Search PubMed⌕ Search

Biomedical subjects

B T Hyman

Publications and source records attributed to B T Hyman.

At least 217 records · Page 12Linked to original sources
PubMed1991

Intracerebral implantation of nerve growth factor-producing fibroblasts protects striatum against neurotoxic levels of excitatory amino acids.

With the exception of L-DOPA pharmacological treatment in Parkinson's disease, the neurodegenerative diseases lack effective treatment. Previous studies of neurodegenerative diseases suggest that symptoms arise secondary to defects in local neuronal circuitry and cannot be treated effectively with systemic drug delivery. Therefore, a promising treatment is the application of fetal or genetically engineering cells which protect or replace neurons in deficient regions. Engineered cells can be derived from cell lines or grown from recipient host fibroblasts or other cells, then modified to produce and secrete substances at a specific area of the brain. A previous study using parallel intracerebral infusions of nerve growth factor and an excitotoxic amino acid into the rat striatum demonstrated a protective effect of nerve growth factor on neurons [Aloe L. (1987) Biotechnology 5, 1085-1086]. In order to further test this paradigm, we have utilized a biological delivery system of nerve growth factor by implanting fibroblasts into the rat striatum which secrete high levels of nerve growth factor, prior to infusing the neurotoxins quinolinate or quisqualate. Animals in this group had smaller lesions than did a group implanted with a similar non-nerve growth factor-producing graft. In addition, marked neuronal sparing was noted within areas of lesions in those animals containing a nerve growth factor-producing graft. These results indicate that implantation of genetically engineered nerve growth factor-secreting cells can be used to protect neurons at a specific target from excitotoxin-induced lesions.

Animals↗
PubMed1991

Aminooxyacetic acid results in excitotoxin lesions by a novel indirect mechanism.

Aminooxyacetic acid (AOAA) is an inhibitor of several pyridoxal phosphate-depedent enzymes in the brain. In the present experiments intrastriatal injections of AOAA produced dose-dependent excitotoxic lesions. The lesions were dependent on a pyridoxal phosphate mechanisms because pyridoxine blocked them. The lesions were blocked by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 and by coinjection of kynurenate, a result indicating an NMDA receptor-mediated excitotoxic process. Electrophysiologic studies showed that AOAA does not directly activate ligand-gated ion channels in cultured cortical or striatal neurons. Pentobarbital anesthesia attenuated the lesions. AOAA injections resulted in significant increases in lactate content and depletions of ATP levels. AOAA striatal lesions closely resemble Huntington's disease both neurochemically and histologically because they show striking sparing of NADPH-diaphorase and large neurons within the lesioned area. AOAA produces excitotoxic lesions by a novel indirect mechanism, which appears to be due to impairment of intracellular energy metabolism, secondary to its ability to block the mitochondrial malate-aspartate shunt. These results raise the possibility that a regional impairment of intracellular energy metabolism may secondarily result in excitotoxic neuronal death in chronic neurodegenerative illnesses, such as Huntington's disease.

Aminooxyacetic Acid↗
PubMed1991

Studies of amyloid beta-protein precursor expression in Alzheimer's disease.

The generation of the beta/A4 peptide and its accumulation into insoluble amyloid deposits represent key events in the neuropathologic process of Alzheimer's disease (AD). This posit has gained further support from recent reports that beta/A4 is directly responsible for the death of neurons. Potential therapies for AD aimed at abating the production of beta/A4 will require the basic knowledge of where it comes from. The 4.2-kD peptide is derived from a much larger amyloid precursor protein (APP) encoded by a gene that produces multiple transcripts. Employing in situ hybridization with biotinylated oligonucleotide probes, we set out to define which forms of the precursor are synthesized in affected regions of AD brain (e.g., hippocampal formation) and to determine the cell populations responsible for their manufacture.

Aged↗
PubMed1990

Alz-50 immunoreactivity in the thalamic reticular nucleus in Alzheimer's disease.

