RESUMO
OBJECTIVE: The University of California, San Diego, Moores Cancer Center implemented a systematic approach for patients to communicate with their health-care team in real-time regarding psychosocial problem-related distress using touch-screen technology. The purpose of this report is to describe our experience in implementing touch-screen problem-related distress screening as the standard of care for all outpatients in a health-care setting. Although early identification of distress has recently gained wide attention, the practical issues of implementing psychosocial screening with and without the use of technology have not been fully addressed or investigated. METHODS: 'The How Can We Help You and Your Family?' screening instrument was used to identify and address patient problem-related distress for clinical services, program development, research and education. Using a HIPPA-compliant approach, the touch-screen technology also helped to identify patients interested in clinical trials and additional support services. RESULTS: We found that the biggest barrier to implementing this technology was the attitude of the front desk staff (i.e. schedulers, clerks, administrative staff) who felt that the touch-screen would be burdensome. Our experience suggested that it was essential to actively involve these personnel from the beginning of the planning process. As specifically acknowledged in the recent 2007 Institute of Medicine report (Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs. The National Academies Press: Washington, DC, 2007), use of this computerized version of the screening instrument was able to bridge the gap between the detection of problem-related distress and referrals for assessment or treatment. CONCLUSION: We found that it is feasible to implement a computerized problem-related distress screening program in a comprehensive cancer center.
Assuntos
Assistência Ambulatorial , Ansiedade/diagnóstico , Comunicação , Redes de Comunicação de Computadores , Depressão/diagnóstico , Programas de Rastreamento , Avaliação das Necessidades , Neoplasias/psicologia , Neoplasias/terapia , Equipe de Assistência ao Paciente , Interface Usuário-Computador , Ansiedade/psicologia , Ansiedade/terapia , Atitude do Pessoal de Saúde , California , Institutos de Câncer , Alfabetização Digital , Depressão/psicologia , Depressão/terapia , Feminino , Hospitais Universitários , Humanos , Capacitação em Serviço , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Resolução de Problemas , Encaminhamento e Consulta , Software , Inquéritos e Questionários , Carga de Trabalho/psicologiaRESUMO
Apolipoprotein E (apoE) is known to bind to at least five receptors, including the low-density lipoprotein (LDL) receptor-related protein (LRP), very low density LDL receptor (VLDL-R), LDL-R, apoE receptor 2 (apoER2), and megalin/gp330. In this context, the main objective of the present study was to better understand the contributions of LRP and LDL-R to the in vivo neurotrophic effects of apoE. For this purpose, apoE-deficient and receptor-associated protein (RAP)-deficient mice were infused with recombinant apoE3, RAP, or saline. Infusion of apoE3 into apoE-deficient mice resulted in amelioration of degenerative alterations of pyramidal neurons, but had no effect on somatostatin-producing interneurons. In contrast, infusion of apoE3 into RAP-deficient mice resulted in amelioration of degenerative alterations of somatostatin-producing interneurons. LRP and LDL-R levels were significantly reduced in RAP-deficient mice, but significantly increased in the apoE-deficient mice. In contrast, levels of apoE were reduced in the RAP-deficient mice compared to wildtype controls, suggesting that neurotrophic effects of apoE3 in the RAP-deficient mice were related to a combined deficit in endogenous apoE and selected apoE receptors. Furthermore, in apoE-deficient mice, infusion of apoE3 had a neurotrophic effect on somatostatin-producing interneurons only when combined with RAP, suggesting that increased expression of apoE receptors in apoE-deficient mice prevented apoE from rescuing somatostatin-producing neurons. This study supports the contention that some of the in vivo neurotrophic effects of apoE are mediated by LRP and LDL-R and that a critical balance between levels of apoE and its receptors is necessary for the differential neurotrophic effects to appear.
Assuntos
Apolipoproteínas E/metabolismo , Fatores de Crescimento Neural/metabolismo , Receptores de Lipoproteínas/metabolismo , Animais , Apolipoproteína E3 , Apolipoproteínas E/administração & dosagem , Apolipoproteínas E/deficiência , Apolipoproteínas E/farmacologia , Complexo Antigênico da Nefrite de Heymann , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Injeções Intraventriculares , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Neocórtex/citologia , Neocórtex/efeitos dos fármacos , Neocórtex/metabolismo , Fatores de Crescimento Neural/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Somatostatina/metabolismoRESUMO
The expression levels of three synaptic proteins (synaptophysin, synaptotagmin, and growth-associated protein 43 [GAP43]) in AD cases clinically classified by Clinical Dementia Rating (CDR) score were analyzed. Compared with control subjects (CDR = 0), mild (early) AD (CDR = 0.5 to 1) cases had a 25% loss of synaptophysin immunoreactivity. Levels of synaptotagmin and GAP43 were unchanged in mild AD, but cases with CDR of >1 had a progressive decrement in these synaptic proteins. Thus, synaptic injury in frontal cortex is an early event in AD.
