Matching Clinical Diagnosis and Amyloid Biomarkers in Alzheimer's Disease and Frontotemporal Dementia

Abstract

Background: The aims of this study were to compare the diagnostic accuracy, sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of different cerebrospinal fluid (CSF) amyloid biomarkers and amyloid-Positron Emission Tomography (PET) in patients with a clinical diagnosis of Alzheimer's disease (AD) and Frontotemporal Dementia (FTD); to compare concordance between biomarkers; and to provide an indication of their use and interpretation.

Methods: We included 148 patients (95 AD and 53 FTD), who underwent clinical evaluation, neuropsychological assessment, and at least one amyloid biomarker (CSF analysis or amyloid-PET). Thirty-six patients underwent both analyses. One-hundred-thirteen patients underwent Apolipoprotein E (ApoE) genotyping.

Results: Amyloid-PET presented higher diagnostic accuracy, sensitivity, and NPV than CSF Aβ_1-42 but not Aβ_42/40 ratio. Concordance between CSF biomarkers and amyloid-PET was higher in FTD patients compared to AD cases. None of the AD patients presented both negative Aβ biomarkers.

Conclusions: CSF Aβ_42/40 ratio significantly increased the diagnostic accuracy of CSF biomarkers. On the basis of our current and previous data, we suggest a flowchart to guide the use of biomarkers according to clinical suspicion: due to the high PPV of both amyloid-PET and CSF analysis including Aβ_42/40, in cases of concordance between at least one biomarker and clinical diagnosis, performance of the other analysis could be avoided. A combination of both biomarkers should be performed to better characterize unclear cases. If the two amyloid biomarkers are both negative, an underlying AD pathology can most probably be excluded.

Keywords: Alzheimer’s disease; CSF biomarkers; amyloid-PET; frontotemporal dementia.

Figure 1

Comparison of diagnostic accuracy among different Aβ biomarkers. X-axis represents diagnostic accuracy in % (95% C.I.); different amyloid biomarkers are shown in Y-axis. The area of each square is proportional to the degree of the distribution of values of diagnostic accuracy of each biomarker and to the number of patients for whom each biomarker is available. The whiskers represent 95% C.I. The dotted vertical lines separate accuracy values that are significantly different.

Figure 2

Comparison of sensitivity and specificity among different Aβ biomarkers. (a) X-axis represents sensitivity in % (95% C.I.); different amyloid biomarkers are shown in Y-axis. (b) X-axis represents specificity in % (95% C.I.); different amyloid biomarkers are shown in Y-axis. The area of each square is proportional to the degree of the distribution of values of sensitivity and specificity of each biomarker and to the number of patients for whom each biomarker is available. The whiskers represent 95% C.I. The dotted vertical lines separate sensitivity (a) and specificity (b) values that are significantly different.

Figure 3

Comparison of negative and positive predictive values among different Aβ biomarkers. (a) X-axis represents negative predictive value (NPV) in % (95% C.I.); different amyloid biomarkers are shown in Y-axis. (b) X-axis represents positive predictive value (PPV) in % (95% C.I.); different amyloid biomarkers are shown in Y-axis. The area of each square is proportional to the degree of the distribution of values of positive and negative predictive values of each biomarker and to the number of patients for whom each biomarker is available. The whiskers represent 95% C.I. The dotted vertical lines separate NPV (a) and PPV (b) that are significantly different.

Figure 4

Flow chart for use and interpretation of amyloid biomarkers according to clinical suspect. (a) Indication for interpretation of amyloid biomarkers in the case of a clinical diagnosis of Alzheimer’s disease. (b) Indication for interpretation of amyloid biomarkers in the case of a clinical diagnosis of Frontotemporal dementia.