RESUMO
Chronic inflammation and oxidative stress (OS) are present in Alzheimer's disease (AD) brains in addition to neuronal loss, Amyloid-ß (Aß) plaques and hyperphosphorylated tau-protein neurofibrillary tangles (NFTs). Previously we showed that levels of the pro-inflammatory cytokine, interleukin-18 (IL-18), are elevated in post-mortem AD brains. IL-18 can modulate the tau kinases, Cdk5 and GSK3ß, as well as Aß-production. IL-18 levels are also increased in AD risk diseases, including type-2 diabetes and obesity. Here, we explored other IL-18 regulated proteins in neuron-like SH-SY5Y cells. Differentiated SH-SY5Y cells, incubated with IL-18 for 24, 48, or 72 h, were analyzed by two-dimensional gel electrophoresis (2D-DIGE). Specific altered protein spots were chosen and identified with mass spectrometry (MS) and verified by western immunoblotting (WIB). IL-18 had time-dependent effects on the SH-SY5Y proteome, modulating numerous protein levels/modifications. We concentrated on those related to OS (DDAH2, peroxiredoxins 2, 3, and 6, DJ-1, BLVRA), Aß-degradation (MMP14, TIMP2), Aß-aggregation (Septin-2), and modifications of axon growth and guidance associated, collapsin response mediator protein 2 (CRMP2). IL-18 significantly increased antioxidative enzymes, indicative of OS, and altered levels of glycolytic α- and γ-enolase and multifunctional 14-3-3γ and -ε, commonly affected in neurodegenerative diseases. MMP14, TIMP2, α-enolase and 14-3-3ε, indirectly involved in Aß metabolism, as well as Septin-2 showed changes that increase Aß levels. Increased 14-3-3γ may contribute to GSK3ß driven tau hyperphosphorylation and CRMP2 Thr514 and Ser522 phosphorylation with the Thr555-site, a target for Rho kinase, showing time-dependent changes. IL-18 also increased caspase-1 levels and vacuolization of the cells. Although our SH-SY5Y cells were not aged, as neurons in AD, our work suggests that heightened or prolonged IL-18 levels can drive protein changes of known relevance to AD pathogenesis.
RESUMO
BACKGROUND: Alzheimer's disease (AD) involves increased accumulation of amyloid-ß (Aß) plaques and neurofibrillary tangles as well as neuronal loss in various regions of the neocortex. Neuroinflammation is also present, but its role in AD is not fully understood. We previously showed increased levels of pro-inflammatory cytokine interleukin-18 (IL-18) in different regions of AD brains, where it co-localized with Aß-plaques, as well as the ability of IL-18 to increase expression of glycogen synthase kinase-3ß (GSK-3ß) and cyclin dependent kinase 5, involved in hyperphosphorylation of tau-protein. Elevated IL-18 has been detected in several risk conditions for AD, including obesity, type-II diabetes, and cardiovascular diseases as well as in stress. METHODS: We differentiated SH-SY5Y neuroblastoma cells as neuron-like and exposed them to IL-18 for various times. We examined the protein levels of amyloid-ß precursor protein (APP) and its processing products, its cleaving enzymes, involved in amyloidogenic processing of APP, and markers of apoptosis. RESULTS: IL-18 increased protein levels of the ß-site APP-cleaving enzyme BACE-1, the N-terminal fragment of presenilin-1 and slightly presenilin enhancer 2, both of which are members of the γ-secretase complex, as well as Fe65, which is a binding protein of the C-terminus of APP and one regulator for GSK-3ß. IL-18 also increased APP expression and phosphorylation, which preceded increased BACE-1 levels. Further, IL-18 altered APP processing, increasing Aß40 production in particular, which was inhibited by IL-18 binding protein. Increased levels of soluble APPß were detected in culture medium after the IL-18 exposure. IL-18 also increased anti-apoptotic bcl-xL levels, which likely counteracted the minor increase of the pro-apoptotic caspase-3. Lactate dehydrogenase activity in culture medium was unaffected. CONCLUSIONS: The IL-18 induction of BACE-1, APP processing, and Aß is likely to be linked to stress-associated adaptations in neurons during the course of normal functioning and development. However, in the course of wider changes in the aging brain, and particularly in AD, the effects of heightened or prolonged levels of IL-18 may contribute to the process of AD, including via increased Aß.
