Clinical application of CSF biomarkers for Alzheimer's disease:From rationale to ratios

Biomarker testing is recommended for the accurate and timely diagnosis of Alzheimer's disease (AD). Using illustrative case narratives we consider how cerebrospinal fluid (CSF) biomarker tests may be used in different presentations of cognitive impairment to facilitate timely and differential diagnosis, improving diagnostic accuracy, providing prognostic information, and guiding personalized management in diverse scenarios. Evidence shows that (1) CSF ratios are superior to amyloid beta (Aβ)1‐42 alone; (2) concordance of CSF ratios to amyloid positron emission tomography (PET) is better than Aβ1‐42 alone; and (3) phosphorylated tau (p‐tau)/Aβ1‐42 ratio is superior to p‐tau alone. CSF biomarkers are recommended for the exclusion of AD as the underlying cause of cognitive impairment, diagnosis of AD at an early stage, differential diagnosis of AD in individuals presenting with other neuropsychiatric symptoms, accurate diagnosis of AD in an atypical presentation, and for clinical trial enrichment. HIGHLIGHTS:  : Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker testing may be underused outside specialist centers. CSF biomarkers improve diagnostic accuracy, guiding personalized management of AD. CSF ratios (amyloid beta [Aβ]1‐42/Aβ1‐40 and phosphorylated tau/Aβ1‐42) perform better than single markers. CSF ratios produce fewer false‐negative and false‐positive results than individual markers. CSF biomarkers should be included in diagnostic work‐up of AD and mild cognitive impairment due to AD

Second-generation Elecsys cerebrospinal fluid immunoassays aid diagnosis of early Alzheimer's disease

Timely diagnosis of Alzheimer's disease (AD) is critical for appropriate treatment/patient management. Cerebrospinal fluid (CSF) biomarker analysis is often used to aid diagnosis. We assessed analytical performance of second-generation (Gen II) Elecsys® CSF immunoassays (Roche Diagnostics International Ltd), and adjusted existing cut-offs, to evaluate their potential utility in clinical routine. Analytical performance was assessed using CSF samples measured with Elecsys CSF Gen II immunoassays on cobas e analyzers. Aβ42 Gen I/Gen II immunoassay method comparisons were performed (Passing-Bablok regression). Cut-off values were adjusted using estimated bias in biomarker levels between BioFINDER protocol aliquots/Gen I immunoassays and Gen II protocol aliquots/immunoassays. Distribution of Gen II immunoassay values was evaluated in AD, mild cognitive impairment (MCI), and cognitively normal cohorts; percentage observations outside the measuring range were derived. The Gen II immunoassays demonstrated good analytical performance, including repeatability, intermediate precision, lot-to-lot agreement (Pearson's r: ≥0.999), and platform agreement (Pearson's r: ≥0.995). Aβ42 Gen I/Gen II immunoassay measurements were strongly correlated (Pearson's r: 0.985-0.999). Aβ42 Gen II immunoassay cut-offs were adjusted to 1,030 and 800 ng/L, and pTau181/Aβ42 ratio cut-offs to 0.023 and 0.029, for Gen II and I protocols, respectively. No observations were below the lower limit of the measuring range; above the upper limit, there were none from the AD cohort, and 2.6 and 6.8% from the MCI and cognitively normal cohorts, respectively. Our findings suggest that the Gen II immunoassays have potential utility in clinical routine to aid diagnosis of AD