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D W Dickson

Publications and source records attributed to D W Dickson.

At least 109 records · Page 6Linked to original sources
PubMed1996

Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop.

Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimer's disease (AD). The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinson's disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification.

Dementia↗
PubMed1996

Immunohistochemical localization of capsular polysaccharide antigen in the central nervous system cells in cryptococcal meningoencephalitis.

Cryptococcal meningoencephalitis (CME) is caused by the encapsulated fungus Cryptococcus neoformans (CN) and is a major cause of mortality and morbidity in patients with AIDS. The polysaccharide capsule of CN is important for virulence, and soluble polysaccharide has the potential to cause immune modulation. To better understand the interactions of central nervous system cells and cryptococcal capsular polysaccharide (CNPS) in the pathogenesis of human CME, postmortem brain tissue from 21 patients with CME (13 AIDS and 8 non-AIDS patients) was analyzed. Histopathology and distribution of tissue CNPS antigen were analyzed using monoclonal antibodies against CNPS in combination with cell type-specific markers (glial fibrillary acidic protein for astrocytes, Ricinus communis agglutinin (RCA)-l for macrophage/microglia and endothelial cells; UCHL-1 for T cells, L26 for B cells). The CN cells showed discrete capsular immunoreactivity as expected; however, diffuse and particulate cellular and tissue staining for CNPS was detected in the brain parenchyma and the meninges in all cases. By quantitative analysis, the CNPS immunoreactive area ranged from 0.1 to 88 percent of tissue cross sectional area, and tended to be higher in brains of AIDS (median values from two sections ranged from 1 to 57 percent; mean, 26 percent) than in non-AIDS (0.1 to 40 percent; mean, 9.6 percent) patients. The proportion of CNPS immunoreactive area was positively correlated with the estimated number of CN. None (0/13) of the AIDS patients displayed significant inflammatory responses to CN, whereas most (7/8) non-AIDS patients showed granulomatous inflammatory responses. The phenotype of infiltrating lymphocytes was UCHL-1+/L26-/RC4-, thus consistent with activated T cells, both in AIDS and non-AIDS patients. Double immunolabeling studies revealed that tissue CNPS immunoreactivity was most often localized in macrophages and microglia, less frequently in reactive astrocytes and endothelial cells, but not in lymphocytes. This study demonstrates that CNPS can be detected not only in the serum and cerebrospinal fluid (CSF) of patients, but also in the affected tissue, most often localized in cells of mononuclear phagocyte system. Potential implications of these findings for the pathogenesis of CME are discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Ultrastructural instability of paired helical filaments from corticobasal degeneration as examined by scanning transmission electron microscopy.

Paired helical filaments (PHFs) accumulate in the brains of subjects affected with Alzheimer's disease (AD) and certain other neurodegenerative disorders, including corticobasal degeneration (CBD). Electron microscope studies have shown that PHFs from CBD differ from those of AD by being wider and having a longer periodicity of the helical twist. Moreover, PHFs from CBD have been shown to be primarily composed of two rather than three highly phosphorylated polypeptides of tau (PHF-tau), with these polypeptides expressing no exons 3 and 10. To further explore the relationship between the heterogeneity of PHF-tau and the appearance of abnormal filaments, the ultrastructure and physical parameters such as mass per unit length and dimensions were compared in filaments from CBD and AD using high resolution scanning transmission electron microscopy (STEM). Filament-enriched fractions were isolated as Sarcosyl-insoluble pellets and for STEM studies, samples were freeze-dried without prior fixation or staining. Ultrastructurally, PHFs from CBD were shown to be a heterogeneous population as double- and single-stranded filaments could be identified based on their width and physical mass per unit length expressed in kilodaltons (kd) per nanometer (nm). Less abundant, double-stranded filaments had a maximal width of 29 nm and a mass per unit length of 133 kd/nm, whereas three times more abundant single-stranded filaments were 15 nm wide and bad a mass per unit length of 62 kd/nm. Double-stranded filaments also displayed a distinct axial region of less dense mass, which appeared to divide the PHFs into two protofilament-like strands. Furthermore, these filaments were frequently observed to physically separate along the long axis into two single strands or to break longitudinally. In contrast, PHFs from AD were ultrastructurally stable and uniform both in their width (22 nm) and physical mass per unit length (104 kd/nm). The ultrastructural features indicate that filaments of CBD and AD differ both in stability and packing of tau and that CBD filaments, composed of two distinct protofilaments, are more labile under STEM conditions. As fixed and stained filaments from CBD have been shown to be stable and uniform in size by conventional transmission electron microscopy, STEM studies may be particularly suitable for detecting instability of unstained and unfixed filaments. The results also suggest that molecular heterogeneity and/or post-translational modifications of tau may strongly influence the morphology and stability of abnormal filaments.

