From Cerebrospinal Fluid to Blood: The Third Wave of Fluid Biomarkers for Alzheimer’s Disease

Abstract

The past five years have seen an enormous development in the field of fluid biomarkers for Alzheimer's disease (AD) and related disorders. The proteins that constitute the foundation for the cerebrospinal fluid (CSF) tests for the classical AD pathologies are now being explored as potential blood-based biomarkers, thanks to the recent implementation of ultrasensitive measurement technologies in academic and clinical laboratories worldwide. The current blood-derived data are still less clear than those obtained using CSF as the sample type, but independent research suggests that there are biomarker signals in blood that relate to plaque and tangle pathologies in AD, which are relevant to explore further. Additionally, neurofilament light has emerged as the first robust blood-based biomarker for neurodegeneration in a broad range of central nervous system disorders, as well as for acute brain injuries. Here, we briefly recapitulate the first and second waves of fluid biomarker analysis in AD, i.e., the development and validation of established and novel CSF biomarkers for the disorder, followed by a focused discussion on blood-based biomarkers for AD, which we describe as the third wave of fluid biomarker analysis that hopefully will gain further momentum during the coming five years.

Vitamin D supplementation and neurofilament light chain in multiple sclerosis

“…30 15,25,27,32 In this study, we found a positive correlation at baseline between serum NFL and 25-hydroxyvitamin D. This was surprising as it contradicts a previously reported association between high serum 25hydroxyvitamin D and low CSF NFL. 16 There were also differences between the patient populations in the studies. 16 There were also differences between the patient populations in the studies.…”

“…24 It is unlikely that differences between NFL measurements in serum and CSF have contributed to the discordant results, as the concentrations in serum and CSF have been shown to correlate strongly (correlation coefficients from 0.75 to 0.97) in patients with diseases of the central nervous system. 16 There were also differences between the patient populations in the studies. Sandberg et al included patients also with primary and secondary progressive MS, some of their patients used immunomodulatory drugs that were not used by the patients in our study, and the vitamin D status of their patients seemed to be lower and more variable (median 44, range 5-333 nmol/L).…”

“…16 The concentration of NFL is elevated in the cerebrospinal fluid (CSF) of MS patients, 17 and it is reduced by effective immunomodulatory treatments such as fingolimod and natalizumab. 16 The concentration of NFL is elevated in the cerebrospinal fluid (CSF) of MS patients, 17 and it is reduced by effective immunomodulatory treatments such as fingolimod and natalizumab.…”

“…Neurofilament light chain (NFL) is a sensitive marker of axonal damage and degradation. 16 The concentration of NFL is elevated in the cerebrospinal fluid (CSF) of MS patients, 17 and it is reduced by effective immunomodulatory treatments such as fingolimod and natalizumab. 18,19 The concentrations of NFL in serum and CSF are highly correlated, 20,21 and serum NFL also predicts inflammatory disease activity and brain and spinal cord atrophy.…”

Plasma total prion protein as a potential biomarker for neurodegenerative dementia: diagnostic accuracy in the spectrum of prion diseases

“…However, in peripheral fluids, the concentration of metabolites associated with the physiopathology of neurodegenerative disorders is, in general, lower than in the CSF, and thus ultrasensitive platforms are required for their robust quantification . To date, most work has been conducted in the AD field, where biomarkers associated with tauopathy, amyloidosis or neuronal injury have been studied in plasma and serum . Yet, the diagnostic accuracy of blood‐based biomarkers of neurodegeneration and dementia so far does not significantly improve that of CSF‐based ones .…”