Assuntos
Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/biossíntese , Precursor de Proteína beta-Amiloide/biossíntese , Ácido Aspártico Endopeptidases/biossíntese , Mediadores da Inflamação/fisiologia , Interleucina-18/farmacologia , Neurônios/patologia , Doença de Alzheimer/metabolismo , Linhagem Celular Tumoral , Humanos , Neurônios/metabolismoRESUMO
BACKGROUND: Neuropsychiatric symptoms (NPS) are common manifestations of Alzheimer' s disease (AD). OBJECTIVE: To examine the prevalence and significance of NPS in very mild and mild AD patients with emphasis on their influence on the well-being of the patients and their caregivers. METHODS: The participants were 240 patient-caregiver dyads who participated in a prospective, controlled rehabilitation study (ALSOVA). Three Quality of Life (QoL) instruments were used; generic 15D, disease-specific QoL-AD and Visual Analog Scale (VAS). The disease-specific QoL-AD was both self-rated and caregiver rated. Other scales used were Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), ADCS-ADL, Neuropsychiatric Inventory (NPI) and Beck Depression Inventory (BDI). RESULTS: NPS were present in 76.5% of patients with very mild AD (CDR 0.5) and in 84.9% of patients with mild to moderate AD (CDR 1). The most frequent symptoms were apathy, depression, irritability, and agitation. The strongest predictor of self-reported QoL-AD scores was depressive symptoms whereas functional decline and presence of NPS predicted poor caregiver ratings of patients' QoL. However, caregiver depression also influenced significantly their ratings. CONCLUSION: NPS are common even in the early stages of AD. NPS were significantly associated with caregiver assessment of the patient's QoL but not with patients' self-assessed QoL. Depression decreases QoL, but may remain unrecognized in AD patients, emphasizing the need for careful and structured assessment of NPS before deciding on the appropriate treatment.
Assuntos
Doença de Alzheimer/psicologia , Transtornos Mentais/epidemiologia , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Transtornos Mentais/etiologia , Prevalência , Estudos Prospectivos , Escalas de Graduação PsiquiátricaRESUMO
The tenomodulin gene (TNMD, locus Xq-22) encodes an angiogenesis inhibitor. It is an interesting candidate gene for Alzheimer's disease (AD), since it is expressed in brain, alterations in angiogenesis have been linked to AD and in our previous studies we have observed associations between TNMD and phenotypes, which are related to increased risk of AD. The common sequence variation in the TNMD was not associated with prevalence of AD among 526 cases and 672 controls. However, a significant interaction (p=0.002) between rs5966709 and the APOE ε4-allele status was observed in women. Among the ε4-allele carriers, the women with rs5966709-TT genotype had smaller risk for having AD than those with other genotypes (odds ratio 0.47, p=0.019, false discovery rate 10.4%). According to these results the sequence variation of TNMD is not associated with AD, but might modify the effect of APOE ε4-allele in women.
Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Variação Genética/genética , Proteínas de Membrana/genética , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Finlândia/epidemiologia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
Any complaints from a patient about their memory should be examined. Diagnosis is based on international criteria. The basic evaluation consists of the medical history, clinical evaluation, cognitive tests and brain imaging, especially using MRI. When a diagnosis of Alzheimer's disease, AD with cerebrovascular disease or with Lewy Body disease, or Dementia associated with Parkinson's disease or LBD is made, evidence based medical therapy is indicated as part of comprehensive care. An acetylcholinesterase inhibitor or memantine can be used. These drugs are ineffective in the case of frontotemporal degenerations. For severe behavioural disorders, other psychoactive medications can be applied.
