RESUMO
The biological role of the scrapie isoform of prion protein (PrP(Sc)) as an infectious agent in numerous human and non-human disorders of the central nervous system is well established. In contrast, and despite decades of intensive research, the physiological function of the endogenous cellular form of the prion protein (PrP(C)) remains elusive. In mammals, the ubiquitous expression of PrP(C) suggests biological functions other than its pathological role in propagating the accumulation of its misfolded isotype. Other functions that have been attributed to PrP(C) include signal transduction, synaptic transmission and protection against cell death through the apoptotic pathway. More recently, immunoregulatory properties of PrP(C) have been reported. We review accumulating in vitro and in vivo evidence regarding physiological functions of PrP(C).
Assuntos
Encéfalo/metabolismo , Proteínas PrPC/metabolismo , Proteínas PrPSc/metabolismo , Doenças Priônicas/metabolismo , Animais , Encéfalo/imunologia , Encéfalo/fisiopatologia , Citoproteção/fisiologia , Humanos , Fatores Imunológicos/imunologia , Fatores Imunológicos/metabolismo , Ativação Linfocitária/imunologia , Proteínas PrPC/genética , Proteínas PrPSc/genética , Doenças Priônicas/genética , Doenças Priônicas/imunologia , Transdução de Sinais/imunologia , Transmissão Sináptica/fisiologiaRESUMO
Verbal fluency tests are commonly used in neurocognitive and mental status examinations in patients with suspected dementia. Inflation of test scores as a result of practice effects may yield false-negative results in test-retest and multidisciplinary settings, particularly among patients with mild cognitive deficits. To address this issue, animal naming was administered twice within a 1-week period to a group of individuals referred for suspected dementia who were ultimately diagnosed with mild cognitive impairment (MCI; amnestic form), probable Alzheimer disease (AD), or no dementia. A 2 x 3 repeated-measures analysis of variance revealed a statistically significant interaction between administration time and group. Post hoc analyses indicated that nondemented controls were the only group to demonstrate a significant practice effect, producing an average of approximately three more animal names at time two. Like patients with a diagnosis of AD, subjects with amnestic MCI failed to benefit from repeated exposure to the animal naming test, and only controls showed an average improvement upon retest. This underscores the cognitive similarity between individuals diagnosed with amnestic MCI and AD and suggests that improvement upon retest may be a diagnostically useful finding.
Assuntos
Doença de Alzheimer/complicações , Transtornos Cognitivos/classificação , Idoso , Doença de Alzheimer/psicologia , Transtornos Cognitivos/etiologia , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Psicometria , Reprodutibilidade dos Testes , Semântica , Análise e Desempenho de TarefasAssuntos
Pesquisa Biomédica/legislação & jurisprudência , Eficiência Organizacional/tendências , National Institutes of Health (U.S.)/tendências , Privatização/tendências , Eficiência Organizacional/legislação & jurisprudência , Moral , National Institutes of Health (U.S.)/legislação & jurisprudência , Redução de Pessoal/legislação & jurisprudência , Redução de Pessoal/tendências , Privatização/legislação & jurisprudência , Estados UnidosRESUMO
Platelets, like neurons, contain 120- to 130- and 110-kd amyloid precursor proteins (APPs). Their ratio is reduced in AD, further reductions correlating with reduced Mini-Mental Status Examination scores [r(11) = 0.69, p < 0.05]. As statins alter APP processing, platelet APPs were analyzed in patients with AD given anticholesterol drugs for 6 weeks. APP ratios increased [t(37) = -3.888, p = 0.0004], proportionally with reduced cholesterol [r(36) = -0.45, p = 0.005]. Longer trials may reveal slowed cognitive loss, validating this index.
Assuntos
Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/sangue , Precursor de Proteína beta-Amiloide/sangue , Plaquetas/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lovastatina/farmacologia , Pravastatina/farmacologia , Sinvastatina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Plaquetas/metabolismo , Colesterol/sangue , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lovastatina/uso terapêutico , Niacina/farmacologia , Niacina/uso terapêutico , Pravastatina/uso terapêutico , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Sinvastatina/uso terapêutico , Método Simples-CegoAssuntos
Acesso à Informação/legislação & jurisprudência , Ensaios Clínicos como Assunto/normas , Conflito de Interesses/economia , Indústria Farmacêutica/normas , Revisão por Pares/normas , Publicações Periódicas como Assunto/normas , Pesquisa/normas , Animais , Ensaios Clínicos como Assunto/economia , Humanos , Publicações Periódicas como Assunto/economia , Pesquisa/economiaRESUMO
Authors' right to access to all data obtained in their study
Assuntos
Ensaios Clínicos como Assunto/estatística & dados numéricos , Conflito de Interesses , Apoio à Pesquisa como Assunto , Autoria , Interpretação Estatística de Dados , Ética , Humanos , EditoraçãoAssuntos
Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Ensaios Clínicos como Assunto/economia , Conflito de Interesses/economia , Ética Médica , Humanos , Projetos de Pesquisa/normas , Projetos de Pesquisa/tendências , Apoio à Pesquisa como Assunto/economia , Apoio à Pesquisa como Assunto/normasRESUMO
We examined the validity of the revised Hopkins Verbal Learning Test (HVLT-R) by comparing performances on the HVLT-R and the California Verbal Learning Test (CVLT) in participants with Alzheimer's disease (AD). Total learning, delayed recall, intrusion errors, and recognition performance were significantly related across tests, but the number of perseverative responses showed no linear association. Despite similar results across measures, some of the variables were only modestly correlated, which may reflect differences in test procedures and the limited range of scores for some variables. Furthermore, the HVLT-R may not be challenging enough to elicit some of the types of recall errors commonly seen in AD to the same extent as the CVLT Nonetheless, the HVLT-R shows promise for providing a multidimensional assessment of verbal learning and memory and may be ideal in cases where brief assessment ofmemory and/or serial evaluations are needed.
