Update on fluid biomarkers for neurodegenerative diseases

Published on August 31, 2022   31 min

Other Talks in the Series: The Genetic Basis of Neurological Disorders

Other Talks in the Series: Drug Discovery and Development in the Neurosciences

My name is Henrik Zetterberg. I'm a professor of neurochemistry at the University of Gothenburg, Sweden, and also at University College London in the UK. I will give you an update on fluid biomarkers for neurodegenerative diseases in this talk.
This is a little bit of a busy slide. It depicts a neuron and some other cell types of the brain, and what I wanted to show on this slide is a selection of the biomarkers that we can measure in biofluids now that represent different compartments of the neuron and other cell types in the brain. To the right, you see synaptic markers, like SNAP-25, synaptotagmin-1 (SYT1), and NSP2a. Then you have tau as an axonal marker and neurofilament light (NfL) as another axonal marker. A common difference between tau and NfL is that NfL is richer in large caliber myelinated axons. Whereas, tau is mostly expressed in thin, unmyelinated axons. To the left, you see the neuronal soma, at the neuronal body, that is rich in different proteins like neuron-specific enolase (NSE), spectrin breakdown products (SBDPs) and UCHL1. You also see phosphorylated tau depicted. Phosphorylated-tau is regarded as a marker of tangle pathology and that's the traditional view. But my view on phospho-tau is that it is more of a direct marker of tau phosphorylation, which then results in tangle pathology. To the very left, is the dendritic tree of the neuron which is rich in neurogranin, which is also a biomarker we can measure in biofluids. Astrocytes and microglia, the astroglial cells, are rich in in S100B, GFAp, and they also secrete some interleukins and other proteins that often are inflammation-related. Other important biomarkers are the biomarkers for blood-brain barrier dysfunctions, CSF/serum albumin ratio and CSF PDGFRβ. To the lower right, you also see amyloid plaques with Aβ proteins that mark this pathology, have been measured in cerebrospinal fluid and, as you will hear, also in blood. We're still missing valid biomarkers for TDP-43 pathology, a common pathology in amyotrophic lateral sclerosis and frontotemporal dementia. A lot of research work is ongoing to develop better biomarkers for TDP-43 pathology, but we're not there yet. α-synuclein, which is a typical inclusion of Parkinson's disease and other synucleinopathies, we still do not have a quantitative measure of α-synuclein pathology in biofluids. But there is a technology called RT-QuiC, with which one can take a lumbar CSF sample, from a patient, spike in the recombinant α-synuclein and monitor seeded aggregation of α-synuclein. The seeded aggregate is then initiated by factors that are in the patient sample. That's a very interesting concept to detect α-synuclein pathology qualitatively. Now, I will continue to go in-depth into some of these markers that are close to clinical implementation and also use in clinical trials.

Update on fluid biomarkers for neurodegenerative diseases

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