Executive function loss may indicate neurodegeneration FXTAS

According to new UC Davis research, men with a FMR1 premutation who had poor executive function were more likely to develop fragile X-associated tremor/ataxia syndrome (FXTAS).

FXTAS is a hereditary disorder that causes mobility problems as well as cognitive impairment. These findings, which were published in the journal Movement Disorders, may help clinicians predict which premutation carriers may develop FXTAS.

“There’s converging evidence that the premutation is affecting certain circuits in the brain before any movement problems show up on a clinical exam,” said David Hessl, a professor in the Department of Psychiatry and Behavioral Sciences at UC Davis and the paper’s first author. “We’re getting closer to determining which carriers are most likely to develop full-fledged FXTAS.” We may be able to avoid or greatly slow it if we intervene early.”

Patients with FXTAS, which was discovered at the MIND Institute in 2001, have cognitive deterioration as well as Parkinson’s-like movement difficulties. Many persons with FMR1 premutations, however, do not acquire the disease. Hessl and colleagues have been looking for markers that could identify which FMR1 carriers are at the most danger.

We’re getting closer to identifying the carriers who are most likely to develop full-blown FXTAS. If we could intervene early, we might be able to prevent it or slow it down significantly.”—David Hessl, professor of Psychiatry and Behavioral Sciences

Executive function as a criterion
The MIND Institute has been investigating persons with FMR1 mutations for many years in order to better understand the natural history of FXTAS. The team monitored 66 persons with FMR1 premutations and 31 controls for up to nine years in this most current investigation. Participants and their spouses completed executive function inventories and other measures to assess the carriers’ function during follow-up visits.

“Executive function refers to the cognitive abilities that help us organize our behavior: to resist impulses, be patient and not jump into things too quickly,” he said. “They also regulate our attention and working memory, which allows us to keep information in our heads while doing other things.” For example, remembering where you set your phone after you’ve moved on to another task.”

When the study began, the executive function of premutation carriers was comparable to that of controls. However, a considerable number of FMR1 carriers acquired executive function issues over time. Overall, carriers who had issues with working memory, organization, task monitoring, and other features were more likely to develop FXTAS.

“It’s one of the earliest indicators we’ve been able to identify that has some predictive value for who would develop FXTAS later,” he added. “We don’t have enough data to know how strong of a predictor it is, but it did significantly associate with later conversion, which was eye-opening.”

The authors emphasize that this is only the first stage in a protracted process of developing precise clinical tools to predict which patients will develop FXTAS. While the results of this study were statistically significant, they do not imply the clinical precision of the marker.

“It doesn’t tell us whether a patient with X amount of executive function change has double the risk, five times the risk, or 10 times,” he said. “We don’t yet know how strong these predictors are, and we want to build models that will tell us that.”

Nonetheless, this new understanding may help clinicians better monitor FMR1 carriers. While no FXTAS therapies are now available, medications are being explored, and measuring executive function may be important in establishing their success.

“We’re looking at a number of different markers associated with disease progression,” he said. “These include behavioral issues such as executive function, molecular biomarkers, and brain MRI data.” We feel that there may be risk factor combinations that might be investigated together. There may be growing machine learning and other statistical tools that can help us achieve far better predictions, identify who is at higher risk, and perhaps discover protective variables.”

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