Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset

BACKGROUND: The Scale for Assessment and Rating of Ataxia (SARA) is widely used in different types of ataxias and has been chosen as the primary outcome measure in the European natural history study for Friedreich ataxia (FA). METHODS: To assess distribution and longitudinal changes of SARA scores and its single items, we analyzed SARA scores of 502 patients with typical-onset FA (<25 years) participating in the 4-year prospective European FA Consortium for Translational Studies (EFACTS). Pattern of disease progression was determined using linear mixed-effects regression models. The chosen statistical model was re-fitted in order to estimate parameters and predict disease progression. Median time-to-change and rate of score progression were estimated using the Kaplan-Meier method and weighted linear regression models, respectively. RESULTS: SARA score at study enrollment and age at onset were the major predictive factors of total score progression during the 4-year follow-up. To a less extent, age at evaluation also influenced the speed of SARA progression, while disease duration did not improve the prediction of the statistical model. Temporal dynamics of total SARA and items showed a great variability in the speed of score increase during disease progression. Gait item had the highest annual progression rate, with median time for one-point score increase of 1 to 2 years. INTERPRETATION: Analyses of statistical properties of SARA suggest a variable sensitivity of the scale at different disease stages, and provide important information for population selection and result interpretation in future clinical trials

Protocol of a randomized, double-blind, placebo-controlled, parallel-group, multicentre study of the efficacy and safety of nicotinamide in patients with Friedreich ataxia (NICOFA)

Introduction: Currently, no treatment that delays with the progression of Friedreich ataxia is available. In the majority of patients Friedreich ataxia is caused by homozygous pathological expansion of GAA repeats in the first intron of the FXN gene. Nicotinamide acts as a histone deacetylase inhibitor. Dose escalation studies have shown, that short term treatment with dosages of up to 4 g/day increase the expression of FXN mRNA and frataxin protein up to the levels of asymptomatic heterozygous gene carriers. The long-term effects and the effects on clinical endpoints, activities of daily living and quality of life are unknown.Methods: The aim of the NICOFA study is to investigate the efficacy and safety of nicotinamide for the treatment of Friedreich ataxia over 24 months. An open-label dose adjustment wash-in period with nicotinamide (phase A: weeks 1-4) to the individually highest tolerated dose of 2-4 g nicotinamide/day will be followed by a 2 (nicotinamide group): 1 (placebo group) randomization (phase B: weeks 5-104). In the nicotinamide group, patients will continue with their individually highest tolerated dose between 2 and 4 g/d per os once daily and the placebo group patients will be receiving matching placebo. Safety assessments will consist of monitoring and recording of all adverse events and serious adverse events, regular monitoring of haematology, blood chemistry and urine values, regular measurement of vital signs and the performance of physical examinations including cardiological signs. The primary outcome is the change in the Scale for the Assessment and Rating of Ataxia (SARA) over time as compared with placebo in patients with Friedreich ataxia based on the linear mixed effect model (LMEM) model. Secondary endpoints are measures of quality of life, functional motor and cognitive measures, clinician's and patient's global impression-change scales as well as the up-regulation of the frataxin protein level, safety and survival/death.Perspective: The NICOFA study represents one of the first attempts to assess the clinical efficacy of an epigenetic therapeutic intervention for this disease and will provide evidence of possible disease modifying effects of nicotinamide treatment in patients with Friedreich ataxia

The role of protein aggregation in Huntington's disease

Huntington’s disease (HD) is a hereditary progressive neurodegenerative disorder characterised by chorea, general motor impairment, psychiatric disturbances and dementia, leading to death within 10 to 20 years of onset. It is caused by a (CAG)n trinucleotide repeat expansion in the gene IT15 that is translated into a prolonged polyglutamine tract in the protein huntingtin. This mutation leads to the self-association of huntingtin to form aggregates in the brains of affected people. Work in Professor Nicotera’s group at the MRC Toxicology Unit identified expression changes in Rab11, a protein involved in endosomal recycling, in a cell culture model of HD. The aim of this thesis was to investigate whether endosomal recycling is affected in this model. Monitoring the trafficking of labelled transferrin by Western blotting and live-cell imaging showed rapid uptake of transferrin into all cells, but a significantly reduced rate of clearance in cells containing huntingtin aggregates, which was associated with the accumulation of transferrin in the endosomal recycling compartment (ERC). This finding demonstrates an aggregate-specific lesion in the exit of cargo from the ERC in the absence of cell death. As endosomal recycling is essential for correct neuronal function, this process provides a mechanism whereby protein inclusions may contribute to the cognitive and motor deficits seen in HD. A second project focused on purification of aggregates to determine if they could sequester material important for cellular function. Many attempts to purify the aggregates in their intact globular form revealed their highly unspecific affinity towards other proteins, which renders purification methods very susceptible to artefacts. The large globular aggregates could, however, be dispersed by SDS-treatment into fibrils of approximately 10 nm diameter, which were subsequently purified and visualised by electron microscopy

