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Biomedical subjects

B T Hyman

Publications and source records attributed to B T Hyman.

At least 181 records · Page 10Linked to original sources
PubMed1994

Neuropathologic changes of the temporal pole in Alzheimer's disease and Pick's disease.

OBJECTIVE: To describe the pattern of neuropathologic changes in temporal polar cortex in Alzheimer's disease (AD) in comparison with changes in Pick's disease (PD) and normal elderly cytoarchitecture. DESIGN: Examination of degenerative changes, neurofibrillary tangles, and senile plaques in the temporal poles of 10 patients with AD, three patients with PD, and five age-compatible control subjects, by means of thionein and thioflavine S stains and Alz-50 and ubiquitin immunocytochemistry. SUBJECTS: All patients had a documented history of dementia and AD or PD confirmed on neuropathologic examination. Control subjects were without a history of cognitive impairment or evident neuropathologic changes. OUTCOME MEASURES: Cytoarchitecture, neuronal loss, neurofibrillary tangles, senile plaques, and Pick bodies. RESULTS: All patients with AD showed atrophy of the temporal pole and marked neuronal loss, especially in layers III and V and, to a lesser degree, in layers II and VI. Heavy accumulation of neurofibrillary tangles was found in layers II, III, V, and VI. Patients with PD showed extensive neuron loss throughout, although this appeared to be most prominent in layer III. CONCLUSIONS: Both AD and PD pathologic changes severely affect the layers of the temporal pole that mediate widespread reciprocal connections with temporal and frontal cortices and limbic cortical and subcortical structures. Neural systems that interconnect temporal polar cortex with sensory association areas and memory-related limbic structures are, therefore, disrupted, and it is likely that these lesions play a role in the multifaceted cognitive and behavioral changes of AD and PD.

Adult↗
PubMed1994

Localization of non-N-methyl-D-aspartate glutamate receptors in normal and Alzheimer hippocampal formation.

The hippocampi and adjacent temporal cortices of 24 human brains were examined with antibodies to the GluR1, GluR2/3, and GluR4 subunits of the D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-preferring glutamate receptor. GluR1 immunoreactivity was most dense in the dentate gyrus, with lower densities in other hippocampal and cortical regions. GluR2/3 immunoreactivity was the most intense of the three antibodies, with high levels throughout most hippocampal subfields, where it was localized to cell bodies, proximal axons, and dendrites. GluR4 immunoreactivity was very sparse in all regions. In Alzheimer's disease brains, the general pattern of staining was similar to that seen in control brains. GluR1 and GluR4 immunoreactivity was seen in some but not all neuritic plaques. All three antibodies recognized some neurons undergoing neurofibrillary degeneration.

Aged↗
PubMed1994

Systemic or local administration of azide produces striatal lesions by an energy impairment-induced excitotoxic mechanism.

Sodium azide is an inhibitor of cytochrome oxidase which produces selective striatal lesions in both rodents and primates. In the present study we investigated the neurochemical and histologic effects of both intrastriatal and systemic administration of sodium azide, as well as the age dependence and mechanism of the lesions. Intrastriatal administration of sodium azide produced dose-dependent lesions. Neurochemical and histologic evaluation showed that markers of both spiny projection neurons (GABA, substance P) and aspiny interneurons (somatostatin, neuropeptide Y, NADPH-diaphorase) were equally affected. Subacute systemic administration of sodium azide resulted in lesions with a similar neurochemical profile; however, in contrast to intrastriatal injections there was sparing of dopaminergic striatal afferents. Prior decortication significantly attenuated lesions produced by intrastriatal administration of sodium azide, consistent with an excitotoxic process. Chronic administration of sodium azide for 1 month lead to striatal neuropathological changes. Lesions produced by intrastriatal administration of sodium azide in 1-, 4-, and 12-month-old animals showed age dependence. Both freeze-clamp measurements and chemical-shift magnetic resonance spectroscopy confirmed that sodium azide impairs oxidative phosphorylation in the striatum following either intrastriatal or systemic administration. These results show that the striatum is particularly vulnerable to oxidative stress produced by sodium azide, and that it produces striatal lesions by a secondary excitotoxic mechanism.