Assuntos
Doença de Alzheimer/metabolismo , Proteínas de Ligação ao Cálcio , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Sinapses/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Progressão da Doença , Lobo Frontal/química , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Proteína GAP-43/análise , Proteína GAP-43/metabolismo , Humanos , Immunoblotting , Glicoproteínas de Membrana/análise , Proteínas do Tecido Nervoso/análise , Índice de Gravidade de Doença , Sinapses/química , Sinaptofisina/química , Sinaptofisina/metabolismo , SinaptotagminasRESUMO
OBJECTIVE: To analyze changes in frequency of systemic AIDS pathology over time and its relationship to central nervous system pathology. DESIGN AND METHODS: A total of 390 AIDS autopsy cases obtained at University of California at San Diego Medical Center from 1982 to 1998 were reviewed retrospectively and linear regression analysis was used to evaluate significance of changes over time. RESULTS: Overall, the frequency of cytomegalovirus, Pneumocystis carinii pneumonia and Mycobacterium avium complex decreased, whereas bacterial infections increased and the frequency of fungal infection remained unchanged over time. The frequency of non-Hodgkin's lymphoma showed an upward trend over time, while the frequency of Kaposi's sarcoma remained unchanged. Following involvement of the lung (84%), the brain continued to be the second most frequently affected organ (63%). Whereas alterations of the brain by opportunistic infections or non-Hodgkin's lymphoma showed a downward trend, HIV encephalitis continued to be detected in at least 25% of the cases. Cases with advanced HIV-related neuropathology and cases with no HIV involvement of the brain showed significant systemic pathology with opportunistic infections and neoplasms. In contrast, cases with early brain pathology (e.g., lymphocytic meningitis) showed minimal systemic pathology. Overall these trends remained unchanged throughout the total period covered by this study. CONCLUSIONS: This study suggests that despite the beneficial effects of antiretroviral and anti-opportunistic infection therapy, involvement of the brain by HIV continues to be a frequent autopsy finding.
Assuntos
Síndrome da Imunodeficiência Adquirida/patologia , HIV-1 , Infecções Oportunistas Relacionadas com a AIDS/etiologia , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Infecções Oportunistas Relacionadas com a AIDS/patologia , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/mortalidade , Autopsia/estatística & dados numéricos , Encéfalo/patologia , Causas de Morte , Coleta de Dados , Humanos , Neoplasias/etiologia , Neoplasias/mortalidade , Neoplasias/patologiaRESUMO
How to assess the substantial neuronal loss in a neurodegenerative disease such as Alzheimer disease is still being debated. Recently, stereological procedures have been proposed that claim improved accuracy and statistical power, but the results of some of these investigations have been controversial. In this study we compared and correlated the cell density results calculated per unit of volume obtained by a stereological technique, the "selector," with the cell counts per unit area obtained by computer-aided image analysis morphometry, in the same sections of midfrontal cortex in Alzheimer disease and control cases. The "selector" revealed a significant decrease in neuronal density that correlated well with a similar fall in large neuronal counts per unit area, as estimated by image analysis morphometry. These results indicate that stereological techniques and image analysis morphometry are complementary methods in reliably assessing cellular populations in neurodegenerative disorders.
Assuntos
Doença de Alzheimer/patologia , Lobo Frontal/patologia , Neurologia/métodos , Neurônios/patologia , Idoso , Contagem de Células , Tamanho Celular , Humanos , Processamento de Imagem Assistida por Computador , Pessoa de Meia-IdadeRESUMO
Reactive glial cells are consistently found in the brain tissue of Alzheimer's disease (AD) patients. Both clustered and scattered glial cells occur in AD brain. A number of clustered microglial cells, but not astrocytes, had a positive correlation with neurite plaque numbers, suggesting that clustered micro-glial cells are uniquely associated with plaques whereas clustered astrocytes may have functions outside the plaques as well. APOE epsilon 4, the major genetic risk factor for AD, had a dose-dependent effect to increase the numbers of scattered microglial cells whereas the APOE risk showed no correlation with any of the clustered glial cells or scattered astrocytes. These findings raise the possibility that the increased levels of scattered, but not clustered, microglial cells are the immediate response to APOE risk and might be primarily involved in AD pathogenesis.