The role of protein aggregation in Huntington's disease

Huntington’s disease (HD) is a hereditary progressive neurodegenerative disorder characterised by chorea, general motor impairment, psychiatric disturbances and dementia, leading to death within 10 to 20 years of onset. It is caused by a (CAG)n trinucleotide repeat expansion in the gene IT15 that is translated into a prolonged polyglutamine tract in the protein huntingtin. This mutation leads to the self-association of huntingtin to form aggregates in the brains of affected people. Work in Professor Nicotera’s group at the MRC Toxicology Unit identified expression changes in Rab11, a protein involved in endosomal recycling, in a cell culture model of HD. The aim of this thesis was to investigate whether endosomal recycling is affected in this model. Monitoring the trafficking of labelled transferrin by Western blotting and live-cell imaging showed rapid uptake of transferrin into all cells, but a significantly reduced rate of clearance in cells containing huntingtin aggregates, which was associated with the accumulation of transferrin in the endosomal recycling compartment (ERC). This finding demonstrates an aggregate-specific lesion in the exit of cargo from the ERC in the absence of cell death. As endosomal recycling is essential for correct neuronal function, this process provides a mechanism whereby protein inclusions may contribute to the cognitive and motor deficits seen in HD. A second project focused on purification of aggregates to determine if they could sequester material important for cellular function. Many attempts to purify the aggregates in their intact globular form revealed their highly unspecific affinity towards other proteins, which renders purification methods very susceptible to artefacts. The large globular aggregates could, however, be dispersed by SDS-treatment into fibrils of approximately 10 nm diameter, which were subsequently purified and visualised by electron microscopy.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Application of Quantitative Motor Assessments in Friedreich Ataxia and Evaluation of Their Relation to Clinical Measures

Friedreich’s ataxia (FRDA) is a rare autosomal-recessive slowly progressive neurodegenerative disorder. As common clinical measures for this devastating disease lack sensitivity, we explored whether (a) the quantitative motor assessments of the Q-Motor battery can enhance clinical characterisation of FRDA; (b) clinical measures can predict Q-Motor outcomes and (c) Q-Motor is sensitive to longitudinal change. At baseline 29 patients and 23 controls and in a 1-year follow-up 14 patients and 6 controls were included. The Q-Motor included lift (manumotography), finger tapping (digitomotography) and pronate/supinate (dysdiadochomotography) tasks. To model responses, a search of generalised linear models was conducted, selecting best fitting models, using demographic and clinical data as predictors. Predictors from selected models were used in linear mixed models to investigate longitudinal changes. Patients with FRDA performed worse than controls on most measures. Modelling of the pronate/supinate task was dominated by SCAFI (SCA functional index) subtasks, while tapping task and lift task models suggested a complex relationship with clinical measures. Longitudinal modelling implied minor changes from baseline to follow-up, while clinical scales mainly showed no change in this sample. Overall Q-Motor likely has favourable properties for assessing distinct motor aspects in severe FRDA as it can be administered in wheelchair-bound patients. Further longitudinal research is warranted to fully characterise its relation to routinely used measures and scales for FRDA

Structural characteristics of the central nervous system in Friedreich ataxia: an in vivo spinal cord and brain MRI study

Friedreich ataxia (FRDA) is a spinocerebellar neurodegenerative disorder and the most common autosomal recessive ataxia, mainly caused by GAA-triplet expansions in the FXN gene. This severely debilitating disease usually manifests around adolescence with a slowly progressive phenotype of spinocerebellar signs, areflexia, sensory neuropathy, pyramidal signs and non-neurological features.Neuropathological studies described reductions of dorsal root ganglia, the spinal cord at all levels and dentate nuclei.1 In vivo MRI approaches confirmed spinal cord alterations in FRDA, which were however focused on upper cervical cord areas,2 while quantitative measurements along the entire spinal cord length are lacking. We therefore aimed to investigate the morphometric pattern of the cervical and thoracic spinal cord in FRDA. In order to provide a more comprehensive picture of spinocerebellar-cerebral alterations, we additionally analysed anatomical brain MRI data and investigated the relative contribution of spinal and brain measurements for the prediction of clinical severity in FDRA

Increased brain tissue sodium concentration in Friedreich ataxia: A multimodal MR imaging study

