Since the discovery of chronic traumatic encephalopathy (CTE), a progression of recognition has taken place within the medical community regarding the long-term health implications of concussion and repeated head trauma. Since then, the rapid rate of awareness for CTE has outpaced the science, which remains at this time a pathological disorder that cannot be diagnosed in living patients due to lack of evidence that a clinical syndrome exists. The constellation of symptoms associated with CTE makes it difficult to pinpoint how, when, and why the pathological process takes shape in the brain. Moreover, these symptoms often do not begin to emerge until decades after the head traumas that are likely to have caused them.
Although the nuances of CTE are beyond the current scope of scientific knowledge, development is underway for biomarkers that may produce a viable means of detecting the condition. These biomarkers include blood tests, imaging technologies, and cerebrospinal fluid (CSF). Another potential technology that may provide insight into the disorder is MRI. A report published last year detailed the use of an MRI volumetric signature in discovering progressive focal gray matter volume loss in a former football player, raising the possibility of distinct MRI findings in the detection of CTE.1 Ahead, study co-author David A. Merrill, MD, PhD, Professor of Geriatric Psychiatry at UCLA Medical Center, sheds more light on the study and the potential of MRI technology to play a role in the broader effort to one day diagnose CTE in living patients.
Patterns of Volume Loss
While overseeing a memory and mood clinic in Los Angeles for older adults, Dr. Merrill became interested in CTE when he began to notice an increasing number of younger patients coming to the clinic who had played football earlier in their lives. “The case we examined was a person who grew up normally and was a youth football player who later started a family,” Dr. Merrill recounts. “He presented to us in his late 40s with complex mood and cognitive symptoms. The symptoms began in his late 30s, but he did not seek treatment for several years.” Standard neuropsychological testing confirmed the patient’s impairments in attention, impulse control, and other measures of executive function, although it indicated that his memory was normal. An initial MRI scan showed no evidence of Alzheimer’s disease, stroke, or dementia. However, using an MRI software analysis tool called Neuroreader, Dr. Merrill and his team of researchers found that the scan revealed a few small lesions consistent with the patient’s history of brain trauma.
Structural MRI volumetrics may provide useful information regarding the progression of volume loss. While early findings are compelling, more research is needed to confirm the specific utility of MRI technology as a helpful tool in the possible detection of CTE.
After performing a second scan four years later, Dr. Merrill and his colleagues discovered abnormally low volumes in the brainstem, ventral diencephalon, and frontal lobes, suggesting a progression of disease. The patient’s brain lost about 14 percent of its total gray matter volume (the volume taken up by brain cells, not nerve fibers) during the four-year interval. In addition, the locations of volume loss are particularly notable, according to Dr. Merrill. “The locations are parallel to areas of tau tangles found in autopsies or tau PET scans,” says Dr. Merrill.
The observed volume loss is similar to that observed in Alzheimer’s disease, which may offer a blueprint regarding the trajectory of biomarker development, according to Dr. Merrill. “The Alzheimer’s Disease Neuroimaging Initiative did quantitative volumetrics and learned that you could quantify the size of the hippocampus as a predictor of Alzheimer’s and memory loss progression,” says Dr. Merrill. “In CTE, our case report finding suggests that we can identify patterns in CTE in the same fashion, for instance, looking at the frontal lobes, brain stem, and other areas affected by concussive impact.” It starts with a 3D MRI, which takes multiple “slices” of the brain and puts them back together to calculate volumes of anatomically defined regions of the brain. “Traditionally, this was done manually with a laborious process for hours and days by specially trained individuals, but now there are computer programs leveraging technological advances to automate this process,” Dr. Merrill observes.
The ability to generate brain analysis volumetrics in less than five minutes through an automated process is a major advance, but according to Dr. Merrill the big question is what to do with that information. “It’s too early to say whether the data is ready to be used on its own, but if you combine that information with the human element of a skilled radiologist, we do see pathology in area of volume loss,” he says. Thus, the automated approach becomes a way to guide the visualization of the scan and bring attention to subtle changes that may be otherwise overlooked or not appreciated. “It’s intended to be a helpful guide, not its own definitive standalone tool,” he points out.
Future Paths for Structural MRI and CTE
Nearly one year later, while the case report findings remain somewhat controversial, Dr. Merrill believes they offer clues toward understanding patterns in suspected cases of CTE. “Although we still have many questions to answer and are only at the start of this, there seems to be added value in quantifying these structural MRIs to suspect CTE,” says Dr. Merrill. “Structural MRIs are already being done as standard of care for memory loss and headache. We should be using this information to the fullest extent possible.” He adds that even one scan allows physicians to compare data to normative databases or sequential scans in years to come. He is hopeful that large studies will explore this possibility further. “Large multi-centered trials should consider using this or adapting this approach into their protocols, whether it’s a PET study or MRI study,” says Dr. Merrill. “It would be great if the automated quantification method with MRIs could be integrated into a structured observation research protocol for patients like this. This would become one tool in the diagnostic assessment toolbox both at baseline of clinical care or research studies.”
Volumetric MRI also has potential in assessing the effectiveness of interventions, whether they’re pharmacologic or lifestyle-based, according to Dr. Merrill. “For example, aerobics have been shown to increase hippocampal volume in people with mild cognitive impairment or early stages of memory loss. This method provides a way to track response to potential interventions for CTE, such as exercise, dietary approaches, or other brain health techniques.”
Structural MRI is one of many ways to look at the brain to detect patterns of complex conditions such as CTE. Dr. Merrill believes the preliminary work to uncover some of these patterns warrant further study to test its relevance in a broader way. He and his colleagues are hoping to do larger studies to analyze MRI data for people with histories of head trauma, which would help determine whether the technique is broadly useful in detecting CTE.
While Dr. Merrill believes that structural MRI holds great promise, he emphasizes that the work so far represents the beginning of a long journey ahead. “There are three million diagnosed cases of sports-related concussion per year,” he notes. “From a public health standpoint, the already established technology of structural MRI seems like something worth investigating to verify whether this method could be useful or not.”
To that end, Dr. Merrill emphasizes that multi-modal collaborative efforts among various disciplines is important to doing the necessary work to better understand CTE and concussions more broadly. “There is so much more possibility for forward momentum when everyone works together,” he remarks.
David A. Merrill, MD, PhD is an Assistant Clinical Professor of Psychiatry and Biobehavioral Sciences at the Semel Institute for Neuroscience and Human Behavior at UCLA Medical Center in Los Angeles, CA.
1. Raji CA, Merrill DA, Barrio JR, Omalu B, Small GW. Progressive Focal Gray Matter Volume Loss in a Former High School Football Player: A Possible Magnetic Resonance Imaging Volumetric Signature for Chronic Traumatic Encephalopathy. Am J Geriatr Psychiatry. 2016 Oct; 24(10): 784-90.