Biomarkers: Technology that is changing neuroscience

But when something goes wrong, these very layers of protection have also kept scientists and physicians locked out, making it difficult to determine the cause and ensure that prospective treatments reach their targets.

“For decades, neurological diseases have been defined in the clinic based on constellations of symptoms, for example, in Alzheimer’s disease (AD), forgetfulness, loss of ability to speak with typical complexity, etc. Indeed, the pathology of the disease (amyloid and tau in the case of AD) were only defined in postmortem brain tissue,” says John Beaver Ph.D., head of biomarkers at Biogen.

John Beaver Ph.D.
Vice President and head of Biomarkers at Biogen

Over the past two decades, however, new technologies have enabled scientists and physicians to look into the brain of living patients using biomarkers that directly measure brain pathologies.

Biomarkers are physiological measurements that provide insight into biological processes in our bodies, helping to guide clinical diagnosis, estimate disease risk or prognosis, evaluate disease stage, and monitor progression or response to therapy.³ These technologies have been used in other fields of medicine, like oncology, for both research and clinical practice. Due to the brain’s additional layers of protection, biomarkers have only now started to become more broadly accessible to neurologists and are more recently becoming a major part of neuroscience drug development.

“New biomarker measurement technologies that unlock a window into the brain, along with genetics, are driving a major resurgence in neuroscience drug development,” says John. “We really think we're at an inflection point where new technologies have enabled us to measure these biomarkers in ways that five or 10 years ago just weren't possible for neuroscience.”

More importantly, advances in biomarker science and improved technology for measuring biomarkers are enabling a targeted approach toward matching treatment to pathology at the molecular level.

John leads a team of scientists who work on discovering and applying biomarkers in drug development to help identify patients who are most likely to respond to treatment and determine the best dose and biological effects of the drug. Today, these measurements are most frequently acquired through imaging or cerebral spinal fluid (CSF), which have been instrumental in propelling neuroscience research forward. But they still have limitations.

Advanced imaging equipment is expensive and typically only available in large, affluent geographic areas with sophisticated, local medical infrastructure. CSF technologies typically can be centralized since biosamples can be rapidly transported, but the process of acquiring the sample is more invasive because a trained neurologist must perform a lumbar puncture, and the patient may require anesthesia.

Testing for biomarkers in blood samples, on the other hand, is a well-established paradigm in medicine in every culture. However, whereas blood samples are easy to acquire and can be readily transported, the concentration of biomarkers that are related to the brain is very low in the blood. Additionally, they are affected by other processes in the body, for example, our kidneys or liver clearing proteins from our blood.

“We are now seeing the emergence of ultra-sensitive technologies that can reliably detect, and in some instances even quantify, brain biomarkers in blood samples, including pathological amyloid and tau in Alzheimer’s,” says John.

The impact of this capability is significant for drug development in neurology. “If we can detect a given brain biomarker in a blood sample, we can get biomarker measurements from every single patient enrolled in our trials, not just a subset with easy access to imaging or lumbar puncture capabilities. We can also pull blood samples when patients come in for monthly drug infusions, enabling us to see how biomarkers are changing month by month instead of just the typical one or two times following treatment. This, combined with imaging and CSF could potentially help us optimize dosing regimens and potentially shorten clinical trials, ultimately getting better treatments to patients faster.”

Imaging, John says, provides a window into the patient’s history, for example, showing long-term damage in the brain, while CSF and blood provide a snapshot of the patient’s current state.

But beyond drug development, could the same blood biomarkers help make clinical decisions in neurology? There is reason to believe that this could be possible within the next few years for several neurological diseases. John points to multiple sclerosis (MS) research using MRI technology to measure inflammation biomarkers during research and development. “Now inflammation on MRI is a common biomarker used in clinical decision making for diagnosis and treatment monitoring in MS.”

Looking ahead, John is excited by the possibilities these technologies, in conjunction with genetics, can create. And in the case of some diseases that are caused by a single gene mutation, like some forms of ALS, that future may not be that far away.

“Through genotyping, we can identify individuals at risk for ALS, and then monitor for the neurofilament biomarker in their blood to determine if people are about to become symptomatic. Then, we can potentially start them on treatment before they develop symptoms, targeting that specific form of ALS to try to slow disease onset and progression,” he says.

A neuroscientist by training, John reflects on his own journey and how the use of brain biomarker technologies has changed throughout his career.

“As a Ph.D. student in the early 2000s, imaging was really just beginning to emerge giving us a direct glimpse inside the human brain,” he says. “It was difficult and complex and limited in what we could measure, but the ability to see neurons firing in the brain was an important breakthrough for neuroscience. It really is astonishing to think that just 20 years later, not only can we see the neurons firing, but also interrogate brain pathologies through imaging and, just as importantly, measure the downstream effects of these pathologies in CSF and blood.”

For neuroscience drug development, this has been a significant leap forward, as scientists can now measure the effectiveness of a drug in addressing the pathologies of a disease. And according to John this is just the beginning.

“These technologies are creating new possibilities for the future in terms of helping us predict and potentially address neurological diseases early on.”