3,4-Dihydroxyphenylacetic Acid↗
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↗
PubMed1994

Development of the superior temporal neocortex is anomalous in trisomy 21.

Trisomy 21 (Down syndrome) is the most common inherited form of mental retardation in the United States, however, the basis of impaired cognition is unknown. We have used recently developed stereological cell counting techniques to quantitatively examine the pattern of neuronal migration and maturation in one neocortical area during gestation in normal development and in trisomy 21. Normal development of the cerebral cortex occurs in two general sequences: Beginning at approximately 7-8 weeks gestation, migration of cells destined to become neurons results in the accumulation of cells in the cortical mantle. This process is largely complete by 20-21 weeks. Over the next 7-10 weeks an "inside-out" differentiation into lamina of different neuronal densities occurs. Our data suggest that the second phase of cortical development, the emergence of lamination, is both delayed and disorganized in trisomy 21. The observed pattern of cortical maturation may reflect an abnormality in axonal and dendritic arborization that subsequently subserve the connectional and functional units underlying normal cognition.

Cell Movement↗
PubMed1994

Reduced apolipoprotein epsilon 4 allele frequency in the oldest old Alzheimer's patients and cognitively normal individuals.

Recent genetic studies show that the apolipoprotein E epsilon 4 allele (ApoE-epsilon 4) is a risk factor for Alzheimer's disease (AD). If ApoE-epsilon 4 individuals develop AD as they get older, we would expect a decrease in ApoE-epsilon 4 allele frequency with increasing age. We found a marked decline in ApoE-epsilon 4 allele frequency with advancing age in both AD and cognitively normal controls (p < 0.003), although in all age groups the ApoE-epsilon 4 allele was overrepresented (p < 0.0001). Nonetheless, a few cognitively normal nonagenarians were ApoE-epsilon 4 positive. Thus, our data support two new conclusions: (1) the ApoE-epsilon 4 associated risk for AD is age-dependent, probably due to censoring by the earlier development of AD in ApoE-epsilon 4 individuals, and (2) despite the ApoE-epsilon 4 associated risk for AD, it is possible to reach extreme old age with normal cognition.

Aged↗
PubMed1994

Extracellular signal regulated kinases. Localization of protein and mRNA in the human hippocampal formation in Alzheimer's disease.

MAP kinases (MAPK) are a family of serine/threonine (Ser/Thr) kinases that link cell surface signals to changes in enzyme activity and gene expression. They are the products of the newly described gene family referred to as extracellular signal regulated kinases (ERKs). Moreover, MAPKs phosphorylate tau in vitro at Ser/Thr Proline sites, generating a multiply phosphorylated tau protein that is similar to the hyperphosphorylated tau found in Alzheimer neurofibrillary tangles (NFTs). We studied MAPK immunoreactivity and in situ hybridization patterns of the two major genes that comprise MAPK activity, ERK1 and ERK2, in the human hippocampal formation. Our goal was to determine whether the pattern of ERK expression is consistent with the hypothesis that MAPKs contribute to NFT formation. ERK1 mRNA is present in small amounts and confined primarily to dentate gyrus granule cells. ERK2 mRNA, by contrast, gives a much stronger hybridization signal and is present in dentate gyrus granule cells and pyramidal cells throughout all hippocampal subfields and adjacent temporal neocortex. Quantitative measures of ERK2 mRNA reveal that NFT-bearing neurons contain approximately 15% less ERK2 mRNA than nearest neighbors that do not contain NFT. NFT-bearing neurons contain approximately 25% less polyA mRNA, suggesting a relative preservation of ERK2 mRNA even in metabolically compromised cells. MAPK immunoreactivity (which represents both ERK1 and ERK2) is seen in neuronal soma, dendrites, axons, and in reactive astrocytes. In Alzheimer's disease, neurons that contain NFTs are also MAPK immunoreactive, but neurons that contain the highest amounts of MAPK immunoreactivity are not necessarily vulnerable for NFT. MAPK immunoreactivity is present in the same neurons as NFT and in the same subcellular compartments as tau, supporting a role for MAPKs in tau phosphorylation in Alzheimer's disease. However, the presence of ERK immunoreactivity is not sufficient to predispose neurons to NFT formation.