Assuntos
Transtornos da Memória/diagnóstico , Transtornos da Memória/tratamento farmacológico , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Demência/diagnóstico , Demência/tratamento farmacológico , Diagnóstico por Imagem , Humanos , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/tratamento farmacológico , Anamnese , Testes Neuropsicológicos , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológico , Guias de Prática Clínica como AssuntoRESUMO
The evaluation of cognitive functions by using CERAD (Consortium to Establish a Registry for Alzheimer's Disease) is recommended as a tool in basic health care for screening of memory diseases. The reliability of this method, adopted in Finland in 1999, has been impaired by the fact that there have been no comprehensive Finnish norms to serve as the basis for the cut-off limits of the test tasks. This article presents the new, revised cut-off values for the CERAD procedure, based on the comparison of Finnish population-based normative data with those of persons having very mild or mild Alzheimer's disease.
Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/fisiopatologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/fisiopatologia , Finlândia , Humanos , Testes NeuropsicológicosRESUMO
OBJECTIVE: Amyloid-ß(Aß) aggregates are presumed to be found in the brain at an early stage of Alzheimer's disease (AD) but have seldom been assessed by brain biopsy during life in often elderly patients. METHODS: Between 1991 and 2006 we evaluated 468 patients with suspected normal pressure hydrocephalus with intraventricular pressure monitoring and a right frontal cortical biopsy sample immunostained for Aß and hyperphosphorylated tau (HPτ). Adequate samples and the clinical follow-up data until death or the end of 2008, available in 433 cases, were reviewed for the clinical signs of dementia, including AD. Logistic regression analysis was used to analyze whether Aß and/or HPτ in the biopsy samples obtained during life predicted development of cognitive impairment, in particular, AD. RESULTS: Of the 433 frontal cortical samples, 42 (10%) displayed both Aß and HPτ, 144 (33%) Aß only, and 247 (57%) neither Aß nor HPτ. In a median follow-up time of 4.4 years, 94 patients (22%) developed clinical AD. The presence of both Aß and HPτ was strongly associated (odds ratio [OR], 68.2; 95% confidence interval [CI], 22.1-210) and Aß alone significantly associated (OR, 10.8; 95% CI, 4.9-23.8) with the clinical diagnosis of AD. INTERPRETATION: This is the largest follow-up study of patients assessed for the presence of Aß and HPτ in frontal cortical brain biopsy samples. 1) The presence of Aß and HPτ spoke strongly for the presence or later development of clinical AD; 2) Aß alone was suggestive of AD; and 3) the absence of Aß and HPτ spoke against a later clinical diagnosis of AD.
Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral/metabolismo , Proteínas tau/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Biópsia/métodos , Transtornos Cognitivos/etiologia , Feminino , Finlândia , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
Treatment is initiated when the McDonald criteria for relapsing-remitting multiple sclerosis (RRMS) are fulfilled. High-risk patients with clinically isolated syndrome are followed using magnetic resonance imaging for one year after the first imaging. Interferon-beta or glatiramer acetate are the first-line immunomodulating drugs (IMD) for RRMS. MxA protein is measured 12 and 24 months after initiation of Interferon-beta to evaluate possible development of neutralizing antibodies. If MxA protein may not be detected repeatedly interferon-beta treatment is discontinued. If the disease is active in spite of treatment with first-line IMD, natalizumab may be considered as a second-line therapy. IMD is stopped when the transition to secondary progressive phase has occurred (or upon transition to secondary progressive phase).
Assuntos
Imunossupressores/uso terapêutico , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Progressão da Doença , Proteínas de Ligação ao GTP/análise , Acetato de Glatiramer , Humanos , Interferon Tipo I/uso terapêutico , Imageamento por Ressonância Magnética , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Proteínas de Resistência a Myxovirus , Peptídeos/uso terapêutico , Proteínas Recombinantes , Resultado do TratamentoRESUMO
Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10(-4) were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 x 10(-10), OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.
Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único/genética , Fator de Transcrição STAT3/genética , Alelos , Pareamento de Bases/genética , Estudos de Casos e Controles , Genética Populacional , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Reprodutibilidade dos TestesRESUMO
Alzheimer's disease (AD) is a pathologically complex and aetiologically multifactorial dementing disorder affecting millions of people worldwide. The pathological brain changes are assumed to occur decades prior to the onset of clinical symptoms. The diagnosis of early AD remains problematic and is mainly based on clinical and neuropsychological findings after the onset of symptoms. Currently available drugs are able to delay the symptom progression of the disease but not to attenuate the progression of pathological brain changes. Many studies exploring AD proteomes have been conducted as the middle of 1990s as a consequence of recent advances in the development of both gel-based and gel-free proteomics approaches. It is hoped that proteomics can contribute to improving the understanding, diagnosis, and follow-up of the progression of AD. In this review, we summarise the present status of proteome alterations, with emphasis on quantitative approaches, in AD brain, CSF and blood, and their relevance to dementia research.
Assuntos
Doença de Alzheimer , Pesquisa Biomédica , Encéfalo/metabolismo , Proteômica/métodos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Animais , Encéfalo/patologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/patologia , Humanos , Testes NeuropsicológicosRESUMO
Recently, the P86L alteration in CALHM1 (calcium homeostasis modulator-1) was reported to be associated with Alzheimer's disease (AD). Moreover, the risk allele increased amyloid-beta (A beta) levels in conditioned media from cultured cells. Therefore, we hypothesized that CALHM1 P86L may modulate A beta or tau levels in cerebrospinal fluid (CSF). Nearly 200 individuals with AD or other cognitive disorders were included for CSF analysis and CALHM1 genotyping. No significant differences in CSF levels of A beta 42, tau or phospho-tau were found across the various CALHM1 genotypes. In conclusion, we found no evidence that CALHM1 P86L is associated with altered CSF levels of the investigated AD biomarkers.
Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Canais de Cálcio/genética , Glicoproteínas de Membrana/genética , Fragmentos de Peptídeos/líquido cefalorraquidiano , Polimorfismo Genético , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Canais de Cálcio/metabolismo , Transtornos Cognitivos/líquido cefalorraquidiano , Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Estudos de Coortes , Feminino , Finlândia , Genótipo , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Fragmentos de Peptídeos/metabolismo , Fosforilação , Análise de Sequência de DNA , Suécia , População Branca/genética , Proteínas tau/metabolismoRESUMO
The aim of this study was to evaluate the association between dementia and common vascular risk factors including blood pressure, blood lipids, homocysteine and diabetes mellitus in a population of very old people. This study is a 9-year follow-up prospective population-based study monitoring 339 non-demented subjects aged 85 years or over in the city of Vantaa, Southern Finland. During the follow-up, those individuals with diabetes mellitus at the baseline and new incident stroke had a higher probability for developing dementia. History of hypertension or higher level of education were associated with a lower probability of dementia. It seems that the contribution of vascular risk factors to the risk of dementia may be age-dependent and their role in the very old subjects may be mediated through their influence on cerebrovascular morbidity. Thus, prevention of stroke and diabetes mellitus may reduce the risk of cognitive decline in the very old.
Assuntos
Demência/epidemiologia , Doenças Vasculares/epidemiologia , Distribuição por Idade , Fatores Etários , Idoso de 80 Anos ou mais , Estudos de Coortes , Comorbidade , Demência/metabolismo , Demência/fisiopatologia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus/prevenção & controle , Escolaridade , Feminino , Finlândia/epidemiologia , Humanos , Hiper-Homocisteinemia/epidemiologia , Hiper-Homocisteinemia/fisiopatologia , Hiperlipidemias/epidemiologia , Hiperlipidemias/fisiopatologia , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Incidência , Masculino , Prevalência , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/prevenção & controle , Doenças Vasculares/metabolismo , Doenças Vasculares/fisiopatologiaRESUMO
Alzheimer's disease is the most common cause of dementia. Early diagnosis of diseases leading to dementia is cost-effective. However, early diagnosis of Alzheimer's disease may be difficult and should not be based on exclusion of other reasons for dementia. A decreased CSF amyloid beta-peptide-42 level together with elevated tau or phosphorylated tau levels can differentiate patients with AD from control subjects or patients with other neurologic conditions with relatively high accuracy. We evaluated the use of these biomarkers in 452 patient cohort during 2005-2007 in clinical practice. Cerebrospinal fluid biomarkers seem to be useful especially to confirm Alzheimer's disease diagnosis.
Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , HumanosRESUMO
OBJECTIVES: The main objective is to examine the sense of coherence (SOC) of spouse caregivers. The aim was further investigate the association of SOC, health-related quality of life (HRQoL), depressive symptoms, distress and how severity of Alzheimer's disease (AD) affects SOC. METHOD: 17O patient-spouse caregiver dyads in which the patient has recently diagnosed mild AD. Caregivers completed SOC scale (SOC-29), HRQoL (15D), Beck depression and general health questionnaire scale. The assessment of AD-related symptoms was made using mini mental state examination, clinical dementia rating, neuropsychiatric inventory and functional performance using activities of daily living (ADCS-ADL) scale. RESULTS: Male caregivers' SOC was significantly higher than female caregivers. The main predictor for low SOC was depression, with 37% of spousal caregivers reporting depressive symptoms. Women reported more depressive symptoms and distress. Caregivers' HRQoL was as high as 0.8714, and a significant correlation was found between SOC and depression, r = -0.632 and distress r = -0.579. Furthermore, significant correlations were found between HRQoL and depression (r = -0.572) and distress (r = -0.568). The main predictors for high HRQoL were female gender and low distress. CONCLUSION: Spouse caregivers with low SOC seem to be a vulnerable group of caregivers. The many negative effects of perceived health accumulate in these caregivers during the very early phases of the caregiving process. Vulnerable caregivers need to be recognized at the time of AD diagnosis so that they can receive psychological support and counselling in addition to prevent morbidity in these caregivers.
Assuntos
Adaptação Psicológica , Doença de Alzheimer/epidemiologia , Cuidadores/psicologia , Cognição , Transtorno Depressivo/epidemiologia , Qualidade de Vida/psicologia , Idoso , Atitude Frente a Saúde , Cuidadores/estatística & dados numéricos , Estudos de Coortes , Transtorno Depressivo/psicologia , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Estudos Prospectivos , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Índice de Gravidade de Doença , Distribuição por Sexo , Cônjuges/psicologia , Cônjuges/estatística & dados numéricos , Estresse Psicológico/epidemiologia , Inquéritos e QuestionáriosRESUMO
CONTEXT: Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted. OBJECTIVE: To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. DESIGN, SETTING, AND PARTICIPANTS: The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD. RESULTS: During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. CONCLUSIONS: This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Transtornos Cognitivos/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfotreonina , Sensibilidade e Especificidade , Proteínas tau/químicaRESUMO
BACKGROUND: Alzheimer's disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group. METHODS: Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Abeta(42):tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia. FINDINGS: The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26.8, 95% CI 1.6-456.4). INTERPRETATION: AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up. FUNDING: European Commission; Ana Aslan International Foundation.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Transtornos Cognitivos/líquido cefalorraquidiano , Transtornos Cognitivos/diagnóstico , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/análise , Biomarcadores/análise , Biomarcadores/líquido cefalorraquidiano , Transtornos Cognitivos/fisiopatologia , Estudos de Coortes , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fragmentos de Peptídeos/análise , Valor Preditivo dos Testes , Prevalência , Prognóstico , Estudos Prospectivos , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Proteínas tau/análiseRESUMO
PURPOSE: Whether repeated brief seizures can cause neuronal damage is controversial. Cerebrospinal fluid (CSF) total tau (T-tau) and phosphorylated tau (P-tau) measurements have been suggested for the diagnosis of Alzheimer's disease, and T-tau may also be a marker of axonal damage and neuronal degeneration. We studied T-tau and P-tau levels and P-tau/T-tau ratio in CSF after epileptic seizures in order to determine whether they are increased after seizures. METHODS: A total of 54 patients with tonic-clonic or partial secondarily generalized seizures due to various etiologies were studied and CSF obtained within 48h after the seizure. RESULTS: There were no statistical differences in the levels of T-tau (p=0.09, ANOVA) or P-tau (p=0.60) between different etiologic groups or controls. No patients with epilepsy of unknown origin had abnormal CSF T-tau whereas 11 patients with acute or remote symptomatic seizures had abnormal T-tau levels and the P-tau/T-tau ratio showed significant differences between the groups and controls (p=0.003). CONCLUSIONS: Epileptic seizures with unknown etiology did not increase CSF tau levels. Abnormal tau levels were associated with either acute or remote symptomatic seizures with known etiology. The presence of elevated CSF tau increases the probability of symptomatic cause in a patient with a seizure.