Aged↗
PubMed1995

Interleukin-1, nitric oxide and reactive astrocytes.

Recent work in many laboratories has revealed that cytokines are important mediators of inflammation, host defense, and tissue injury in a variety of neurological diseases. A role for astrocytes and microglia in these diseases has been considered pivotal, since both cell types readily produce and respond to cytokines in vitro and show morphologic and immunocytochemical evidence for activation in vivo. Although much of the work documenting these events has been generated in rodent systems, our laboratory has focused on human cell culture systems to define the nature of the activating signals for human microglia and astrocytes and their responses to activating cytokines and growth factors and evidence for activation. The results have shown that interleukin-1 (IL-1) is a potent activator of human astrocytes and induces cytokines such as tumor necrosis factor alpha and interleukin-6, and is a potent activator of nitric oxide generation in astrocytes. Astrocytes also promote microglial growth and differentiation through production of colony-stimulating factors, an activity that is enhanced following activation with IL-1. This review will summarize the human glia data generated in this and other laboratories and present hypotheses how glia may participate in certain human central nervous system diseases.

Astrocytes↗
PubMed1995

Epitope expression and hyperphosphorylation of tau protein in corticobasal degeneration: differentiation from progressive supranuclear palsy.

Corticobasal degeneration (CBD) is a rare, progressive neurological disorder characterized by widespread neuronal and glial accumulation of abnormal tau protein. Using immunohistochemistry we analyzed tau epitope expression and phosphorylation state in CBD and compared them to cytoskeletal changes in Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Epitopes spanning the entire length of the tau protein were present in CBD inclusions. An antibody against the alternatively spliced exon 3 did not recognize cytoskeletal lesions in CBD, but did in AD and PSP. Tau epitopes from each region of the molecule were present in cytoskeletal inclusions in CBD, including gray matter astrocytic plaques, gray and white matter threads, and oligodendroglial inclusions. As in AD, tau from CBD was highly phosphorylated. Antibodies that recognized phosphorylated tau epitopes reacted with material from CBD in a highly phosphatase-dependent manner. Again, all types of inclusions contained phosphorylated epitopes. We conclude that abnormal tau protein in CBD comprises the entire tau molecule and is highly phosphorylated, but is distinguished from AD and PSP by the paucity of epitopes contained in the alternatively spliced exon 3.

Aged↗
PubMed1995

Human microglia mediate anti-Cryptococcus neoformans activity in the presence of specific antibody.

The interaction of the opportunistic fungus Cryptococcus neoformans with human microglia was studied in vitro in the presence and absence of capsule binding antibody. In the absence of capsule binding antibody there was little or no phagocytosis. Addition of the murine monoclonal antibody (mAb) 2H1 (IgG1, kappa) to the capsular glucuronoxylomannan (GXM) produced a dose-dependent enhancement of C. neoformans phagocytosis by microglia. Phagocytosis resulted in marked inhibition of fungal proliferation. Microglial antifungal activity was studied by colony forming unit assay, L-[3H]leucine incorporation assay, and phase contrast microscopy. At microglia: C. neoformans ratios of 10:1 to 80:1 fungal growth was reduced by 61-95%. Inhibitors of nitric oxide synthase and reactive oxygen intermediates did not prevent antifungal activity mediated by human microglia. Transmission electron microscopic studies revealed that although some internalized yeast cells were killed, the majority were intact consistent with fungistasis. Human microglia cells are potent effector cells against C. neoformans in vitro in the presence of specific antibody. Enhancement of microglial activity in vivo by opsonins may be a useful therapeutic strategy.

