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Background: Friedreich's ataxia (FRDA), the most common genetic cause of ataxia, is characterised by progressive neurodegeneration and cardiomyopathy. Initial treatments are likely to slow progression rather than reverse morbidity. An appropriate and sensitive scale to measure disease progress is critical to detect the benefit of treatments.Objective: To compare the Friedreich Ataxia Rating Scale (FARS) with other scales proposed as outcome measures for FRDA.Methods: 76 participants were assessed with the FARS and the International Cooperative Ataxia Rating Scale (ICARS) and 72 of these participants were also assessed with the Functional Independence Measure and the Modified Barthel Index. 43 participants had repeat measures at an interval of 12 months. Sensitivity and responsiveness were assessed using the effect size for each measure and the sample size required for a placebo-controlled clinical trial.Results: The FARS showed a high correlation with the other three measures. A significant change in the score over 12 months was detected by the FARS, the International Cooperative Ataxia Rating Scale and the Functional Independence Measure. The FARS had the greatest effect size and requires fewer patients for an equivalently powered study.Conclusions: Of the scales assessed, the FARS is the best to use in clinical trials of FRDA. This is based on effect size, and power calculations that show that fewer participants are required to demonstrate the same effect of an intervention. Further work is required to develop more sensitive and responsive instruments. [ABSTRACT FROM AUTHOR]

Speech disturbances (e.g., altered prosody) have been described in symptomatic Huntington's Disease (HD) individuals, however, the extent to which speech changes in gene positive pre-manifest (PreHD) individuals is largely unknown. The speech of individuals carrying the mutant HTT gene is a behavioural/motor/cognitive marker demonstrating some potential as an objective indicator of early HD onset and disease progression. Speech samples were acquired from 30 individuals carrying the mutant HTT gene (13 PreHD, 17 early stage HD) and 15 matched controls. Participants read a passage, produced a monologue and said the days of the week. Data were analysed acoustically for measures of timing, frequency and intensity. There was a clear effect of group across most acoustic measures, so that speech performance differed in-line with disease progression. Comparisons across groups revealed significant differences between the control and the early stage HD group on measures of timing (e.g., speech rate). Participants carrying the mutant HTT gene presented with slower rates of speech, took longer to say words and produced greater silences between and within words compared to healthy controls. Importantly, speech rate showed a significant correlation to burden of disease scores. The speech of early stage HD differed significantly from controls. The speech of PreHD, although not reaching significance, tended to lie between the performance of controls and early stage HD. This suggests that changes in speech production appear to be developing prior to diagnosis., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: To determine the effects of inpatient intervention for people with Friedreich ataxia (FRDA), and to identify whether improvements gained were sustained postdischarge., Design: This retrospective observational cohort study comprised people with FRDA admitted to inpatient rehabilitation., Setting: All participants in the study were referred by a specialist multidisciplinary FRDA clinic to inpatient rehabilitation., Participants: From 2003 until 2010, people (N=29; men, n=17; women, n=12) with FRDA were admitted to rehabilitation, representing 42 admissions. On admission, 9 participants were ambulant and 33 participants were nonambulant., Interventions: Each participant was prescribed goal-related therapy on an individual basis by the multidisciplinary team, and this consisted of a range of treatment approaches., Main Outcome Measure: The FIM was used to determine the efficacy of inpatient rehabilitation., Results: Consistent with the progressive nature of the condition, FIM scores, as measured on an annual basis preintervention, declined over time. However, FIM scores increased by a mean of 8.5 points during periods of inpatient rehabilitation and continued to increase by a mean of 2.0 points during the period immediately after rehabilitation. Results demonstrate these increases during and immediately after inpatient rehabilitation were significant (P<.001)., Conclusions: To the best of our knowledge, this study provides the first evidence that a period of inpatient rehabilitation reverses or halts the downward decline in function for people with FRDA. The benefits from this intervention continued during the period immediately after inpatient rehabilitation, indicating that these gains are more than just short-term achievements. Further exploration of intensity, type, and length of rehabilitation is required to ensure that the most appropriate rehabilitation is provided., (Copyright © 2012 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Friedreich ataxia (FRDA), the most common of the hereditary ataxias, is an autosomal recessive, multisystem disorder characterised by progressive ataxia, sensory symptoms, weakness, scoliosis and cardiomyopathy. FRDA is caused by a GAA expansion in intron one of the FXN gene, leading to reduced levels of the encoded protein frataxin, which is thought to regulate cellular iron homeostasis. The cerebellar and spinocerebellar dysfunction seen in FRDA has known effects on motor function; however until recently slowed information processing has been the main feature consistently reported by the limited studies addressing cognitive function in FRDA. This chapter will systematically review the current literature regarding the neuropathological and neurobehavioural phenotype associated with FRDA. It will evaluate more recent evidence adopting systematic experimental methodologies that postulate that the neurobehavioural phenotype associated with FRDA is likely to involve impairment in cerebello-cortico connectivity.

