EBioMedicine | 2021
Blood biomarkers of neurodegeneration—progress on non-invasive diagnostics
Abstract
Diagnosing degenerative diseases of the nervous system including multiple sclerosis (MS) and Alzheimer’s disease (AD) can be a complicated process that could necessitate expensive procedures to image the brain, or invasive tests to assess cerebrospinal fluid by lumbar puncture. Either procedure might also be available only in certain treatment centres, limiting access to an accurate diagnosis. Yet, early and definitive diagnosis is essential for optimising treatment decisions and for helping patients and their families prepare for the future. Non-invasive tests to measure early and specific biomarkers of neurodegeneration are needed not only to monitor disease progression and manage care, but will also be an important and scalable mean of measuring outcomes during large clinical trials for neurodegenerative disease therapies. Blood tests that have the potential to detect disease before the patient presents with symptoms will be especially important in cases for which early interventions are deemed necessary to achieve the best treatment success. In the midst of a raging pandemic, 2020 saw some great strides toward the development of ultrasensitive blood tests to detect Alzheimer’s disease. Two clinical studies published in The Lancet Neurol ogy and the Journal of the American Medical Association measured variants of tau in the blood, a protein that normally functions to help stabilise microtubules within neurons. These studies found that a blood test measuring one of two phosphorylated forms of tau (ptau181 or p-tau217) were able to differentially diagnose AD from other neurodegenerative diseases as accurately as more costly and invasive standard diagnostics. Moreover, these blood tests were also able to identify the disease early in the course of cognitive decline. Three recent papers from the University of Gothenburg (Gothenburg, Sweden) build on these findings by analysing the performance of these markers in patients from the Alzheimer’s Disease Neuroimage Initiative—a longitudinal, multi-centre project aimed at tracking the brain’s structure and function using imaging techniques at different ages and over the course of the disease. Studies in Brain and Molecular Psychiatry found that p-tau181 levels could predict disease symptoms several years before the onset of dementia, and a third paper in JAMA Neurology went further to show that increases in ptau181 over time were proportional to cognitive decline and to neurodegeneration in AD-indicative brain regions measured by MRI and PET brain imaging. Because these changes in p-tau181 track with pathological changes before symptoms occur, it could be an especially useful tool for early interventional clinical studies. Another biomarker, neurofilament light chain (NfL), showed a similar coupling to neurodegeneration in the JAMA Neurology study, but was not specific for AD—both amyloid beta positive and amyloid beta negative groups saw increases of NfL. MS is another neurodegenerative disease that can be difficult to diagnose. NfL also shows some promise as a blood-based marker that