Imaging May Detect CTE Tau Pattern in Living Patients

Pauline Anderson

October 25, 2016

A neuroimaging technique that detects tau deposits in the brains of living patients can be used to diagnose chronic traumatic encephalopathy (CTE), authors of a new paper suggest.

Positron emission tomography (PET) using a still-investigational tracer ([18F]T807, also known as AV1451) can pick up a pattern of tau strikingly similar to that found at autopsy in patients with CTE, said study author Kristen Dams-O'Connor, PhD, co-director of the Brain Injury Research Center at Mount Sinai in New York City.

Dr Kristen Dams-O'Connor

"At this point, this is probably being considered as the most promising suggestion that we are getting closer to being able to diagnose CTE during life," said Dr Dams-O'Connor.

Using such neuroimaging might help develop diagnostic specificity and identify the underlying pathology so doctors can track and treat patients with CTE, she said.

The article was published online September 27 in Translational Psychiatry.

CTE is a neurodegenerative disease seen in individuals with a history of repetitive brain trauma. The condition is characterized neuropathologically by progressive deposits of neurofibrillary tangles consisting of hyperphosphorylated tau.

Patients with CTE may display symptoms that overlap with those of Alzheimer's disease (AD), including impairments in memory and executive function. However, CTE is more frequently characterized by irritability, emotional lability, aggression, impulsivity, suicidality, and substance abuse.

Currently, CTE can be definitively diagnosed only at postmortem examination. "The distribution of tau that we see in CTE is quite distinct from what we see in other neurodegenerative diseases," said Dr Dams-O'Connor.

Researchers are beginning to track this pattern in the brains of living patients by using PET radiotracers. One ligand, [18F]T807, has been shown to have a high affinity and selectivity for tau over amyloid-β peptide. It has demonstrated utility in revealing tauopathy in a variety of abnormalities, including AD and fronto-temporal dementia, as well as CTE.

Retired Athlete

This paper presented the case of a 39-year-old retired National Football League (NFL) player who had sustained 22 concussions, 4 of which resulted in loss of consciousness, during an 11-year professional career. He reported irritability, emotional lability, behavioral disturbances, and cognitive decline.

He was evaluated in 2015 at the Icahn School of Medicine at Mount Sinai as part of a larger study comparing individuals with a history of multiple concussions to healthy controls and those with mild cognitive impairment with no concussion history. He also released medical records from a 2010 evaluation that took place elsewhere.

Detailed neurologic examinations conducted in 2010 and in 2015 were normal. APOE genotyping in 2010 showed that the man is a carrier for the E3 allele, not the allele most implicated in AD.

The relatively recent PET amyloid-β scan showed "a real absence of β amyloid pathology, which means that whatever this person has, it's not Alzheimer's disease," said Dr Dams-O'Connor.

Neuroimaging using the new tracer showed extensive tau deposits, particularly perivascular tauopathy at the depths of the cerebral cortical sulci.

"What was really striking to us was how similar the distribution of tauopathy that we could see with this PET ligand in this living person was in comparison to those pathognomonic lesions that we see in the postmortem brain," said Dr Dams-O'Connor.

The [18F]T807/AV1451 retention in the ex-NFL player was consistent with recent conclusions of the first National Institute of Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering consensus panel of neuropathologists, published in Acta Neuropathologica in January 2016. According to the panel, the hyperphosphorylated tau pathology of CTE is "clearly distinct" from other tauopathies.

"The panel concluded that there is a pathognomonic lesion of CTE that consists of an accumulation of abnormal tau in neurons and astroglia distributed around small blood vessels at the depths of sulci in the cortex in an irregular spatial pattern," consensus panel members write.

The preinjury intellectual status of the former NFL player was deemed to be in the superior range.

Neuropsychological testing revealed that between 2010 and 2015, certain deficits became more pronounced, particularly in areas of processing speed, executive function, and motor dexterity, said Dr Dams-O'Connor.

The patient still performed in the average-to-superior range on several tests of short-term memory but reported problems with working memory in his daily life. Difficulties with attention and distractibility may explain these complaints because he had reported related symptoms and was being treated for them.

The neuropsychological battery identified a pattern different from other neurodegenerative diseases, such as AD, commented the authors. Aggression, irritability, and disinhibition are a triad of seriously disabling symptoms. In addition, the patient had relatively new-onset depression with anxiety.

"Altogether, these neuropsychological and psychiatric symptoms undoubtedly contribute to the significant functional impairment reported in 2015," they write.

The patient underwent MRI in 2011 and in 2015. Analysis of structural brain changes suggested diffuse atrophy, especially within the frontal lobe, basal ganglia, and lateral temporal lobe, with apparent sparing of the medial temporal lobes. Atrophy in some of these areas may contribute to the patient's reduced motor speed and feeling "slowed down," along with other disabling behavioral symptoms.

Thinning in the left orbitofrontal cortex and temporal pole may underlie the patient's impulsivity, they note.

Little hippocampal or medial temporal lobe atrophy was found, consistent with the high scores seen in the delayed recall tests.

"Exciting Work"

According to Dr Dams-O'Connor, it could be very useful to know the tau pattern in living patients suspected of having CTE. For example, she said, "very exciting work" is being done in developing neurobehavioral interventions for patients with traumatic brain injury.

"There is now evidence for these neurobehavioral interventions for people living with cognitive dysfunction, with mood dysregulation, with impulsivity, and executive dysfunction — all the things that people with CTE often experience."

As well, several drugs are in development that directly target tau, she added.

Some drugs have already been shown to be useful for other neurodegenerative conditions, for example, fronto-temporal dementia, where tau plays "a huge role," said Dr Dams-O'Connor.

"If we can identify with some accuracy during life a person who has the neurobehavioral features that we think are consistent with CTE, and the underlying tauopathy that makes us more confident that it is CTE, then we should be trying these drugs in these people."

These are "early days" in the in vivo detection of complex degenerative disorders such as CTE, and much additional investigation is required, said the authors. They added that there are "a host" of other tauopathy ligands in the pipeline.

Despite the promise of this technique, the authors stressed that definitive radiologic-pathologic correlation will be required to establish that CTE tauopathy is indeed the basis for cerebral [18F]T807/AV1451 retention in patients such as this retired professional football player.

Vin Shen Ban, MBBChir, MRCS, a sports injury specialist at the Department of Neurological Surgery, University of Texas, Southwestern Medical Center, Dallas, commented on these findings for Medscape Medical News.

"Various biomarkers have been studied in hopes of predicting CTE onset or identifying CTE in living individuals," he said. "To date, none of these studies have tissue correlation."

In this study, the authors demonstrated that [18F]T807/AV1451 in a single patient with a history of multiple concussive episodes had a distribution consistent with the current definitions of CTE, he added.

"Whether or not this distribution pattern will be backed up by tissue diagnosis (in the event of a future autopsy) is highly critical in our understanding of CTE," he concluded.

This research was supported by a grant from the Alzheimer's Disease Drug Foundation and grants from the National Institute of Neurological Disorders and Stroke and the National Institute of Child Health and Human Development. The Werber Family Foundation provided additional support. Dr Dams-O'Connor and the other authors have disclosed no relevant financial relationships.

Transl Psychiatry. Published online September 27, 2016. Full text

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