RESUMO
Several types of animal models have been developed to investigate Alzheimer's disease (AD). Okadaic acid (OA), a potent inhibitor of phosphatases 1 and 2A, induces characteristics that resemble AD-like pathology. Memory impairment induced by intra-hippocampal injection of OA has been reported, accompanied by remarkable neuropathological changes including hippocampal neurodegeneration, a paired helical filament-like phosphorylation of tau protein, and formation of ß-amyloid containing plaque-like structures. Rats were submitted to bilateral intrahippocampal okadaic acid-injection (100 ng) and, 12 days after the surgery, behavioral and biochemical tests were performed. Using this model, we evaluated spatial cognitive deficit and neuroglial alterations, particularly astroglial protein markers such as glial fibrillary acidic protein (GFAP) and S100B, metabolism of glutamate, oxidative parameters and alterations in MAPKs. Our results indicate significant hippocampal changes, including increased GFAP, protein oxidation, and phosphorylation of p38(MAPK); and decreases in glutathione content, transporter EAAT2/GLT-1, and glutamine synthetase activity as well as a decrease in cerebrospinal fluid S100B. No alterations were observed in glutamate uptake activity and S100B content. In conclusion, the OA-induced model of dementia caused spatial cognitive deficit and oxidative stress in this model and, for the first time to our knowledge, specific astroglial alterations. Findings contribute to understanding diseases accompanied by cognitive deficits and the neural damage induced by AO administration.
Assuntos
Demência/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Neuroglia/metabolismo , Animais , Transtornos Cognitivos/líquido cefalorraquidiano , Transtornos Cognitivos/complicações , Transtornos Cognitivos/metabolismo , Demência/líquido cefalorraquidiano , Demência/induzido quimicamente , Demência/complicações , Demência/psicologia , Transportador 2 de Aminoácido Excitatório/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Glutamato-Amônia Ligase/metabolismo , Ácido Glutâmico/metabolismo , Glutationa/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Microinjeções , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fatores de Crescimento Neural/líquido cefalorraquidiano , Fatores de Crescimento Neural/metabolismo , Ácido Okadáico/administração & dosagem , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/líquido cefalorraquidiano , Proteínas S100/metabolismoRESUMO
The magnitude of functional impairment that may indicate the threshold between MCI and incipient Alzheimer's disease (AD) has not been clearly defined. The objective was to examine the pattern of functional impairment in the continuum MCI-AD. Eighty-nine older adults (32 cognitively unimpaired, 31 MCI, and 26 AD patients) were examined with the Brazilian version of the Direct Assessment of Functional Status (DAFS-BR) at a university-based memory clinic. MCI patients were sub-divided according to the progression to AD upon follow-up, and had baseline cognitive, functional and biological variables analyzed. MCI patients displayed mild deficits in functional abilities, with intermediate scores as compared to controls and AD. The DAFS-BR items that differentiated MCI from controls involved the ability to deal with finances and shopping skills. At baseline, scores obtained by MCI patients who converted to AD were not significantly different from scores of nonconverters. The magnitude of functional deficits was associated with AD-like pathological findings in the CSF. In conclusion, MCI patients present with early functional changes in complex, instrumental abilities that require the integrity of memory and executive functions. The objective measurement of the functional state may help identify older adults with increased risk of developing dementia in the MCI-AD continuum.
Assuntos
Transtornos Cognitivos/diagnóstico , Demência/diagnóstico , Testes Neuropsicológicos , Atividades Cotidianas , Idoso , Biomarcadores , Transtornos Cognitivos/líquido cefalorraquidiano , Transtornos Cognitivos/epidemiologia , Demência/líquido cefalorraquidiano , Demência/epidemiologia , Feminino , Humanos , Masculino , Índice de Gravidade de DoençaRESUMO
Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid plaques and tau-associated neurofibrillary tangles in the cerebral tissue. The search for antemortem biomarkers is intense including analysis of cerebrospinal fluid (CSF) beta-amyloid and tau proteins concentrations seeking for an accurate and early diagnosis. Levels of hyperphosphorylated tau at threonine 181 were measured in the CSF of 34 patients with AD (19 with senile AD - SAD and eight with presenile AD - PSAD) and seven with other dementias (OD). The levels of CSF phosphotau were significantly higher in the AD patients compared to OD (AUC 0.812), with no association with severity of dementia, age of onset, duration of the disease or scores in the Mini-Mental State Examination. There were no differences of phosphotau levels between SAD and PSAD patients. These findings corroborate some previous studies and indicate that CSF phosphotau may help to differentiate AD from other dementias.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Demência/líquido cefalorraquidiano , Demência/diagnóstico , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Fosforilação , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
A doença de Alzheimer (DA) se caracteriza pelo achado anátomo-patológico de acúmulo de placas senis e emaranhados neurofibrilares associados à proteína tau no tecido cerebral. A pesquisa por marcadores biológicos antemortem está focada nas concentrações das proteínas b-amilóide e tau no líquido cefalorraqueano (LCR) objetivando um diagnóstico mais precoce e acurado da doença. Os níveis de proteína tau hiperfosforilada no sítio 181 foram determinados no LCR de 34 pacientes com DA (19 com DA senil - DAS e oito com DA pré-senil -DAPS) e sete pacientes com outras demências (OD). Os níveis de fosfotau foram significativamente mais elevados em pacientes com DA quando comparados com OD (AUC 0,812), sem relação com gravidade da demência, idade de início, duração da doença e escores do Mini-Exame do Estado Mental. Não foram observadas diferenças entre os níveis de fosfotau em pacientes com DAS e DAPS. Estes achados corroboram os dados encontrados em estudos prévios e indicam que o nível de fosfotau no LCR dos pacientes pode colaborar na diferenciação da DA com outras demências.
Assuntos
Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Alzheimer/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Demência/líquido cefalorraquidiano , Demência/diagnóstico , Entrevista Psiquiátrica Padronizada , Fosforilação , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
BACKGROUND: The presence of 14-3-3 protein in the CSF has been described to have high sensitivity and specificity for Creutzfeldt-Jakob disease (CJD). OBJECTIVE: To relate 14-3-3 protein in the CSF with the clinical diagnoses of diseases causing rapidly progressive dementia. METHODS: The authors studied 46 patients with rapidly progressive dementia that was classified into three diagnostic groups: definitive or probable CJD, possible CJD, and other diagnoses. The definitive or probable CJD group comprised 17 patients (3 definitive sporadic, 1 probable iatrogenic, 3 familial, and 10 probable sporadic CJD cases), the possible CJD group was composed of 7 patients, and the group with other diagnoses had 22 patients. Detection of the 14-3-3 protein was done by the immunoblotting method. RESULTS: In the definitive or probable CJD group, the test for 14-3-3 protein in CSF was positive in 14 (82%) cases, whereas 3 patients (1 probable sporadic and 2 familial cases) had negative results. CSF was positive for 14-3-3 protein in three of seven cases with possible CJD (42%). In the group with other diagnoses, three individuals had false-positive results (13%). Their diagnoses were definitive Alzheimer's disease, hypercalcemia, and multiple intracerebral hemorrhages. CONCLUSIONS: The detection of 14-3-3 protein in CSF is a useful in vivo diagnostic test for CJD and, when used in the appropriate clinical context, shows a good correlation to CJD. The presence of the 14-3-3 protein in the CSF reinforces the CJD clinical diagnosis but may not be able to differentiate CJD from other causes of rapidly progressive dementia in everyday clinical practice.