Biomarkers in CSF in neurodegenerative and disorders
Clinical Neurochemistry Laboratory, Dept. of Neuroscience and Physiology, Gothenburg University, Mölndal Campus, Mölndal, Sweden
Many neurodegenerative disorders such as Alzheimer’s disease (AD), are notoriously difficult to diagnose on clinical grounds, especially in the early stages of disease. Further, the slow and variable clinical course of the disease makes it challenging to identify a drug effect on symptomatology evaluated by clinical rating scales. Thus, in trials on disease-modifying drug candidates, biomarkers are of importance, both to identify target engagement (pharmacodynamic markers) and to identify effects on neurodegeneration (downstream markers).
In AD, cerebrospinal fluid (CSF) biomarkers are increasingly used, and today the AD CSF biomarker toolbox includes total tau (T-tau) reflecting the intensity of neuronal degeneration, phosphorylated tau (P-tau) that correlates with brain tau pathology load, and b-amyloid protein (Ab42 or Ab42/40 ratio) reflecting cortical Ab deposition.
These core CSF biomarkers have very consistently been found to have high diagnostic accuracy. Low CSF Ab42 show high concordance with amyloid PET measures of brain amyloidosis. High CSF T-tau adds to predict progression of symptoms, while high CSF P-tau adds specificity to differentiate from other disorders. The novel synaptic biomarker neurogranin is also seemingly specific for AD.
Recent additions to the AD CSF biomarker toolbox are the neurodegeneration biomarker neurofilament light (NFL) and the synaptic protein neurogranin. While CSF NFL tracks neurodegeneration in several brain disorders, increased CSF neurogranin is seemingly specific for AD, and predicts future rate of cognitive decline.
New ultra-sensitive analytical techniques allow for precise quantification of these biomarkers also in blood samples. Several studies using either immunoassay or mass spectrometry techniques show that low Ab42 (or Ab42/40) ratio in plasma correlates with amyloid deposition evaluated by PET scans. Plasma NFL levels correlate well with CSF levels, and show high promise as a tool to monitor neurodegeneration, not only in AD but also in many other neurodegenerative disorders. Methods to measure plasma levels of P-tau181 have recently been developed, showing a clear increase in AD. Although further studies are needed to validate findings, these blood biomarkers show promise for use as screening tools in the future, especially in the primary care setting, to rule out patients without biomarker evidence of neurodegeneration, which would limit costs for detailed evaluations at specialist clinics for a large proportion of patients.