No abstract

BackgroundA growing body of evidence suggests that the plasma concentration of the neurofilament light chain (NfL) might be considered a plasma biomarker for the screening of neurodegeneration in Alzheimer’s disease (AD).MethodsWith a single molecule array method (Simoa, Quanterix), plasma NfL concentrations were measured in 99 subjects with AD at the stage of mild cognitive impairment (MCI-AD; n = 25) or at the stage of early dementia (ADD; n = 33), and in nondemented controls (n = 41); in all patients, the clinical diagnoses were in accordance with the results of the four core cerebrospinal fluid (CSF) biomarkers (amyloid β (Aβ)1–42, Aβ42/40, Tau, and pTau181), interpreted according to the Erlangen Score algorithm. The influence of preanalytical storage procedures on the NfL in plasma was tested on samples exposed to six different conditions.ResultsNfL concentrations significantly increased in the samples exposed to more than one freezing/thawing cycle, and in those stored for 5 days at room temperature or at 4 °C. Compared with the control group of nondemented subjects (22.0 ± 12.4 pg/mL), the unadjusted plasma NfL concentration was highly significantly higher in the MCI-AD group (38.1 ± 15.9 pg/mL, p < 0.005) and even further elevated in the ADD group (49.1 ± 28.4 pg/mL; p < 0.001). A significant association between NfL and age (ρ = 0.65, p < 0.001) was observed; after correcting for age, the difference in NfL concentrations between AD and controls remained significant (p = 0.044). At the cutoff value of 25.7 pg/mL, unconditional sensitivity, specificity, and accuracy were 0.84, 0.78, and 0.82, respectively. Unadjusted correlation between plasma NfL and Mini Mental State Examination (MMSE) across all patients was moderate but significant (r = −0.49, p < 0.001). We observed an overall significant correlation between plasma NfL and the CSF biomarkers, but this correlation was not observed within the diagnostic groups.ConclusionsThis study confirms increased concentrations of plasma NfL in patients with Alzheimer’s disease compared with nondemented controls.

Neurochemical dementia diagnostics (NDD) can significantly improve the clinically based categorization of patients with early dementia disorders, and the cerebrospinal fluid (CSF) concentrations of amyloid b peptides ending at the amino acid position of 42 (Abx-42 and Ab1-42) are widely accepted biomarkers of Alzheimer's disease (AD). However, in subjects with constitutively high-or low-CSF concentrations of total Ab peptides (tAb), the NDD interpretation might lead to erroneous conclusions as these biomarkers seem to correlate better with the total Ab load than with the pathological status of a given patient in such cases. In this multicenter study, we found significantly increased CSF concentrations of phosphorylated Tau (pTau181) and total Tau in the group of subjects with high CSF Abx-40 concentrations and decreased Abx-42/x-40 concentration ratio compared with the group of subjects with low CSF Abx-40 and normal Ab ratio (p < 0.001 in both cases). Furthermore, we observed significantly decreased Ab ratio (p < 0.01) in the group of subjects with APOE e4 allele compared with the group of subjects without this allele. Surprisingly, patients with low-Abx-40 and the decreased Ab ratio characterized with decreased pTau181 (p < 0.05), and unaltered total Tau compared with the subjects with high Abx-40 and the Ab ratio in the normal range. We conclude that the amyloid b concentration ratio should replace the 'raw' concentrations of corresponding Ab peptides to improve reliability of the neurochemical dementia diagnosis.

(a) the novel Aβ1-40 and Aβ1-42 ELISA assays characterize with very good analytical performance; (b) we reconfirm that the CSF Aβ42/40 concentration ratio shows significantly better diagnostic performance compared to the CSF Aβ1-42 concentration alone.