Friedreich ataxia (FRDA) is the most common of the genetically inherited ataxias. We sought to examine motor planning ability in 13 individuals with FRDA and 13 age- and sex-matched control participants using two experimental paradigms that examined the ability to incorporate different levels of advance information to plan sequential movements. Individuals with FRDA demonstrated a differential pattern of motor response to advance information and were significantly disadvantaged by conditions requiring initiation of movement without a direct visual cue. There was also a significant negative correlation with age of disease onset and differing levels of advance information, suggesting an impact of FRDA on the development of motor cognition, independent of the effect of disease duration. We suggest that deficits are due to cerebellar impairment disrupting cerebro-ponto-cerebello-thalamo-cerebral loops (and thus cortical function), direct primary cortical pathology or a possible combination of the two.

Friedreich ataxia (FRDA) is the most common of the inherited ataxias. We have suggested that people with FRDA may have impairment in cognitive and/or psychomotor capacity either due to disturbance of projections of the cerebellum to the cortex, direct cortical pathology or perhaps both. To further explore this possibility, we used a movement task incorporating Fitts' Law, a robust description of the relationship between movement time and accuracy in goal-directed aiming movements. By manipulating task difficulty, according to target size and distance, we were able to quantify processes related to motor planning in 10 individuals with FRDA and 10 matched control participants. Compared to control participants, people with FRDA were significantly disadvantaged in terms of movement time to targets with an increasing index of difficulty. Successful completion of this task requires both preplanning of movement and online error detection and correction. The cerebellum and its connections to the frontal cortex via cerebro-ponto-cerebello-thalamo-cerebral loops are fundamental to both processes. These results lend further support to our contention that in FRDA these loops are impaired, reflecting a failure to access prefrontal/anterior regions necessary for effective management of preplanning of movement and online error correction., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Friedreich ataxia (FRDA) is the most common of the genetically inherited ataxias. We recently demonstrated that people with FRDA have impairment in motor planning - most likely because of pathology affecting the cerebral cortex and/or cerebello-cortical projections. We used the Simon interference task to examine how effective 13 individuals with FRDA were at inhibiting inappropriate automatic responses associated with stimulus-response incompatibility in comparison with control participants. Participants had to respond to arrow targets according to two features which were either congruent or incongruent. We found that individuals with FRDA were differentially affected in reaction time to incongruent, compared with congruent stimuli, when compared with control participants. There was a significant negative correlation between age of onset and the incongruency effect, suggesting an impact of FRDA on the developmental unfolding of motor cognition, independent of the effect of disease duration. Future neuroimaging studies will be required to establish whether this dysfunction is due to cerebellar impairment disrupting cerebro-ponto-cerebello-thalamo-cerebral loops (and thus cortical function), direct primary cortical pathology, or a possible combination of the two., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The cerebellar and spinocerebellar dysfunction seen in Friedreich ataxia (FRDA) has known effects on motor function. Recently, it was suggested that people with FRDA may also have impairment in motor planning, either because of cortical pathology or because of cerebello-cortical projections. Fifteen adults with FRDA and 15 matched controls completed a task requiring reciprocating movements between two buttons on a tapping board. Occasionally there was one of three "oddball" stimuli requiring reprogramming of movement. These were change in (1) direction, (2) extent or (3) direction and extent. We hypothesized that people with FRDA would have prolonged movement times due to their movement disorder, and that changes in preparation time would be affected in a way similar to controls, unless there was impairment in motor planning in FRDA. Movement execution and, to a lesser degree, movement preparation were impaired in individuals with FRDA. We argue this points to disturbed cortical function. There was a significant negative correlation between age of onset and all three reprogramming conditions, suggesting an impact of FRDA on developing motor planning. Future studies will be required to establish whether this dysfunction is due to cerebellar impairment interrupting cerebro-ponto-cerebello-thalamo-cerebral loops, primary cortical pathology or a combination of the two.

