The blood may hold many clues to damage and degeneration in the brain. New findings bring a blood test for brain disorders closer to reality.
You might think that there is very little you can know about the brain from your blood – because of the blood brain barrier. However, increasingly research is finding that the things that do cross this barrier might be quite informative about what is happening there. While there are not yet simple blood tests for brain disorders, research suggests that they may be on the way. Here are two examples of promising directions – though not without challenges to overcome.
Vasculature in the Brain and the Blood-Brain Barrier
First, a quick primer on the ~400 miles (!) of vasculature in the human brain. Blood enters the brain through the arterial vasculature and branches out into the brain. Peripherally, the layer of epithelial cells that forms a barrier between the vasculature and the cerebrospinal fluid or CSF through tight junctions and efflux pumps (the blood-brain barrier). This serves the role of preventing the transfer of hydrophilic substances, toxins and pathogens. Where the vasculature penetrates the cortex, they are also surrounded by glia or astrocytic feet which plays a role in the regulation of blood flow.
On the venous side, veins exiting the cortex or parenchyma have greater perivascular space than the arteries and are also flanked by an endothelial membrane and astrocytic foot processes. Approximately half a liter of cerebrospinal fluid (CSF) is drained into the blood each day through the venous drainage. The astrocytes clear toxins and metabolites into the veins in what has now been discovered as the lymphatic drainage of the brain or the glymphatic system. Thus the toxins and metabolites drained into the blood can be identified through a blood test.
See [1] for more details.
Blood metabolites and Alzheimer’s
Alzheimer’s is thought to be associated with a degradation of the blood-brain barrier, this means that many of the metabolic products disrupted in Alzheimer’s may be detected in the blood. Previously researchers had tested a number of individual metabolic elements such a plasma phospholipids, amino acid and antioxidant metabolites. However, individual markers often had only suggestive results and failed to replicate. Presently the more promising approaches use panels of metabolites, a field now called metabolomics, to use machine learning methods to classify profiles associated with diagnosis. One study, for instance, using twenty-six metabolites from blood, was able to classify Alzheimer’s patients from healthy controls with 79% accuracy.
Moving towards better accuracy and precision appears within reach. Evidence that the processes of Alzheimer’s occurs in the peripheral nervous system and that it could in fact, originate there and migrate to the CNS to induce pathological changes suggests that Alzheimer’s may be more systemic which would make it easier to detect. However, there are various challenges to overcome. Metabolites measured in the blood may not be specific to the nervous system. Furthermore, Alzheimer’s can only be diagnosed with certainty by examining post-mortem tissue. There are unfortunately no robust and trustable biomarkers available presently for diagnostic purposes so results may also reflect the clinical heterogeneity of Alzheimer’s disease as well as possible misdiagnosis.
Ultimately, having a good blood test for Alzheimer’s will depend on identifying a larger panel of metabolites, improving detection sensitivity, and confirming results against genuine Alzheimer’s cases.
Extracellular vesicles and Traumatic Brain Injury (TBI)
Another interesting possibility lies in something called extracellular vesicles (EVs). These are packaged cargo that cells ship to one another that contain things like RNA pieces and proteins. It’s a different much more tangible sharing of stuff and information among neurons. (Curiously, this ability of neurons to ship cargo to each other comes from RNA of viral origin integrated into our genome that codes for the components that make this possible).
See related post Transport of Proteins, RNA and DNA among Brain Cells
These EVs or ‘exosomes’ also end up draining into the blood and can be harvested and quantitatively examined. Unlike most metabolites, recent work suggests that this exosome cargo can be pretty specific to neurons, reflecting novel biomarkers of neurological challenges. For instance, studies have shown increased concentration of EVs carrying glial fibrillary acidic protein (GFAP), aquaporin-4 [AQP4]) and neuronal neuron-specific enolase (NSE) in blood under conditions such as oxidative stress, cerebral vascular damage and microvascular thrombosis. Consequently it is thought to be a potential marker in Traumatic Brain Injury (TBI).
Bottom line, there are a large number of metabolites and EVs in the blood that can be probed individually and in combination to build profiles of neurological conditions. It may take time, but blood tests for neurological disorders are on the horizon.
References
[3] Karnati HK et al, Neuronal Enriched Extracellular Vesicle Proteins as Biomarkers for Traumatic Brain Injury J Neurotrauma 2019 Apr 1;36(7)
