Biomedical subjects

M Alford

Publications and source records attributed to M Alford.

46 records · Page 3Linked to original sources

PubMed1991

Late onset dementia with argyrophilic grains and subcortical tangles or atypical progressive supranuclear palsy?

Most clinically demented elderly patients are found at autopsy to have Alzheimer's disease, multi-infarct dementia, Parkinson's disease, Pick's disease, or Creutzfeldt-Jakob disease. We studied 5 patients clinically characterized by late onset dementia whose brains showed no pathological evidence of Alzheimer's disease, or any other specific neuropathological diagnosis. We found argyrophilic grains, coiled bodies, abundant Alz-50-positive and thioflavine S-negative neurofibrillary tangles, and neuropil threads in the hippocampus, entorhinal cortex, locus ceruleus, substantia nigra, subthalamic nucleus, and inferior olives. Ultrastructurally, the grains, threads, and tangles were composed of straight tubulofilamentous structures, 25 nm in diameter, similar to those found in patients with progressive supranuclear palsy but different from the paired helical filaments of patients with Alzheimer's disease. These findings suggest that the late onset dementia with argyrophilic grains syndrome is also characterized by the presence of tangles and threads with the topographical distribution of progressive supranuclear palsy.

Aged↗

PubMed1991

Immunoreactivity of CD45, a protein phosphotyrosine phosphatase, in Alzheimer's disease.

Both protein kinases and phosphoprotein phosphatases are important components of signal transduction systems in cells. Recent studies in Alzheimer's disease (AD) have shown abnormal protein phosphorylation in the cortex suggesting an alteration in these enzymes. In the present study, an antibody against CD45 was used to analyze the status of this protein phosphotyrosine phosphatase in AD. We studied and quantified the immunohistochemical and immunochemical distribution of this integral membrane protein in control and AD brain. We found that anti-CD45 immunostained the great majority of microglia, both resting and activated. These cells were Ricinus communis agglutinin I positive and glial fibrillary acidic protein and neurofilament negative. The AD frontal cortex showed a 35% (P less than 0.01) increase in the number of anti-CD45 immunoreactive microglia as compared with controls. These results were consistent with the immunoblot quantification of CD45 immunoreactivity following native gel electrophoresis. In AD, 30% of the CD45-immunostained microglia were clustered in the neuritic plaques (about six per plaque) while the remaining 70% were scattered in the neuropil. The AD hippocampus showed an increase in CD45-immunoreactive microglia in the molecular layer of the dentate gyrus. At the ultrastructural level, CD45 immunoreactivity was localized exclusively to the plasma membrane of the microglia. The presence of the anti-CD45 immunoreactivity in microglia suggests the possibility that they may require the presence of CD45 as a cell surface receptor which may regulate cell function through modulation of intracellular signaling.

Aged↗

PubMed1991

Patterns of aberrant sprouting in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by extensive synaptic and neuronal loss and by plaque formation in the cortex, but the mechanisms responsible for synaptic plasticity in the neocortex are still not completely understood. To analyze the sprouting response in AD cortex, we compared the patterns of GAP-43 with synaptophysin immunoreactivity. In AD, GAP-43 immunohistochemistry revealed extensive sprouting in the hippocampal molecular layer, stratum polymorphous, CA1 region, and prosubiculum. These regions presented abundant anti-GAP-43-immunoreactive coiled fibers and dystrophic neurites in association with plaques. Some of these sprouting structures were colocalized with anti-synapto-physin- and anti-neurofilament-positive neurites. The AD neocortex was characterized by an overall decrease in GAP-43 immunoreactivity accompanied by sprouting neurites in the areas of synaptic pathology. We conclude that GAP-43 might be involved in the mechanisms of synaptic plasticity in the AD cortex, as well as in the process of aberrant sprouting in the neuritic plaques.

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PubMed1991

Cortical and subcortical patterns of synaptophysinlike immunoreactivity in Alzheimer's disease.

Quantification of synaptophysinlike immunoreactivity is a valuable method for studying the presynaptic terminals in the normal and damaged nervous system. The present report shows that in the control brain, the predominant pattern of synaptic immunostaining in the neocortex was that of an evenly distributed densely granular immunolabeling of the neuropil, while in the paleocortex and in subcortical areas of the brain most of the presynaptic terminals were distributed along the dendritic arborizations or around the neuronal somata. The immunochemical and the immunohistochemical analysis of the Alzheimer's disease tissue showed that the frontal and parietal cortex presented the most severe and widespread loss, with a 45% loss in synaptophysin immunoreactivity. These areas showed an average 35% loss of large neurons. The visual cortex, hippocampus, entorhinal cortex, nucleus basalis of Meynert, and locus ceruleus displayed some degree of loss, but to a lesser extent. In addition to this loss, the basic patterns of organization of the presynaptic terminals were altered, with the presence of abundant, enlarged synaptophysin-labeled terminals. This study further supports the role of synaptic pathology in Alzheimer's disease.

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PubMed1990

Inhibition of glucose transport into rat islet cells by immunoglobulins from patients with new-onset insulin-dependent diabetes mellitus.

