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Preanalytical variables and Alzheimer disease biomarker concentrations in cerebrospinal fluid.

Cerebrospinal fluid (CSF)2 β-amyloid (Aβ1–42) is one of the key biological forms of β-amyloid protein in brain tissue that inversely reflects brain amyloid burden with reduced concentrations in Alzheimer disease (AD) (1). Reductions in CSF Aβ1–42 have been shown to occur years before symptom onset (2) and to have good positive predictive value for progression from mild cognitive impairment to clinical AD (3). CSF concentrations of total tau (T-tau), a marker for the intensity of neuronal degeneration, and hyperphosphorylated tau (P-tau181P), thought to be a marker of neurofibrillary tangle pathology, are both increased in AD (4). The combination of low CSF Aβ1–42 with increased ratios of T-tau and P-tau181P to Aβ1–42 has been used to support the diagnosis of AD. One study has suggested that the T-tau:Aβ1–42 ratio is the most robust biomarker combination (5). These biomarkers have been incorporated into the revised diagnostic criteria of AD (6) and also are well established as part of inclusion and exclusion criteria for clinical trials.

A low CSF Aβ1–42 does not always reflect brain amyloid deposition and it can also be seen in other non-AD causes of dementia such as Lewy body disease or vascular dementia (7). More importantly has come the realization that altered concentrations of CSF Aβ1–42 and other markers may be a consequence of both preanalytical and analytical biases that make it difficult to properly interpret the test result. In particular, lack of harmonization of the preanalytical sample handling procedures owing to variations in CSF collection, storage, or processing has hampered the comparison of CSF Aβ1–42, T-tau, and P-tau181P concentrations between different laboratories and studies. An article in this issue of Clinical Chemistry by Le Bastard et al. (8) is therefore very timely, first to raise awareness of preanalytical considerations, but also to provide further insights on sources …