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Biomedical subjects

B T Hyman

Publications and source records attributed to B T Hyman.

At least 91 records · Page 5Linked to original sources
PubMed1999

Application of the National Institute on Aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer disease.

The Khachaturian criteria and the Consortium to Establish a Registry for Alzheimer Disease (CERAD) criteria for the neuropathological assessment of Alzheimer disease (AD) emphasize senile or neuritic plaques, age, and clinical history. A new scheme stressing topographic staging of neurofibrillary changes in addition to neuritic plaques has been proposed by the National Institute on Aging (NIA)-Reagan Institute Consensus Conference. This scheme assigns cases to high, intermediate, or low likelihood categories that the dementia is due to AD. We applied this method to 84 brains from subjects with clinical and neuropathological diagnoses of AD (n = 33), non-AD dementing illnesses (n = 34), including dementia with Lewy bodies (DLB) and progressive supranuclear palsy (PSP), and no neurological disease (n = 17). We also used Khachaturian and CERAD criteria. Neurofibrillary tangle and neuropil thread densities were assessed on 6-micrometer-thick modified Bielschowsky-stained paraffin sections from entorhinal-perirhinal cortex, CA1 of hippocampus, and neocortex including inferior temporal, visual association, and primary visual cortices. Each case was assigned a Braak and Braak stage. Using the NIA-Reagan criteria, we found excellent agreement between clinical history of AD dementia and brains assigned to the high likelihood category that dementia was due to AD. Among brains diagnosed neuropathologically with other degenerative diseases, NIA-Reagan criteria were more conservative than previous criteria, and these cases were likely to be categorized as intermediate or low likelihood that dementia was due to AD. All brains from nondemented subjects were assigned to the low (81%) or intermediate (19%) categories. In summary, we found good correlation between the NIA-Reagan criteria and clinical dementia, and there was generally good agreement between these criteria and existing neuropathological methods, Khachaturian and CERAD, in diagnosing AD. In studying several other neurodegenerative diseases, such as DLB, which shows neuropathological and clinical overlap with AD, the staging of neurofibrillary changes offered potential diagnostic refinement.

Aged↗
PubMed1999

Alpha-synuclein immunoreactivity is present in axonal swellings in neuroaxonal dystrophy and acute traumatic brain injury.

The primary neuroaxonal dystrophies (NAD), which include infantile NAD and Hallervorden-Spatz syndrome (HSS), are characterized by dystrophic terminal axons and axonal swellings. Lewy bodies have been found in some cases. In Parkinson disease (PD) and dementia with Lewy bodies (DLB), Lewy bodies and neurites display prominent alpha-synuclein immunoreactivity. We examined 2 cases of HSS and 4 cases of infantile NAD with alpha-synuclein immunohistochemistry to test the hypothesis that these disorders with similar morphological findings might share a biochemical phenotype. Furthermore, we compared them to 8 cases of secondary or physiologic NAD of various causes and 2 cases of recent traumatic head injury. Alpha-synuclein positive neuronal cytoplasmic inclusions, including Lewy bodies, and neurites were numerous in 1 HSS and 1 infantile NAD case. In addition, axonal spheroids were immunostained in all 6 cases of primary NAD, 5 cases of secondary NAD, and 2 cases of recent head injury. Axonal spheroids were faintly stained in the 3 physiologic NAD cases. Alpha-synuclein positive axonal swellings may suggest a mechanism, such as axonal injury, leading to the neuronal cytoplasmic accumulation of alpha-synuclein in NAD and other disorders.

Acute Disease↗
PubMed1999

Dynamic feedback in an aggregation-disaggregation model.