In patients with Friedreich ataxia, structural MRI is typically used to detect abnormalities primarily in the brainstem, cerebellum, and spinal cord. The aim of the present study was to additionally investigate possible metabolic changes in Friedreich ataxia using in vivo sodium MRI that may precede macroanatomical alterations, and to explore potential associations with clinical parameters of disease progression. Tissue sodium concentration across the whole brain was estimated from sodium MRI maps acquired at 3 T and compared between 24 patients with Friedreich ataxia (21–57 years old, 13 females) and 23 controls (21–60 years old, 12 females). Tensor-based morphometry was used to assess volumetric changes. Total sodium concentrations and volumetric data in brainstem and cerebellum were correlated with clinical parameters, such as severity of ataxia, activity of daily living and disability stage, age, age at onset, and disease duration. Compared to controls, patients showed reduced brain volume in the right cerebellar lobules I-V (difference in means: −0.039% of total intracranial volume [TICV]; Cohen’s d = 0.83), cerebellar white matter (WM) (-0.105%TICV; d = 1.16), and brainstem (-0.167%TICV; d = 1.22), including pons (-0.102%TICV; d = 1.00), medulla (-0.036%TICV; d = 1.72), and midbrain (-0.028%TICV; d = 1.05). Increased sodium concentration was additionally detected in the total cerebellum (difference in means: 2.865 mmol; d = 0.68), and in several subregions with highest effect sizes in left (5.284 mmol; d = 1.01) and right cerebellar lobules I-V (5.456 mmol; d = 1.00), followed by increases in the vermis (4.261 mmol; d = 0.72), and in left (2.988 mmol; d = 0.67) and right lobules VI-VII (2.816 mmol; d = 0.68). In addition, sodium increases were also detected in all brainstem areas (3.807 mmol; d = 0.71 to 5.42 mmol; d = 1.19). After controlling for age, elevated total sodium concentrations in right cerebellar lobules IV were associated with younger age at onset (r = -0.43) and accordingly with longer disease duration in patients (r = 0.43). Our findings support the potential of in vivo sodium MRI to detect metabolic changes of increased total sodium concentration in the cerebellum and brainstem, the key regions in Friedreich ataxia. In addition to structural changes, sodium changes were present in cerebellar hemispheres and vermis without concomitant significant atrophy. Given the association with age at disease onset or disease duration, metabolic changes should be further investigated longitudinally and in larger cohorts of early disease stages to determine the usefulness of sodium MRI as a biomarker for early neuropathological changes in Friedreich ataxia and efficacy measure for future clinical trials

Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset.

Funder: Christina FoundationFunder: EuroAtaxiaFunder: Voyager Therapeutics; doi: http://dx.doi.org/10.13039/100018556BACKGROUND: The Scale for Assessment and Rating of Ataxia (SARA) is widely used in different types of ataxias and has been chosen as the primary outcome measure in the European natural history study for Friedreich ataxia (FA). METHODS: To assess distribution and longitudinal changes of SARA scores and its single items, we analyzed SARA scores of 502 patients with typical-onset FA (<25 years) participating in the 4-year prospective European FA Consortium for Translational Studies (EFACTS). Pattern of disease progression was determined using linear mixed-effects regression models. The chosen statistical model was re-fitted in order to estimate parameters and predict disease progression. Median time-to-change and rate of score progression were estimated using the Kaplan-Meier method and weighted linear regression models, respectively. RESULTS: SARA score at study enrollment and age at onset were the major predictive factors of total score progression during the 4-year follow-up. To a less extent, age at evaluation also influenced the speed of SARA progression, while disease duration did not improve the prediction of the statistical model. Temporal dynamics of total SARA and items showed a great variability in the speed of score increase during disease progression. Gait item had the highest annual progression rate, with median time for one-point score increase of 1 to 2 years. INTERPRETATION: Analyses of statistical properties of SARA suggest a variable sensitivity of the scale at different disease stages, and provide important information for population selection and result interpretation in future clinical trials

Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset

Abstract Background The Scale for Assessment and Rating of Ataxia (SARA) is widely used in different types of ataxias and has been chosen as the primary outcome measure in the European natural history study for Friedreich ataxia (FA). Methods To assess distribution and longitudinal changes of SARA scores and its single items, we analyzed SARA scores of 502 patients with typical‐onset FA (<25 years) participating in the 4‐year prospective European FA Consortium for Translational Studies (EFACTS). Pattern of disease progression was determined using linear mixed‐effects regression models. The chosen statistical model was re‐fitted in order to estimate parameters and predict disease progression. Median time‐to‐change and rate of score progression were estimated using the Kaplan–Meier method and weighted linear regression models, respectively. Results SARA score at study enrollment and age at onset were the major predictive factors of total score progression during the 4‐year follow‐up. To a less extent, age at evaluation also influenced the speed of SARA progression, while disease duration did not improve the prediction of the statistical model. Temporal dynamics of total SARA and items showed a great variability in the speed of score increase during disease progression. Gait item had the highest annual progression rate, with median time for one‐point score increase of 1 to 2 years. Interpretation Analyses of statistical properties of SARA suggest a variable sensitivity of the scale at different disease stages, and provide important information for population selection and result interpretation in future clinical trials