Friedreich Ataxia (FRDA) is the commonest inherited ataxia. Clinical trials of pharmaceuticals are increasingly being conducted in this condition. This requires the most accurate outcome measures to enable trials to be conducted with a minimum number of subjects in the shortest time frame and to minimize the risk of false negative results. Upper limb function is a major area of morbidity in FRDA. We therefore have compared the performance of three tests of upper limb function in FRDA: the Nine Hole Peg Test (9HPT), Box and Blocks Test (BBT) and Jebsen Taylor Hand Function Test (JTHFT). This study was undertaken to ascertain the best test for inclusion in a Friedreich Ataxia Functional Composite (FAFC) test for use in clinical studies and therapeutic trials. The three tests were administered to the dominant and non-dominant upper limbs of 38 individuals with genetically proven FRDA on two occasions, 12 months apart. The results of testing were correlated with the following disease parameters; age at disease onset, disease duration and score for the Friedreich Ataxia Rating Scale (FARS). The responsiveness to change of each test was assessed by measuring the effect size and calculations of the number of subjects required for similarly powered therapeutic trials. Results for all tests correlated significantly with disease duration and FARS score. The only test scores that changed significantly over 12 months were those for the non-dominant 9HPT and BBT. Scores for these two tests also had the largest effect sizes and required the fewest subjects for similarly powered therapeutic trials. We conclude, therefore, that the non-dominant 9HPT and BBT are the best tests for inclusion in a FAFC. Since the 9HPT has already been suggested for inclusion in a FAFC, we recommend that this test is used but that it is the non-dominant limb that is tested.

Objective: The striatum and its projections are thought to be the earliest sites of Huntington's disease (HD) pathology. This study aimed to investigate progression of striatal pathology in symptomatic HD using diffusion tensor imaging., Method: Diffusion weighted images were acquired in 18 HD patients and in 17 healthy controls twice, 1 year apart. Mean diffusivity (MD) was calculated in the caudate, putamen, thalamus and corpus callosum, and compared between groups. In addition, caudate width was measured using T1 high resolution images and correlated with caudate MD. Correlation analyses were also performed in HD between caudate/putamen MD and clinical measures., Results: MD was significantly higher in the caudate and putamen bilaterally for patients compared with controls at both time points although there were no significant MD differences in the thalamus or corpus callosum. For both groups, MD did not change significantly in any region from baseline to year 1. There was a significant negative correlation between caudate width and MD in patients at baseline but no correlation between these parameters in controls. There was also a significant negative correlation between Mini-Mental State Examination scores and caudate MD and putamen MD at both time points in HD., Conclusions: It appears that microstructural changes influence cognitive status in HD. Although MD was significantly higher in HD compared with controls at both time points, there were no longitudinal changes in either group. This finding does not rule out the possibility that MD could be a sensitive biomarker for detecting early change in preclinical HD.

