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Biomedical subjects

R D Terry

Publications and source records attributed to R D Terry.

At least 19 recordsLinked to original sources
PubMed1996

Developmental toxicity of ibutilide fumarate in rats after oral administration.

In two Segment II Teratology studies, timed-pregnant Crl:CD[BR] (Sprague-Dawley) rats were treated orally (gastric intubation) on days 6-15 of gestation with ibutilide fumarate (ibutilide), a class III antiarrhythmic that has been shown to increase the refractory period and action potential duration of myocardial cells. In the first study, ibutilide does of 20, 40, and 80 mg/kg/ day were tested. Although maternal toxicity was equivocal in the 80 mg/kg/day group, all 23 rats that conceived had entirely resorbed liters when the animals were killed on day 20 of gestation. Similarly, 12 of 24 litters were completely resorbed in the 40 mg/kg/day group, with an 87.7% postimplantational loss. Of the surviving fetuses in this group, 48.6% had at least one malformation. The incidences of malformed pharynx and malformed palate, along with adactyly, were statistically significantly higher in this group than in the control group. In addition, a significant (P < 0.05) increase in total malformations (5.7% of the fetuses), relative to the controls (0.8%), was found for the 20 mg/kg/day group. Since a no observed adverse effect level (NOAEL) was not found, a second teratology study was performed. In this study, the ibutilide doses were 5, 10, and 20 mg/kg/day. The 20 mg/kg/day dose was again teratogenic with 9.2% of the fetuses malformed, as compared to a control value of 1.0%. Also, the incidences of scoliosis and interventricular septal defect were statistically significantly higher in this group. Although statistically significant differences were not detected, scoliosis was also found in the 10 mg/kg/day group (3 fetuses in 2 litters), along with a significant dose-response trend for this malformation. As the result, the NOAEL for ibutilide teratogenicity in rats was set at 5 mg/kg/day. This dose is 4 times the proposed maximum clinical dose (two 1 mg doses, each infused over 10 minutes, or 0.033 mg/kg for a 60 kg person), when corrected for 2.6% oral bioavailability in the rat at a dose of 10 mg/kg, as determined in separate studies.

Administration, Oral↗
PubMed1996

The pathogenesis of Alzheimer disease: an alternative to the amyloid hypothesis.

This paper attempts to put together in the form of a flow sheet (Fig. 1) the several known alterations, both chemical and structural, of brain tissue in Alzheimer disease, which ultimately result in dementia. While most investigators in the field believe strongly that amyloid deposition is at the core of the disease, this writer finds that a more coherent, and thus more satisfying, schema can be based on the centrality of cytoskeletal abnormality. Not only do all four identified genes interact one way or another with the cytoskeleton, but abnormality of the latter leads to alterations of the Golgi apparatus with effects on protein processing, and on axoplasmic flow such that one can expect loss of synapses and subsequent loss of neurons with consequent disconnection and loss of neurotransmitters. Dementia is the result.

Alzheimer Disease↗
PubMed1995

Biologic differences between early- and late-onset Alzheimer disease.

Large neurons shrink and synapses are lost in the neocortex as a function of normal aging, but different parts of the central nervous system vary in susceptibility to age changes. Thus, early-onset disease may appear different from late cases due to premorbid age changes rather than because of different pathogenesis.

Age of Onset↗
PubMed1994

Clinical correlates of cortical and nucleus basalis pathology in Alzheimer dementia.

OBJECTIVE: We correlated severity of dementia in Alzheimer's disease with the degree of neuropathology in cortical and subcortical brain regions. METHODS: In 13 patients with Alzheimer's disease who underwent neuropsychological testing before death, we assessed neurofibrillary tangles, senile plaques, and neuronal and synaptic density in the midfrontal cortex and the nucleus basalis of Meynert. RESULTS: In the midfrontal cortex, synapse density was the strongest correlate of dementia severity, followed by neurofibrillary tangles. In the nucleus basalis, by contrast, neurofibrillary tangles were the strongest correlate, followed by synapse density. Stepwise regression analyses showed midfrontal synapse density to be the strongest predictor of tests emphasizing higher cortical functions, but neurofibrillary tangles in the nucleus basalis were the strongest predictor on memory-oriented tests. CONCLUSIONS: The specificity of pathology in cortical vs subcortical locations for predicting a particular quality of neuropsychological deficit probably reflects disruption of corticocortical connections vs derangement of the basal forebrain cholinergic system.

