Dement Neurocogn Disord.  2017 Dec;16(4):114-120. 10.12779/dnd.2017.16.4.114.

Cerebrospinal Biomarker Cut-off Methods Defined Only by Alzheimer's Disease Predict More Precisely Conversions of Mild Cognitive Impairment

• Kim JH
• Lim H
• Lee JU
• Cho JH
• Kim GS
• Choi SH
• Lee JH
• for the Alzheimer's Disease Neuroimaging Initiative

• KMID: 2442728
• DOI: http://doi.org/10.12779/dnd.2017.16.4.114

Abstract

BACKGROUND AND PURPOSE
The cerebrospinal fluid (CSF) biomarkers play an important supportive role as diagnostic and predictive indicators of Alzheimer's disease (AD). About 30% of controls in old age show abnormal values of CSF biomarkers and display a higher risk for AD compared with those showing normal values. The cut-off values are determined by their diagnostic accuracy. However, the current cut-off values may be less accurate, because controls include high-risk groups of AD. We sought to develop models of patients with AD, who are homogenous for CSF biomarkers.
METHODS
We included participants who had CSF biomarker data in the Alzheimer's Disease Neuroimaging Initiative database. We investigated the factors related to CSF biomarkers in patients with AD using linear mixed models. Using the factors, we developed models corresponding to CSF biomarkers to classify patients with mild cognitive impairment (MCI) into high risk and low risk and analyzed the conversion from MCI to AD using the Cox proportional hazards model.
RESULTS
APOE ε4 status and age were significantly related to CSF Aβ1-42. CSF t-tau, APOE ε2 status and sex were significant factors. The CSF p-tau181 was associated with age and frequency of diagnosis. Accordingly, we modeled the three CSF biomarkers of AD. In MCI without APOE ε4, our models were better predictors of conversion.
CONCLUSIONS
We can interpret CSF biomarkers based on the models derived from the data obtained from patients with AD.

Keyword

Alzheimer's disease; cerebrospinal fluid biomarker; mild cognitive impairment; diagnosis; prediction; conversion

MeSH Terms

Alzheimer Disease*
Apolipoproteins E
Biomarkers
Cerebrospinal Fluid
Diagnosis
Humans
Methods*
Mild Cognitive Impairment*
Neuroimaging
Proportional Hazards Models
Reference Values
Apolipoproteins E
Biomarkers

Figure

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  Fig. 1 Correlation of CSF Aβ1-42 with age and APOE ε4 status in Alzheimer's disease. The blue lines represent the fitting models for concentration of CSF Aβ1-42 and the surrounding gray zones denote 95% confidence intervals. The horizontal red dotted line is a cut-off values that distinguishes normality and abnormality as determined by a previous study. CSF: cerebrospinal fluid.

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  Fig. 2 The concentration of cerebrospinal fluid t-tau according to sex and APOE ε2 status in Alzheimer's disease. The horizontal bars are zones of mean±standard deviation.

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  Fig. 3 Age and the concentration of cerebrospinal fluid p-tau181 in Alzheimer's disease.

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  Fig. 4 Classification of patients with MCI based on the new cut-off lines of CSF biomarkers. The converters with high CSF tau (dark triangle) above upper 95% CI line (MCI with abnormalities in Aβ1-42, t-tau, and p-tau181) represent false negatives. The cut-off lines of Aβ1-42 represent the upper 95% CI lines in Fig. 1. The cut-off lines of t-tau and p-tau181 are the lower 95% CI lines of Figs. 2 and 3, respectively. Patients who showed the low tau (black circles) may have non-Alzheimer's disease dementia. CI: confidence interval, CSF: cerebrospinal fluid, MCI: mild cognitive impairment.

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  Fig. 5 Kaplan-Meier curves comparing conversion from MCI to dementia using existing/new diagnostic methods. p was obtained by the Cox proportional hazards model adjusting for age, gender, education years, and clinical dementia rating sum of box. The left column represents the results of current diagnostic methods, and the right column displays results of new diagnostic methods. The upper panels show results for MCI without APOE ε4, and the lower panels displays results of MCI with APOE ε4 heterozygotes. AD: Alzheimer's disease, ADNI: Alzheimer's Disease Neuroimaging Initiative, MCI: mild cognitive impairment.

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