This week, researchers at the University of Rochester Medical Center published a new study that I believe moves us one step closer to making biomarker measurement a clinically useful reality. They solved the puzzle of how biomarkers make their way to the blood -- the so-called glymphatic system. Blocking the glymphatic system prevented biomarkers from reaching the blood, thus establishing the glymphatic system as the "primary highway" by which proteins leaking out of neurons or glial cells after TBI would reach the blood.
However, there is a catch -- the glymphatic system is also damaged in TBI and the extent of damage would impact the levels of biomarkers in the blood. Additionally, some current management strategies for TBI (especially severe TBI), such as ventriculostomy or even just preventing the patient from falling asleep and doing frequent neurologic assessments, may actually further suppress the glymphatic pathway and decrease biomarker levels.
Some have interpreted this study to mean we should abandon blood biomarkers. The study's senior author himself said in a press release that "a blood-based biomarker for TBI is unlikely to be effective for routine clinical use." After all, if both the brain injury and its management can alter glymphatic function and thus blood biomarker levels, how can blood levels of biomarkers ever aid in assessment?
If you've been following the biomarker saga, you may not be so ready to jump on the give-up-on-biomarkers bandwagon. You've probably read a number of other studies showing increased levels of neuronal or glial specific proteins in the blood after head trauma with levels correlating with the degree of trauma.
Target biomarker candidates studied include proteins released from neuronal cell bodies, neuronal axons, or astroglia. Studies in ice hockey players have demonstrated a significant increase in blood markers following concussion, improvement with symptom improvement, and a gradual return to baseline during rehabilitation. Review articles have determined that there is good quality evidence to suggest that biomarkers correlate with the number of hits to the head (in soccer), post-concussive symptoms, acceleration/deceleration forces, and dynamics of different sports, suggesting the potential for them to guide management once validated.
How can we reconcile these results with the current study? Rather than destroying hopes for biomarkers, the variability of glymphatic system transport after TBI is yet another hurdle to add to the list above of biomarker limitations. But it is a hurdle that once mastered may unlock the door of biomarker usability.
The key is actually tucked in at the end of the paper's discussion. The clinical utility of biomarkers depends upon knowing the extent of suppression of the glymphatic system. The authors refer to "developing a clinical tool ... for the evaluation of glymphatic-associated clearance in patients." While figuring out how to measure glymphatic clearance will likely be challenging, the glymphatic system itself was only elucidated recently and now we already understand the vital role it plays in biomarker transport. Once researchers identify techniques to determine glymphatic clearance, it may be the crucial variable in solving the biomarker equation. Time will tell, but don't give up on biomarkers yet.
http://www.medpagetoday.com/Blogs/CohensBrainBits/49569
Emi Hitomi, Weiguo Peng, Yonghong Liao, Nanhong Lou, Rashid
Deane, Maiken Nedergaard. Biomarkers of
Traumatic Injury Are Transported from Brain to Blood via the Glymphatic System.
The Journal of Neuroscience, 14 January 2015, 35(2): 518-526
Abstract
The nonspecific and variable presentation of traumatic brain
injury (TBI) has motivated an intense search for blood-based biomarkers that
can objectively predict the severity of injury. However, it is not known how
cytosolic proteins released from traumatized brain tissue reach the peripheral
blood. Here we show in a murine TBI model that CSF movement through the
recently characterized glymphatic pathway transports biomarkers to blood via
the cervical lymphatics. Clinically relevant manipulation of glymphatic activity,
including sleep deprivation and cisternotomy, suppressed or eliminated
TBI-induced increases in serum S100β, GFAP, and neuron specific enolase. We
conclude that routine TBI patient management may limit the clinical utility of
blood-based biomarkers because their brain-to-blood transport depends on
glymphatic activity.
With their most recent paper, these observations are expanded to encompass brain-to-blood movements of small molecular weight proteins such as S100B. The interest in S100B derives from its use as a marker of BBB disruption in traumatic brain injury or as an accepted marker of mTBI. The experimental design used is similar to the one used for previous studies on glymphatics, but in this instance a traumatic injury to the brain is superimposed.
ReplyDeleteThere are several problems with the current approach, data interpretation, and discussion in the context of findings by many others. Incidentally, none of the work showing passage of S100B across the barrier is cited (e.g., Marchi et al., 2007; Mussack et al. 2006; Vogelbaum et al., 2004; Kanner et al., 2003) nor are the many papers supporting the clinical use of this marker for TBI mentioned (e.g., Unden and Romner, 2006; Blyth et al., 2011). I want to underscore that Unden and Romner (2006) provided a meta analysis of several studies concluding that "Low serum S100B levels accurately predict normal CT findings after MHI in adults" which is in stark contrast to Plog and colleagues' conclusions about the utility of available markers for TBI.
The main reason however for skepticism about the conclusions of the findings by Plog et. al. is that previous studies reported that S100B is increased within minutes after BBB disruption (carotid-jugular measures during endarterectomy (Mussack et al. 2006), venous blood after osmotic disruption (Marchi et al., 2007)) while Plog and colleagues' results were obtained at much later time points. Given also the facts that the passage in systemic circulation of S100B accurately predicts gadolinium extravasation across a leaky BBB (Vogelbaum et al., 2004; Kanner et al., 2003), and that S100B in serum correlates with albumin CSF: blood ratio (Blyth et al., 2011) it is likely that the preferred pathway in human subjects is trans-BBB rather than the slower glymphatic pathway that Plog et al. propose. There are several reasons why these discrepancies may occur, but it seems likely that studies in humans or animals with an intact brain, CSF, and choroid lead one to draw different conclusions compared to highly invasive tools and time frame that are needed to perform the highly sophisticated and innovative studies described in this paper.
Damir Janigro The Journal of Neuroscience, published online January 28, 2015