Antibodies, Fungal↗
PubMed1995

In human fetal astrocytes exposure to interleukin-1 beta stimulates acquisition of the GD3+ phenotype and inhibits cell division.

In human astrocyte cultures established from second-trimester fetal brain tissue, approximately 5-10% of total astrocyte population in unstimulated cultures were GD3+/glial fibrillary acidic protein (GFAP)+. The GD3+ cells were always GFAP+ and grew as flat, highly spread cells but changed to process-bearing cells after interleukin-1 beta (IL-1 beta) stimulation. It is interesting that IL-1 beta, a known mitogen for rat astrocytes, suppressed human fetal astrocyte proliferation as determined by [3H]thymidine incorporation, bromodeoxyuridine (BrdU) labeling, and cell counting. The GD3+ population, however, consistently increased in absolute number after IL-1 beta stimulation, in a dose- and time-dependent manner. The IL-1 beta-mediated increase in number of GD3+ astrocytes was independent of initial cell density or serum concentration. By flow cytometry, IL-1 beta enhanced both the mean fluorescence intensity and the percentage of GD3+ cells. To investigate whether the increase in GD3+ astrocyte cell number was due to proliferation of preexisting GD3+ astrocytes or due to conversion of GD3- to GD3+ cells, we performed BrdU/GD3 double immunocytochemistry. BrdU/GD3 double-positive cells were extremely rare in both control and IL-1 beta-stimulated cultures. Moreover, an increase in number of GD3+ astrocytes was still observed in control and IL-1 beta-stimulated cultures were GD3+ cells had been initially eliminated by cell sorting. These results indicate that GD3+ astrocytes in human fetal culture may represent a postmitotic, differentiated, distinct phenotype.

Astrocytes↗
PubMed1995

The distribution and biochemical properties of a Cdc2-related kinase, KKIALRE, in normal and Alzheimer brains.

The biochemical properties and distribution of a Cdc2-related kinase, KKIALRE, were studied in brain tissues and cultured cells with antibodies to a subregion of KKIALRE protein deduced from cDNA. In adult human brain, the KKIALRE-immunoreactive protein consisted of four or five isoforms having a molecular size of 40-52 kDa, whereas in fetal brain, there was one protein of approximately 48 kDa. Cultured astrocytes, neuroblastoma cells, and mouse brains contained the fetal form of KKIALRE protein. KKIALRE-immunoreactive proteins were capable of phosphorylating histone and synthetic peptides with the X-Ser-Pro-X motif, indicating that these proteins belong to the proline-directed Ser/Thr protein kinase family. The KKIALRE immunoreactivity was detected primarily in fibrous astrocytes in white matter and perivascular and subpial spaces, as well as in Bergmann glia in the cerebellum. In fetal brains radial glia were weakly immunoreactive. Reactive astrocytes were more intensely labeled than other glia. Neurons in normal brains and brains with Alzheimer's disease (AD) displayed no KKIALRE immunoreactivity. KKIALRE immunoreactivity was similar in neurons with and without neurofibrillary tangles. The results indicate that in CNS, the KKIALRE protein is mainly a glial protein that is up-regulated in gliosis and that it probably plays no role in the hyperphosphorylation of tau in AD brains.

Adult↗
PubMed1995

Gerstmann-Sträussler-Scheinker disease (PRNP P102L): amyloid deposits are best recognized by antibodies directed to epitopes in PrP region 90-165.

Gerstmann-Sträussler-Scheinker (GSS) disease is a familial neurological disorder pathologically characterized by accumulation of prion protein (PrP) in the form of fibrillary and non-fibrillary deposits within the cerebrum and cerebellum. We have studied two patients in whom the disease is caused by a leucine for proline amino acid substitution at residue 102 of PrP. In both patients, the neuropathologic findings are similar, consisting of spongiform changes, amyloid deposits, and gliosis. To investigate the antigenic profile of PrP deposits, we used antibodies raised against several peptides that correspond to segments of the N-terminus, repeat region, midregion, and C-terminus of PrP. By immunohistochemistry, PrP amyloid cores are best labeled by antibodies directed to epitopes spanning PrP residues 90-165. In GSS disease caused by a substitution of thymine to cytosine at PRNP codon 198 (Indiana kindred), the major amyloidogenic peptide spans residues 58-150; therefore, in these two genetic forms of GSS disease, amyloid may be composed of different peptides.