Assuntos
Doença de Alzheimer/metabolismo , Apolipoproteínas E/análise , Astrócitos/química , Microglia/química , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/patologia , Astrócitos/citologia , Contagem de Células , Gliose/metabolismo , Humanos , Microglia/citologia , Emaranhados Neurofibrilares/química , Neurônios/química , Neurônios/patologia , Fatores de RiscoRESUMO
The mechanisms of synapse damage in Alzheimer's disease (AD) are not fully understood. Deficient functioning of glutamate transporters might be involved in synaptic pathology and neurodegeneration by failing to clear excess glutamate at the synaptic cleft. In AD, glutamate transporter activity as assessed by D-[3H]aspartate binding is decreased; however, it is not clear to what extent it is associated with the neurodegenerative process and cognitive alterations. For this purpose, levels of D- and L-[3H]aspartate binding in midfrontal cortex were correlated with synaptophysin levels, brain spectrin degradation product levels, and clinical and neuropathological indicators of AD. Compared to control brains, AD brains displayed a 34% decrease in levels of D-[3H]aspartate binding, a 30% decrease in L-[3H]aspartate binding, and a 48% loss of synaptophysin immunoreactivity. Increased levels of brain spectrin degradation products correlated with a decrease in levels of D-[3H] and L-[3H]aspartate binding, and decreased levels of synaptophysin immunoreactivity. Levels of L-[3H]aspartate binding correlated with levels of synaptophysin immunoreactivity. These results suggest that decreased glutamate transporter activity in AD is associated with increased excitotoxicity and neurodegeneration, supporting the possibility that abnormal functioning of this system might be involved in the pathogenesis of synaptic damage in AD.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Ácido Aspártico/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Degeneração Neural , Idoso , Sistema X-AG de Transporte de Aminoácidos , Autopsia , Transporte Biológico , Biomarcadores , Lobo Frontal/metabolismo , Humanos , Emaranhados Neurofibrilares/patologia , Especificidade de Órgãos , Valores de Referência , Análise de Regressão , Espectrina/análise , Sinaptofisina/análiseRESUMO
The non-Abeta component of Alzheimer's disease amyloid (NAC) is copurified with amyloid from the brain tissue of Alzheimer's disease victims and is immunohistochemically localized to amyloid fibrils. NAC is a hydrophobic peptide fragment from the NAC precursor protein (NACP/alpha-synuclein) that is localized to presynaptic terminals. We used a polymorphic dinucleotide repeat sequence in a genomic clone of NACP for genetic association and linkage studies. Screening of Alzheimer's disease families failed to establish linkage between NACP and Alzheimer's disease. Nevertheless, one of the NACP polymorphisms (NACP allele 2) was shown to have significant association with healthy elderly control individuals with apolipoprotein E risk. This may indicate a possible protective function of the allele.
Assuntos
Doença de Alzheimer/genética , Amiloide/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético/genética , Precursores de Proteínas/genética , Idoso , Alelos , Precursor de Proteína beta-Amiloide/genética , Apolipoproteínas E/genética , Sequência de Bases , Técnicas de Cultura , Ligação Genética , Humanos , Imuno-Histoquímica , Dados de Sequência Molecular , Mutação Puntual , Sinucleínas , Transcrição GênicaRESUMO
Stathmin (p19), a 19-kDa cytosolic phosphorotein, plays a key role in converting extracellular signals into intracellular biochemical changes. Antibodies and cDNA specific for stathmin were used to study its levels and localization in normal and Alzheimer's disease (AD) brain tissue. The stathmin protein concentration was reduced in AD neocortex as assessed by Western blotting, whereas the concentration of its mRNA detected by both in situ hybridization and slot blot were increased in AD. The alteration of the stathmin protein concentration was negatively correlated with neurofibrillary tangle numbers but not with plaque numbers. Immunoreactivity was evenly localized to the cytoplasm of neurons in control cortical sections, whereas in AD it was preferentially localized to some of the neurofibrillary tangle-bearing neurons. Numbers of stathmin-positive neurons were inversely correlated with tangle numbers but not with plaque numbers in the frontal cortex of AD patients.