Assuntos
Doença de Alzheimer/complicações , Deficiências da Aprendizagem/diagnóstico , Deficiências da Aprendizagem/etiologia , Testes Neuropsicológicos , Vocabulário , Idoso , Humanos , Deficiências da Aprendizagem/epidemiologia , Transtornos da Memória/diagnóstico , Transtornos da Memória/epidemiologia , Transtornos da Memória/etiologia , Índice de Gravidade de DoençaAssuntos
Genoma Humano , Genômica , Doenças do Sistema Nervoso/genética , Fenômenos Fisiológicos do Sistema Nervoso , Animais , Genética Comportamental , Projeto Genoma Humano , Humanos , Técnicas de Diagnóstico Molecular , Doenças do Sistema Nervoso/terapia , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo GenéticoAssuntos
Distinções e Prêmios , Aprendizagem , Neurologia , Pediatria , Centros Médicos Acadêmicos , Encéfalo/crescimento & desenvolvimento , Criança , Transtornos do Comportamento Infantil/diagnóstico , Transtornos do Comportamento Infantil/história , Diagnóstico Diferencial , História do Século XX , Humanos , Neurologia/história , Pediatria/história , Texas , Estados UnidosRESUMO
The Alzheimer's disease (AD) related amyloid precursor protein (APP) is stored, cleaved and released similarly from neurons and from platelets. We have reported that the proportion of 120-130 to 110 kDa carboxyl-cleaved APP present in the platelets of AD patients is significantly lower than that of platelets of age-matched controls. This reduced APP isoform ratio, not seen in several other disease groups, is further reduced as the severity of AD increases. Since the neuropathology of AD is believed to begin many years before the onset of cognitive loss, we have also compared platelet APP ratios of four pre-symptomatic young adults carrying a presenilin-1 mutation to seven siblings homozygous for the normal PS-1 gene in an effort to determine whether reduced APP ratios are present before apparent cognitive loss in familial AD. Decreased platelet APP ratios were not seen in any of these subjects at this time. We will continue to monitor these subjects as they near the mean age of AD onset in these families. As the magnitude of the APP ratio reduction is proportional to the severity of cognitive loss in sporadic AD, these cognitively normal incipient AD subjects would not be expected to present significant reductions in this AD severity index at this time. Alternatively, the absence of platelet APP ratio reductions may result from a failure of platelets from familial PS-1 AD subjects to manifest altered APPs, as has been reported for PS-2 AD subjects, unlike those of sporadic AD patients. Continued monitoring of cognitive status in our sub-set of controls with AD-like low APP ratios may yet validate the ability of this assay to detect incipient sporadic AD.
Assuntos
Doença de Alzheimer/sangue , Precursor de Proteína beta-Amiloide/sangue , Proteínas de Membrana/sangue , Mutação Puntual/genética , Adulto , Doença de Alzheimer/genética , Humanos , Proteínas de Membrana/genética , Presenilina-1 , Isoformas de Proteínas/sangue , Estatísticas não ParamétricasRESUMO
Evaluation of patients with suspected Alzheimer's disease (AD) often involves clinicians of multiple disciplines working in collaboration to maximize diagnostic accuracy. Accordingly, repeated administrations of some common tests of mental status may occur within a relatively brief time period. The effect of such retesting on subsequent results is largely unknown for many cognitive tasks, despite the possibility that repeated administrations may artificially inflate scores. To assess the potential impact of practice effects on a commonly administered verbal fluency task, animal naming was administered twice within a 1-week period to 111 patients with probable AD and 12 persons without dementia. Non-demended subjects were the only group to demonstrate a small (3 point), but statistically significant practice effect. Regardless of level of cognitive impairment, patients with AD did not show significant practice effects over repeated administrations of animal naming after a relatively brief test-retest interval, suggesting the robust nature of this task in AD.
