A distinct pattern of frontal-temporal atrophy discernible on magnetic resonance imaging (MRI) may flag chronic traumatic encephalopathy (CTE) in living patients, new research suggests.

“These new results offer some hope for clinicians who are really struggling to confidently diagnose or detect CTE during life,” said lead author Michael L. Alosco, PhD, associate professor of neurology, codirector of the Boston University Alzheimer’s Disease Research Center, and investigator at the Boston University CTE Center.

The findings were published online Dec. 7, 2021, in Alzheimer’s Research & Therapy.

A new way to diagnose?

CTE is a neurodegenerative disease associated with exposure to repetitive blows to the head, such as those sustained playing contact sports. Currently, the condition can only be reliably diagnosed at autopsy using neuropathological diagnostic criteria.

There are four pathological stages of CTE, ranging from mild to severe. Each progressive stage reflects mounting accumulation of hyperphosphorylated tau (p-tau).

The study included 55 male brain donors with confirmed CTE, all with a history of repetitive head injury. Most (n = 52) played football, but two played ice hockey and one had military and combat exposure. The analysis also included 31 men with normal cognition (NC). Of these, some were living and some were deceased.

The study sample was restricted to participants age 60 and older and to those who had an MRI obtained through a medical record request.

Most referrals for MRI in the CTE group were related to dementia or neurodegenerative disease (65%). In the NC group, MRI indications were mostly related to cerebrovascular causes (22.6%), memory complaints (16.1%), or vertigo (9.7%).

From MRIs, neuroradiologists visually rated patterns of shrinkage in the brain, microvascular disease, and presence of cavum septum pellucidum (CSP) – a large hole in the tissue separating ventricles of the brain.

More atrophy

Results showed that compared with the NC group, the CTE group had significantly greater atrophy in several brain regions, including the orbital-frontal cortex, dorsolateral frontal cortex, superior frontal cortex, anterior temporal lobes, and medial temporal lobe.

The dorsolateral frontal cortex showed the largest group difference (estimated marginal mean difference, 1.31; 95% confidence interval, .42-2.19; false discovery rate-adjusted P = .01).

Previous research has shown early p-tau involvement in this area among CTE patients. Although the hippocampus is also affected in CTE, this occurs later in the disease course, the investigators noted.

The unique pattern, type, and distribution of p-tau pathology in CTE is different from Alzheimer’s disease. CTE is also distinct from Alzheimer’s disease in that there is no accumulation of beta-amyloid plaque.

The new results add to “converging evidence” for frontotemporal and medial temporal lobe atrophy in CTE “that might be able to be visualized on MRI,” the investigators noted.

Almost two-thirds of the CTE group had an additional neurodegenerative disease. Furthermore, the effect sizes remained similar in analyses that excluded CTE donors with frontotemporal lobar degeneration or Alzheimer’s disease.

“This suggests to us that these other diseases were not accounting for the atrophy,” Dr. Alosco said.

Individuals with CTE were 6.7 times more likely to have a CSP versus those with NC (odds ratio, 6.7; 95% CI, 1.5-50.1; P = .049).

Although previous research suggested an association between CSP and repetitive concussion, CSP is also frequently found in the general adult population. However, when combined with data on frontal lobe shrinkage, it may be a supportive differential diagnostic feature for CTE, Dr. Alosco said.

An important first step

The investigators also examined ventricle size. The lateral ventricles in the CTE group were significantly larger (mean difference, 1.72; 95% CI, .62-2.82; P = .01), as was the third ventricle (mean difference, .80; 95% CI, .26-1.35; P = .01).

When neuropathologists rated tau severity and atrophy at autopsy, they found that more severe p-tau pathology was associated with greater atrophy among those with CTE (beta = .68; P < .01).

Dr. Alosco called the finding “exciting,” noting that it suggests “this tau is a precipitant for neurodegeneration.”

He noted that, although some researchers have used positron emission tomography (PET) tau tracers to uncover a CTE pattern, MRI is relatively inexpensive and routinely used as part of dementia assessment.

While the new study is “an important first step” in using MRI to diagnose CTE, larger sample sizes are needed, Dr. Alosco said. “We also need to look at other disease groups and really nail down the difference with CTE in terms of patterns” (vs. Alzheimer’s disease and vs. frontotemporal lobar degeneration), he added.

“Once those differences are cleared, we will be ready to be more confident when we interpret these images.”.

‘Not unexpected’

Commenting on the research, neurologist and concussion expert Francis X. Conidi, DO, director, Florida Center for Headache and Sports Neurology, Port St. Lucie, said that, although the study was “well thought out and interesting,” the results were “not completely unexpected.”

Frontal and anterior temporal lobe atrophy and prominent third ventricles are very common in patients with traumatic brain injury (TBI), which is “a prerequisite to develop CTE,” said Dr. Conidi, who was not involved with the research.

The current study’s findings mirror observations found in a National Football League cohort he and his colleagues are following – and in his patients with TBI in general.

Dr. Conidi noted that there is a “significant subjective component” to the study results because they relied on the opinion of neuroradiologists. He is not convinced MRI findings of frontotemporal and medial temporal lobe atrophy necessarily represent CTE and not TBI. In fact, he noted that patients with TBI have a significantly greater chance of not developing a neurodegenerative disorder.

Dr. Conidi added that he doesn’t think MRI will ever be the gold standard for diagnosing or even assessing risk of developing CTE. “That lies in tau PET imaging,” he said.

Overstated conclusion?

Also commenting on the research findings, Kristen Dams-O’Connor, PhD, professor, vice chair of research, and director, Brain Injury Research Center, Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai in New York, said the sensitivity analyses, particularly those designed to clarify contributions of Alzheimer’s disease and other neuropathological contributions to associations between p-tau and atrophy, “increase our confidence” in the findings.

“What’s exciting about this paper is that it provides very preliminary support for adding another tool to our arsenal as we try to establish a constellation of in vivo diagnostic markers that, together, will help us rule in a post-traumatic neurodegenerative process and rule out other brain diseases.”

A possible study limitation is that the MRI scans were from low-field strength magnets, although that makes the study more “ecologically valid”, said Dr. Dams-O’Connor. “Many clinical scanners are built around a 1.5T magnet, so what the researchers see in this study is what a radiologist may see in the clinic.”

The conclusion that frontal-temporal atrophy is an MRI marker of CTE is “an overstatement” as this pattern of atrophy is not specific to CTE, said Dr. Dams-O’Connor. “The association of p-tau with atrophy is unsurprising and doesn’t bring us much closer to understanding how, or whether, the patterns of p-tau accumulation observed in CTE contribute to the clinical expression of symptoms.”

Dr. Alosco and Dr. Conidi report no relevant financial relationships. Disclosures for the other study authors are listed in the original journal article. The study was funded by grants from the National Institute on Aging, the National Institute on Neurological Disorders and Stroke, National Institute of Aging Boston University AD Center, Department of Veterans Affairs Merit Award, the Nick and Lynn Buoniconti Foundation, and BU-CTSI.

A version of this article first appeared on Medscape.com.

MRI is key to diagnosing CTE in living patients?