Agreement of amyloid PET and CSF biomarkers for Alzheimer's disease on Lumipulse

Abstract

Objective: To determine the cutoffs that optimized the agreement between ¹⁸ F-Florbetapir positron emission tomography (PET) and Aβ1-42, Aβ1-40, tTau, pTau and their ratios measured in cerebrospinal fluid (CSF) on the LUMIPULSE G600II instrument, we quantified the levels of these four biomarkers in 94 CSF samples from participants of the Sant Pau Initiative on Neurodegeneration (SPIN cohort) using the Lumipulse G System with available ¹⁸ F-Florbetapir imaging.

Methods: Participants had mild cognitive impairment (n = 35), AD dementia (n = 12), other dementias or neurodegenerative diseases (n = 41), or were cognitively normal controls (n = 6). Levels of Aβ1-42 were standardized to certified reference material. Amyloid scans were assessed visually and through automated quantification. We determined the cutoffs of CSF biomarkers that optimized their agreement with ¹⁸ F-Florbetapir PET and evaluated concordance between markers of the amyloid category.

Results: Aβ1-42, tTau and pTau (but not Aβ1-40) and the ratios with Aβ1-42 had good diagnostic agreement with ¹⁸ F-Florbetapir PET. As a marker of amyloid pathology, the Aβ1-42/Aβ1-40 ratio had higher agreement and better correlation with amyloid PET than Aβ1-42 alone.

Interpretation: CSF biomarkers measured with the Lumipulse G System show good agreement with amyloid imaging in a clinical setting with heterogeneous presentations of neurological disorders. Combination of Aβ1-42 with Aβ1-40 increases the agreement between markers of amyloid pathology.

Figure 1

Receiver operating characteristic analysis of individual (A) and combined (B) CSF biomarkers' diagnostic utility to detect amyloid visual status. AUC, Area under the curve.

Figure 2

Accuracy of all possible cutoff levels of individual (A, C, E) and combined (B, D, F) CSF biomarkers. Only those biomarkers that yielded areas under the curve above 0.70 and their ratios with Aβ1‐42 are shown. Vertical dotted lines indicate cutoffs with maximum Youden J index. PPA, Positive Percent Agreement; NPA, Negative Percent Agreement; OPA, Overall Percent Agreement.

Figure 3

Agreement of visual amyloid status with single and combined CSF biomarkers. Panels A, B and C display scatterplots of CSF biomarker levels. Dashed lines indicate cutoffs that yielded maximum Youden J Index in the receiver operating characteristic analysis for each biomarker or ratio. PPA, Positive Percent Agreement; NPA, Negative Percent Agreement; OPA, Overall Percent Agreement.

Figure 4

Agreement between raters' visual classification and amyloid quantification. OPA, Overall Percent Agreement; SUVR, Standardized Uptake Value Ratio. Panel A shows the agreement between amyloid quantification and rater's individual and global visual assessments. Panel B shows the agreement between amyloid quantification and visual assessment stratified by the number of raters that assessed scans as positive.

Figure 5

Scatterplots and correlations of amyloid quantification values with individual biomarkers (A, C, E) and ratios (B, D, F). Correlation between SUVR values and CSF biomarkers was assessed by fitting quadratic models for all participants (black) and after stratifying by visual amyloid status (red and green). Shaded areas indicate 95% confidence intervals. Dashed vertical lines indicate the SUVR cutoff of 1.11 as in Landau et al. Horizontal lines correspond to cutoffs for each CSF biomarker and ratio. PPA, NPA and OPA values correspond to the agreement between amyloid quantification and CSF biomarkers. PPA, Positive Percent Agreement; NPA, Negative Percent Agreement; OPA, Overall Percent Agreement; SUVR, Standardized Uptake Value Ratio.