We study an aggregation-disaggregation model which is relevant to biological processes such as the growth of senile plaques in Alzheimer disease. In this model, during the aggregation each deposited particle has a probability of producing a new particle in its vicinity, while during disaggregation the particles are anihilated randomly. The model is held in a dynamic equilibrium by a feedback mechanism which changes the disaggregation probability in proportion to the change in the total number of particles. We also include surface diffusion which influences the morphology of growing aggregates and colonies. A colony includes the descendents of a single particle. We investigate the statistical properties of the model in two dimensions. We find that unlike the colonies, individual aggregates are fractals with a fractal dimension of D(f)=1.92+/-0.06 in the absence of surface diffusion. We show that the surface diffusion changes the fractal dimension of aggregates: at a small aggregation-disaggregation rate, D(f) is independent of the strength of the surface diffusion, D(f)=1.73+/-0.03. At larger aggregation-disaggregation rates and different strengths of surface diffusion, aggregates with fractal dimensions between D(f)=1.73 and 1.92 form. The steady-state distribution of aggregate sizes is shown to be power law if the aggregation-disaggregation process dominates over the surface diffusion. In the limit of weak aggregation-disaggregation and strong surface diffusion the size distribution is log-normal.

Alzheimer Disease↗
PubMed1999

Risperidone treatment of behavioral disturbances in outpatients with dementia.

The authors retrospectively assessed the effectiveness and side effects of risperidone used to treat behavioral disturbances in elderly outpatients with dementia. In 41 patients treated with risperidone 1.8 +/- 1.4 mg/day, there was complete suppression of the target symptom in 15%, partial response in 41%, and no response in 44%. Risperidone appeared equally effective in treating agitation and psychosis. New or worsening extrapyramidal side effects (EPS) occurred in 32%, associated with longer duration of treatment and possibly with concomitant use of serotonergic anti-depressants. Risperidone was a useful adjunct in the treatment of agitation and psychosis in outpatients with dementia but was limited by EPS in about one-third of patients.

Age Factors↗
PubMed1999

Functional domains of the very low density lipoprotein receptor: molecular analysis of ligand binding and acid-dependent ligand dissociation mechanisms.

The very low density lipoprotein (VLDL) receptor is closely related in structure to the low density lipoprotein receptor. The ectodomain of these endocytic receptors is composed of modules which include clusters of cysteine-rich class A repeats, epidermal growth factor (EGF)-like repeats, tyrosine-tryptophan-threonine-aspartic acid (YWTD) repeats and an O-linked sugar domain. To identify important functional regions within the ectodomain of the VLDL receptor, we produced a mutant receptor in which the EGF, YWTD and O-linked sugar domains were deleted. Cells transfected with the mutant receptor were able to bind and internalize (125)I-labeled receptor associated protein (RAP). In contrast to the wild-type receptor, however, RAP did not dissociate from the mutant receptor and consequently was not degraded. Immunofluoresence data indicated that once bound to the mutant receptor, fluorescent-labeled RAP co-localized with markers of the endosomal pathway, whereas, in cells expressing the wild-type receptor, RAP fluorescence co-localized with lysosomal markers. Thus this deleted region is responsible for ligand uncoupling within the endosomes. To identify regions responsible for ligand recognition, soluble receptor fragments containing the eight cysteine-rich class A repeats were produced. (125)I-RAP and (125)I-labeled urokinase-type plasminogen activator:plasminogen activator inhibitor type I (uPA:PAI-1) complexes bound to the soluble fragment with K(D, app) values of 0.3 and 14 nM, respectively. Deletion analysis demonstrate that high affinity RAP binding requires the first four cysteine-rich class A repeats (L1-4) in the VLDL receptor while the second repeat (L2) appears responsible for binding uPA:PAI-1 complexes. Together, these results confirm that ligand uncoupling occurs via an allosteric-type mechanism in which pH induced changes in the EGF and/or YWTD repeats alter the ligand binding properties at the amino-terminal portion of the molecule.

