PubMed Health⌕ Search

Biomedical subjects

D W Dickson

Publications and source records attributed to D W Dickson.

213 records · Page 12Linked to original sources
PubMedDate not supplied

Neuroimmunology of Alzheimer's disease: a conference report.

A multidisciplinary group met under the auspices of the National Institute on Aging and the Dell Foundation at the Princess Resort in San Diego, CA on April 5-6, 1991. The meeting was organized by Dr. Caleb E. Finch, University of Southern California, Dr. Zaven Khachaturian, National Institute on Aging, Dr. William Markesbery, University of Kentucky, Dr. Patrick McGeer, University of British Columbia, and Dr. Joseph Rogers, Institute for Biogerontology Research, and covered recent data suggesting neuroimmune correlates of Alzheimer's disease (AD). These findings span many of the major immune system phenomena, from major histocompatibility complex (MHC) antigens through cytokines and the complement cascade and suggest that some facets of AD pathogenesis may be immune related.

Alzheimer Disease↗
PubMedDate not supplied

Regional synaptic pathology in Alzheimer's disease.

Synaptic pathology in Alzheimer's disease (AD) may occur diffusely or may have regional predilections. A new antibody called EP10 which detects synaptophysin-like immunoreactivity was used to study synapses in postmortem brain tissue. Four brain regions from cases of AD and controls were studied. Controls with a wide range of ages were used to investigate the possibility of age-related changes in synaptophysin-like immunoreactivity. A significant reduction in the EP10 antigen was observed to occur with age in the control caudate but not in the hippocampus or temporal or occipital cortices. Antigen levels were significantly reduced in the hippocampus (77%) and the temporal cortex (54%) in AD. The expected abnormal pallor of the outer two-thirds of the dentate gyrus molecular layer was observed with immunocytochemistry. In the temporal cortex, the reduction in synaptophysin-like immunoreactivity was inversely correlated with the neurofibrillary tangle count. No such relationship existed in the hippocampus. These results suggest that at least certain components of the synaptic loss in AD occur regionally and are disproportionately large in the hippocampus.

Alzheimer Disease↗
PubMedDate not supplied

Correlations of synaptic and pathological markers with cognition of the elderly.

It has been suggested that the physical basis for dementia is structural or functional loss of synapses. To confirm this finding, we performed an enzyme-linked immunoassay (ELISA) with a monoclonal antibody (EP10) to a synaptophysin-like protein in brain samples from 45 prospectively studied elderly subjects with an average age of 83.3 +/- 10.1 years. We compared the synaptic marker to immunoreactivity with a newly developed PHF antibody (TG3). The cases were selected on the basis of availability of frozen tissue, and included subjects ranging from clinically normal to end-stage dementia. As an initial assessment, we determined Pearson product moment correlations for two clinical measures--the Blessed test of information, concentration, and memory (BICM) and the Fuld object Memory Evaluation (FOME)--with ELISA data and with traditional pathologic markers. We found strong correlations (p < 0.01-0.001) for BICM with brain weight, neuronal loss in the basal nucleus of Meynert (nbM), counts of senile plaques (SP) in the neocortex and hippocampus, and neurofibrillary tangles (NFT) in all areas except the parahippocampal cortex. Except in the occipital lobe, where paired helical filament changes are relatively uncommon, TG3-immunoreactivity also correlated strongly with BICM. Weak correlations (p < 0.05) were found for BICM with EP10-immunoreactivity in only the temporal and parietal lobes. Only the pathologic variables showed any significant correlations with FOME. Because inclusion of normal subjects with few or no pathologic lesions could have been driving the strong correlations with pathologic markers, we limited the analysis to those subjects with dementia (BICM; 8). After making this correction, EP10-immunoreactivity in all cortical areas and the hippocampus correlated better (p < 0.05-0.01) with BICM but not FOME. The present univariate analysis suggests that synaptic markers may not be the best structural correlate of dementia and that markers indicative of cytoskeletal changes, e.g., SP, NFT and PHF protein accumulation, may be better correlates of dementia in the elderly.

Aged↗
PubMedDate not supplied

Alzheimer neurofibrillary lesions: molecular nature and potential roles of different components.