Adult↗
PubMed1994

Apolipoprotein E4 and beta amyloid in senile plaques and cerebral blood vessels of aged rhesus monkeys.

Recent studies of late onset familial and sporadic Alzheimer's disease (AD) show a genetic disequilibrium between inheritance of the epsilon 4 allele of the apolipoprotein E (ApoE) gene and development of AD. beta-Amyloid (A beta)-positive senile plaques and blood vessels in AD are immunoreactive for ApoE, suggesting that ApoE plays a role in amyloid deposition. We examined the brains of nine rhesus monkeys (Macaca mulatta) to determine the immunohistochemical distribution of ApoE and to investigate the association of ApoE with A beta in this species. Antibodies to ApoE and A beta labeled senile plaques and vessels in the brains of aged monkeys, indicating cross-species homogeneity of the association of these two proteins. Polymerase chain reaction/restriction enzyme analysis of the ApoE epsilon 3/epsilon 4 allelic site (residue 112) in the rhesus monkey revealed that the rhesus has an arginine at this site like the human epsilon 4 allele, the cynomolgus monkey, baboon, cow, pig, mouse, and rat but unlike the human epsilon 3 allele and the rabbit. These results emphasize the value of aged nonhuman primates as animal models for A beta deposition and ApoE4-A beta interactions in AD and aging.

Aging↗
PubMed1993

The pattern of NADPH-diaphorase staining, a marker of nitric oxide synthase activity, is altered in the perforant pathway terminal zone in Alzheimer's disease.

NADPH-diaphorase positive neurons are relatively spared in Alzheimer's disease (AD). We show here, however, that the pattern of NADPH-diaphorase staining in the neuropil of the hippocampus changes dramatically in the brains of patients with AD. Control individuals displayed a striking band of NADPH-diaphorase staining in the middle 1/3 of the molecular layer of the dentate gyrus; this band was absent in AD. Staining in the molecular layer was reduced 18-31% in AD (P < 0.001) with the greatest loss in the most severely affected cases. NADPH diaphorase is thought to reflect the presence of nitric oxide synthase. Because nitric oxide has been implicated in long-term potentiation, changes in its expression could reflect loss of synapses important for memory formation.

Adult↗
PubMed1993

Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases?

The pathogenesis of nerve cell death in neurodegenerative diseases is unknown. An attractive hypothesis is that an impairment of energy metabolism may underlie slow excitotoxic neuronal death. Several studies have demonstrated mitochondrial or oxidative defects in neurodegenerative diseases. Impaired energy metabolism results in decreases in high-energy phosphate stores and a deteriorating membrane potential. Under these conditions, the voltage-sensitive Mg2+ block of NMDA receptors is relieved, allowing the receptors to be persistently activated by endogenous concentrations of glutamate. In this way, metabolic defects may lead to neuronal death by a slow 'excitotoxic' mechanism. Recent studies indicate that such a mechanism occurs in vivo, and it may play a role in animal models of Huntington's disease and Parkinson's disease. If a similar mechanism occurs in neurodegenerative diseases in humans it may be possible to use either excitatory amino acid antagonists or agents to improve neuronal bioenergetics as therapeutic treatments for these disorders.

Brain↗
PubMed1993

Cellular specificity and regional distribution of amyloid beta protein precursor alternative transcripts are unaltered in Alzheimer hippocampal formation.

Studies comparing the expression of the amyloid beta protein precursor (APP) gene in brains of patients with Alzheimer's disease (AD) and control individuals have resulted in contradictory findings indicative of selective reductions and relative increases of APP alternative transcripts in AD brain. It has been suggested that changes in APP expression in relation to AD neuropathology may represent highly specific and localized events involving only select populations of cells in particular brain regions. For example, reported AD-related alterations in ratios of APP alternative transcripts could be attributed to changes in expression of APP in specific neuronal subpopulations, and/or reactive astrocytes and/or microglia. To address this question, we have employed in situ hybridization using biotinylated oligonucleotide probes designed to localize specific APP mRNA transcripts in the hippocampal formation of AD patients and age-matched controls since this method allows a clear distinction of the classes of neurons and glia containing a particular message.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Nonisotopic in situ hybridization of amyloid beta protein precursor in Alzheimer's disease: expression in neurofibrillary tangle bearing neurons and in the microenvironment surrounding senile plaques.