Adult↗
PubMed1995

Gerstmann-Sträussler-Scheinker disease with mutation at codon 102 and methionine at codon 129 of PRNP in previously unreported patients.

We present two patients with Gerstmann-Sträussler-Scheinker disease (GSS), one from a previously undescribed kindred and one from the Canadian branch of a previously reported British kindred. In both patients, GSS is caused by a substitution of thymine for cytosine at codon 102 of the prion protein gene (PRNP). In each patient, we confirmed the clinical diagnosis by neuropathologic examination. The mutation, causing a substitution of leucine for proline at residue 102 (P102L) of the prion protein, has been previously reported in at least 30 other families. In the patients described here, the mutation was in coupling with methionine at PRNP codon 129.

Adult↗
PubMed1995

Widespread cytoskeletal pathology characterizes corticobasal degeneration.

Corticobasal degeneration (CBD) is a rare, progressive neurological disorder characterized by widespread neuronal and glial pathology. Using immunohistochemistry and laser confocal microscopy, we demonstrate that the nonamyloid cortical plaques of CBD are actually collections of abnormal tau in the distal processes of astrocytes. These glial cells express both vimentin and CD44, markers of astrocyte activation. Glial pathology also includes tau-positive cytoplasmic inclusions, here localized to Leu 7-expressing oligodendrocytes. In addition, a wide array of neuronal pathology is defined with tau-positive inclusions in multiple domains of a variety of cortical neurons. CBD thus exhibits widespread glial and neuronal cytoskeletal pathology, including a novel structure, the astrocytic plaque. CBD is a disease of generalized cytoskeletal disruption affecting several cell types and multiple domains of these cells. The further definition of CBD pathology refines the diagnosis and pathophysiological understanding of this unique disease and has important implications for other neurodegenerative diseases, like Alzheimer's disease, characterized by abnormal tau deposition.

Aged↗
PubMed1995

Detection of a Cdc2-related kinase associated with Alzheimer paired helical filaments.

By immunocytochemical staining and Western blotting, we detected a Cdc2-related kinase in human brains. The kinase is recognized by antibodies against the carboxyl and the amino termini of p34Cdc2 but is not recognized by antibodies against the PSTAIRE motif. It is slightly smaller than p34Cdc2 in molecular mass (approximately 33 kd). This 33-kd Cdc2-related kinase is present in intracellular neurofibrillary tangles in neurons of elderly humans and in Alzheimer's disease, and it is associated with paired helical filaments (PHF) from Alzheimer's disease brains. Unlike the antibodies to the carboxyl and amino termini of p34Cdc2, antibodies to an abundant brain Cdc2-related kinase PSSLARE/Cdk5 did not immunolabel Alzheimer's disease neurofibrillary lesions. PHF preparations were demonstrated to contain kinases capable of phosphorylating histone H1, PHF-Tau, and a synthetic peptide (VAVVRTPPKSPSSAK). By virtue of its physical association with PHF, the 33-kd Cdc2-related kinase may play a role in transforming normal Tau proteins to PHF-Tau characteristic of Alzheimer's disease.

Alzheimer Disease↗
PubMed1995

Multicystic encephalopathy: review of eight cases with etiologic considerations.