Examination of the thalamic reticular nucleus (Rt) with the monoclonal antibody Alz-50 in brains of Alzheimer's disease patients reveals dense extracellular and terminal-like immunoreactivity in the absence of neurofibrillary tangles or neuritic plaques. Similar terminal-like immunoreactivity is not present in other thalamic nuclei of AD brains or in the brains of controls. Based on (1) an immunocytochemical and histopathological analysis of areas known to project to the Rt, (2) that Alz-50 immunocytochemistry reveals immunoreactive neurons, neurofibrillary tangles and neuritic plaques, and (3) evidence that Alz-50 immunoreactivity can be demonstrated in the terminal fields of immunoreactive neurons, the terminal-like immunoreactivity in the Rt probably corresponds to altered preterminal axons and terminals from degenerating basal forebrain neurons. Given the presumed physiological role of the Rt, these selective lesions could alter thalamocortical processing and contribute to the cognitive impairment in Alzheimer's disease.

Alzheimer Disease↗
PubMed1990

Neuropsychological correlates of bilateral amygdala damage.

We conducted an extensive neuropsychological investigation in a patient with bilateral amygdala damage due to Urbach-Wiethe disease. The patient had significant defects in nonverbal visual memory, in social behavior, and in "executive control" functions, findings consistent with the proposal, based on experimental animal work, that the amygdala plays important roles in memory and in the modulation of social and emotional behavior. General intellect and language were normal. A psychophysiological study showed that she had normal electrodermal activity (skin conductance responses), an important finding in view of the role that has been attributed to the amygdala in the central control of autonomic responses.

Adult↗
PubMed1990

Pathological alterations in the amygdala in Alzheimer's disease.

The amygdala is severely and consistently affected by pathology in Alzheimer's disease. The distribution of Thioflavin S-stained neurofibrillary tangles and neuritic plaques was examined in the various nuclei that form the amygdala in 20 cases of clinically diagnosed Alzheimer's disease and five non-demented control cases. Large numbers of neurofibrillary tangles and neuritic plaques were observed in the accessory basal and cortical nuclei and the cortical transition area, while there was lesser involvement of the mediobasal nucleus. The medial, lateral, laterobasal and central nuclei were relatively spared. The distribution of neurofibrillary tangles and neuritic plaques was compared with neuroanatomic connections known from non-human primate experimental studies. This comparison suggests that (1) nuclei receiving and giving rise to hippocampal projections are consistently affected by neuropathological alterations in Alzheimer's disease; (2) the nuclei which receive strong cholinergic projections from the nucleus basalis of Meynert (e.g. laterobasal nucleus) have, in general, relatively few neuritic plaques; and (3) nuclei which receive olfactory projections are not uniformly affected, the cortical nucleus being heavily affected but the medial nucleus consistently spared.

Aged↗
PubMed1990

Hippocampal formation: anatomy and the patterns of pathology in Alzheimer's disease.

Anatomical studies of the primate brain have shown that the subicular and CA1 allocortices give rise to hippocampal efferents that course to numerous telencephalic and diencephalic targets including other parts of the cortex. The hippocampal formation is damaged heavily in Alzheimer's disease, and is a focal point for pathology. We examined the anteroposterior extent of the hippocampal formation in 52 cases of Alzheimer's disease, 6 cases of other types of dementia and 10 age-compatible controls, to determine the patterns of pathology. We have observed that only certain subfields of the hippocampal formation are affected by cell loss, neurofibrillary tangles and neuritic plaques, while adjacent, anatomically distinct subfields are relatively spared. The portions of the hippocampal formation most crucial for both cortical and subcortical efferent projections are severely affected by Alzheimer pathological changes. Most notable are neurofibrillary tangles in the subicular and CA1 subfields. Layer IV of entorhinal cortex, specifically affected by neurofibrillary tangles. Hippocampal input is also compromised. For example, layer II of entorhinal cortex, which gives rise to perforant pathway hippocampal afferents, also undergoes severe neurofibrillary changes. Neuritic plaques appear in a distinct layer in the terminal zone of the perforant pathway, which carries the majority of corticohippocampal afferents. Plaques are also common in a zone that receives serotoninergic projections from the raphe complex, thus compromising another hippocampal afferent. In sum, these changes disrupt intrinsic and extrinsic hippocampal circuitry at multiple levels, and the pathological dissection deprives the hippocampal formation of many of its efferent and afferent connections with cortical and subcortical structures important in memory-related neural systems. These changes likely contribute to the memory impairment that characterizes Alzheimer's disease and the devastating intellectual decline that ensues.

