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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
PubMed2000

Do neuronal inclusions kill the cell?

Neurofibrillary tangles, Pick bodies and Lewy bodies are considered quantitatively in relation to neuron loss. It would seem that the inclusions are not themselves the cause of neuron death.

Alzheimer Disease↗
PubMed2000

Cell death or synaptic loss in Alzheimer disease.

It is an erroneous but common assumption that loss of neuronal perikarya causes the cognitive change in Alzheimer disease. Neither are senile plaques nor neurofibrillary tangles primarily to blame. In fact, it is the loss of synaptic contact that leads directly to the personal devastation. The death of neocortical synapses in the neuropil between plaques is probably the factor that activates the microglia.

Alzheimer Disease↗
PubMed1998

The cytoskeleton in Alzheimer disease.

The strongest physical correlate with the severity of dementia in Alzheimer's disease and its most rational cause are the loss of neocortical and hippocampal synapses. Evidence, showing that beta-amyloid causes that loss is weak despite the popularity of that hypothesis. Other changes can better explain that damaging phenomenon. Axonal terminals are dependent on axoplasmic flow, and that function requires intact microtubules and the motor proteins kinesin, dynein and dynamin. It has been known since the earliest electron microscopic studies of AD that neuronal microtubules are lessened in number. Tubules are normally in equilibrium with unpolymerized tubulin, and the stability of the formed elements is dependent on normal binding of tau to the tubule. But, as is well known, tau is abnormally hyperphosphorylated in AD leading to tangle formation and to dissolution of the tubules. Tangles are insufficient in number to account for the cortical loss of neurons and synapses, but hyperphosphorylated tau in the unpolymerized pre-tangle state undoubtedly plays a role. Abnormalities in the motor proteins are now being investigated (some have already been found) and these too would contribute to the loss of synapses in AD by way diminished axoplasmic flow.

Alzheimer Disease↗
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↗