D8 Biomarkers in blood and CSF (tau, amyloid, neurofilaments)

Topic

Fluid biomarkers are quantitative measurements of specific molecules in blood or cerebrospinal fluid that directly reflect the underlying pathological processes of a given disease.

The concentration of beta-amyloid 42 in fluid biomarkers—and the ratio of that beta-amyloid 42 concentration to the concentration of beta-amyloid 40—derive directly from the beta-amyloid aggregation kinetics described by the Alzheimer's disease model: the further this beta-amyloid aggregation progresses within the brain, the more that progression is reflected in the beta-amyloid 42 concentration measured in fluid biomarkers.

Similarly, plasma phosphorylated tau—one of the fluid biomarkers measured in blood—directly reflects the same phosphorylated tau described internally by the Alzheimer's disease model: the greater the accumulation of phosphorylated tau according to that Alzheimer's disease model, the higher the concentration of plasma phosphorylated tau detected in the blood.

Neurofilament light chain is another fluid biomarker; unlike beta-amyloid 42 and plasma phosphorylated tau, it is not specific to a single disease but serves as a sensitive marker of general axonal damage. Neurofilament light chain directly extends the cytoskeleton integrity variable already used in both the traumatic brain injury model and the amyotrophic lateral sclerosis model; thus, the more that cytoskeletal integrity deteriorates according to either of those models, the higher the concentration of neurofilament light chain appearing in fluid biomarkers. In addition to reflecting the underlying pathological process, each of these fluid biomarkers follows its own kinetics of release into and clearance from the blood: it enters the bloodstream at a rate determined by its production in the tissue of origin and leaves at a rate determined by the body's elimination speed—much like a compartment filling on one side and emptying on the other.

The diagnostic performance of each of these fluid biomarkers is formally evaluated using two metrics: sensitivity—how well it detects individuals who actually have the disease—and specificity—how well it rules out individuals who do not. Both the sensitivity and specificity of a fluid biomarker depend on the cutoff point selected to classify a measured concentration as positive or negative.

To summarize how a fluid biomarker's sensitivity and specificity change in relation to one another across all possible cutoff points, a curve is plotted showing one metric against the other; the area under this curve encapsulates the biomarker's overall diagnostic performance in a single figure: the larger the area, the better the fluid biomarker distinguishes between diseased and healthy individuals.

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