Correlation between CSF biomarkers of Alzheimer's disease and global cognition in a psychogeriatric clinic cohort

Objective: The relationship between biomarkers of amyloid-beta aggregation (Aβ1-42) and/or neurodegeneration (Tau protein) in cerebrospinal fluid (CSF) and cognitive decline is still unclear. We aimed to ascertain whether CSF biomarkers correlate with cognitive performance in healthy and cognitively impaired subjects, starting from clinical diagnoses. Methods: We tested for correlation between CSF biomarkers and Mini-Mental State Examination (MMSE) scores in 208 subjects: 54 healthy controls, 82 with mild cognitive impairment (MCI), 46 with Alzheimer's disease (AD), and 26 with other dementias (OD). Results: MMSE correlated weakly with all CSF biomarkers in the overall sample (r = 0.242, p < 0.0006). Aβ1-42 and MMSE correlated weakly in MCI (r = 0.247, p = 0.030), and moderately in OD (r = 0.440, p = 0.027). t-Tau showed a weak inverse correlation with MMSE in controls (r = -0.284, p = 0.043) and MCI (r = -0.241, p = 0.036), and a moderate/strong correlation in OD (r = 0.665), p = 0.0003). p-Tau correlated weakly with MMSE in AD (r = -0.343, p = 0.026) and moderately in OD (r = -0.540, p = 0.0005). The Aβ1-42/p-Tau ratio had a moderate/strong correlation with MMSE in OD (r = 0.597, p = 0.001). Conclusion: CSF biomarkers correlated best with cognitive performance in OD. t-Tau correlated weakly with cognition in controls and patients with MCI. In AD, only p-Tau levels correlated with cognitive performance. This pattern, which has been reported previously, seems to indicate that CSF biomarkers might not be reliable as indicators of disease severity.

Biological markers of Alzheimers disease / Biomarcadores da doenca de Alzheimer

The challenges for establishing an early diagnosis of Alzheimer’s disease (AD) have created a need for biomarkers that reflect the core pathology of the disease. The cerebrospinal fluid (CSF) levels of total Tau (T-tau), phosphorylated Tau (P-Tau) and beta-amyloid peptide (Aβ42) reflect, respectively, neurofibrillary tangle and amyloid pathologies and are considered as surrogate markers of AD pathophysiology. The combination of low Aβ42 and high levels of T-tau and P-Tau can accurately identify patients with AD at early stages, even before the development of dementia. The combined analysis of the CSF biomarkers is also helpful for the differential diagnosis between AD and other degenerative dementias. The development of these CSF biomarkers has evolved to a novel diagnostic definition of the disease. The identification of a specific clinical phenotype combined with the in vivo evidence of pathophysiological markers offers the possibility to make a diagnosis of AD before the dementia stage with high specificity.

O desafio de se estabelecer o diagnóstico precoce de doença de Alzheimer (DA) levou ao desenvolvimento de biomarcadores que reflitam os aspectos patológicos centrais da doença. As dosagens no líquor da proteína Tau total (T-Tau), Tau fosforilada (P-Tau) e peptídeo beta-amiloide (Aβ42) no líquido cefalorraquidiano (LCR) refletem, respectivamente, as patologias Tau e amiloide, sendo consideradas como marcadores da fisiopatologia da DA. Os biomarcadores do LCR podem identificar acuradamente pacientes com DA em estágios precoces da doença, mesmo antes do desenvolvimento da demência. A análise combinada dos biomarcadores permite também fazer o diagnóstico diferencial entre DA e outras demências degenerativas. O desenvolvimento dos biomarcadores de DA conduziu a uma nova definição diagnóstica da doença. A identificação de um fenótipo clínico específico associado a uma evidência fisiopatológica in vivo provida por um biomarcador possibilita estabelecer, com alta especificidade, o diagnóstico de DA antes do estágio demencial.

Chemokines in CSF of Alzheimer's disease patients / Quimiocinas no LCR de pacientes portadores da doença de Alzheimer

Some studies have linked the presence of chemokines to the early stages of Alzheimer's disease (AD). Then, the identification of these mediators may contribute to diagnosis. Our objective was to evaluate the levels of beta-amyloid (BA), tau, phospho-tau (p-tau) and chemokines (CCL2, CXCL8 and CXCL10) in the cerebrospinal fluid (CSF) of patients with AD and healthy controls. The correlation of these markers with clinical parameters was also evaluated. The levels of p-tau were higher in AD compared to controls, while the tau/p-tau ratio was decreased. The expression of CCL2 was increased in AD. A positive correlation was observed between BA levels and all chemokines studied, and between CCL2 and p-tau levels. Our results suggest that levels of CCL2 in CSF are involved in the pathogenesis of AD and it may be an additional useful biomarker for monitoring disease progression.

Alguns estudos têm relacionado a presença de quimiocinas com estágios iniciais da doença de Alzheimer (ALZ). A identificação desses mediadores pode contribuir para um diagnóstico precoce. O objetivo deste estudo foi avaliar os níveis de beta-amiloide (BA), tau, fosfo-tau (p-tau) e quimiocinas (CCL2, CXCL8 e CXCL10) no líquido cefalorraquidiano dos pacientes com ALZ e controles saudáveis e a correlação destes marcadores com parâmetros clínicos. Os níveis de p-tau foram maiores nos pacientes com ALZ em relação aos controles, enquanto a razão tau/p-tau foi menor. Houve um aumento significativo de CCL2. Uma correlação positiva foi encontrada entre os níveis de BA e todas as quimiocinas estudadas e também entre os níveis de CCL2 e p-tau. Nossos resultados sugerem que a presença de CCL2 está envolvida na patogênese da ALZ e que esta quimiocina pode ser um marcador adicional para monitorar a progressão da doença.

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.

Cien años de la enfermedad de Alzheimer: La inmunoterapia ¿una esperanza? / One hundred years of Alzheimer's disease: Immunotherapy a hope?

In 1906 Alois Alzheimer, described the cerebral lesions characteristic of the disorder that received his name: senile plaques and neurofibrillary tangles. Alzheimer's disease (AD) is now, 100 years after, the most prevalent form of dementia in the world. The longer life expectancy and aging of the population renders it as a serious public health problem of the future. Urgent methods of diagnosis and treatment are required, since the definitive diagnosis of AD continues to be neuropathologic. In the last 30 years several drugs have been approved to retard the progression of the disease; however, there are still no curative or preventive treatments. Although still in experimentation, the visualization of amyloid deposition by positron emission tomography or magnetic resonance imaging will allow in vivo diagnosis of AD. In addition, experiments with the amyloid vaccine are still ongoing, and very recent data suggest that intravenous gammaglobulins may be beneficial and safe for the treatment of AD.

Enfermedad de Alzheimer. Situación actual y estrategias terapéuticas / Present situation of and therapeutical strategies for Alzheimer disease

Se revisaron los conceptos más actuales en relación con la epidemiología y el impacto de la enfermedad de Alzheimer en el nivel mundial. Se describieron los marcadores biológicos potenciales, en particular la atrofia hipocampal, la presencia de la proteína Tau y el beta/amiloide en líquido cefalorraquídeo, así como el ser portador del genotipo de la apolipoproteína E4 y la alfa 2 macroglobulina. Se propuso una secuencia diagnóstica para el estudio de pacientes con trastornos cognitivos. Se hizo referencia a las estrategias terapéuticas actuales en el tratamiento de las manifestaciones cognitivas y conductuales de esta enfermedad