Relevance of Aβ42/40 Ratio for Detection of Alzheimer Disease Pathology in Clinical Routine: The PLMR Scale

Abstract

Background: Cerebrospinal fluid (CSF) biomarkers (Aβ peptides and tau proteins) improved the diagnosis of Alzheimer’s disease (AD) in research and clinical settings. We previously described the PLM-scale (Paris-Lille-Montpellier study), which combines Aβ42, tau, and phosphorylated ptau(181) biomarkers in an easy to use and clinically relevant way. The purpose of this work is to evaluate an optimized PLMR-scale (PLM ratio scale) that now includes the Aβ42/Aβ40 ratio to detect AD versus non-AD (NAD) participants in clinical routine of memory centers.Methods: Both scales were compared using 904 participants with cognitive impairment recruited from two independent cohorts (Mtp-1 and Mtp-2). The CSF Aβ42/Aβ40 ratio was measured systematically in Mtp-1, and only on biologically discordant cases in Mtp-2. Two different ELISA kit providers were also employed. The distribution of AD and NAD patients and the discrepancies of biomarker profiles were computed. Receiver Operating Characteristic curves were used to represent clinical sensitivity and specificity for AD detection. The classification of patients with the net reclassification index (NRI) was also evaluated.Results: Nine hundred and four participants (342 AD and 562 NAD) were studied; 400 in Mtp-1 and 504 in Mtp-2. For AD patients, the mean CSF Aβ42 and CSF Aβ42/40 ratio was 553 ± 216 pg/mL and 0.069 ± 0.022 pg/mL in Mtp-1 and 702 ± 335 pg/mL and 0.045 ± 0.020 pg/mL in Mtp-2. The distribution of AD and NAD differed between the PLM and the PLMR scales (p < 0.0001). The percentage AD well-classified (class 3) increased with PLMR from 38 to 83% in Mpt-1 and from 33 to 53% in Mpt-2. A sharp reduction of the discordant profiles going from 34 to 16.3% and from 37.5 to 19.8%, for Mtp-1 and Mtp-2 respectively, was also observed. The AUC of the PLMR scale was 0.94 in Mtp-1 and 0.87 in Mtp-2. In both cohorts, the PLMR outperformed CSF Aβ42 or Aβ42/40 ratio. The diagnostic performance was improved with the PLMR with an NRI equal to 44.3% in Mtp-1 and 28.8% in Mtp-2.Conclusion: The integration of the Aβ42/Aβ40 ratio in the PLMR scale resulted in an easy-to-use tool which reduced the discrepancies in biologically doubtful cases and increased the confidence in the diagnosis in memory center.

Frontotemporal dementia is the leading cause of “true” A−/T+ profiles defined with Aβ42/40 ratio

“…In the present study, we showed that the Aβ 42/40 ratio changes half of previously considered “uninformative” CSF profiles into A+T+, the biological definition of AD [16] . This result is strikingly similar to the ones of previous studies [33] , [34] , [46] .…”

Diagnosis of Alzheimer’s disease utilizing amyloid and tau as fluid biomarkers

“…Another derivative of Aβ that can act as a potential AD biomarker is Aβ40, which is the most abundant isoform present in the CSF. Although there are no substantial changes in the levels of CSF Aβ40 in AD patients and the CSF concentration of Aβ40 does not correlate with amyloid deposits in the brain, a significant decrease can be seen when amyloidogenic peptide levels are compared by the CSF Aβ42/Aβ40 ratio [15][16][17][18][19][20][21][22] . This ratiometric analysis is more reliable than solely observing Aβ42 concentrations because it compensates for intraindividual fluctuations within AD patients.…”

“…Commercial ELISA CSF Aβ42 has an inverse correlation with amyloid burden, as measured by PIB-PET [10][11][12][13][14] Commercial immunoassays Ratios of CSF Aβ42 to other Aβ isoforms (Aβ40 or Aβ38) are strongly correlated with accurate AD diagnosis [15][16][17][18][19][20][21][22][23][24][25][26]…”

“…Brain imaging plays a critical role in diagnosis because neurodegeneration often parallels and precedes the cognitive decline that is symptomatic of AD. The four types of imaging modalities are structural MRI, functional MRI, 18 F-2-fluoro-2-deoxy-D-glucose (FDG) PET, and amyloid-PET. Structural or compositional abnormalities can be monitored with MRI scans, while FDG-PET monitors glucose metabolism mechanisms to identify areas of decreased brain activity.…”

Investigation of the intercellular transmission of α-synuclein, amyloid-β and TDP-43

“…In the cerebrospinal fluid (CSF) of AD patients, Aβ1-38 and particularly Aβ1-40 are elevated relative to healthy controls, whereas Aβ1-42 is decreased [39][40][41] . Currently, the CSF Aβ42/40 ratio is one of the most widely used diagnostic marker for mild cognitive impairment (MCI) and AD patients, and may be used to predict further cognitive decline 39,40,42,43 .…”