also seems to act as a neurotransmitter in the central nervous system (CNS). We have found that in Alzheimer's, the concentrations of CRF-like immunoreactivity (CRF-IR) are reduced and that there are reciprocal increases in CRF receptor binding in affected cortical areas. These changes are significantly correlated with decrements in ChAT activity. Our results strongly support a neurotransmitter role for CRF in brain and demonstrate, for the first time, a modulation of CNS CRF receptors associated with altered CRF content. These observations further suggest a possible role for CRF in the pathophysiology of the dementia. Future therapies directed at increasing CRF levels in brain may prove useful for treatment.

Aged↗
PubMedDate not supplied

Evidence for neuromelanin involvement in MPTP-induced neurotoxicity.

Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduces certain clinical, pathological, and neurochemical features of Parkinson's disease. MPTP is metabolized by monoamine oxidase Type B to 1-methyl-4-phenylpyridine (MPP+), which is selectively accumulated by high-affinity uptake mechanisms into dopaminergic neurons. Lyden et al. described low-affinity binding of MPTP to synthetic and retinal melanin. We showed that MPP+ binds to neuromelanin with high affinity, suggesting that in MPTP neurotoxicity, MPP+ enters nigral neurons by the dopamine uptake system and binds to neuromelanin, which serves as a depot, continuously releasing MPP+ until it destroys the cells. This model predicts that agents which compete with MPP+ binding to neuromelanin should partially protect the dopamine neurons from MPTP-induced toxicity. The most potent identified competitor for MPP+ binding to melanin is the antimalarial drug chloroquine, which has a high affinity for melanins. In the present study, chloroquine, administered to monkeys in conventional anti-malarial doses before MPTP, protects them from MPTP-induced parkinsonian motor abnormalities, dopamine depletion in the striatum, and neuropathological changes in the substantia nigra.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMedDate not supplied

Cholinergic immunoreactive fibers in monkey anterior temporal cortex.

Cholinergic processes in anterior temporal cortex of rhesus monkeys were identified using immunocytochemical techniques for ChAT. Labeled fibers were present throughout the temporal pole and anterior aspects of the superior temporal, middle temporal, and inferior temporal gyri. ChAT-immunoreactive fibers were most dense in layer I to superficial layer III throughout anterior temporal cortex. In temporal pole, agranular and dysgranular regions had a greater density of labeled fibers in superficial layers as compared to granular regions. In addition to the superficial concentration of cholinergic fibers in lateral temporal regions, numerous labeled fibers were also present in deep cortical layers in the inferior temporal gyrus of lateral temporal cortex, with lesser concentrations of immunoreactive fibers present in these layers in superior and middle temporal gyri. These patterns of cholinergic innervation may reflect the degree of cholinergic modulation of functions in anterior temporal cortex.

Animals↗
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The pathogenesis of reactive axonal swellings: role of axonal transport.

The role of axonal transport in the pathogenesis of the axonal swellings which develop at the severed ends of transected axons was studied by electron microscopic (EM) autoradiography. Proteins carried by fast anterograde transport in rat sciatic nerves were labeled with [3H]-leucine or [3H]-fucose; [3H]-leucine, [3H]-fucose, and [125I]-tetanus toxin were used to label components of retrograde transport. After the labeling procedure, the nerves were ligated and 2 to 24 hours later the animals were perfused with fixatives. The axonal swellings in both the proximal and distal stumps contained densely packed membranous organelles. The transported radioactivity in the swellings was strictly associated with these organelles, particularly pleomorphic vesicles and branched tubules derived from smooth endoplasmic reticulum. The endogenous (tritiated) substances had a similar association with the organelle collections in both the proximal stump (fast anterograde transport) and in the distal stump (retrograde transport). The exogenous marker of retrograde transport (125I-tetanus toxin) had the same autoradiographic localization. These results suggest that fast anterograde and retrograde transport are very similar processes carrying predominantly membranous organelles and constituting a system of bidirectional fast transport. The accumulations of organelles in reactive swellings are interpreted as the consequence of the acute focal interruption of this system. Studies of axonal transport provide a means for investigation of the origin and fate of axonal organelles in pathologic processes.

Animals↗