Elevated levels of tau in cerebrospinal fluid: implications for the antemortem diagnosis of Alzheimer's disease elevated levels of tau in cerebrospinal fluid: implications for the antemortem diagnosis of Alzheimer's disease

Alzheimer's disease (AD) is a heterogeneous group of dementias characterized by progressive cognitive impairments as well as by the accumulation of abundant extracellular deposits of Ass and intra-neuronal neurofibrillary lesions in selective-ly vulnerable regions of the AD brain. The latter abnormalities (e.g. neurofibrillary tangles, dystrophic neurites, neuropil threads) are aggregates of paired helical filaments (PHFs) formed from altered tau proteins (PHFtau). Although PHF tau and normal central nervous system (CNS) tau are phosphorylated at nearly the same sites, PHFtau is phosphorylated to a greater extent, and alterations in the activity of CNS kinases and phosphatases most likely contribute to the pathogenesis of PHFtau. Since the abundance of neurofibrillary lesions correlates with the dementia in AD, the generation of PHFtau and the formation of neurofibrillary lesions may be part of a cell death pathway leading to massive neuron loss and dementia in AD. Building upon these and other insights into altered tau metabolism in AD, a series of studies suggest that the diagnosis of AD may be supported in living patients by determining the concentration of tau in cerebrospinal fluid (CSF). We review these promising studies here, and discuss them in the context of current understanding of the pathobiology of AD.     

Alzheimer病早期脑脊液tau蛋白与ApoE基因的关系

目的探讨Alzheimer病患者脑脊液tau蛋白与ApoE基因型的关系。方法对84例患者脑脊液微管相关蛋白(tau蛋白)应用ELISA法对进行定量,其中41例临床诊断为早期Alzheimer病(AD),23例伴其他类型的痴呆,6例为Down综合征患者;14例非痴呆患者为对照组。结果多变量ANOVA分析显示痴呆患者与ApoE等位基因者脑脊液tau蛋白升高,AD患者脑脊液tau蛋白浓度明显高于对照组。而非AD痴呆患者脑脊液tau蛋白浓度与AD患者和对照组无明显差异,伴ApoEε4等位基因的AD病人与不伴ε4等位基因的AD病人相比,tau蛋白浓度升高。结论脑脊液tau蛋白浓度升高提示携带ε4等位基因AD病人早期发生神经变性和神经纤维病理学改变,应用ELISA法检测脑脊液tau蛋白对诊断早期AD及与其他类型的痴呆相鉴别缺乏敏感性和特异性,应首先考虑ApoE基因类型。     

tau protein in cerebrospinal fluid

Cerebrospinal fluid (CSF) biochemical markers for Alzheimer disease (AD) would be of great value to improve the clinical diagnostic accuracy of the disorder. As abnormally phosphorylated forms of the microtubule-associated protein tau have been consistently found in the brains of AD patients, and since tau can be detected in CSF, two assays based on several well-defined monoclonal tau antibodies were used to study these proteins in CSF. One assay detects most normal and abnormal forms of tau (CSF-tau), while the other is highly specific for phosphorylated tau (CSF-PHFtau). A marked increase in CSF-PHFtau was found in AD (2230±930 pg/mL), as compared with controls (640±230 pg/mL;p<0.0001), vascular dementia, VAD (1610±840 pg/mL;p<0.05), frontal lobe dementia, FLD (1530±1000 pg/mL;p<0.05), Parkinson disease, PD (720±590 pg/mL;p<0.0001), and patients with major depression (230±130 pg/mL;p<0.0001). Parallel results were obtained for CSF-tau. No less than 35/40 (88%) of AD patients had a CSF-PHFtau value higher than the cutoff level of 1140 pg/mL in controls. The present study demonstrates that elevated tau/PHFtau levels are consistently found in CSF of AD patients. However, a considerable overlap is still present with other forms of dementia, both VAD and FLD. CSF-tau and CSF-PHFtau may therefore be useful as a positive biochemical marker, to discriminate AD from normal aging, PD, and depressive pseudodementia. Further studies are needed to clarify the sensitivity and specificity of these assays, including follow-up studies with neuropathological examinations.     