Assuntos
Epilepsia Generalizada/líquido cefalorraquidiano , Epilepsia Tônico-Clônica/líquido cefalorraquidiano , Neurônios/patologia , Proteínas tau/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Epilepsia Tônico-Clônica/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação , Estatísticas não ParamétricasRESUMO
BACKGROUND: There is a clear need to develop an objective diagnostic test for Alzheimer disease (AD). Changes in the levels of cerebrospinal fluid (CSF) tau protein and beta-amyloid 42 (Abeta42) peptide in patients with AD have been well documented, but the relationship between these biomarkers and neuropathologic changes in the brain is not established. OBJECTIVE: To study the relationship between antemortem CSF biomarker levels and Alzheimer-type neuropathologic changes in the brain. DESIGN: Cross-sectional study to correlate levels of CSF Abeta42, total tau, and phosphorylated tau protein with neuropathologic changes in the brain. SETTING: Academic research. Patients The study included 123 patients (79 with clinically diagnosed AD, 29 with other dementia, and 15 with other neurologic disease). All underwent clinical evaluation and provided antemortem lumbar CSF samples, and neuropathologic data were collected from September 11, 1990, to March 13, 2003, in the Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland. MAIN OUTCOME MEASURES: Levels of CSF Abeta42, total tau, and phosphorylated tau protein were measured using standard commercial immunoassays. Neuropathologic evaluations included the classic silver impregnation method and immunohistochemistry for Abeta, hyperphosphorylated tau, and alpha-synuclein. RESULTS: Cerebrospinal fluid Abeta42 and tau protein levels were related to amyloid load and the presence of neurofibrillary pathologic abnormalities in the brain. Cerebrospinal fluid Abeta42 level correlated inversely with total Abeta load in the brain, and CSF tau level correlated with results of immunohistochemistry for hyperphosphorylated tau and with the presence of neocortical neurofibrillary tangles. In multivariate logistic regression analysis, the number of neuritic plaques in the brain remained a significant predictor of decreased CSF Abeta42 level and of increased CSF tau level. Based on the ratio of phosphorylated tau level to Abeta42 level, sensitivity was 91.6%, and specificity was 85.7%, with an overall accuracy of 90.2% for the presence of pathologic neuritic plaque in the brain. CONCLUSIONS: Cerebrospinal fluid Abeta42 and tau proteins are biomarkers of AD-associated pathologic changes in the brain. The combination of abnormally low CSF Abeta42 level and abnormally high CSF tau level predicted the presence of AD pathologic features with high accuracy. This combination assay may be helpful in diagnosing the presence of AD pathologic changes in the brain.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Encéfalo/patologia , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Estudos Transversais , Demência/líquido cefalorraquidiano , Demência/genética , Demência/patologia , Feminino , Humanos , Imunoensaio/métodos , Modelos Logísticos , Masculino , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Placa Amiloide/patologia , Curva ROC , Estudos Retrospectivos , Coloração pela Prata/métodos , Estatísticas não ParamétricasRESUMO
A possible role of allelic variation on chromosome 19q13 in multiple sclerosis (MS) susceptibility has been suggested. We tested association of sixteen 19q13 markers with MS in 459 families. Nominally significant associations were tested in an independent set of 323 families as well as in the pooled set of 782 families. We were not able to confirm previously suggested associations with APOE, GIPR, ZNF45, ILT6 and D19S585. In the screening dataset nominally significant associations were found with D19S867 and with APOE haplotype (p=0.007 in both), but these were not replicated in the independent dataset nor in the pooled analysis of 757 families. Thus, we were not able to detect any statistically significant allelic associations. Re-sequencing based approaches may be required for elucidating the role chromosome 19q13 with MS.