Association of APOE genotype and cerebrospinal fluid Aß and tau biomarkers with cognitive and motor phenotype in amyotrophic lateral sclerosis.

OBJECTIVE: Little is known about amyotrophic lateral sclerosis (ALS)-nonspecific cognitive deficits - most notably memory disturbance - and their biological underpinnings. We investigated the associations of the Alzheimer's disease (AD) genetic risk factor APOE and cerebrospinal fluid (CSF) biomarkers Aß and tau proteins with cognitive and motor phenotype in ALS. METHODS: APOE haplotype was determined in 281 ALS patients; for 105 of these, CSF levels of Aß42, Aß40, total tau (T-tau), and phosphorylated tau (P-tau181) were quantified by chemiluminescence enzyme immunoassay (CLEIA). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was employed to evaluate the neuropsychological phenotype. RESULTS: APOE-E4 allele was associated with worse ECAS memory score (median, 14.0 in carriers vs. 16.0 in non-carriers) and lower CSF Aß42 (-0.8 vs. 0.1, log-transformed values) and Aß42/40 ratio (-0.1 vs. 0.3). Some 37.1% of ALS patients showed low Aß42 levels, possibly reflecting cerebral Aß deposition. While lower Aß42/40 correlated with lower memory score (ß = 0.20), Aß42 positively correlated with both ALS-specific (ß = 0.24) and ALS-nonspecific (ß = 0.24) scores. Although Aß42/40 negatively correlated with T-tau (ß = -0.29) and P-tau181 (ß = -0.33), we found an unexpected positive association of Aß42 and Aß40 with both tau proteins. Regarding motor phenotype, lower levels of Aß species were associated with lower motor neuron (LMN) signs (Aß40: ß = 0.34; Aß42: ß = 0.22). CONCLUSIONS: APOE haplotype and CSF Aß biomarkers are associated with cognitive deficits in ALS and particularly with memory impairment. This might partly reflect AD-like pathophysiological processes, but additional ALS-specific mechanisms could be involved.

Cerebrospinal fluid analysis in the HIV infection and compartmentalization of HIV in the central nervous system / Análise de LCR na infeção pelo HIV e compartimentalização do HIV no sistema nervoso central

The nervous system plays an important role in HIV infection. The purpose of this review is to discuss the indications for cerebrospinal fluid (CSF) analysis in HIV infection in clinical practice. CSF analysis in HIV infection is indicated for the diagnosis of opportunistic infections and co-infections, diagnosis of meningitis caused by HIV, quantification of HIV viral load, and analysis of CNS HIV compartmentalization. Although several CSF biomarkers have been investigated, none are clinically applicable. The capacity of HIV to generate genetic diversity, in association with the constitutional characteristics of the CNS, facilitates the generation of HIV quasispecies in the CNS that are distinct from HIV in the systemic circulation. CSF analysis has a well-defined and valuable role in the diagnosis of CNS infections in HIV/AIDS patients. Further research is necessary to establish a clinically applicable biomarker for the diagnosis of HIV-associated neurocognitive disorders.

O sistema nervoso representa um papel importante na infecção pelo HIV. O objetivo desta revisão é discutir as indicações para análise do líquido cefalorraquidiano (LCR) na infecção pelo HIV na prática clínica. A análise do LCR na infecção pelo HIV é indicada para o diagnóstico de infecções oportunistas e co-infecções, meningite pelo HIV, quantificação da carga viral de HIV e compartimentalização do HIV no SNC. Uma série de biomarcadores no LCR foi investigada, na literatura, porém não apresentam aplicabilidade clínica. A grande capacidade do HIV de gerar diversidade genética, associado a características constitucionais do SNC propicia o desenvolvimento quasiespécies distintas no SNC das circulantes sistemicamente. A análise do LCR na infecção pelo HIV é bem estabelecida no diagnóstico de infecções no CNS, contudo mais pesquisas é necessária para estabelecer a aplicabilidade clínica dos biomarcadores no diagnóstico de desordens cognitivas associadas ao HIV.