Acids↗
PubMed1999

Chemokines/chemokine receptors in the central nervous system and Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, and the fourth leading cause of death in the United States. Its pathological changes include amyloid beta deposits, neurofibrillary tangles and a variety of 'inflammatory' phenomenon such as activation of microglia and astrocytes. The pathological significance of inflammatory responses elicited by resident central nervous system (CNS) cells has drawn considerable attention in recent years. Chemokines belongs to a rapidly expanding family of cytokines, the primary function of which is control of the correct positioning of cells in tissues and recruitment of leukocytes to the site of inflammation. Study of this very important class of inflammatory cytokines may greatly help our understanding of inflammation in the progress of AD, as well as other neurodegenerative diseases. So far, immunoreactivity for a number of chemokines (including IL-8, IP-10, MIP-1beta, MIPalpha and MCP-1) and chemokine receptors (including CXCR2, CXCR3, CXCR4, CCR3, CCR5 and Duffy antigen) have been demonstrated in resident cells of the CNS, and upregulation of some of the chemokines and receptors are found associated with AD pathological changes. In this review, we summarize findings regarding the expression of chemokines and their receptors by CNS cells under physiological and pathological conditions. Although little is known about the potential pathophysiological roles of chemokines in CNS, we have put forward hypotheses on how chemokines may be involved in AD.

Alzheimer Disease↗
PubMed1998

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyride neurotoxicity is attenuated in mice overexpressing Bcl-2.

The proto-oncogene Bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests that Bcl-2 protects against free radicals and that it increases mitochondrial calcium-buffering capacity. The neurotoxicity of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyride (MPTP) is thought to involve both mitochondrial dysfunction and free radical generation. We therefore investigated MPTP neurotoxicity in both Bcl-2 overexpressing mice and littermate controls. MPTP-induced depletion of dopamine and loss of [3H]mazindol binding were significantly attenuated in Bcl-2 overexpressing mice. Protection was more profound with an acute dosing regimen than with daily MPTP administration over 5 d. 1-Methyl-4-phenylpyridinium (MPP+) levels after MPTP administration were similar in Bcl-2 overexpressing mice and littermates. Bcl-2 blocked MPP+-induced activation of caspases. MPTP-induced increases in free 3-nitrotyrosine levels were blocked in Bcl-2 overexpressing mice. These results indicate that Bcl-2 overexpression protects against MPTP neurotoxicity by mechanisms that may involve both antioxidant activity and inhibition of apoptotic pathways.

1-Methyl-4-phenylpyridinium↗
PubMed1998

Immunohistochemical and in situ analysis of amyloid precursor-like protein-1 and amyloid precursor-like protein-2 expression in Alzheimer disease and aged control brains.

Amyloid precursor protein (APP) is a ubiquitously expressed membrane spanning glycoprotein which is endoproteolytically processed to Abeta, a 39-43 amino acid peptide that is the main component of senile plaques in Alzheimer Disease (AD). APP is a member of a highly conserved gene family, including Amyloid Precursor-Like Proteins (APLPs) APLP1 and APLP2. We now characterize APLP1 and APLP2 mRNA and protein expression in AD and aged control brains. Using in situ hybridization in hippocampal tissue from control and AD brain, we show that APLP1 and APLP2 mRNA are expressed primarily in the granule cells of the dentate gyrus, in areas CA1-CA3, and subiculum. Immunohistochemistry reveals staining for both APLP1 and APLP2 in neurons and blood vessels in AD and control cases. In addition, in AD brain, large dystrophic neurites in a subset of senile plaques are conspicuously labeled with APLP1 and APLP2 antibodies. The aged control brains have significantly fewer immunoreactive plaques and dystrophic neurites. The regional, cellular, and subcellular distribution of APLP1 and APLP2 overlap with each other and with APP. These observations support the hypothesis that the members of this family of proteins may perform similar functions.

Aged↗
PubMed1998

Lack of specific association of presenilin 1 (PS-1) protein with plaques and tangles in Alzheimer's disease.

