Previous studies have indicated the potential of cerebrospinal fluid (CSF) a-synuclein (a-syn) to be an additional biomarker for improving differential diagnosis of Alzheimer's disease (AD). We evaluated a-syn diagnostic performance across a well-characterized patient cohort with long-term follow-up. For this purpose, CSF a-syn levels were determined in 25 subjects diagnosed with stable mild cognitive impairment (stable MCI; n = 25), 27 MCI cases due to AD (MCI-AD; n = 32), 24 MCI cases due to Lewy body disease (MCI-LBD; n = 24) and control subjects (Ctrl; n = 18). CSF a-syn levels discriminate between the four groups. There were higher a-syn levels in MCI-AD patients and lower levels in MCI-LBD patients. The combination of a-syn and P-tau resulted in a specificity of 99% and a sensitivity of 97% for MCI-AD. MCI-AD patients with early psychotic symptoms (n = 9) displayed a trend towards a decrease in P-tau and a-syn compared to the MCI-AD patients without psychotic symptoms (n = 23). We conclude that adding CSF a-syn to central core AD biomarkers improves an early differential diagnosis of MCI-AD from other forms of MCI.

There is increasing interest in the value of CSF biomarkers to predict those individuals with mild cognitive impairment who will progress to dementia. However, lumbar puncture is not routine in these patients and biomarker assays are not universally available. To change clinical practice there must be very good evidence that biomarkers are helpful over and above clinical impression. Here we discuss the merits of CSF biomarkers compared with clinicians using simple bedside cognitive tests. Although every biomarker has a superior positive predictive value, most have inferior negative predictive values. When predicting the progression of mild cognitive impairment, the overall misclassification rate by clinicians using bedside cognitive tests is approximately 38% but this could be reduced to approximately 30% by using Abeta1-42 and to 24% with phosphorylated tau or total tau (or a combination of CSF biomarkers). Clinicians and patients together should decide whether this is sufficient to warrant the additional burden of a lumbar puncture, and the cost of the test, or whether further studies are needed before useful and clinically practical conclusions can be reached.

No abstract

The study of biomarkers in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) is a technique used with increasing frequency in the early diagnosis of Alzheimers disease (AD). Our objectiv was to gain an own experience while evaluating the reliability, sensitivity, and reproducibility of this technique in Spanish patients. Thirty-seven patients with MCI and twenty-four control subjects were studied by means of AD biomarker analysis in CSF. xMAP Luminex and INNO-BIA Alzbio3 reagents of Innogenetics were used. The study variables assessed were levels of Aβ(1-42), T-tau and P-tau(181p) proteins as well as the ratios of T-tau/Aβ(1-42) and P-tau(181p)/Aβ(1-42). Samples from nineteen patients were examined twice. Intra-class correlation coefficients for the three biomarkers used showed values higher than 0.95. We observed significant differences between the control group and the MCI groups. In the 6 months following lumbar puncture (LP), eleven (29%) patients with MCI developed AD. These patients showed significant lower levels in Aβ(1-42) protein (276.35 ± 78 vs. 367.13 ± 123.49, P < 0.03) and higher ratios (T-tau/Aβ(1-42) [0.38 ± 0.2 vs. 0.22 ± 0.14, P < 0.01] and P-tau(181p)/Aβ(1-42) [0.27 ± 0.13 vs. 0.16 ± 0.1, P < 0.008]) to those in the same group who remained stable. We obtained similar results to those in the most recent reliable literature with our ROC curves, especially with our P-tau(181p) values and T-tau/Aβ(1-42) ratio in order to differentiate between control and AD groups. Our experience showed that the analysis of CSF-AD biomarkers in patients with MCI is reliable, sensitive and reproducible. In our knowledge, this is the first experience in Spanish patients.

Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are currently being assessed with two different assays. Our objective was to study if there is a correlation between values obtained by both techniques, to compare their validity and search for conversion factor between values obtained for every protein. We compared the performances of two commonly used platforms, an enzyme-linked immunosorbent assay (ELISA) and a multiplex (xMAP) technology for measurement of CSF Aβ 1–42, total tau (T-tau), and phosphorylated tau 181 (P-tau181p) proteins, in 30 AD patients and 28 control subjects. The relations between the variables of both techniques were evaluated using the Spearman p correlation coefficient (α = 0.05). Receiver operating characteristic and area under the curve (AUC) analyses were calculated for the variables of both techniques. The two assays platforms yielded different absolute values for the various analytes, always higher in ELISA. We found some correction factor between values: 2,1- to 3-fold for Aβ 1–42; 4,1- to 4,6-fold for T-tau; and 1,4- to 1,6-fold for P-tau181p. In addition, those values were highly correlated (Aβ 1–42: r = 0.70, P < 0.01; T-tau: r = 0.90, P < 0.01; P-tau181p: r = 0.85, P < 0.01) and the AUC for the variables showed very similar values. In conclusion, the results obtained with ELISA and xMAP platforms were highly correlated and its validity is very similar. Differences in absolute values point to the need for a clear description of the technique used. Moreover, we found some conversion factor between values of every protein that may be useful for transformation between both techniques.