Aged↗
PubMed1994

A simple dot-immunobinding assay for quantification of synaptophysin-like immunoreactivity in human brain.

Neocortical decreases in synaptic density correlate significantly with the cognitive impairment seen in Alzheimer disease. Recently available monoclonal antibodies (MAb) have made possible the highly specific and sensitive detection of synapse-associated proteins in immunocytochemical and immunochemical techniques. We describe a simple yet highly sensitive dot-immunobinding assay for relative quantification of the synapse marker protein synaptophysin in human brain homogenate fractions with the mouse MAb SY38. Fractions prepared from control and Alzheimer specimens were blotted to nitrocellulose membranes and reacted with SY38, rabbit secondary antibody, and iodinated protein A. A relative standard curve was constructed to normalize results from multiple assay runs. We correlated the results with the more complex immunocytochemical synaptic density measurement technique of immunolabeling coupled with laser confocal imaging, showing good correlation at r = 0.821. Results from Alzheimer cases showed a 40% decrease in synaptophysin immunoreactivity in midfrontal cortex compared with normal controls.

Aged↗
PubMed1993

The synaptic organization of the neocortex in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by a progressive deterioration of cognitive functions. Recent studies have shown that, in addition to the classically described lesions (plaques and tangles) found in AD, this neurodegenerative disorder is characterized by neuronal and synaptic loss and by synapto-axonal pathology. Stepwise regression analysis has shown that the major correlate of cognitive deficiency is the synapse loss in the prefrontal cortex, contributing about 70% of the strength of the correlation with global psychometric tests. We review evidence that supports the theory that most of the synaptic loss in the neocortex is derived from loss of cortico-cortical associational input into the modules. This hypothesis also predicts that neuritic plaque formation in the neocortical modules could represent an aberrant sprouting reaction of associational fibers responding to abnormal growth stimuli or to local damage. On these bases, it is also proposed that the cellular substrate of AD pathology is synapto-axonal, while in certain other forms of dementia such as Creutzfeldt-Jacob disease (CJD) and HIV encephalitis (HIVE) it is primarily dendritic.

Afferent Pathways↗
PubMed1993

Re-evaluation of the structural organization of neuritic plaques in Alzheimer's disease.

We re-examined the relationship among synaptic pathology, subcellular abnormalities within neurites in the plaques and beta-amyloid deposits of Alzheimer's disease (AD) using laser confocal imaging and computer-aided serial section reconstruction techniques. Analysis of serial optical sections of neuritic plaques double-immunolabeled for anti-beta-amyloid/anti-tau-2 revealed that 35% of this type of plaque contained a dense amyloid core with clusters of peripheral abnormal neurites. The other 65% were without a dense core and were mainly composed of abundant abnormal neuritic clusters with bundles of amyloid distributed throughout the neuritic plaque. While two-dimensional (2-D) analysis of the plaques has suggested that neurites are distributed in the plaque periphery with beta-amyloid localized in its center, serial section analysis showed the opposite arrangement can also be true. Three-dimensional (3-D) reconstructions of serial optical sections showed that the tau-positive tortuous axons clustered in the neuritic plaques were often continuous with synaptophysin-positive distended terminals. Analysis of electron micrographs from serial sections showed continuity among the different segments of the neurites. Further analysis of the computer generated 3-D reconstructed neuritic plaques (both from serial electron micrographs and serial optical sections), viewed as continuous rotating loops, confirmed that a great majority of the plaque volume was occupied by the clustered and continuous abnormal neurites, while the amyloid fibrils were compressed and displaced to the periphery of the plaque. The 3-D imaging of the neuritic plaques in AD suggests a more widespread and active neuritic damage than that predicted from 2-D observations.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Plaque-only Alzheimer disease is usually the lewy body variant, and vice versa.