Missense mutations in the presenilin-1 (PS-1) gene are causally related to the majority of familial early-onset Alzheimer's disease (FAD). PS-1 immunohistochemical expression in normal human brain and in brains with Alzheimer's disease (AD) has so far been controversial. Here, we report a study of PS-1 expression in brains, cell lines and peripheral blood mononuclear cells using a panel of well characterized PS-1-specific antibodies. These antibodies were characterized by immunofluorescent staining of PS-1 transfectants followed by flow cytometric analysis. In human brain, widespread neuronal staining was observed. PS-1 immunoreactivity was primarily confined to neuronal cell bodies and proximal dendrites. Weaker staining of microglia was also detected, in accord with the finding of PS-1 immunoreactivity in monocytes. PS-1 expression is not particularly associated with neurons either containing or spared from neurofibrillary tangles, nor with senile plaques. The level of PS-1 expression does not differ between normal and AD brains. Immunoprecipitation from AD, FAD and control brains revealed only a 32 kDa N-terminal fragment and an 18-20 kDa C-terminal fragment. Little or no full length PS-1 was detected. The enriched presence of PS-1 in neurons implies an important role in neuronal function, however, the lack of apparent association of its expression with AD pathology signifies the need for a better understanding of its pathophysiological role.

Alzheimer Disease↗
PubMed1998

Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. Alzheimer's Disease Centers Consortium on Apolipoprotein E and Alzheimer's Disease.

BACKGROUND: The epsilon4 allele of the gene encoding apolipoprotein E (APOE) is strongly associated with Alzheimer's disease, but its value in the diagnosis remains uncertain. METHODS: We reviewed clinical diagnoses and diagnoses obtained at autopsy in 2188 patients referred to 1 of 26 Alzheimer's disease centers for evaluation of dementia. The sensitivity and specificity of the clinical diagnosis or the presence of an APOE epsilon4 allele were calculated, with pathologically confirmed Alzheimer's disease used as the standard. The added value of the APOE genotype was estimated with pretest and post-test probabilities from multivariate analyses to generate receiver-operating-characteristic curves plotting sensitivity against the false positive rate. RESULTS: Of the 2188 patients, 1833 were given a clinical diagnosis of Alzheimer's disease, and the diagnosis was confirmed pathologically in 1770 patients at autopsy. Sixty-two percent of patients with clinically diagnosed Alzheimer's disease, as compared with 65 percent of those with pathologically confirmed Alzheimer's disease, had at least one APOE epsilon4 allele. The sensitivity of the clinical diagnosis was 93 percent, and the specificity was 55 percent, whereas the sensitivity and specificity of the APOE epsilon4 allele were 65 and 68 percent, respectively. The addition of information about the APOE genotype increased the overall specificity to 84 percent in patients who met the clinical criteria for Alzheimer's disease, although the sensitivity decreased. The improvement in specificity remained statistically significant in the multivariate analysis after adjustment for differences in age, clinical diagnosis, sex, and center. CONCLUSIONS: APOE genotyping does not provide sufficient sensitivity or specificity to be used alone as a diagnostic test for Alzheimer's disease, but when used in combination with clinical criteria, it improves the specificity of the diagnosis.

Aged↗
PubMed1998

Apolipoprotein E genotype and deposits of Abeta40 and Abeta42 in Alzheimer disease.

OBJECTIVE: To examine the differential deposition of amyloid beta (Abeta) peptide isoforms Abeta40 and Abeta42 in the Alzheimer disease (AD) brain in relation to the apolipoprotein E (APOE) genotype. BACKGROUND: The APOE epsilon4 genotype is an inherited risk factor for AD and is associated with increased deposition of Abeta protein in the cerebral cortex. Previous data from familial AD due to mutations in presenilin 1 and presenilin 2 genes and the amyloid precursor protein suggest that the long form of Abeta peptide, Abeta42, is selectively increased in these circumstances. Herein, we examine whether APOE genotype influenced the species of Abeta peptide deposited. DESIGN AND METHODS: The amount of Abeta40, Abeta42, and total Abeta deposited in immunostained temporal lobe tissue of 28 cases of AD of known APOE genotype was determined. RESULTS: Individuals with the APOE epsilon4 genotype (APOE epsilon4/4) were associated with both increased Abeta40 (P<.05) and Abeta42 (P<.05) compared with individuals without the APOE epsilon4/4 genotype. CONCLUSION: Our results differ from the data from AD due to mutations in presenilin 1 and presenilin 2 genes and the amyloid precursor protein and suggest that the APOE epsilon4 genotype mediates increased Abeta deposition by a mechanism that differs from that found in other genetic causes of AD.