Cognitive impairment and major depressive disorder in HIV infection and cerebrospinal fluid biomarkers / Alteracao cognitiva e desordem depressiva maior na infeccao do HIV e biomarcadores no liquido cefalorraquidiano

Cognitive impairment and major depressive disorder (MDD) are common HIV-1 central nervous system (CNS) complications. Their frequencies in AIDS patients are 36% and 45%, respectively. The diagnoses of HIV cognitive impairment are made by clinical criteria, no single laboratory test or biomarker establishes the diagnosis. Factors of indirect neuronal injury related with the pathophysiology of the HIV infection in the CNS, are the factors studied as biomarkers. In the present no biomarker is established to the diagnosis of HIV cognitive impairment, much still needs to be done. We review in this paper some biomarkers in cerebrospinal fluid that could be valuable to the diagnosis of HIV cognitive impairment. Diagnosing depression in the context of HIV can be challenging, to identify a biomarker that could help in the diagnosis would be very important, although MDD risks and neurobiology are still poorly understood.

A alteração cognitiva e a desordem depressiva maior (MDD) são complicações comuns da AIDS no sistema nervoso central (CNS). Suas frequências, em pacientes com AIDS são 36 % e 45 %, respectivamente. O diagnósticos de alteração cognitiva pelo HIV é feito por critérios clínicos, não há nenhum teste único de laboratório ou biomarcador que estabeleçam o diagnóstico. Os fatores inflamatórios relacionados com dano neuronal indireto e com a patofisiologia da infecção do HIV no CNS, são os fatores estudados como biomarcadores. No presente nenhum biomarcador é estabelecido para o diagnóstico de alteração cognitiva pelo HIV, muito ainda tem para ser feito. Nesta revisão abordaremos alguns biomarcadores no líquido cefalorraquidiano que podem auxiliar no diagnóstico da alteração cognitiva e HIV. Da mesma forma o diagnostico de depressão no contexto da aids pode ser desafiante, identificar um biomarcador que possa ajudar no diagnóstico seria muito importante, embora os riscos de desenvolvimento de MDD e a neurobiologia ainda sejam pobremente entendidos.

Pacientes con deterioro cognitivo leve y reducción de la proteína Aβ 1-42 en LCR evolucionan rápidamente a enfermedad de Alzheimer / Patients with mild cognitive impairment and a reduced CSF A_1-42 protein progress rapidly to Alzheimer’s disease

Introducción: En muchos artículos recientes, el análisis de las proteínas Aβ 1-42, tau total (T-tau) y tau fostorilada (P-tau) en LCR puede discriminar entre los pacientes con deterioro cognitivo leve (DCL) estables y aquellos otros que van a progresar a enfermedad de Alzheimer (EA). Nuestro objetivo fue comprobar la capacidad de estas proteínas del LCR para discriminar, entre nuestros pacientes DCL, según la evolución clínica en el año siguiente a la punción lumbar. Material y métodos: Se incluyó a 36 pacientes DCL amnésico (criterios de Petersen 2006) procedentes de la consulta de deterioro cognitivo del Hospital General de Alicante. Usando los reactivos INNO-BIA Alzbio-3 (Innogenetics), cuantificamos las proteínas Aβ1-42, T-tau, P-tau181p en LCR, y calculamos los cocientes T-tau/Aβ1-42 y P-tau181p/Aβ1-42. El estudio fue aprobado por el comité ético de investigación del Hospital General de Alicante. Resultados: En los 12 meses posteriores a la punción lumbar, 14 pacientes DCL (38%) evolucionaron a EA. Estos pacientes, presentaron menores niveles de Aβ1-42 (285,3 vs. 377,7 ng/ml, p<0,02), y un aumento en el valor del cociente P-tau181p/Aβ1-42 (0,25 vs. 0,16, p<0,02) que los pacientes que se mantuvieron estables. No hubo diferencias significativas en el resto de las variables estudiadas. Conclusiones: Nuestros pacientes DCL que presentaron niveles reducidos de la proteína Aβ1-42 y elevación del cociente P-tau181p/Aβ1-42 en LCR, evolucionaron rápidamente a EA. Estos resultados pueden ayudar a conseguir el objetivo de identificar de forma precoz a los pacientes DCL con peor pronóstico (AU)