Multicystic encephalomalacia (MCE) is a rare lesion that arises during the perinatal period. Although hypoxic-ischemic insults may be responsible for this lesion, recent evidence suggests that herpesviruses may represent another etiologic agent. To elucidate the pathogenesis of MCE, eight cases collected over a 34-year period were evaluated for destructive lesions in gray and white matter. Immunocytochemical methods, in situ hybridization and polymerase chain reaction (PCR) methodology were employed to search for herpes simplex viruses types 1 and 2 (HSV1 and HSV2), cytomegalovirus (CMV), varicella zoster virus (VZV), Epstein-Barr virus (EBV) and JC variant of papovavirus (JCV). Review of the clinical histories revealed that there had been a complicated labor and delivery in 6/7 cases. Neuropathological lesions consisted of extensive tissue destruction, neuronal loss and gliosis in hemispheric white matter, cerebral cortex, basal ganglia, thalamus, cerebellum and brainstem tegmentum. Only one case showed evidence of latent HSV infection by PCR. CMV, VZV, JCV and EBV were not detected. Arteriopathy was noted in one case. The widespread nature of the lesions and their association with perinatal ischemia suggest that severe hypoxia may be the more common etiology of MCE. Term infants appear especially susceptible to this type of cerebral damage.

Autopsy↗
PubMed1995

Cryptococcus neoformans survive and replicate in human microglia.

BACKGROUND: Cryptococcus neoformans (CN) is an opportunistic pathogen that can cause fatal meningoencephalitis in patients with immune deficiency. Among the central nervous system (CNS) cells that are infected by CN are perivascular microglia and macrophages. Little is known about the interaction of CN and CNS phagocytes at the cellular level. EXPERIMENTAL DESIGN: To better understand the fate of CN in microglia, we followed Ab-opsonized CN in human fetal microglial culture by phase-contrast microscopy, combined lighted microscopy and transmission electron microscopy of plastic-embedded monolayers, and immunocytochemistry for localization of capsular Ag. RESULTS: Phase-contrast microscopy revealed that microglia initially internalized and contained Ab-opsonized yeast cells within phagolysosomes. However, CN escaped from microglia and resumed extracellular growth 16 to 24 hours after being phagocytosed. Transmission electron microscopy/1-mu epoxy sections revealed that intracellular CN were localized in two types of phagosomes in microglia: spacious phagosomes (SP) and close-fitting phagosomes (CP). Three lines of evidence indicate that SP are the primary sites for intracellular CN survival and replication: (a) SP contained multiple, budding yeast cells, whereas CP contained only single yeast cells within a tightly bound phagosomal membrane; (b) the number of SP and the number of CN within SP increased considerably at 24 hours compared with at 2 hours; and (c) microglial cultures challenged with heat- or amphotericin B-treated CN had significantly fewer SP than those challenged with live CN. Both SP and CP phagosomes fused with lysosomes, suggesting that CN survival in SP was not due to failure of phagolysosomal fusion. In SP, there was attenuation and diffusion of capsular polysaccharide within the phagosome, whereas in CP the fungal capsules remained compact and homogeneous. Immunocytochemistry with an mAb directed to capsular glucoronoxylomannan supported continued synthesis of polysaccharide within SP. CONCLUSION: The results suggest that, in human microglia, CN survive and replicate within SP. Modification of CN capsular polysaccharide within SP may be a contributing factor to this aberrant microglial-CN interaction.

Animals↗
PubMed1994

Human astrocytes inhibit Cryptococcus neoformans growth by a nitric oxide-mediated mechanism.

Cryptococcus neoformans is an opportunistic fungus that causes life-threatening meningoencephalitis in 5-10% of patients with acquired immune deficiency syndrome. Cryptococcal meningoencephalitis is characterized by a lymphohistiocytic infiltrate, accumulation of encapsulated forms of C. neoformans, and varying degrees of glial reaction. Little is known about the contribution of endogenous central nervous system cells to the pathogenesis of cryptococcal infections. In this study, we investigated the role of astrocytes as potential effector cells against C. neoformans. Primary cultures of human fetal astrocytes, activated with interleukin 1 beta plus interferon gamma inhibited the growth of C. neoformans. The inhibition of C. neoformans growth was paralleled by production of nitrite, and reversed by the inhibitors of nitric oxide (NO.) synthase, NG-methyl-mono-arginine and NG-nitro-arginine methyl ester. The results suggest a novel function for human astrocytes in host defence and provide a precedent for the use of NO. as an antimicrobial effector molecule by human cells.

Arginine↗