Ooh Ooh Ooh! They Finally Did It!
I am positively giddy that this paper has finally been published since it not only supports a hypothesis some collaborators of mine and I developed a few years back, but also because it demonstrates a very important approach that is needed in studies of neurocognitive endophenotypes or risk prodromes associated with disease onset or progression. This important approach is to unsimplify task design and assess the role of cognitive or attentional interference in task performance. In this case, cognitive-motor interactions.
The paper I am writing about in this post is “Cognitive-motor interference during postural control indicates at-risk cerebellar profiles in females with the FMR1 premutation” by Claudine Kraan and colleagues with Kim Cornish. It appears in Behavioural Brain Research.
What is Being Studied and Why?
Kraan and colleagues chose to evaluate motor function in female carriers of the fragile X premutation. This is the population of women that are likely to give birth to children with fragile X syndrome. Additionally, fragile X premutation carriers can develop a late onset neurodegenerative disorder called Fragile X-Associated Tremor/Ataxia Syndrome, or FXTAS. FXTAS usually presents as an intention tremor and cerebellar gait ataxia with cognitive decline and a progressive dysexecutive syndrome. Although at present only 16ish% of female carriers will show FXTAS symptoms, it is important to assay their cognitive performance as any findings in this population of women will be directly applicable to male carriers, since men show a higher frequency of FXTAS relative to women (upwards of 40ish%).
Earlier studies have demonstrated some motor performance deficits in females with FXTAS, but female carriers asymptomatic for FXTAS have not been thoroughly studied. The most important aspect of how Kraan and colleagues proceeded was to study the phenomenon that motor performance deteriorates when non-motor cognitive tasks are presented at the same time (e.g., walking and talking on a cellular phone at the same time leads to tripping). By studying the effects of this cognitive interference on motor performance, the authors were able to identify clear deficits in relatively young (mean age 40 years of age) female premutation carriers long before any FXTAS symptomatology would be observed.
An Innovative Approach
Kraan and colleagues used a standardized assessment to evaluate proprioceptive and motor function in premutation carrier females with an age, IQ, and education matched control group. When there was no second task presented, then the control and premutation carrier participants performed nominally on all the motor and proprioceptive tasks.
When a very simple verbal fluency task was presented concurrently with the postural assessment, the female premutation carriers demonstrated poorer proprioceptive awareness (could not return to previous position as easily), slower reaction time, and greater postural displacement (i.e., wobbling) relative to the control participants. Something as simple as taxing attention was sufficient to unmask postural instability and demonstrate impaired proprioception in premutation carriers.
Take Home Message
As stated by the authors
“… These findings highlight the sensitivity of postural control paradigms in identifying early cerebellar postural changes that may act as surrogate markers of future decline in female [premutation] carriers”
Taking these data bit further, what Kraan and colleagues were able to demonstrate was that female premutation carriers do in fact show what appear to be cerebellum-dependent motor impairments. These deficits, however, are revealed only when behavioral tasks become increasingly difficult and require attention to focus on more than just maintaining stability. This interpretation comes from numerous the anecdotal reports suggesting premutation carriers are hyper-aware of their deficits and show increased focus on task performance because they often describe “foggy thinking” and reveal they were always a bit clumsy or a “butterfingers” in school (which can often be interpreted as a subclinical apraxia) or that they often “trip over their own feet” (potentially a subclinical ataxia).
By using a dual task paradigm, Kraan and colleagues were able to uncover these motor abnormalities or difficulties. As they stated in the manuscript, these motor performance deficits are important as they give clinicians a potential target for intervention studies.
The overall implications of this study is that, as has been demonstrated in female mice modeling the premutation Link, Link, there are clear motor deficits in female premutation carriers. These deficits, however, can be overcome by the participant if they are allowed to concentrate on their motor stability and proprioception. On the other hand, when the premutation carriers are distracted by second task, albeit a simple one, these motor deficits become manifest.
More importantly, these effects scale with the magnitude of the mutation and age.this scaling suggests that these motor effects provide scalable biomarkers that can be used as outcome measures. Similarly, these results add another neurocognitive endophenotype to the literature, demonstrating that collections of cognitive strengths and weaknesses can be used to define genetic disorders with high levels of precision.
Also, as to the broader implications, these results replicate the findings of subtle motor abnormalities in the mouse model. In other words, when behavioral tasks are properly developed across species, the mouse model can phenocopy the motor abnormalities present in the human population. As such, the mouse model can now be used as a preclinical screen for functional improvements in drug sides since there is a directly analogous outcome measure in the human premutation carrier population. Furthermore, these results beg to be replicated and extended into male premutation carriers, perhaps even becoming part of a screen that may be used to predict or model neurodegenerative trajectories in premutation carriers from outwardly unaffected toward a diagnosis of FXTAS.