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N A Simonian

Publications and source records attributed to N A Simonian.

28 records · Page 2Linked to original sources
PubMed1995

Functional alterations in Alzheimer's disease: decreased glucose transporter 3 immunoreactivity in the perforant pathway terminal zone.

Positron emission tomography (PET) studies measuring glucose utilization have demonstrated cerebral hypometabolism in Alzheimer's disease (AD). The anatomic and biochemical basis for this observation remains unknown. We have examined the distribution in the hippocampal formation of the neuron-specific glucose transporter 3 (Glut3) protein. Using quantitative immunohistochemistry, we find a large reduction (49.5%) in Glut3 immunoreactivity in the outer portion of the molecular layer of the dentate gyrus in AD brains. This region corresponds to the terminal zone of the perforant pathway, whose cells of origin in layer II of the entorhinal cortex are selectively destroyed in AD. Because glucose uptake reflects metabolic demand, these results suggest a decrement of functional activity in the deafferented dentate gyrus granule cells. Generalizing from this observation, decreased glucose uptake seen on PET studies may reflect, in part, decreased glucose transport and utilization in functionally deafferented cortical fields.

Aged↗
PubMed1994

Calcium/calmodulin-dependent protein kinase II immunostaining is preserved in Alzheimer's disease hippocampal neurons.

Alterations in protein phosphorylation may be important in the pathogenesis of Alzheimer's disease and recent observations suggest that a subset of protein kinase pathways may be selectively altered. Calcium/calmodulin-dependent protein kinase II CaM kinase II) is the most abundant protein kinase in the brain and is believed to play an important role in the regulation of synaptic transmission, long-term potentiation and other forms of neuronal plasticity. We have now evaluated brains of individuals with Alzheimer's disease for changes in the distribution and density of immunoreactivity for the alpha subunit of CaM kinase II. CaM kinase II immunoreactivity was found in cytoarchitectural areas and neurons vulnerable to the formation of neurofibrillary angles and senile plaques. Over 80% of neurons bearing neurofibrillary tangles expressed CaM kinase II. Loss of CaM kinase II immunoreactivity was found in CA1, commensurate with neuronal loss in this area. Remaining CA1 neurons, however, had preserved CaM kinase II immunoreactivity. Preservation in the distribution and density of CaM kinase II immunoreactivity was observed in other hippocampal regions and in a multimodal association area, area 20. These results suggest CaM kinase II expression in the Alzheimer's disease brain is unaltered despite marked neuropathological changes.

Aged↗
PubMed1994

Functional alterations in Alzheimer's disease: selective loss of mitochondrial-encoded cytochrome oxidase mRNA in the hippocampal formation.

The activity of cytochrome oxidase (CO), the terminal enzyme of the electron transport chain, has been reported to be decreased in the brains of individuals with Alzheimer's disease (AD). In experimental models, CO activity decreases following functional deafferentation of neural circuits. CO is a holoenzyme composed of 13 nuclear- and mitochondrial-encoded subunits and experimental data indicate that the change in CO activity following deafferented is controlled primarily by regulation of mitochondrial CO gene expression. It has been proposed that the hippocampal formation is deafferented in AD. We therefore hypothesized that an alteration in mitochondrial CO gene expression might underlie the reduction in CO activity in AD. Using in situ hybridization, we found a selective reduction in mRNA levels for a mitochondrial-encoded subunit, CO II, with preservation of mRNA for a nuclear-encoded subunit, CO IV, in the hippocampal formation of individuals with AD. The reduction in CO II mRNA levels was seen both in regions with neurofibrillary tangles, senile plaques, and neuronal loss and regions relatively spared from these neuropathological changes. These data suggest that the reduction in CO activity in brain regions from individuals with AD may be a result of an alteration in mitochondrial CO gene expression that extends beyond neurons directly affected by structural pathology.

Alzheimer Disease↗
PubMed1993

Ifosfamide causes a diazepam-sensitive encephalopathy.

An encephalopathy characterized by confusion, stupor, and mutism frequently occurs during administration of the chemotherapeutic drug ifosfamide (IFX). We investigated two patients who developed encephalopathy during IFX infusion. Both exhibited a rapid and near-complete restoration of baseline mental status functioning concurrent with EEG improvement after administration of intravenous diazepam. We recommend an EEG and trial of benzodiazepines in patients with IFX encephalopathy.

Adult↗
PubMed1993

Functional alterations in Alzheimer's disease: diminution of cytochrome oxidase in the hippocampal formation.

In Alzheimer's disease, the relationship between structural alterations such as neurofibrillary tangles and senile plaques and neuronal function is unknown. Cytochrome oxidase, the terminal enzyme of the electron transport, is a marker of neuronal functional activity. Its activity is diminished in experimentally deafferented neurons. Based on evidence that the molecular layer of the dentate gyrus is deafferented in the brains of individuals with Alzheimer's disease, we hypothesized that cytochrome oxidase activity would be diminished in this region secondary to reduced glutamatergic input. Using cytochrome oxidase histochemistry, we found a change in the distribution of cytochrome oxidase in the molecular layer of the dentate gyrus and a decrease in activity in both the dentate gyrus and hippocampal subfields in Alzheimer's disease. In contrast, we found relatively little structural pathology in the dentate gyrus, CA4, and CA3 in these individuals. These results suggest that neurons that remain structurally intact in Alzheimer's disease may nonetheless undergo changes in metabolic function as neural systems fail.

Afferent Pathways↗
PubMed1990

Specific infection of central nervous system white matter by a variant of gross murine leukemia virus.

Exposure of neonatal Balb.B mice to a variant of Gross murine leukemia virus, termed WB91-GV, resulted in selective white matter infection within the central nervous system. Viral antigens were detected in brain sections of animals inoculated by either intracerebral or intraperitoneal routes, but were only seen in mice exposed within the first day after birth. This distinct tropism was confirmed by virus replication and gp70 expression in isolated glial cultures in vitro. Analysis of gp70 expression in highly enriched glial subpopulations indicated that oligodendrocytes and perhaps a subset of astrocytes were the targets of this infection.

AKR murine leukemia virus↗
PubMedDate not supplied

Functional alterations in neural circuits in Alzheimer's disease.

While a correlation exists at the regional level between the distribution of neurofibrillary tangles and the predicted sites of brain dysfunction based on clinical and functional neuroimaging studies, the relationship between neurofibrillary tangles and neuronal dysfunction is poorly understood. Using cytochrome oxidase activity as a marker of neuronal functional activity, we found reductions in metabolic activity both in a hippocampal subfield with a high density of neurofibrillary tangles (CA1) as well as in subfields relatively spared (CA3, dentate granule cells). In contrast, we found no reduction in activity in primary visual cortex. Using in situ hybridization, we found a selective reduction in a mitochondrial-encoded cytochrome oxidase mRNA transcript with sparing of a nuclear-encoded transcript. These results suggest that the reduction in cytochrome oxidase activity in Alzheimer's disease brain may be related to an alteration in mitochondrial gene expression. The absence of a direct correlation between structural pathology and cytochrome oxidase activity suggests that neurons that remain structurally intact in Alzheimer's disease may nonetheless undergo substantial changes in metabolic activity.

Aged↗