Aged↗
PubMed1998

Structure and functions of human cerebrospinal fluid lipoproteins from individuals of different APOE genotypes.

Recent data have implicated apolipoprotein E (apoE) in neuritic outgrowth, synaptic stability, and Alzheimer's disease; these data led us to examine the normal role of apoE-containing lipoproteins in the central nervous system (CNS). We isolated lipoproteins from human cerebrospinal fluid (CSF) in order to examine their composition and potential functions. CSF particles were composed of approximately one-third protein, one-third phospholipid, and one-third cholesterol. ApoE3 formed homodimers and heterodimers with apoA-II, while apoE4, as expected, was monomeric. We addressed the function of CSF lipoproteins with assays of cholesterol efflux and cholesterol influx. CSF lipoproteins decreased intracellular levels of cholesterol in cholesterol-loaded fibroblasts, suggesting these particles can act to remove excess lipids from cells. CSF lipoproteins competed for 125I-labeled LDL degradation by fibroblasts, suggesting they can also interact with the LDL receptor. Furthermore, CSF lipoproteins labeled with the fluorescent dye Dil were internalized by neuroglioma cells and primary neurons and astrocytes in culture. Together, these data support a model of CSF lipoproteins acting to remove lipids from degenerating cells and delivering lipids to cells for new membrane synthesis or storage.

Aged↗
PubMed1998

Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer's disease brains.

Chemokines belong to an expanding family of cytokines the primary function of which is recruitment of leukocytes to inflammatory sites. Recent evidence has shown their presence in the central nervous system. Because inflammatory responses have been implicated in the pathogenesis of Alzheimer's disease (AD), we studied the expression of CCR3, CCR5, and their ligands in normal and AD brains by immunohistochemistry. CCR3 and CCR5 are present on microglia of both control and AD brains, with increased expression on some reactive microglia in AD. Immunohistochemistry for MIP-1beta, MIP-1alpha, RANTES, eotaxin, and MCP-3 (ligands for CCR5 and/or CCR3) revealed the presence of MIP-1beta predominantly in a subpopulation of reactive astrocytes, which were more widespread in AD than control brains, and MIP-1alpha predominantly in neurons and weakly in some microglia in both AD and controls. Many of the CCR3+ or CCR5+ reactive microglia and MIP-1beta+ reactive astrocytes were found associated with amyloid deposits. Immunoreactivity for eotaxin, RANTES, and MCP-3 were not detected. Detection of these beta-chemokine receptors on microglia and some of their ligands in reactive astrocytes and neurons as well as microglia suggests a role for this system in glial-glial and glial-neuronal interactions, potentially influencing the progression of AD.

Adult↗
PubMed1998

Dissociation of apolipoprotein and apolipoprotein receptor response to lesion in the rat brain: an in situ hybridization study.

