Detecting Disease Biomarkers: Brain, Blood, and Beyond

In recent decades, biomarkers have become increasingly important in the neurology field, particularly to meet the clinical need of a substantial neurodegenerative disease burden globally. There is research demand for reliable, highly specific reagents for sensitive biomarker detection and tools that selectively measure disease-related post-translationally modified biomarker states, particularly phosphorylated tau (pTau). While mechanisms and etiologies differ between neurodegenerative disorders, many share the benefit of detectable fluid biomarkers, which aid disease characterization and offer opportunities for new therapeutically-relevant discoveries.¹

What Makes a Good Biomarker and Detection Method?

Good biomarkers are specific, accessible, and detectable. Until recently, researchers and clinicians relied on surgically collected brain tissue samples to investigate and measure neurodegenerative disease biomarkers.² Widespread efforts to identify markers in circulating biological fluids, such as cerebrospinal fluid (CSF) and serum, have enabled quicker, inexpensive, and less invasive identification, screening, and staging of neurological conditions in the laboratory and clinic.²

Given the prevalence of neurodegenerative diseases, there is also a significant need for new and ideal biomarker detection methods. Regardless of the research focus, reliable biomarker testing should be sensitive and specific to the target analyte, easy to measure with reproducible results, and reflective of disease progression. Additionally, detection in different sample types is challenging but crucial for new screening methods, especially in clinical biomarker testing. Molecular biomarkers measured in the CSF or blood typically include nucleic acids such as microRNA and proteins such as pTau, beta amyloid (Aβ), or alpha-synuclein.^1,2

BIOMARKER SPECIFICITY

Disease heterogeneity within and between conditions drives the need for accurate and specific biomarkers in neurodegenerative disorder research. Currently, several fluid biomarkers can differentiate neurodegenerative diseases, and there is great interest in establishing biomarkers that may differentiate normal aging from pathological cognitive decline.¹ For example, there are three CSF biomarkers included in the diagnostic criteria for Alzheimer’s disease (AD): Aβ, total tau protein, and pTau.² In conjunction with other markers, elevated total tau in circulation reflects molecular differences between AD and age-matched healthy individuals. Hyperphosphorylated tau species are the major component of the neurofibrillary tangles (NFTs) that are characteristically present in AD brains. Certain pTau variants are also specific to AD and may help differentiate AD from frontotemporal dementia.¹ Additionally, increased pTau at threonine positions 181, 217, and 231 in either the CSF or blood can be used alongside Aβ biomarkers to monitor AD onset and progression.^2,3

SENSITIVE AND SELECTIVE SAMPLE DETECTION

Although brain imaging and CSF samples yield highly accurate and validated biomarkers that have been widely used in research settings, blood-based tests are increasingly adopted in the field of neurology.³ Recent techniques and optimized detection tools allow researchers to measure serum analytes at very low concentrations, providing scientists with sensitive detection and less invasive sample options.⁴ At the same time, reported variations in biomarker performance for different plasma pTau species highlight the importance of using selective reagents for detecting modified protein states. For example, pTau217 reflects abnormal CSF and PET biomarker status with higher accuracy than pTau181, and it better differentiates AD from other neurodegenerative disorders.³

Reliable Biomarker Immunoassays

Several immunoassays have been developed to detect different pTau species in tissue, cells, CSF, and plasma. However, scientists must thoughtfully choose immunoassay components such as antibodies, reagents, and detection systems, as each component may affect the reliability of biomarker measurements. For instance, studies comparing commercially-available plasma pTau immunoassays have revealed a certain degree of performance variability for pTau species, including pTau217 and pTau181.³ It is critical that researchers use validated and reliable immunoassays to ensure that they measure the desired and most informative biomarker species. Neurology biomarker detection, discovery, and implementation is steadily increasing in laboratories and clinical settings, driven by technological advancements that enhance precision and sensitivity, as well as insights gained from various disease subfields. This growth is expected to continue as measurement capabilities improve and more specific, selective, and reliable biomarkers emerge through optimized, targeted assays.⁴

References

1. Luebke M, et al. Fluid biomarkers for the diagnosis of neurodegenerative diseases. Biomark Neuropsychiatry. 2023;8:100062.
2. Doroszkiewicz J, et al. Molecular biomarkers and their implications for the early diagnosis of selected neurodegenerative diseases. Int J Mol Sci. 2022;23(9):4610.
3. Janelidze S, et al. Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer’s disease. Brain. 2022;146(4):1592-1601.
4. Lleó A. Biomarkers in neurological disorders: a fast-growing market. Brain Commun. 2021;3(2).