Complexity based measures of postural stability provide novel evidence of functional decline in fragile X premutation carriers

Abstract

Background Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative movement disorder characterized by tremor, ataxic gait, and balance issues resulting from a premutation of the Fragile X Mental Retardation 1 (FMR1) gene. No biomarkers have yet been identified to allow early diagnosis of FXTAS, however, recent studies have reported subtle issues in the stability of younger premutation carriers, before disease onset. This study investigates the efficacy of multiscale entropy analysis (MSE) in detecting early changes in the motor system of premutation carriers without FXTAS. Methods Sway complexity of 12 female Premutation carriers and 15 healthy Controls were measured under four conditions: eyes open, closed, and two dual-task conditions. A Sustained Attention Response Task (SART) and a working memory based N-Back task were employed to increase cognitive load while standing on the forceplate. A Complexity Index (Ci) was calculated for anterior-posterior (AP) and mediolateral (ML) sway. Independent t-tests were used to assess between-group differences and Oneway repeated measures ANOVA were used to assess within group differences with Bonferroni corrections to adjust for multiple comparisons. Results Group performances were comparable with eyes open and closed conditions. The Carrier group’s Ci was consistent across tasks and conditions while the Control group’s AP Ci increased significantly during the cognitive dual-task ( p = 0.001). There was also a strong correlation between CGG repeat length and complexity for the Carrier group ( p = 0.004). Significance Increased sway complexity is believed to stem from reallocation of attention to facilitate the increased cognitive demands of dual-tasks. Carriers’ complexity did not change during dual-tasks, possibly indicating capacity interference and inefficient division of attention. Lower sway complexity in carriers suggests diminished adaptive capacity under stress as well as degradation of motor functioning. Therefore, sway complexity may be a useful tool in identifying early functional decline in FMR1 premutation carriers as well as monitoring progression towards disease onset.

Multiscale Entropy of Cardiac and Postural Control Reflects a Flexible Adaptation to a Cognitive Task

“…In agreement with these interpretations, experimental applications have demonstrated a degraded entropy in cardiac and postural dynamics associated with frailty, aging, impairments, or diseases [ 1 , 3 , 4 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. By contrast, high entropy is generally associated with an elevated capacity to adjust to an ever-changing environment [ 8 ], and elevated values are often observed in young healthy people [ 1 ].…”

Cerebellar-cortical function and connectivity during sensorimotor behavior in aging FMR1 gene premutation carriers

“…Atypical postural control has been demonstrated in premutation carriers without FXTAS, including increased postural sway when presented with conflicting visual information, implicating deficits in the integration of multi-sensory feedback inputs during motor behavior ( O'Keefe et al, 2015 ). Reduced complexity of postural sway also has been demonstrated and is associated with increased CGG repeat length in asymptomatic premutation carriers, indicating quantitative sensorimotor measurements may track with disease risk ( O'Keeffe et al, 2019 , Wang et al, 2019 ). Similarly, using tests of precision manual force, we recently documented increased motor variability in aging premutation carriers (between 44 and 77 years of age; Park et al, 2019 ) and reduced motor complexity associated with more severe clinical motor issues and increased CGG repeats ( McKinney et al, 2019 ).…”

Differential Progression of Motor Dysfunction Between Male and Female Fragile X Premutation Carriers Reveals Novel Aspects of Sex-Specific Neural Involvement

“…In males, the studies based on MRI analyses revealed subtle changes in the integrity of white matter without, or prior to, the occurrence of FXTAS (Wang et al, 2012 , 2013 ; Battistella et al, 2013 ), and abnormal trajectories of cerebellar and brain stem volume loss from early adulthood (Wang et al, 2017 ). In female carriers, the findings of deficits on a range of tasks of executive functioning requiring rapid temporal responses (Shelton et al, 2016 ), or of subtle impairment of postural stability (O'Keeffe et al, 2019 ), compared with control non-carriers, suggested that there may be a slow but measurable decline in executive functioning and/or degradation of motor control in apparently asymptomatic individuals. The presence of intranuclear inclusions typical of FXTAS has been reported in both FXTAS and non-FXTAS female carriers (Tassone et al, 2012 ), and reinforces evidence for an accumulation of subclinical pathological processes over a broad age range associated with PM carriage.…”