Vascular risk factors are associated with longitudinal changes in cerebrospinal fluid tau markers and cognition in preclinical Alzheimer's disease

IntroductionVascular factors increase the risk of Alzheimer's disease (AD). We investigated the associations between such factors, longitudinal AD cerebrospinal fluid biomarkers, and cognition.Methods433 cognitively normal participants were classified into four biomarker groups using their baseline amyloid (A+/−) and tau status (T+/−). 184 participants had undergone serial cerebrospinal fluid collection. Frequencies of risk factors and the Framingham Risk Score (FRS) were compared, and we tested the influence of risk factors on change in biomarker concentrations and cognition.ResultsThe absence of obesity, presence of hypertension, and a high FRS were associated with an increase in tau levels, particularly in A+T+ individuals. Risk factors were not associated with amyloid. Depression was associated with higher cognitive scores, whereas high FRS was associated with lower scores and a faster decline.DiscussionOur results demonstrate that vascular risk factors may enhance neurodegeneration but not amyloid accumulation in preclinical AD.     

The measurement of phosphorylated tau in human cerebrospinal fluid as a diagnostic marker for Alzheimer's disease]

We examined total 570 cerebrospinal fluid (CSF) samples from a variety of diseases, including Alzheimer's disease (AD; n = 236), non-AD-demented and nondemented diseases (n = 239), and normal controls (n = 95) to quantitate levels of tau protein phosphorylated at serine 199 (CSF/p-tau199) by a recently established sandwich ELISA. The CSF/p-tau199 levels in the AD group were significantly elevated compared to those in all the other non-AD groups. Receiver operating characteristics curves showed that the diagnostic sensitivity and specificity for the AD group vs all the other non-AD group using the CSF/p-tau199 were 85. 2% and 85.0%, respectively. Although there was a significant positive correlation between CSF/p-tau199 and CSF total tau (CSF/t-tau) levels in the AD group, CSF/p-tau199 classifies patients with AD and other disorders more accurately than the CSF/t-tau. Our study suggests that CSF/p-tau199 testing will help in supporting antemortem diagnosis of AD and in conducting emerging therapies that should be based on an accurate detection of AD while patients are alive.     

Increased cerebrospinal fluid cAMP levels in Alzheimer's disease

Since increasing evidence suggests that upregulation of the cAMP-second messenger system may be implicated in Alzheimer's disease neurodegeneration, we have compared the cAMP and cGMP levels in cerebrospinal fluid (CSF) from patients with dementia of the Alzheimer type (DAT, n=10) with those from nondemented age-matched controls (n=10). Our results show that cAMP levels, but not cGMP, are significantly (p<0.01) elevated in CSF from patients with DAT compared to those from nondemented controls. Moreover, a linear regression analysis demonstrated a significant correlation (r=0.62; p<0.01) between cAMP and tau protein levels in CSF when controls and patients with DAT were studied together. These results suggest that upregulation of cAMP-signaling pathway is implicated in Alzheimer's disease physiopathology.     

Neurotransmitter amino acids in cerebrospinal fluid of patients with Alzheimer's disease

Summary. We measured the CSF and plasma levels of glutamate, glutamine, aspartate (only in plasma), asparagine, glutamine, glycine and GABA in 37 patients with Alzheimer's disease and in 32 matched controls. We used an ion-exchange chromatography method. When compared to controls, AD patients had higher CSF glutamate and glycine levels, higher plasma levels of aspartate and glycine, and lower plasma levels of asparagine and GABA. When expressed relative to CSF proteins, CSF levels of glutamate and glycine remained higher, and CSF asparagine levels were lower in AD patients than in controls. The CSF levels of the amino acids measured were not correlated with the clinical features of AD with the exception of plasma GABA levels with duration of the disease. Our results might suggest a possible pathogenetic role of neurotransmitter amino acids in AD. Accepted December 2, 1997; received August 30, 1997     

Altered glycosylation of cerebrospinal fluid butyrylcholinesterase in Alzheimer's disease

Our previous studies have shown that a minor isoform of acetylcholinesterase (AChE) is increased in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients. In the present study, the glycosylation of butyrycholinesterase (BuChE) was found to be altered in AD CSF. By combining an analysis of CSF AChE and BuChE glycosylation, it is possible to identify cases of AD with more than 90% sensitivity and specificity.     

beta-Endorphin-like immunoreactivity in cerebrospinal fluid of patients with Alzheimer's disease and Parkinson's disease

beta-Endorphin-like immunoreactivity (beta-EP-LI) in cerebrospinal fluid (CSF) was measured in 42 patients with Alzheimer's disease (AD), 36 patients with Parkinson's disease (PD), and 35 controls. Values for patients with Alzheimer's disease (10.9 +/- 2.8 pmol/l) seemed to be lower than those for controls (12.9 +/- 2.5 pmol/l) (P less than 0.05). In addition, the severely demented patients had lower values than the moderately demented (P less than 0.01). In patients with Parkinson's disease no significant difference in beta-EP-LI values was observed compared to the controls. The data suggest, that processing of pro-opiomelanocortin, precursor of beta-endorphin, and the mechanism of cognitive impairment may differ in Alzheimer's disease and Parkinson's disease.     