A minority of neuropathologically confirmed Alzheimer disease (AD) brains lack neocortical neurofibrillary tangles or have very few, constituting a form of "plaque-only AD." A significant percentage of clinically diagnosed AD patients are found at autopsy to have both AD and brainstem and neocortical Lewy bodies. Many of these Lewy body variants of AD (LBV) have numerous senile plaques but no neocortical neurofibrillary tangles, and so resemble plaque-only AD. In this study, we sought to determine if plaque-only AD was usually LBV, and, conversely, if LBV was usually plaque-only AD. We analyzed 147 consecutively accessioned cases of neuropathologically confirmed AD, diagnosed according to criteria from the National Institute on Aging and the Consortium to Establish a Registry for Alzheimer's Disease. Twenty-five percent of all AD cases in this series were plaque-only AD, and 75% were plaque and tangle AD. Twenty-eight percent of AD cases in this series were LBV, and 72% were pure AD. Of the plaque-only AD cases, 75% were LBV and only 25% were pure AD. Of the LBV, 66% were plaque-only AD and only 33% were plaque and tangle AD. These results indicate that most plaque-only AD is LBV, and, conversely, that most LBV is plaque-only AD.

Aged↗
PubMed1993

Quantitative synaptic alterations in the human neocortex during normal aging.

We quantified the synaptic population density in the frontal cortex of 25 individuals without dementia 16 to 98 years old, using sections double-immunolabeled for beta/A4 amyloid and for synaptophysin, and found a significant inverse correlation between the presynaptic terminal (PT) counts and age (r = -0.7, p < 0.001). Individuals older than 60 years had an average 20% decrease in PT density compared with individuals younger than 60 years. There were no significant correlations between the age and the number of beta/A4 amyloid-positive plaques or between synaptic density and the number of amyloid plaques. Further analysis of the digitized serial optical images showed focal areas of synapse loss and distended synaptophysin-containing boutons in the mature plaques of the normal aged cases. However, we found no microscopic changes in the synaptic content inside and outside the diffuse plaques. We suggest that a loss of synaptic input in the neocortex is an age-dependent factor that contributes to the overall synaptic loss in Alzheimer's disease, but that this might be largely independent of the beta/A4-amyloid deposition.

Adolescent↗
PubMed1993

Making the diagnosis of Alzheimer's disease. A primer for practicing pathologists.

There is demand on community pathologists to perform autopsies to confirm the clinical diagnosis of Alzheimer's disease, the most common cause of dementia in our increasingly aging society. Yet many pathologists are reluctant to examine autopsy brains because they have little experience with neuropathology and with the common histopathologic staining methods needed to evaluate dementia cases. This article provides interested pathologists with a simple, practical protocol to use in meeting this demand. While there is no absolute diagnostic gold standard for Alzheimer's disease and the histopathologic diagnosis remains imperfect, the guidelines presented are adapted from those used by many neuropathologists at Alzheimer's disease research centers participating in CERAD, the Consortium to Establish a Registry for Alzheimer's Disease. Recipes for appropriate stains and specific case examples are provided for convenience.

Age Factors↗
PubMed1992

Spectrum of human immunodeficiency virus-associated neocortical damage.

A spectrum of neurocognitive defects, termed human immunodeficiency virus type 1 (HIV-1)-associated cognitive/motor complex, has been described in patients with acquired immunodeficiency syndrome (AIDS). AIDS dementia complex (ADC) is a severe form of this disease seen in 20 to 30% of terminally ill patients. The etiology of this complex is distinct from commonly observed opportunistic infections seen in brains of patients with AIDS and has been attributed to HIV infection within the brain. At autopsy, the brains of patients with ADC contain numerous HIV-infected macrophages/microglia with prominent subcortical damage, together termed HIV encephalitis. We retrospectively analyzed all 107 brains from a three-year period (1988-1990) of AIDS autopsies using immunocytochemistry to detect HIV. Rather than breaking into distinct groups of HIV encephalitis versus non-HIV encephalitis, the specimens revealed a spectrum of severity of HIV infection. Although only 16% of the brains showed the histological hallmarks of HIV encephalitis, more than 50% of the autopsies showed moderate to severe HIV infection. In a subset of 23 AIDS autopsies during which short postmortem times and absence of significant opportunistic infection permitted quantitative analysis of dendritic and synaptic complexities, we identified a strong correlation between neocortical dendritic and presynaptic damage and abundance of HIV envelope protein in the neocortical gray and deep white matter. This correlation suggests that the presence of HIV-1 in the neocortex may be responsible by direct or indirect mechanisms for dendritic and synaptic damage.

AIDS Dementia Complex↗