Assuntos
Doença de Alzheimer/psicologia , Anomia/psicologia , Rememoração Mental , Entrevista Psiquiátrica Padronizada/estatística & dados numéricos , Prática Psicológica , Aprendizagem Verbal , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Anomia/diagnóstico , Viés , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Valores de Referência , Reprodutibilidade dos TestesRESUMO
Many neurological disorders involve cell death. During development of the nervous system, cell death is a normal feature. Elimination of substantial numbers of initially generated cells enables useful pruning of "mismatched" or excessive cells produced by exuberance during the proliferative and migratory phases of development. Such cell death, occurring by "programmed" pathways, is termed apoptosis. In mature organisms, cells die in two major fashions, either by necrosis or apoptosis. In the adult nervous system, because there is little cell production during adulthood, there is little normal cell death. However, neurological disease is often associated with significant neural cell death. Acute disorders, occurring over minutes to hours, such as brain trauma, infarction, hemorrhage, or infection, prominently involve cell death, much of which is by necrosis. Chronic disorders, with relatively slow central nervous system degeneration, may occur over years or decades, but may involve cell losses. Such disorders include motor neuron diseases such as amyotrophic lateral sclerosis (ALS), cerebral dementing disorders such as Alzheimer's disease and frontotemporal dementia, and a variety of degenerative movement disorders including Parkinson's disease, Huntington's disease, and the inherited ataxias. There is evidence that the mechanism of neuronal cell death in these disorders may involve apoptosis. Direct conclusive evidence of apoptosis is scarce in these chronic disorders, because of the swiftness of cell death in relation to the slowness of the disease. Thus, at any particular time point of assessment, very few cells would be expected to be undergoing death. However, it is clearly of importance to define the type of cell death in these disorders. Of significance is that while treating the underlying causes of these conditions is an admirable goal, it may also be possible to develop productive therapies based on alleviating the process of cell death. This is particularly likely if this cell loss is through apoptosis, a programmed process for which the molecular cascade is increasingly understood. This article reviews our understanding of apoptosis in the nervous system, concentrating on its possible roles in chronic neurodegenerative disorders.
Assuntos
Apoptose/fisiologia , Doenças do Sistema Nervoso/fisiopatologia , Senescência Celular/fisiologia , Humanos , Necrose , Doenças do Sistema Nervoso/patologiaAssuntos
Encéfalo/metabolismo , Síndrome do Golfo Pérsico/diagnóstico , Gânglios da Base/metabolismo , Gânglios da Base/patologia , Encéfalo/patologia , Dopamina/metabolismo , Ácido Homovanílico/sangue , Humanos , Imageamento por Ressonância Magnética , Metoxi-Hidroxifenilglicol/sangue , Síndrome do Golfo Pérsico/classificação , Síndrome do Golfo Pérsico/psicologia , Veteranos/psicologiaAssuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Terapia Genética , Doença de Alzheimer/terapia , Animais , Apolipoproteínas E/genética , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Presenilina-1 , Presenilina-2 , Receptores de Lipoproteínas/genéticaRESUMO
BACKGROUND: Platelets and neurons both contain large quantities of two carboxyl-truncated 120 to 130 and 110 kDa Alzheimer amyloid precursor proteins (APPs). Platelets taken from patients with AD have been reported to contain a reduced ratio of these APPs. OBJECTIVE: To further study the AD specificity of reduced platelet APP ratios and to determine whether, after 3 years, cognitive losses in AD are accompanied by similarly reduced platelet APP ratios. METHODS: To test the AD specificity of reduced platelet APP ratios, we quantitated these APPs in eight patients with PD and six patients with hemorrhagic stroke (HS). To determine whether further cognitive losses correlate with platelet APP ratio reductions in patients with AD, the authors re-examined platelet APPs and Mini-Mental State Examination (MMSE) scores of 10 patients with AD and 11 controls, who were tested 3 years ago. APP ratios were determined by the average of six assays using Western blotting with m22C11 monoclonal antibody, enhanced chemoluminescence, and digital scanning of autoradiographs. RESULTS: APP ratios were normal in the patients with PD and HS, further supporting the AD specificity of this assay. After 3 years, the MMSE scores and APP ratios of our control subjects changed by <4%. However, the average MMSE scores of our patients with AD declined from 16.4 to 8.3, and their average 120 to 130/110 kDa APP ratios declined from 5.8 to 3.6. The difference between AD and control APP ratios, with no overlap, is significant and the correlation between the 3-year decline in AD MMSE scores and reduced APP ratios (r = 0.69) was significant. CONCLUSIONS: Although the number of subjects analyzed was limited, reduced platelet APP ratios appear to be a specific biological marker of AD and a biological index of the severity of cognitive loss in AD.