Friedreich ataxia (FRDA), the commonest of the inherited ataxias, is a multisystem neurodegenerative condition that affects ocular motor function. We assessed eye movement abnormalities in 20 individuals with genetically confirmed FRDA and compared these results to clinical measures. All subjects were assessed with infrared oculography. Fifteen individuals underwent a full protocol of eye movement recordings. Ten subjects were analysed using two-dimensional scleral coil equipment and five using three-dimensional scleral coil recording equipment. We also recorded visual quality of life, Sloan low contrast letter acuity and Friedreich Ataxia Rating Scale scores to compare to the visual measures. Whilst saccadic velocity was essentially normal, saccadic latency was prolonged. The latency correlated with clinical measures of disease severity, including the scores for the Friedreich Ataxia Rating Scale and the Sloan low contrast letter acuity tests. Fixation abnormalities consisting of square wave jerks and ocular flutter were common, and included rare examples of vertical square wave jerks. Vestibular abnormalities were also evident in the group, with markedly reduced vestibulo-ocular reflex gain and prolonged latency. The range of eye movement abnormalities suggest that neurological dysfunction in FRDA includes brainstem, cortical and vestibular pathways. Severe vestibulopathy with essentially normal saccadic velocity are hallmarks of FRDA and differentiate it from a number of the dominant spinocerebellar ataxias. The correlation of saccadic latency with FARS score raises the possibility of its use as a biomarker for FRDA clinical trials.

The aim of this study was to examine the impact of Friedreich ataxia (FRDA) on quality of life (QOL) using a generic tool to explore factors potentially associated with health status. Sixty-three individuals with genetically confirmed FRDA, self completed the Medical Outcomes Study 36 item Short Form Health Survey Version 2 (SF-36V2) and were assessed using the FRDA Rating Scale. Disease-specific, demographic, and social characteristics were also recorded. SF-36V2 results were compared with Australian population norms. Sample subgroups of disease severity and age at disease onset were reviewed. Physical and mental component summaries were examined in relation to clinical and social characteristics using multiple linear regression. QOL is significantly worse in individuals with FRDA compared with population norms. Those with severe disease did not perceive a lower QOL than those with mild or moderate disease except in their physical functioning. A later age of onset and increased disease severity were negatively associated with physical QOL, whilst, increased disease duration was positively associated with mental QOL. There were limitations associated with the use of SF-36V2 in the FRDA population. Further exploration of health-related QOL and FRDA may benefit from the use of a more appropriate generic tool.

The injury associated with implantation of an inert gelatin matrix (gel foam) into normal mouse striatum induces a long-lived increase in binding of [3H]mazindol to presynaptic dopamine uptake sites, probably due to proliferation of striatal dopaminergic terminals. Because of the known effects of leukaemia inhibitory factor (LIF) on catecholaminergic cells, we tested the hypothesis that LIF may alter the striatal dopaminergic response to injury in vivo. Application of LIF to mouse striatum in a gel foam implant abolished the usual injury induced proliferation of dopamine uptake sites. The ability of LIF to prevent proliferation of dopamine terminals may have important implications for our understanding of neural regeneration, the aetiology of Parkinson's disease and its treatment by intrastriatal grafting.

A series of compensatory mechanisms within the dopaminergic system have been shown to maintain clinical function in the presence of dopamine loss. Experimental evidence for increased presynaptic dopamine turnover owing to increased dopamine synthesis, release, and reduced reuptake exists. Direct evidence that these mechanisms maintain extracellular dopamine levels is provided by intracerebral microdialysis techniques. Postsynaptic denervation supersensitivity clearly occurs with D2 dopamine receptors, although this is less evident with D1 receptors. Similarly, mechanisms of plasticity have been shown to be relevant in human postmortem and Positron Emission Tomographic studies of patients with Parkinson's disease. However, although presynaptic increases in dopamine turnover are well documented, postsynaptic D1 and D2 receptor changes have been more difficult to establish, mainly because of methodological difficulties. D2, but not D1, receptor increases have been documented in drug naive Parkinsonian patients with PET techniques. In transplantation of adrenal gland to striatum in animal models and patients with Parkinsonism where clinical improvement occurs, plasticity of host response may be as important as plasticity of the graft. Although some elements of the compensatory mechanism of dopamine plasticity may be deleterious, such as dyskinesias owing to dopamine receptor supersensitivity, the overall effect of delay and minimization of the clinical expression of disease is advantageous. An even greater understanding of the mechanisms involved may assist in developing future therapeutic strategies.