Assuntos
Doença de Alzheimer/metabolismo , Proteínas dos Microtúbulos , Emaranhados Neurofibrilares/metabolismo , Fosfoproteínas/metabolismo , Northern Blotting , Contagem de Células , Humanos , Imuno-Histoquímica , Hibridização In Situ , EstatminaRESUMO
NACP, the precursor of non-A beta component of Alzheimer's disease (AD) amyloid (NAC), is a synaptic protein that could potentially be involved in AD. We studied, by dot-blot, NACP levels in the frontal cortex of AD cases staged according to severity of disease and correlated them with cognitive performance and neuropathological markers. Early AD cases showed one fold higher levels of NACP immunoreactivity (IR) compared to moderate and severe AD. Levels of NACP-IR were correlated with tangle counts (r = -0.305, P = 0.04) and Blessed score (r = -0.356, P = 0.01), but not with plaque counts (r = 0.132, P = 0.39). This study suggests that the abnormal accumulation of NACP during the early stages of AD might play an important role in the mechanisms of neurodegeneration and synaptic damage in AD.
Assuntos
Doença de Alzheimer/metabolismo , Amiloide/biossíntese , Proteínas do Tecido Nervoso , Precursores de Proteínas/biossíntese , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Cognição/fisiologia , Progressão da Doença , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Immunoblotting , Masculino , Emaranhados Neurofibrilares/patologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , SinucleínasRESUMO
Both genetic and environmental factors affect the progression of Alzheimer's disease (AD). The presence of cortical Lewy bodies in AD patients is associated with an altered presentation of AD pathology suggestive of an interaction between the pathogenesis of Lewy bodies and AD lesions. Since the CYP2D6B mutant allele is often present in patients with Lewy body diseases (Parkinson's disease and Lewy body variant of AD), we extended these prior observations by studying the neuropathology associated with the presence of the CYP2D6B mutant allele in a pure AD population without Lewy bodies. AD patients who possessed the CYP2D6B mutant allele, in comparison with those without the CYP2D6B allele, were found to have a smaller decline in two synaptic markers, choline acetyltransferase and synaptophysin, in the frontal cortex relative to normal control values. On the other hand, senile plaques and neurofibrillary tangles were not significantly affected by the presence of the CYP2D6B mutant allele in the frontal cortex of AD patients. Association of the CYP2D6B mutant allele with Lewy body formation in both Parkinson's disease and the Lewy body variant of AD and with the milder synaptic pathology in pure AD without Lewy bodies suggest that depending on the contribution of other genetic and environmental factors, this mutant allele may be involved with different aspects of neurodegeneration.
Assuntos
Alelos , Doença de Alzheimer/enzimologia , Sistema Enzimático do Citocromo P-450/genética , Oxigenases de Função Mista/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/patologia , Colina O-Acetiltransferase/análise , Citocromo P-450 CYP2D6 , Genótipo , HumanosRESUMO
In the present study we observed that while platelet-derived growth factor (PDGF)-BB is exclusively expressed by neurons in the human brain, PDGF-AA is expressed in neurons and blood vessels. In Alzheimer's disease (AD), antibodies against PDGF-BB (but not PDGF-AA) recognized the neurofibrillary alterations of this disease. The levels of PDGF-BB correlated with the patterns of synaptic loss and sprouting while PDGF-AA immunostaining of the vessels was correlated with glial proliferation. Immunostaining was completely abolished when the antibodies were preincubated with their respective purified recombinant PDGF. Western blot analysis showed that antibodies against PDGF recognized a 31 kDa protein that was mildly increased in AD. These data suggest that PDGF, as well as other neurotrophic factors, play an important role in the mechanisms of neurofibrillary pathology in AD.
Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/patologia , Fator de Crescimento Derivado de Plaquetas/fisiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Western Blotting , Encéfalo/metabolismo , Gliose/metabolismo , Gliose/patologia , Humanos , Imuno-Histoquímica , Microscopia Confocal , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Neuroglia/patologia , Neurônios/patologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Análise de RegressãoRESUMO
OBJECTIVE: We correlated severity of dementia in Alzheimer's disease with the degree of neuropathology in cortical and subcortical brain regions. METHODS: In 13 patients with Alzheimer's disease who underwent neuropsychological testing before death, we assessed neurofibrillary tangles, senile plaques, and neuronal and synaptic density in the midfrontal cortex and the nucleus basalis of Meynert. RESULTS: In the midfrontal cortex, synapse density was the strongest correlate of dementia severity, followed by neurofibrillary tangles. In the nucleus basalis, by contrast, neurofibrillary tangles were the strongest correlate, followed by synapse density. Stepwise regression analyses showed midfrontal synapse density to be the strongest predictor of tests emphasizing higher cortical functions, but neurofibrillary tangles in the nucleus basalis were the strongest predictor on memory-oriented tests. CONCLUSIONS: The specificity of pathology in cortical vs subcortical locations for predicting a particular quality of neuropsychological deficit probably reflects disruption of corticocortical connections vs derangement of the basal forebrain cholinergic system.