Because glucose-stimulated insulin secretion is selectively impaired during the development of insulin-dependent diabetes mellitus (IDDM), we tested the possibility that the glucose transporter of pancreatic islet beta cells is a target of the autoimmune process in patients with IDDM. We measured the uptake of 3-O-methyl-beta-D-glucose by dispersed islet cells from rats after a 15-minute incubation with purified IgG from 27 patients with newly diagnosed IDDM, 28 normal subjects, and 5 patients with non-insulin-dependent diabetes mellitus (NIDDM). The IgG fractions from 26 of the 27 patients with IDDM (96 percent), but from none of the 5 patients with NIDDM, reduced the initial rates of 3-O-methyl-beta-D-glucose uptake to at least 1 SD below the mean of the rates observed in the presence of IgG fractions from normal subjects (P less than 0.001). In contrast, the uptake of L-leucine by islet cells was not affected by any of the IgG fractions. The inhibitory activity of IgG from the patients with IDDM was abolished by preincubation with islet cells and membranes from hepatocytes, which contain the same glucose transporter as beta cells, but not with erythrocytes, which do not contain this transporter. We conclude that IgG from patients with IDDM of recent onset, but not from those with NIDDM, inhibits glucose uptake by rat islet cells. The results are consistent with the presence of an antibody against a protein involved in glucose transport by beta cells that would thereby impair glucose-stimulated insulin secretion.

3-O-Methylglucose↗

PubMed1990

Quantitative immunohistochemistry of synaptophysin in human neocortex: an alternative method to estimate density of presynaptic terminals in paraffin sections.

Currently available specific synaptic markers have made it possible to estimate the synaptic density by immunochemical techniques. In the present study we labeled the neocortical presynaptic terminals in histological sections of human autopsy tissue with a monoclonal antibody against synaptophysin. The characteristic granular neuropil reaction was quantified by measuring the average optical density (OD) in the different layers of the parietal cortex with the aid of image analysis equipment. The raw neuropil OD was corrected by subtracting the OD of the white matter in the same section. Our study showed that consistent microdensitometric results can be obtained on 5-microns paraffin sections from specimens with less than 8 hr of post-mortem time before fixation, incubated with 5 micrograms/ml of anti-synaptophysin. The corrected OD measurements were slightly larger in neocortical layers II, III, and V than in layers I, IV, and VI, but the differences were not statistically significant. In area 17, layer IV was denser than the others. We conclude that with certain precautions this method can be used to measure relative amounts of synaptophysin-like immunoreactivity and to infer the density of presynaptic boutons in human situations and in animal models.

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PubMed1990

Diffuse plaques do not accentuate synapse loss in Alzheimer's disease.

Applying the relatively new technique of laser confocal imaging, vibratome sections which were double immunolabeled for amyloid beta protein and the presynaptic terminal marker synaptophysin were examined. It was found that while synaptic density was generally diminished in Alzheimer's disease (AD) cortical neuropil as compared to controls, the reduction was no greater within the diffuse plaques than outside them. Synapse loss was accentuated, however, within immature and mature plaques. These findings suggest that the pathogenetic process in AD might commence with synapse loss and neurodegeneration rather than with deposition of amyloid beta protein.

Aged↗

PubMed1988

Neocortical morphometry and cholinergic neurochemistry in Pick's disease.

With a computerized image-analysis apparatus for neocortical morphometry and chemical methods for evaluation of the cholinergic system, five brain specimens of Pick's disease (PD) were studied and the results compared to those from specimens of age-matched normal subjects and Alzheimer's disease (AD). The PD specimens showed major reductions in brain weight, frontal and temporal cortical thickness, and large neuron populations, compared with controls. Lesser reductions were seen in small neurons and thickness of the inferior parietal cortex. The authors found no relationship between age of onset or disease duration and either the degree of cortical thinning or neuron loss or the number of Pick bodies in the neocortex and hippocampus. PD specimens were more atrophic than AD brains, having lower brain weights and more fronto-temporal thinning. Large neurons were comparably reduced in the two conditions in the frontal and temporal lobes, but small neuron losses were greater in the PD midfrontal area. Only the AD cases showed loss of large neurons in the inferior parietal region. Levels of choline acetyltransferase were normal in PD and reduced in AD, whereas muscarinic receptor binding was decreased in both.

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PubMedDate not supplied

PDGF is associated with neuronal and glial alterations of Alzheimer's disease.

In the present study we observed that while platelet-derived growth factor (PDGF)-BB is exclusively expressed by neurons in the human brain, PDGF-AA is expressed in neurons and blood vessels. In Alzheimer's disease (AD), antibodies against PDGF-BB (but not PDGF-AA) recognized the neurofibrillary alterations of this disease. The levels of PDGF-BB correlated with the patterns of synaptic loss and sprouting while PDGF-AA immunostaining of the vessels was correlated with glial proliferation. Immunostaining was completely abolished when the antibodies were preincubated with their respective purified recombinant PDGF. Western blot analysis showed that antibodies against PDGF recognized a 31 kDa protein that was mildly increased in AD. These data suggest that PDGF, as well as other neurotrophic factors, play an important role in the mechanisms of neurofibrillary pathology in AD.

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PubMedDate not supplied

The effect of continuous subcutaneous insulin infusion on endogenous insulin secretion in type I diabetes.

In an attempt to elucidate possible mechanisms for the success of continuous subcutaneous insulin infusion (CSII), we evaluated the C-peptide response to a standard breakfast in seven type I diabetic patients while they were on conventional insulin treatment and again after 4 wk of near-normal glycemia achieved with CSII. While on conventional therapy their 24-h mean blood glucose level was 211 +/- 12 mg/dl and their glycosylated hemoglobin level was 10.6 +/- 0.6%. After 4 wk of CSII their 24-h mean blood glucose level fell to 95 +/- 7 mg/dl and their glycosylated hemoglobin level fell to 6.5 +/- 0.4%. Plasma C-peptide levels were undetectable in all seven patients both while on conventional therapy and after 4 wk of CSII. We conclude that the success of CSII is related to an improved method of insulin delivery and not to either the selection of type I diabetic patients who have some residual insulin secretory capacity or to some change in endogenous insulin secretion produced by the treatment itself.

Adolescent↗