The epsilon4 allele of apolipoprotein E is associated with increased risk for developing Alzheimer's disease. To further understand the anatomical distribution of apolipoprotein E and its native receptors in the brain, we studied their messenger RNA expression in the adult rat brain under normal conditions and in response to an excitotoxic lesion to the hippocampus. In situ hybridization using oligonucleotide probes for apolipoprotein E, apolipoprotein J, the low density lipoprotein receptor, very low density lipoprotein receptor, low density lipoprotein receptor related protein, 39,000 mol. wt receptor-associated protein and glycoprotein 330/Megalin messenger RNA were performed on adjacent sections throughout the rat forebrain. Apolipoprotein E messenger RNA was abundantly expressed in the rat brain in both white and gray matter localizing to astrocytes but not neurons. Low density lipoprotein receptor-related protein and receptor-associated protein messenger RNA had a similar regional distribution but low density lipoprotein receptor-related protein messenger RNA was expressed by both neurons and glia, while the expression of receptor-associated protein messenger RNA was more highly expressed in neurons. Apolipoprotein J messenger RNA was expressed by neurons, glia and choroid plexus. The low density lipoprotein receptor and very low density lipoprotein receptor messenger RNA were found in both neurons and glia. Glycoprotein 330/Megalin messenger RNA was not detectable in the adult rat brain. In response to hippocampal lesions, apolipoprotein E and apolipoprotein J messenger RNAs were significantly up-regulated seven and 11 days post-lesion but the expression of low density lipoprotein receptor, low density lipoprotein receptor-related protein, receptor-associated protein, glycoprotein 330/Megalin, and very low density lipoprotein receptor messenger RNAs were unchanged. The expression of apolipoprotein E messenger RNA increased gradually beginning at three days while the expression of apolipoprotein J messenger RNA began to increase at seven days post-lesion. These findings further implicate apolipoproteins in the response of the brain to injury in vivo and suggest that transcriptional up-regulation of the apolipoprotein receptors studied is not a prominent feature in the response.

Animals↗
PubMed1998

Alpha-2 macroglobulin is genetically associated with Alzheimer disease.

Alpha-2-macroglobulin (alpha-2M; encoded by the gene A2M) is a serum pan-protease inhibitor that has been implicated in Alzheimer disease (AD) based on its ability to mediate the clearance and degradation of A beta, the major component of beta-amyloid deposits. Analysis of a deletion in the A2M gene at the 5' splice site of 'exon II' of the bait region (exon 18) revealed that inheritance of the deletion (A2M-2) confers increased risk for AD (Mantel-Haenzel odds ratio=3.56, P=0.001). The sibship disequilibrium test (SDT) also revealed a significant association between A2M and AD (P=0.00009). These values were comparable to those obtained for the APOE-epsilon4 allele in the same sample, but in contrast to APOE-epsilon4, A2M-2 did not affect age of onset. The observed association of A2M with AD did not appear to account for the previously published linkage of AD to chromosome 12, which we were unable to confirm in this sample. A2M, LRP1 (encoding the alpha-2M receptor) and the genes for two other LRP ligands, APOE and APP (encoding the amyloid beta-protein precursor), have now all been genetically linked to AD, suggesting that these proteins may participate in a common neuropathogenic pathway leading to AD.

Age of Onset↗
PubMed1998

Genetic association of an alpha2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease.

alpha2-Macroglobulin (A2M) is a proteinase inhibitor found in association with senile plaques (SP) in Alzheimer's disease (AD). A2M has been implicated biochemically in binding and degradation of the amyloid beta (Abeta) protein which accumulates in SP. We studied the relationship between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule. In an initial exploratory data set (90 controls and 171 Alzheimer's disease) we noted an increased frequency of the G/G genotype from 0.07 to 0.12. We therefore tested the hypothesis that the G/G genotype is over-represented in Alzheimer's disease in an additional independent data set: a group of 359 controls and 566 Alzheimer's disease patients. In the hypothesis testing cohort, the G/G genotype increased from 0.07 in controls to 0.12 in Alzheimer's disease (P < 0.05, Fisher's exact test). The odds ratio for Alzheimer's disease associated with the G/G genotype was 1.77 (1.16-2.70, P < 0.01) and in combination with APOE4 was 9.68 (95% CI 3.91-24.0, P < 0.001). The presence of the G allele was associated with an increase in Abeta burden in a small series. The A2M receptor, A2M-r/LRP, is a multifunctional receptor whose ligands include apolipoprotein E and the amyloid precursor protein. These four proteins have each been genetically linked to Alzheimer's disease, suggesting that they may participate in a common disease pathway.

Alleles↗