Assuntos
Doença de Alzheimer/patologia , Córtex Cerebral/patologia , Substância Inominada/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Humanos , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/patologia , Testes Neuropsicológicos , Sinapses/patologiaRESUMO
Extensive synaptic and neuritic alterations in the neocortex and limbic system are characteristically found in Alzheimer's disease (AD). However, it is not known how early in the development of the disease these alterations occur. For the present study, we compared the synaptic and neuritic alterations among cases classified clinically and neuropathologically as early, mild and advanced AD. In early AD there was a 20% loss of synaptophysin-immunoreactive presynaptic terminals in the outer molecular layer of the hippocampal dentate gyrus (but not in the neocortex and entorhinal cortex), accompanied by increased amyloid precursor protein (APP) and Alz50 immunoreactivity in hippocampal and entorhinal cortex pyramidal neurons. These results suggest that abnormal neuronal expression of APP and cytoskeletal proteins in early stages might be involved in the mechanisms of synaptic pathology in AD.
Assuntos
Doença de Alzheimer/patologia , Neuritos/fisiologia , Sinapses/fisiologia , Idoso , Idoso de 80 Anos ou mais , Amiloide/imunologia , Amiloide/metabolismo , Córtex Cerebral/patologia , Citoesqueleto/metabolismo , Córtex Entorrinal/patologia , Hipocampo/patologia , Humanos , Proteínas do Tecido Nervoso/metabolismo , Células Piramidais/metabolismo , Sinaptofisina/imunologia , Sinaptofisina/metabolismoRESUMO
We re-examined the relationship among synaptic pathology, subcellular abnormalities within neurites in the plaques and beta-amyloid deposits of Alzheimer's disease (AD) using laser confocal imaging and computer-aided serial section reconstruction techniques. Analysis of serial optical sections of neuritic plaques double-immunolabeled for anti-beta-amyloid/anti-tau-2 revealed that 35% of this type of plaque contained a dense amyloid core with clusters of peripheral abnormal neurites. The other 65% were without a dense core and were mainly composed of abundant abnormal neuritic clusters with bundles of amyloid distributed throughout the neuritic plaque. While two-dimensional (2-D) analysis of the plaques has suggested that neurites are distributed in the plaque periphery with beta-amyloid localized in its center, serial section analysis showed the opposite arrangement can also be true. Three-dimensional (3-D) reconstructions of serial optical sections showed that the tau-positive tortuous axons clustered in the neuritic plaques were often continuous with synaptophysin-positive distended terminals. Analysis of electron micrographs from serial sections showed continuity among the different segments of the neurites. Further analysis of the computer generated 3-D reconstructed neuritic plaques (both from serial electron micrographs and serial optical sections), viewed as continuous rotating loops, confirmed that a great majority of the plaque volume was occupied by the clustered and continuous abnormal neurites, while the amyloid fibrils were compressed and displaced to the periphery of the plaque. The 3-D imaging of the neuritic plaques in AD suggests a more widespread and active neuritic damage than that predicted from 2-D observations.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/análise , Córtex Cerebral/patologia , Neuritos/patologia , Idoso , Córtex Cerebral/química , Diagnóstico por Computador , Humanos , Imuno-Histoquímica , Microscopia Eletrônica , Neuritos/química , Sinapses/química , Sinapses/patologia , Sinaptofisina/análise , Proteínas tau/análiseRESUMO
About one quarter of Alzheimer's disease patients have been found to have concomitant subcortical and neocortical Lewy bodies (LBs). We compared the aberrant neuronal sprouting and the extent of neuritic and synaptic damage in these Lewy body variants of Alzheimer's disease (LBV), with the same pathologic alterations in Alzheimer's disease without LBs (AD). More of the thioflavine-S-positive senile plaques of the LBVs contained growth associated protein 43 (GAP-43), a marker of neuritic growth and sprouting. Compared to AD, the LBVs had 39% more GAP-43-positive plaques in the frontal cortex, and 53% more in the hippocampus. These neuritic alterations were accompanied by an accumulation of amyloid precursor protein and phosphorylated neurofilaments. Synapse loss was the same in LBV and AD. These results suggest more extensive aberrant neuronal sprouting in LBV than in AD.