Aged↗
PubMed1990

Memory-related neural systems in Alzheimer's disease: an anatomic study.

In the primate brain, there are strong connections among the entorhinal cortex, the hippocampal formation, and the amygdala, 3 structures of the ventromedial temporal lobe that are related to memory function. Because memory impairment is a central feature of Alzheimer's disease, we examined the probable cells of origin and terminal zones of these connections in the brains of humans affected by the disease, using thioflavine S, Alz-50, and anti-A4 amyloid protein immunocytochemistry. Specific cytoarchitectural areas and lamina that give rise to projections from the entorhinal cortex, the hippocampal formation, and the amygdala consistently contained neurofibrillary tangles. The terminal zones of many of these projections contained neuritic plaques, Alz-50-positive neuritic alterations, and A4 deposition. Other cytoarchitectural areas and lamina, sometimes immediately adjacent, were consistently spared from these Alzheimer changes. This pattern of Alzheimer-related alterations would disrupt projections among the entorhinal cortex, hippocampal formation, and amygdala at multiple sites, and also disrupt projections between these structures and cortical and subcortical targets. In functional terms, this pattern of structural damage is likely to be as devastating as bilateral destruction of the ventromedial temporal lobe, and thus contribute substantially to the memory disorder seen in this condition.

Aged↗
PubMed1990

Progressive aphasia in a patient with Pick's disease: a neuropsychological, radiologic, and anatomic study.

Although Pick's disease is generally considered as a dementia characterized by signs of frontal lobe dysfunction, it can present with selective language defects rather than with cognitive decline. In this study, we report prospective and serial clinical, neuropsychological, and neuroradiologic observations in a 59-year-old man whose prominent disturbance was in the retrieval and learning of names denoting concrete entities and actions. Postmortem study confirmed the diagnosis of Pick's disease and revealed that neuronal loss and gliosis were most prominent in left anterior temporal cortices. The findings are in keeping with evidence that the left anterior temporal cortices and interconnected hippocampal system are critically involved in the learning and retrieval of verbal lexical items. The evidence from this patient, along with similar evidence from the literature we reviewed, suggests that when patients present with a progressive aphasia characterized by anomia, Pick's disease should be considered as the probable diagnosis.

Aphasia↗
PubMed1989

A4 amyloid protein immunoreactivity is present in Alzheimer's disease neurofibrillary tangles.

Neurofibrillary tangles and neuritic plaques are the neuropathological hallmarks of Alzheimer's disease. The latter consist of a core of A4 amyloid protein. We now report that some neurofibrillary tangles ('tombstone tangles') are also A4 immunoreactive. This observation is consistent with the hypothesis that A4 amyloid accumulation is a component of both neurofibrillary tangles and neuritic plaques.

Alzheimer Disease↗
PubMed1989

Alz-50 immunoreactivity in the neonatal rat: changes in development and co-distribution with MAP-2 immunoreactivity.

Alz-50 is a monoclonal antibody that recognizes pathological alterations in Alzheimer's disease. It has recently been noted also to mark some subplate neurons in human infants under the age of 2 years. We now report that Alz-50 recognizes many neurons in the normal neonatal rat in a pattern that changes with development. Immunoreactivity decreases substantially in intensity as the rat matures. This immunoreactivity co-distributes with microtubule-associated protein-2 (MAP-2) immunoreactivity in terms of topography, cellular localization and changes over the developmental time-course. This observation raises the possibility of exploring cytologic triggers that may lead to re-expression of Alz-50 immunoreactivity in aging and in pathological conditions.

Alzheimer Disease↗
PubMed1989

Hemianesthesia and aphasia. An anatomical and behavioral study.

