Blood Biomarkers of Neurodegenerative Diseases

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Background

Timely and accurate diagnoses are necessary for the clinical management of neurodegenerative diseases. These diseases often involve biological changes in the central nervous system that result in specific markers being released or secreted into biofluids. Such markers can be very useful for disease prognoses and diagnoses as well as for monitoring disease progression and the effects of therapeutic treatments.

Cerebrospinal fluid (CSF) concentrations of specific neuronal proteins and peptides are well-established biological markers of neurodegenerative dementias, in particular Alzheimer's disease (AD). In fact, biochemical measurements of phosphorylated tau, total tau and amyloid beta are incorporated into major diagnostic and research guidelines as biological evidence for AD. In other neurodegenerative disorders, these biomarkers largely remain at normal levels. In Parkinson's disease, CSF alpha-synuclein is increased with disease severity and provides insights into disease progression. Real-time quaking-induced conversion (RT-QuIC) is a highly sensitive marker for prion disease. Moreover, synaptic proteins including neurogranin, GAP-43, SNAP-25, and several others provide insights into synaptic degeneration and loss, yet are still seemingly specific to AD-type pathology. The axonal protein, neurofilament light chain (NfL), has been widely validated as a biomarker of neurodegeneration in many disease contexts. The neurodegeneration markers NfL and total tau are elevated in traumatic brain injury, stroke and in anesthetized patients during surgery. Several other prospective biomarkers of neurological disorders have been reported in CSF.

Blood, the most widely used biofluid in clinical chemistry investigations, is more accessible compared with CSF. The use of ordinary blood samples bypasses the need for lumbar puncture, which is required for CSF analyses. Since blood sampling requires minimal training, it can be performed outside of a medical facility either by field healthcare officers or by trained patient carers. Blood testing for neurodegenerative diseases therefore presents with exciting possibilities.

Two decades of explorative plasma proteomics yielded a multitude of candidates but failed to demonstrate clinical utility. This is likely because the predominant source of these candidate analytes were from peripheral tissues. More recently, mass spectrometric and immunoassay (e.g, Single molecule array [Simoa], immunomagnetic reduction, and Meso Scale Discovery) technologies with improved sensitivity have been developed. These tools have allowed reliable quantification of brain-derived proteins and peptides in blood, including biomarkers already validated in CSF. These advances have key advantages for the future of neurological care. It is conceivable that in the near future blood biomarkers will have the needed diagnostic and analytical accuracies to replace specific CSF and imaging biomarkers. However, several questions need to be answered to pave the way for this anticipated progress. For example, the molecular and biochemical processes underlying brain-to-blood release of neurodegenerative biomarkers are not well understood, neither is the potential contribution of biomarkers from peripheral tissues. Moreover, different molecular forms of the same neurodegenerative proteins may function as biomarkers potentially at different disease stages. Additionally, the sequence of events involved in the pathogenesis of neurodegenerative diseases are still being explored.

The aim of this Research Topic is to provide a platform for the publication of new research on blood biomarkers of neurodegenerative diseases. This Research Topic is widely open to contributions that target the following topics:

• Original articles that report on the development, analytical validation and clinical performance of new blood biomarkers covering all aspects of neurodegenerative conditions
• Original articles that describe mechanistic basis and factors that affect brain-to-blood release of biomarkers
• Impact of biomarker measures from peripheral sources
• Distinct molecular forms of biomarkers that become available in blood at the same or different disease stages
• Time course of biomarker changes in neurodegenerative diseases
• Novel insights and clinical/diagnostic utility of previously described blood biomarkers (NfL, p-tau, amyloid, GFAP)
• Studies on blood biomarker performance in diverse populations
• Studies that characterize the impact of analytical and logistic parameters (e.g., sample processing, storage and pre-analytical conditions) on blood biomarker measures
• Review and perspective articles that discuss recent advances, potential contexts of use and future perspectives of blood biomarkers

Keywords: Blood biomarker, Alzheimer's disease, tau, amyloid, neurofilament

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