Assuntos
Doença de Alzheimer/patologia , Corpos de Lewy/patologia , Neuritos/patologia , Neurônios/patologia , Sinapses/patologia , Idoso , Precursor de Proteína beta-Amiloide/análise , Proteína GAP-43 , Substâncias de Crescimento/análise , Humanos , Imuno-Histoquímica , Glicoproteínas de Membrana/análise , Proteínas do Tecido Nervoso/análise , Neurônios/ultraestruturaRESUMO
We studied axonal damage in Alzheimer's disease frontal cortex and hippocampus with a novel monoclonal antibody (SMI 312) against phosphorylated neurofilaments. This antibody immunolabeled, with great detail, the neuropil axonal network. In aged normal cases only a few pyramidal cell perikarya were immunostained. In Alzheimer's disease there was a two- to four-fold increase in neuronal SMI 312 immunolabeling, and neuropil neuritic processes were severely disrupted. Double-immunolabeling analysis showed that 88% of SMI 312-immunolabeled abnormal neuritic clusters were associated with amyloid, whereas the remaining 12% were not. Serial section analysis and 3-D reconstructions suggested that dystrophic neurites of classical plaques were derived from long axons. These abnormal neurites were also growth-associated protein 43 positive and occasionally tau positive. The present study supports the contention that a subpopulation of aberrantly sprouting axons in the neuritic plaque is derived from cortico-cortico fibers. This disruption of the neocortical association fibers and neuritic microcircuitry could underlie the cognitive impairment of Alzheimer's disease.
Assuntos
Doença de Alzheimer/patologia , Anticorpos Monoclonais/imunologia , Axônios/patologia , Encéfalo/patologia , Filamentos Intermediários/imunologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Humanos , Imuno-Histoquímica , Filamentos Intermediários/metabolismo , Neuritos/metabolismo , FosforilaçãoRESUMO
We quantified the synaptic population density in the frontal cortex of 25 individuals without dementia 16 to 98 years old, using sections double-immunolabeled for beta/A4 amyloid and for synaptophysin, and found a significant inverse correlation between the presynaptic terminal (PT) counts and age (r = -0.7, p < 0.001). Individuals older than 60 years had an average 20% decrease in PT density compared with individuals younger than 60 years. There were no significant correlations between the age and the number of beta/A4 amyloid-positive plaques or between synaptic density and the number of amyloid plaques. Further analysis of the digitized serial optical images showed focal areas of synapse loss and distended synaptophysin-containing boutons in the mature plaques of the normal aged cases. However, we found no microscopic changes in the synaptic content inside and outside the diffuse plaques. We suggest that a loss of synaptic input in the neocortex is an age-dependent factor that contributes to the overall synaptic loss in Alzheimer's disease, but that this might be largely independent of the beta/A4-amyloid deposition.
Assuntos
Envelhecimento/fisiologia , Córtex Cerebral/citologia , Sinapses , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloide/análise , Humanos , Processamento de Imagem Assistida por Computador , Pessoa de Meia-Idade , Valores de ReferênciaRESUMO
A spectrum of neurocognitive defects, termed human immunodeficiency virus type 1 (HIV-1)-associated cognitive/motor complex, has been described in patients with acquired immunodeficiency syndrome (AIDS). AIDS dementia complex (ADC) is a severe form of this disease seen in 20 to 30% of terminally ill patients. The etiology of this complex is distinct from commonly observed opportunistic infections seen in brains of patients with AIDS and has been attributed to HIV infection within the brain. At autopsy, the brains of patients with ADC contain numerous HIV-infected macrophages/microglia with prominent subcortical damage, together termed HIV encephalitis. We retrospectively analyzed all 107 brains from a three-year period (1988-1990) of AIDS autopsies using immunocytochemistry to detect HIV. Rather than breaking into distinct groups of HIV encephalitis versus non-HIV encephalitis, the specimens revealed a spectrum of severity of HIV infection. Although only 16% of the brains showed the histological hallmarks of HIV encephalitis, more than 50% of the autopsies showed moderate to severe HIV infection. In a subset of 23 AIDS autopsies during which short postmortem times and absence of significant opportunistic infection permitted quantitative analysis of dendritic and synaptic complexities, we identified a strong correlation between neocortical dendritic and presynaptic damage and abundance of HIV envelope protein in the neocortical gray and deep white matter. This correlation suggests that the presence of HIV-1 in the neocortex may be responsible by direct or indirect mechanisms for dendritic and synaptic damage.