Dataset Information

Upper and Lower Limb Movement Kinematics in Aging FMR1 Gene Premutation Carriers.

ABSTRACT: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with a premutation cytosine-guanine-guanine (CGG) trinucleotide repeat expansion of the FMR1 gene. FXTAS is estimated to be the most common single-gene form of ataxia in the aging population. Gait ataxia and intention tremor are the primary behavioral symptoms of FXTAS, though clinical evaluation of these symptoms often is subjective, contributing to difficulties in reliably differentiating individuals with FXTAS and asymptomatic premutation carriers. This study aimed to clarify the extent to which quantitative measures of gait and upper limb kinematics may serve as biobehavioral markers of FXTAS degeneration. Nineteen premutation carriers (aged 46-77 years), including 9 with possible, probable, or definite FXTAS and 16 sex- and IQ-matched healthy controls, completed tests of non-constrained walking and reaching while both standing (static reaching) and walking (dynamic reaching) to quantify gait and upper limb control, respectively. For the non-constrained walking task, participants wore reflective markers and walked at their preferred speed on a walkway. During the static reaching task, participants reached and lifted boxes of different sizes while standing. During the dynamic reaching task, participants walked to reach and lift the boxes. Movement kinematics were examined in relation to clinical ratings of neuromotor impairments and CGG repeat length. During non-constrained walking, individuals with FXTAS showed decreased stride lengths and stride velocities, increased percentages of double support time, and increased variabilities of cadence and center of mass relative to both asymptomatic premutation carriers and controls. While individuals with FXTAS did not show any static reaching differences relative to the other two groups, they showed multiple differences during dynamic reaching trials, including reduced maximum reaching velocity, prolonged acceleration time, and jerkier movement of the shoulder, elbow, and hand. Gait differences during non-constrained walking were associated with more severe clinically rated posture and gait symptoms. Reduced maximum reaching velocity and increased jerkiness during dynamic reaching were each related to more severe clinically rated kinetic dysfunction and overall neuromotor symptoms in FMR1 premutation carriers. Our findings suggest kinematic alterations consistent with gait ataxia and upper limb bradykinesia are each selectively present in individuals with FXTAS, but not asymptomatic aging premutation carriers. Consistent with neuropathological and magnetic resonance imaging (MRI) studies of FXTAS, these findings implicate cerebellar and basal ganglia degeneration associated with neuromotor decline. Our results showing associations between quantitative kinematic differences in FXTAS and clinical ratings suggest that objective assessments of gait and reaching behaviors may serve as critical and reliable targets for detecting FXTAS risk and monitoring progression.

SUBMITTER: Wang Z

PROVIDER: S-EPMC7823457 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Upper and Lower Limb Movement Kinematics in Aging <i>FMR1</i> Gene Premutation Carriers.

Wang Zheng Z Lane Callie C Terza Matthew M Khemani Pravin P Lui Su S McKinney Walker S WS Mosconi Matthew W MW

Brain sciences 20201224 1

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with a premutation cytosine-guanine-guanine (CGG) trinucleotide repeat expansion of the <i>FMR1</i> gene. FXTAS is estimated to be the most common single-gene form of ataxia in the aging population. Gait ataxia and intention tremor are the primary behavioral symptoms of FXTAS, though clinical evaluation of these symptoms often is subjective, contributing to difficulties in reliably differentiating indi ...[more]

PMID: 33374331

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Project description:BackgroundIndividuals with premutation alleles of the fragile X mental retardation 1 (FMR1) gene are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS) during aging. Characterization of motor issues associated with aging in FMR1 premutation carriers is needed to determine neurodegenerative processes and establish new biobehavioral indicators to help identify individuals at greatest risk of developing FXTAS.MethodsWe examined postural stability in 18 premutation carriers ages 46-77 years and 14 age-matched healthy controls. Participants completed a test of static stance and two tests of dynamic postural sway on a force platform to quantify postural variability and complexity. CGG repeat length was measured for each premutation carrier, and MRI and neurological evaluations were conducted to identify carriers who currently met criteria for FXTAS. Of the 18 premutation carriers, seven met criteria for definite/probable FXTAS (FXTAS+), seven showed no MRI or neurological signs of FXTAS (FXTAS-), and four were inconclusive due to insufficient data.ResultsCompared to controls, premutation carriers showed increased center of pressure (COP) variability in the mediolateral (COPML) direction during static stance and reduced COP variability in the anterior-posterior (COPAP) direction during dynamic AP sway. They also showed reductions in COPML complexity during each postural condition. FXTAS+ individuals showed reduced COPAP variability compared to FXTAS- carriers and healthy controls during dynamic AP sway. Across all carriers, increased sway variability during static stance and decreased sway variability in target directions during dynamic sways were associated with greater CGG repeat length and more severe neurologically rated posture and gait abnormalities.ConclusionOur findings indicate that aging FMR1 premutation carriers show static and dynamic postural control deficits relative to healthy controls implicating degenerative processes of spinocerebellar and cerebellar-brainstem circuits that may be independent of or precede the onset of FXTAS. Our finding that FXTAS+ and FXTAS- premutation carriers differed on their level of intentional AP sway suggests that neural mechanisms of dynamic postural control may be differentially impacted in patients with FXTAS, and its measurement may be useful for rapidly and precisely identifying disease presence and onset.

Project description:The FMR1 premutation confers a 40-60% risk for males of developing a neurodegenerative disease called the Fragile X-associated Tremor Ataxia Syndrome (FXTAS). FXTAS is a late-onset disease that primarily involves progressive symptoms of tremor and ataxia, as well as cognitive decline that can develop into dementia in some patients. At present, it is not clear whether changes to brain function are detectable in motor regions prior to the onset of frank symptomatology. The present study therefore aimed to utilize an fMRI motor task for the first time in an asymptomatic premutation population. Premutation carriers without a diagnosis of FXTAS (n = 17) and a group of healthy male controls (n = 17), with an age range of 24-68 years old, were recruited for this cross-sectional study. This study utilized neuroimaging, molecular and clinical measurements, employing an fMRI finger-tapping task with a block design consisting of sequential finger-tapping, random finger-tapping and rest conditions. The imaging analysis contrasted the sequential and random conditions to investigate activation changes in response to a change in task demand. Additionally, measurements were obtained of participant tremor, co-ordination and balance using the CATSYS-2000 system and measures of FMR1 mRNA were quantified from peripheral blood samples using quantitative real-time PCR methodology. Premutation carriers demonstrated significantly less cerebellar activation than controls during sequential versus random finger tapping (FWEcorr < 0.001). In addition, there was a significant age by group interaction in the hippocampus, inferior parietal cortex and temporal cortex originating from a more negative relationship between brain activation and age in the carrier group compared to the controls (FWEcorr < 0.001). Here, we present for the first time functional imaging-based evidence for early movement-related neurodegeneration in Fragile X premutation carriers. These changes pre-exist the diagnosis of FXTAS and are greatest in older carriers suggesting that they may be indicative of FXTAS vulnerability.

Dataset Information

Upper and Lower Limb Movement Kinematics in Aging FMR1 Gene Premutation Carriers.

Publications

Upper and Lower Limb Movement Kinematics in Aging <i>FMR1</i> Gene Premutation Carriers.

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