We have used nonisotopic in situ hybridization techniques with biotinylated junctional oligonucleotide probes to study expression of amyloid precursor protein (APP) 695 and 751 mRNA in the hippocampal formation of Alzheimer's disease. Both mRNAs are strongly expressed in neurons of the hippocampal formation, particularly in the dentate gyrus granule cells and the pyramidal neurons of CA3. The patterns of expression of neither APP695 nor APP751 mRNA correlate well with the stereotyped topography of neurofibrillary tangles or senile plaques, which occur primarily in CA1 and subiculum. We double-labeled in situ sections with immunohistochemical reagents for neurofibrillary tangles or senile plaques. Neurons that contain neurofibrillary tangles continue to express APP mRNA. The level of APP695 and APP751 was measured semiquantitatively by optical density measurements in neurons that were close to (within 25 microns) or father from a senile plaque (more than 100 microns). There was no increase in expression in neurons in the immediate microenvironment of senile plaques. Our results suggest that no major change in distribution or type of APP mRNA accompanies neurofibrillary tangle or senile plaque development.

Adult↗
PubMed1993

Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions.

An increased prevalence of apolipoprotein E (ApoE) epsilon 4 allele exists in late onset familial Alzheimer's disease. We found, in sporadic Alzheimer's disease, that 62% of patients possessed an ApoE-epsilon 4 allele, compared with 20% of controls. ApoE-epsilon 4/4 patients had more senile plaques (SPs) than epsilon 3/3 patients. ApoE immunoreactivity of SPs was equivalent in both groups. Two receptors bind ApoE complexes, the low density lipoprotein (LDL) receptor and the LDL receptor-related protein (LRP). In normal brain, anti-LRP antibodies strongly stained neurons and lightly stained astrocytes; anti-LDL receptor antibodies stained only the neuropil and astrocytes. In Alzheimer's disease, SPs and reactive astrocytes were also strongly LRP immunoreactive. Colocalization of ApoE and LRP to SPs implies that these molecules may be involved in metabolism of components of SPs.

Adult↗
PubMed1993

Isolation and characterization of APLP2 encoding a homologue of the Alzheimer's associated amyloid beta protein precursor.

Familial Alzheimer's disease (FAD) is a genetically heterogeneous disorder that includes a rare early-onset form linked to mutations in the amyloid b protein precursor (APP) gene. Clues to the function of APP derive from the recent finding that it is a member of a highly conserved protein family that includes the mammalian amyloid precursor-like protein (APLP1) gene which maps to the same general region of human chromosome 19 linked to late-onset FAD. Here we report the isolation of the human APLP2 gene. We show that APLP2 is a close relative of APP and exhibits a very similar pattern of expression in the brain and throughout the body. Like APP, APLP2 contains a cytoplasmic domain predicted to couple with the GTP-binding protein G(o) indicating that it may be an additional cell surface activator of this G protein.

Alzheimer Disease↗
PubMed1993

The lack of accumulation of senile plaques or amyloid burden in Alzheimer's disease suggests a dynamic balance between amyloid deposition and resolution.

A beta, a nearly insoluble peptide, is generally assumed to irreversibly deposit and accumulate as senile plaques (SP) during the course of Alzheimer's disease (AD). We have studied temporal neocortex of normal elderly subjects, AD patients, and elderly Down syndrome (DS) patients to determine whether A beta accumulates with age or with increasing duration of illness. We measured the number, size distribution, and total area (amyloid burden) of A beta immunoreactive deposits using computerized image analysis techniques. We found far fewer SP in normal control subjects than in AD patients, who in turn have fewer SP than elderly DS patients. No measure of A beta correlated with age in the control subjects, nor duration of illness in AD or DS patients. These data indicate that A beta may not continue to accumulate during these disease processes and support the view that the amount of A beta observed at autopsy may reflect competing processes of deposition and resolution of amyloid.

Aged↗