Neurofibrillary lesions found in Alzheimer disease (AD) are known to react with antibodies raised against different molecules. At least 20 components have been detected in neurofibrillary tangles. These components can be roughly categorized into five groups, which include structural proteins, kinases and other cytosolic enzymes, stress-related molecules, amyloid and amyloid binding proteins, and others. Among them, an abnormal form of microtubule associated protein tau, PHF-tau, is a major component of Alzheimer NFT. Kinases associated with NFT, especially those belonging to the family of proline-directed Ser/Thr kinases, are considered to be important for PHF-tau hyperphosphorylation. A potentially significant kinase is a Cdc2-related kinase, which is associated tightly with paired helical filaments, has a molecular weight of 33kDa and is different from other known Cdc2-related kinases. The possibility that some of the NFT-associated elements may play an active role in the pathogenesis of Alzheimer's disease was supported by recent studies, in which advanced glycated products and markers of oxidant stress were located in NFT. In addition, PHF-tau was found to be glycated, and in vitro glycated tau was capable of inducing oxidant stress. Further characterization of different components of NFT by biochemical and other approaches will be important for understanding the mechanisms involved in the supramolecular aggregation of PHF within NFT.

Alzheimer Disease↗
PubMedDate not supplied

Glycation and microglial reaction in lesions of Alzheimer's disease.

Single, double, and triple immunostaining of cryostat sections of elderly normal and Alzheimer disease (AD) brain was performed with monoclonal and polyclonal antibodies to advanced glycation end products (AGE). The sections were counterstained with thioflavin-S or with immunocytochemistry for A beta and also stained with markers for microglia. AGE-immunoreactivity was detected in senile plaques and neurofibrillary tangles (NFT). AGE immunoreactivity was most intense in dense or reticular amyloid deposits and extracellular NFT, while intracellular NFT and diffuse amyloid had less AGE immunoreactivity. This pattern of immunoreactivity was similar to that noted in previous studies with antibodies to apolipoprotein-E (apo-E). Therefore, double labeling with antibodies to apo-E and AGE was performed. AGE immunoreactivity colocalized to a very high degree with apo-E immunoreactivity, except that relatively more intense apo-E immunoreactivity was detected in amyloid deposits and more intense AGE immunoreactivity in NFT. The lesions that were immunostained with antibodies to AGE and apo-E were often, but not always, associated with a local microglial reaction. The results raise the possibility that apo-E or a fragment of apo-E may be glycated. Biochemical studies are needed to determine the extent of possible apo-E glycation in AD. The present results raise the possibility that glycation may serve as one of the signals for activation of microglia associated with amyloid deposits and extracellular NFT.

Aged↗
PubMedDate not supplied

Neuropathological diagnosis of Alzheimer's disease: a perspective from longitudinal clinicopathological studies.

Alzheimer's disease (AD) is the most common cause of primary progressive dementia. It is defined by its pathological features, because the clinical syndrome of dementia lacks specificity. Although the brain in AD has many structural alterations, the two cardinal pathological features and sine qua non of AD are senile plaques and neurofibrillary degeneration. The latter takes the form of neurofibrillary tangles composed of paired helical filaments, as well as degenerating neurites within the neuropil ("neuropil threads") and within a diagnostically significant subset of SP, referred to as "neuritic plaques." All SP contain amyloid, but not all have pair helical filament-type neurites. The presence of even a small number of plaques with paired helical filament-type neurites in the neocortex is associated with cognitive impairment, and this lesion may be the most specific histopathological feature of AD. Although these observations suggest that the major difference between SP in aging and AD relate to differences in neuritic degeneration, more recent studies have also indicated that amyloid deposits are biochemically heterogenous and that amyloid deposits in aging may be different from those in AD. As more specific markers become available for recognizing AD-specific structural lesions, refined neuropathological diagnostic criteria will evolve. In the meantime, a practical neuropathological approach to the diagnosis of AD requires both widespread neocortical SP and an advanced stage of neurofibrillary degeneration. Using these criteria, it is very unlikely that AD will be diagnosed in an individual who was not demented in life. The rationale for adopting this conservative approach is that our knowledge is incomplete with respect to fundamental differences between the lesions in aging and AD.

Adult↗
PubMedDate not supplied

Mitotic phosphoepitopes precede paired helical filaments in Alzheimer's disease.

We have shown previously that the TG-3 and MPM-2 antibodies recognize phosphoepitopes common to mitosis and degenerating neurons of Alzheimer's disease(AD) brain. Here, we have evaluated their occurrence in human brain biopsy tissue, and confirm that they are absent in mature neurons of adult brain, but reappear during neurodegeneration in AD. The TG-3 epitope appears ahead of the MPM-2 epitope and is distributed throughout the neuronal soma. Tau is the major TG-3 antigen in AD brain. The initial localization of MPM-2 immunoreactivity in primary dendrites, it's robust occurrence in granulovacuolar bodies, and the increased immunoreactivity with 300-350-kDa proteins, suggest MAPI B as a candidate MPM-2 antigen in AD. Production of mitotic phosphepitopes in more than one type of human neurodegenerative lesion implicates mitotic kinases as common mediators of neuronal death. Because mitotic phosphoepitopes appear before paired helical filaments, it is suggested that mitotic kinase activation triggers neurofibrillary tangle formation. Future studies will need to focus on factors influencing mitotic kinase activity, a point with potential for early diagnosis and disease abrogation.