Novel ventriculo-peritoneal shunt in Alzheimer's disease cerebrospinal fluid biomarkers

Alzheimer's disease is an age-related dementia and its incidence is rising in developed countries as the population ages. Amyloid plaques and tau-rich neurofibrillary tangles are pathologic hallmarks of the disease. Treatment is symptomatic, consisting of compounds that block enzymatic acetylcholine degradation (acetylcholinesterase inhibitors). Cognitive benefits of the four approved antidementia drugs are typically modest and limited in duration. While Alzheimer's disease is undoubtedly multifactorial in cause, advancing age is the most important risk factor. Any robust theory of pathogenesis must account for the profound influence of age on the emergence of Alzheimer's disease. There is evidence that senescent changes in cerebrospinal fluid production, circulation, turnover and clearance of amyloid beta-peptides may be a key factor in the onset and progression of Alzheimer's disease. The effect of increasing cerebrospinal fluid circulation and turnover in Alzheimer's disease patients by implanting a novel, low-flow drainage system (COGNIshunt) has been studied and promising trends in cognitive stabilization and improvement in cerebrospinal fluid biomarkers have been found.     

Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels,brain amyloid load,and risk for Alzheimer's disease

A common polymorphism of the gene encoding acyl-coenzyme A: cholesterol acyltransferase 1 (SOAT1), which is involved in the regulation of beta-amyloid peptide generation, is associated with low brain amyloid load (P=0.03) and with low cerebrospinal fluid levels of cholesterol (P=0.005). This polymorphism of SOAT1 is also associated with reduced risk for Alzheimer's disease in ethnically distinct populations (P=0.0001, odds ratio: 0.6, 95% confidence interval 0.4-0.8).     

Cholinesterases in cerebrospinal fluid. Correlations with clinical measures in Alzheimer's disease

Acetylcholinesterase and butyrylcholinesterase activities in cerebrospinal fluid were measured in 17 patients with Alzheimer's disease and 6 control patients, as potential clinical measures of impaired cholinergic neurotransmission in Alzheimer's disease. The activity of butyrylcholinesterase was decreased in patients with Alzheimer's disease compared to that observed in control patients, but there was overlap between values in the 2 groups. Low butyrylcholinesterase activity was correlated with severity of dementia, memory impairment, and language disorder. Acetylcholinesterase activity was significantly correlated with visual contrast sensitivity, but not with dementia severity, and did not differentiate patients with Alzheimer's disease from control cases. These results suggest that cholinesterases in cerebrospinal fluid are related to brain cholinesterases, and indicate that the activities of acetylcholinesterase and butyrylcholinesterase should be distinguished in studies of cerebrospinal fluid.     

Phosphorylated tau in cerebrospinal fluid as a marker for Creutzfeldt-Jakob disease

OBJECTIVE: To determine the concentrations of microtubule associated protein tau and multiple phosphorylated tau epitopes in the cerebrospinal fluid of patients with sporadic Creutzfeldt-Jakob disease (sCJD), dementias, and controls, in order to evaluate their diagnostic use and clinical relevance. METHODS: The CSF concentrations of total tau and phosphorylated tau at epitope 181 were determined by enzyme linked immunosorbent assay in 66 definite and nine probable sCJD patients, and in 97 controls. Other phosphorylated tau epitopes were investigated by western blot. RESULTS: In the sCJD population, determination of 14-3-3 protein and total tau protein concentrations was of the highest diagnostic value, with a sensitivity of 96% and 92%, respectively, and a specificity of 94% and 97%. Two distinct subgroups could be identified among the 75 sCJD patients based on the detection of phosphorylated tau at threonine 181 and serines 199, 202, and 404. A high phosphorylated tau concentration was clinically correlated with a significantly shorter disease duration, early onset of akinetic mutism, and a higher rate of typical EEGs (p < 0.05). CONCLUSIONS: Although the determination of phosphorylated tau levels cannot be used as a diagnostic biomarker, it may prove useful for estimating the prognosis of an sCJD patient. These experiments reconfirm that sCJD is a disease with a complex pathology.