Introduction: Some studies have shown that CSF amyloid-beta 1-42 (A_1-42), total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau181p) proteins are useful diagnostic markers for distinguishing between clinically stable mild cognitive impairment (MCI) patients and those who will develop Alzheimer's disease (AD). Our objective was to test the ability of this technique to discriminate in our cohort of MCI patients, according to the clinical outcome, one year after the lumbar puncture. Material and methods: A total of 36 MCI patients were included from the local hospital memory clinic. Using INNO-BIA Alzbio-3 reagents from Innogenetics, we measured CSF A_1-42, T-tau and P-tau181p proteins, and calculated the T-tau/A_1-42 y P-tau181p/A_1-42 ratios. Thisproject was approved by the local ethics committee. Results: One year after the lumbar puncture, 14 MCI patients (38%) developed AD. These patients had lower A_ 1-42 protein levels (285.3 vs 377 ng/ml, P < .02) and higher P-tau181p/A_1-42 ratio (0,25 vs 0,16, p < .02) than the clinically stable patients. Conclusions: Our MCI patients with lower A_1-42 protein levels and an increased P-tau181p /A_1-42 ratio progressed quickly to AD. These results may help to identify those MCI patients with a poorer prognosis (AU)

Clinical and biological predictors of Alzheimer's disease in patients with amnestic mild cognitive impairment / Preditores clínicos e biológicos da evolução para doença de Alzheimer em pacientes com comprometimento cognitivo leve amnéstico

OBJECTIVE: To identify predictors of the progression from pre-dementia stages of cognitive impairment in Alzheimer's disease is relevant to clinical management and to substantiate the decision of prescribing antidementia drugs. METHOD: Longitudinal study of a cohort of elderly adults with amnestic mild cognitive impairment and healthy controls, carried out to estimate the risk and characterize predictors of the progression to Alzheimer's disease. RESULTS: Patients with amnestic mild cognitive impairment had a higher risk to develop Alzheimer's disease during follow-up (odds ratio = 4.5, CI95 percent [1.3-13.6], p = 0.010). At baseline, older age, lower scores on memory tests and presence of the APOE*4 allele predicted the progression from amnestic mild cognitive impairment to Alzheimer's disease. In a sub sample of amnestic mild cognitive impairment patients, those who progressed to Alzheimer's disease had lower cerebrospinal fluid concentrations of amyloid-beta peptide (Aβ42, p = 0.020) and higher concentrations of total TAU (p = 0.030) and phosphorylated TAU (p = 0.010), as compared to non-converters. DISCUSSION: This is the first Brazilian study to report cerebrospinal fluid biomarkers in the prediction of the conversion from MCI to Alzheimer's disease. Our data are in accordance with those reported in other settings. The measurement of cerebrospinal fluid total-TAU, phospho-TAU and Aβ42 may help identify patients with mild cognitive impairment at higher risk for developing Alzheimer's disease.

OBJETIVO: A identificação de preditores da conversão para a doença de Alzheimer em pacientes com comprometimento cognitivo leve é relevante para o manejo clínico e para decidir sobre a prescrição de drogas antidemência. MÉTODO: Estudo longitudinal em coorte de indivíduos idosos com comprometimento cognitivo leve amnéstico e controles saudáveis; estimativa do risco da progressão para doença de Alzheimer nos dois grupos; determinação das variáveis preditivas desse desfecho. RESULTADOS: Pacientes com comprometimento cognitivo leve amnéstico apresentaram maior risco de desenvolver doença de Alzheimer ao longo do seguimento (odds ratio = 4,5, CI95 por cento [1,3-13,6], p = 0,012). Na avaliação inicial, idade mais avançada, escores mais baixos nos testes cognitivos e do alelo APOE*4 foram preditores da conversão do comprometimento cognitivo leve amnéstico para doença de Alzheimer. Em uma subamostra de pacientes com comprometimento cognitivo leve amnéstico, aqueles que progrediram para doença de Alzheimer tinham concentrações liquóricas mais baixas do peptídeo beta-amilóide (Aβ42, p = 0,020) e mais altas da proteína TAU total (p = 0,030) e TAU fosforilada (p = 0,010) do que os pacientes que não progrediram para doença de Alzheimer. DISCUSSÃO: Este é o primeiro estudo brasileiro com biomarcadores liquóricos a relatar preditores da conversão comprometimento cognitivo leve-doença de Alzheimer. Nossos dados biológicos (aumento de TAU total e fosfo-TAU; redução de Aβ42), e podem auxiliar na identificação dos pacientes com comprometimento cognitivo leve com maior risco de evolução para demência.