Adult↗
PubMedDate not supplied

CT appearance of primary CNS lymphoma in patients with acquired immunodeficiency syndrome.

Cranial CT studies of 32 patients with biopsy-proven AIDS-related primary CNS lymphoma were reviewed retrospectively. A wide variety of different CT appearances were identified. Mass lesions varied in location, size, and number. Most lesions were either iso- or hyperdense and all enhanced with contrast medium. Several different patterns of enhancement were observed. Mass effect and edema were seen in almost all patients. After radiotherapy, most tumors decreased in diameter, became hypodense, and no longer enhanced with contrast medium. Edema and mass effect decreased or resolved in all but one patient. Postradiotherapy CT scans also revealed interval enlargement of the ventricles and cortical sulci. This study demonstrates the wide diversity of CT appearances of AIDS-related primary CNS lymphoma. The CT findings cannot be used in lieu of biopsy for diagnosis of this disorder. The appearance of postradiotherapy CT scans was consistent with regressing lymphoma.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Human immunodeficiency virus within the brains of children with AIDS.

Infants and children with symptomatic human immunodeficiency virus (HIV) infection frequently develop neurologic disease with symptoms and signs of acquired microcephaly, developmental delays, encephalopathy, pyramidal tract signs, and less often, movement disorders and ataxia. However, clinical courses vary and, based upon progression of neurologic findings, we have classified them into 2 broad categories; progressive (loss of previously acquired language and cognitive skills) and plateau (failure to acquire additional developmental skills). We have used immunocytochemistry to localize HIV within the brains of neurologically involved children with AIDS. Interestingly, the brains of those children with a progressive neurologic course showed readily detectable HIV antigen, while those with a plateau course showed little or no detectable HIV. These findings suggest that in children with symptomatic HIV infection, the progressive neurologic deterioration is due to continued presence of HIV within deep white matter and gray matter, while the plateau neurologic course is due to HIV induced damage followed by either limited penetration of virus into the central nervous system, or clearance of virus below detectable limits.

AIDS Dementia Complex↗
PubMedDate not supplied

Solitary midbrain toxoplasmosis and olivary hypertrophy in a patient with acquired immunodeficiency syndrome.

Toxoplasmosis, one of the most common central nervous system lesions in patients with the acquired immunodeficiency syndrome (AIDS), has not been reported as a solitary lesion in the brainstem. This report describes a patient with AIDS that presented with third cranial nerve palsy and contralateral cerebellar signs, who at autopsy had a necrotic midbrain lesion due to toxoplasma. Inferior olivary hypertrophy, due to interruption of olivary afferent fibers by the lesion, in addition to subacute encephalitis and vacuolar myelopathy were other CNS findings.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Intranuclear inclusion bodies in an elderly demented woman: a form of intranuclear inclusion body disease.

Intranuclear inclusion body disease (INIBD) is a rare neuropathological entity characterized by eosinophilic intranuclear bodies in neurons and/or glia. While this disease generally occurs in children, in whom it presents as a multiple systems degeneration, a few adult cases are also described. Only 4 previously reported adult cases have had an associated dementia and all of these patients had additional significant neurological abnormalities. We report a 72-year-old woman with primary degenerative dementia in whom intranuclear inclusion bodies (INIB) were a major neuropathologic finding. The INIB were most easily found in astrocytes of Alzheimer II type, which had proliferated in the cortex and white matter. Occasional neurons were affected. The inclusions consisted of 13 nm diameter filaments associated with amorphous electron-dense material, arranged in a random pattern without lattice formation. They did not stain with antibodies against all 3 neurofilament subunits, glial fibrillary acidic protein, tau-1 protein, vimentin, keratin or actin. We conclude that INIBD is a rare substrate of primary degenerative dementia in elderly patients.

Aged↗
PubMedDate not supplied

Microglial nodule encephalitis: limited CNS infection despite disseminated systemic cryptococcosis.

A 28-year-old patient with AIDS was found at autopsy to have disseminated cryptococcal infection involving the lungs, spleen, lymph nodes, kidneys, gastrointestinal tract, thyroid, bone marrow, and liver. Despite widespread organ dissemination the patient did not have clinical or pathological evidence of meningitis. Microscopic examination of the brain showed cryptococci limited to the brainstem and basal ganglia; microglial nodules with multinucleate giant cells, a histological hallmark of HIV-1 encephalitis, were shown to contain Cryptococcus neoformans. This feature may suggest a form of synergism between HIV-1 and Cryptococcus neoformans. This case demonstrates an unusual form of cryptococcal neurotropism with limited CNS involvement.

AIDS-Related Opportunistic Infections↗