Graduation Year

2014

Document Type

Dissertation

Degree

Ph.D

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Molecular Pharmacology and Physiology

Major Professor

Lynn Wecker, Ph.D.

Co-Major Professor

Alison Willing, Ph.D.

Committee Member

Alison Willing, Ph.D.

Committee Member

Keith Pennypacker, Ph.D.

Committee Member

Theresa Zesiewicz, MD, FAAN

Committee Member

Seok Hun Kim, PT, Ph.D.

Committee Member

Laura Lee Swisher, PT, Ph.D.

Keywords

cerebellar ataxia, gait variability, neurodegenerative disease, postural control, sensory ataxia, spatiotemporal gait analysis

Abstract

Friedreich's Ataxia (FA) is an autosomal-recessive, neurodegenerative disease characterized by progressive lower extremity muscle weakness and sensory loss, balance deficits, limb and gait ataxia, and dysarthria. FA is considered a sensory ataxia because the dorsal root ganglia and spinal cord dorsal columns are involved early in the disease, whereas the cerebellum is affected later. Balance deficits and gait ataxia are often evaluated clinically and in research using clinical rating scales. Recently, quantitative tools such as the Biodex Balance System SD and the GAITRite Walkway System have become available to objectively assess balance and gait, respectively. However, there are limited studies using instrumented measures to quantitatively assess and characterize balance and gait disturbances in FA, and longitudinal, quantitative analyses of both balance and gait have not been investigated in this patient cohort. The purpose of the present study was to characterize gait patterns of adults with FA and to identify changes in gait and balance over time using clinical rating scales and quantitative measures. Additionally, this study investigated the relationship between disease duration, clinical rating scale scores and objective measures of gait and balance.

This study used a longitudinal research design to investigate changes in balance and gait in 8 adults with genetically confirmed FA and 8 healthy controls matched for gender, age, height, and weight. Subjects with FA were evaluated using the Berg Balance Scale (BBS), the Friedreich's Ataxia Rating Scale (FARS) and instrumented gait and balance measures at baseline, 6 months, 12 months and 24 months. Controls underwent the same tests at baseline and 12 months. Gait parameters were measured utilizing the GAITRite Walkway system with a focus on gait velocity, cadence, step and stride lengths, step and stride length variability and percent of the gait cycle in swing, stance and double limb support. Balance was assessed using the BBS and the Biodex Balance System; the latter included tests of postural stability and limits of stability.

At baseline, there were significant differences in gait and balance parameters, BBS scores and FARS total scores between FA subjects and controls as determined using paired t-tests (p<0.05). Adults with FA walked slower, showed decreased cadence, took shorter strides, exhibited greater gait variability and spent less time in swing phase and more time in stance phase and double limb support. In addition, subjects with FA exhibited higher postural stability indices and lower limits of stability overall directional control scores (p<0.05). In the control group, with the exception of the limits of stability forward directional control score (p=0.008), no other significant changes in clinical rating scale scores or gait and balance measures were apparent. Using linear mixed effect (LME) modeling, several gait parameters of subjects with FA exhibited a significant linear change from baseline to 24 months including: gait velocity and cadence during comfortable and fast walking, step and stride length during comfortable and fast walking, and step length variability during fast walking (p<0.05). The LME also revealed a significant linear change in BBS scores, in the postural stability overall stability and anterior posterior indices, and in the limits of stability backward directional control scores (p<0.05). Numerous significant correlations were noted between disease duration, BBS scores and FARS total scores and balance and gait parameters. Of particular note was the strong association between clinical rating scale scores, balance parameters and step and stride length variability (p<0.05).

This is the first longitudinal study to demonstrate changes over time in gait and balance of adults with FA using both quantitative measures and clinical rating scales. This study provided a detailed characterization of the gait pattern and balance of adults with FA. The GAITRite Walkway system proved to be a sensitive measure, and able to detect subtle changes in gait parameters over time in adults with FA. In addition, the BBS was an appropriate and sensitive assessment to detect changes in static and dynamic balance in this patient cohort. Finally, results revealed a strong and consistent relationship between clinical rating scale scores, postural stability indices, limits of stability scores, and step and stride length variability in individuals with FA.

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