A 61-year-old right-handed man with a history of lacunar cerebrovascular disease and hypertension had the sudden onset of right-sided numbness and difficulty speaking. Neurologic evaluation revealed a dense right hemianesthesia that included the face, trunk, arm, and leg. Neuropsychological examination documented a conduction aphasia, which resolved nearly completely several months later. Computed tomographic and magnetic resonance imaging studies showed a lesion in the left hemisphere that involved the posterior insula and disrupted thalamocortical connections but entirely spared the thalamus proper. We suggest that the combination of hemianesthesia and aphasia indicates a white matter lesion subjacent to inferior parietal and posterior temporal cortices.

Aphasia↗
PubMed1988

A direct demonstration of the perforant pathway terminal zone in Alzheimer's disease using the monoclonal antibody Alz-50.

The perforant pathway links the entorhinal cortex with the hippocampal formation and provides this structure with its major cortical input. The cells of origin of the perforant pathway are destroyed in Alzheimer's disease (AD) and a marked depletion of glutamate, the putative neurotransmitter in its terminal zone, occurs. We report that the monoclonal antibody Alz-50 recognizes an antigen in the terminal zone of the perforant pathway in AD. This observation provides direct evidence for the involvement of the perforant pathway in AD, and demonstrates that Alz-50 can be used to study neural connectivity in AD brains.

Alzheimer Disease↗
PubMed1988

Alz-50 antibody recognizes Alzheimer-related neuronal changes.

Alz-50 is a monoclonal antibody directed against an antigen present in Alzheimer's disease. Unlike conventional pathological stains that reveal only neurons with neurofibrillary tangles (NFTs), Alz-50 recognizes neurons that contain NFTs and additional neurons that do not. Our investigation of the topographical distribution of both NFT-containing and non-NFT-containing neurons recognized by Alz-50 reveals that they are both found primarily in certain cytoarchitectural areas and lamina that have been established as consistent sites for NFT pathology. Some of the neurons recognized by Alz-50 appear histopathologically normal. We suggest that Alz-50 recognizes an antigen in neurons that both precedes and accompanies NFT formation. Thus, it may mark a point early in cellular pathology before irreversible cytoskeletal and degenerative changes occur.

Aged↗
PubMed1987

Reinnervation of the hippocampal perforant pathway zone in Alzheimer's disease.

The perforant pathway originates from the entorhinal cortex of the anterior parahippocampal gyrus and terminates on the outer dendritic branches of the granule cells of the dentate gyrus and pyramidal cells of the subiculum and hippocampus. It carries the principal cortical input to the hippocampal formation. Destruction of the perforant pathway in experimental animals leads to a partial deafferentation of its target neurons, followed by a robust sprouting of acetylcholinesterase (AChE) terminals in the deafferented perforant pathway zone. In Alzheimer's disease, the cells of origin of the perforant pathway are laden with neurofibrillary tangles. AChE staining in the terminal zone of the perforant pathway in Alzheimer's disease shows several distinct patterns that are not found in control brains. These changes are consistent with the results of experimental studies demonstrating reinnervation in laboratory mammals, including nonhuman primates. The results suggest that in Alzheimer's disease sprouting of AChE-containing systems occurs in the hippocampal formation in response to disease-related cellular damage in the entorhinal cortex.

Acetylcholinesterase↗
PubMed1987

Alzheimer's disease: glutamate depletion in the hippocampal perforant pathway zone.

The perforant pathway is the primary source of cortical input to the hippocampal formation. Its cells of origin, in the entorhinal cortex, are destroyed in Alzheimer's disease. Because the principal neurotransmitter of the perforant pathway's excitatory action is thought to be glutamate, we microdissected a portion of the pathway's terminal zone and assayed the excised tissue for glutamate. There was an 83% decrease in the level of free glutamate in subjects with Alzheimer's disease as compared to control subjects not affected by dementia (p less than 0.005). We believe that this diminution in the glutamate content is a direct neurochemical correlate of perforant pathway destruction and that disruption of this crucial corticolimbic pathway contributes to the memory dysfunction in Alzheimer's disease.

Aged↗