Biomarcadores en el líquido cefalorraquídeo de pacientes con deterioro cognitivo leve: metaanálisis de su capacidad predictiva para el diagnóstico de la enfermedad de Alzheimer / Biomarkers in the cerebrospinal fluid of patients with mild cognitive impairment: a meta-analysis of their predictive capacity for the diagnosis of Alzheimer’s disease

Introducción. Varios estudios han descrito alteraciones en los biomarcadores del líquido cefalorraquídeo (proteínas Abeta- 42, T-tau y P-tau), tanto en la enfermedad de Alzheimer (EA) como en el deterioro cognitivo leve (DCL). Objetivo. Realizar un metaanálisis sobre la rentabilidad diagnóstica de esta técnica para la predicción de los pacientes con DCL que van a progresar a EA. Materiales y métodos. Tras una búsqueda en PubMed y Embase de los artículos publicados entre 1999 y septiembre de 2008, se incluyeron sólo estudios prospectivos para la revisión sistemática. Se estudió la sensibilidad y especificidad para cada biomarcador por separado y también de forma conjunta.Resultados. De los 12 estudios incluidos, 6 cuantificaron la proteína Abeta-42, 11 la proteína T-tau y 7 la proteína P-tau. En tres estudios se pudieron obtener los datos de los tres biomarcadores de forma combinada. La sensibilidad de la cuantificación de las proteínas T-tau y P-tau es del 82%, con una odds ratio diagnóstica de 12,09 (intervalo de confianza al 95%, C 95% = 7,71-18,99; p = 0,1) y 16,29 (IC 95% = 9,69-27,4; p = 0,9), respectivamente. La alteración de alguno de los tres biomarcadores tiene una especificidad del 87%, con una odds ratio diagnóstica de 35,97 (IC 95% = 7,8-164,6; p = 0,04). Conclusiones. La alteración aislada de los niveles de T-tau o P-tau en el líquido cefalorraquídeo es muy sensible para diferenciar entre los pacientes con DCL que van a desarrollar EA de los que van a permanecer estables. La normalidad de los tres biomarcadores es muy fiable para descartar la evolución a EA en pacientes con DCL (AU)

Introduction. Several studies have reported alterations in the cerebrospinal fluid biomarkers (Abeta-42, T-tau and P-tau proteins), both in Alzheimer’s disease (AD) and in mild cognitive impairment (MCI). Aim. To perform a meta-analysis of the diagnostic yield of this technique for the prediction of patients with MCI who are going to progress to AD. Materials and methods. A search was conducted in PubMed and Embase of papers published between 1999 and September 2008, and as a result only prospective studies were included for the systematic review. The sensitivity and specificity for each biomarker were studied separately and also jointly. Results. Of the 12 studies that were included, 6 quantified the Abeta-42 protein, 11 the T-tau protein and seven the P-tau protein. In three of the studies data was obtained from the three biomarkers in combination. The sensitivity of the quantification of the T-tau and P-tau proteins is 82%, with a diagnostic odds ratio of 12.09 (confidence interval 95%, CI 95% = 7.71-18.99; p = 0.1) and 16.29 (CI 95% = 9.69-27.4; p = 0.9), respectively. Alteration of any of the three biomarkers has a specificity of 87%, with a diagnostic odds ratio of 35.97 (CI 95% = 7.8-164.6; p = 0.04). Conclusions. The isolated alteration of T-tau or P-tau levels in cerebrospinal fluid is very sensitive for differentiating between patients with MCI who are going to develop AD and those who are going to remain stable. Normality of the three biomarkers is a very reliable way of ruling out the progression of AD in patients with MCI (AU)