Gradient of microstructural damage along the dentato-thalamo-cortical tract in Friedreich ataxia.

OBJECTIVE: The dentato-thalamo-cortical tract (DTT) is the main cerebellar efferent pathway. Degeneration of the DTT is a core feature of Friedreich ataxia (FRDA). However, it remains unclear whether DTT disruption is spatially specific, with some segments being more impacted than others. This study aimed to investigate microstructural integrity along the DTT in FRDA using a profilometry diffusion MRI (dMRI) approach. METHODS: MRI data from 45 individuals with FRDA (mean age: 33.2 ± 13.2, Male/Female: 26/19) and 37 healthy controls (mean age: 36.5 ± 12.7, Male/Female:18/19) were included in this cross-sectional multicenter study. A profilometry analysis was performed on dMRI data by first using tractography to define the DTT as the white matter pathway connecting the dentate nucleus to the contralateral motor cortex. The tract was then divided into 100 segments, and dMRI metrics of microstructural integrity (fractional anisotropy, mean diffusivity and radial diffusivity) at each segment were compared between groups. The process was replicated on the arcuate fasciculus for comparison. RESULTS: Across all diffusion metrics, the region of the DTT connecting the dentate nucleus and thalamus was more impacted in FRDA than downstream cerebral sections from the thalamus to the cortex. The arcuate fasciculus was minimally impacted. INTERPRETATION: Our study further expands the current knowledge about brain involvement in FRDA, showing that microstructural abnormalities within the DTT are weighted to early segments of the tract (i.e., the superior cerebellar peduncle). These findings are consistent with the hypothesis of DTT undergoing anterograde degeneration arising from the dentate nuclei and progressing to the primary motor cortex.

Insights into the effects of Friedreich ataxia on the left ventricle using T1 mapping and late gadolinium enhancement.

BACKGROUND: The left ventricular (LV) changes which occur in Friedreich ataxia (FRDA) are incompletely understood. METHODS: Cardiac magnetic resonance (CMR) imaging was performed using a 1.5T scanner in subjects with FRDA who are homozygous for an expansion of an intron 1 GAA repeat in the FXN gene. Standard measurements were performed of LV mass (LVM), LV end-diastolic volume (LVEDV) and LV ejection fraction (LVEF). Native T1 relaxation time and the extracellular volume fraction (ECV) were utilised as markers of left ventricular (LV) diffuse myocardial fibrosis and late gadolinium enhancement (LGE) was utilised as a marker of LV replacement fibrosis. FRDA genetic severity was assessed using the shorter FXN GAA repeat length (GAA1). RESULTS: There were 93 subjects with FRDA (63 adults, 30 children, 54% males), 9 of whom had a reduced LVEF (<55%). A LVEDV below the normal range was present in 39%, a LVM above the normal range in 22%, and an increased LVM/LVEDV ratio in 89% subjects. In adults with a normal LVEF, there was an independent positive correlation of LVM with GAA1, and a negative correlation with age, but no similar relationships were seen in children. GAA1 was positively correlated with native T1 time in both adults and children, and with ECV in adults, all these associations independent of LVM and LVEDV. LGE was present in 21% of subjects, including both adults and children, and subjects with and without a reduced LVEF. None of GAA1, LVM or LVEDV were predictors of LGE. CONCLUSION: An association between diffuse interstitial LV myocardial fibrosis and genetic severity in FRDA was present independently of FRDA-related LV structural changes. Localised replacement fibrosis was found in a minority of subjects with FRDA and was not associated with LV structural change or FRDA genetic severity in subjects with a normal LVEF.

Nerve ultrasound in Friedreich's Ataxia: enlarged nerves as a biomarker of disease severity.

OBJECTIVE: In Friedreich's ataxia research, the focus is on discovering treatments and biomarkers to assess disease severity and treatment effects. Our study examines high-resolution nerve ultrasound in these patients, seeking correlations with established clinical markers of disease severity. METHOD: Ten patients with Friedreich's Ataxia underwent a comprehensive clinical assessment with established scales (SARA, FARS, mFARS, INCAT, ADL 0-36, IADL). Additionally, they underwent nerve conduction studies and high-resolution nerve ultrasound. Quantitative evaluation of nerve cross-sectional area, conducted at 24 nerve sites using high-resolution nerve ultrasound, was compared with data obtained from 20 healthy volunteers. RESULTS: All the patients had a severe sensory axonal neuropathy. High-resolution nerve ultrasound showed significant increase, in cross sectional area, of median and ulnar nerves at the axilla and arm. The cumulative count of affected nerve sites was directly associated with clinical disability, as determined by SARA, FARS, mFARS, ADL 0-36, and INCAT score, while displaying an inverse correlation with IADL. CONCLUSIONS: Our study shows that high-resolution ultrasound reveals notable nerve abnormalities, primarily in the upper limbs of patients diagnosed with Friedreich's Ataxia. The observed correlation between these nerve abnormalities and clinical disability scales indicates the potential use of this technique as a biomarker for evaluating disease severity and treatment effects. SIGNIFICANCE: Nerve Ultrasound is a potential biomarker of disease severity in Friedreich's Ataxia.

Free-Water Imaging in Friedreich Ataxia Using Multi-Compartment Models.

BACKGROUND: The neurological phenotype of Friedreich ataxia (FRDA) is characterized by neurodegeneration and neuroinflammation in the cerebellum and brainstem. Novel neuroimaging approaches quantifying brain free-water using diffusion magnetic resonance imaging (dMRI) are potentially more sensitive to these processes than standard imaging markers. OBJECTIVES: To quantify the extent of free-water and microstructural change in FRDA-relevant brain regions using neurite orientation dispersion and density imaging (NODDI), and bitensor diffusion tensor imaging (btDTI). METHOD: Multi-shell dMRI was acquired from 14 individuals with FRDA and 14 controls. Free-water measures from NODDI (FISO) and btDTI (FW) were compared between groups in the cerebellar cortex, dentate nuclei, cerebellar peduncles, and brainstem. The relative sensitivity of the free-water measures to group differences was compared to microstructural measures of NODDI intracellular volume, free-water corrected fractional anisotropy, and conventional uncorrected fractional anisotropy. RESULTS: In individuals with FRDA, FW was elevated in the cerebellar cortex, peduncles (excluding middle), dentate, and brainstem (P < 0.005). FISO was elevated primarily in the cerebellar lobules (P < 0.001). On average, FW effect sizes were larger than all other markers (mean ηρ 2 = 0.43), although microstructural measures also had very large effects in the superior and inferior cerebellar peduncles and brainstem (ηρ 2 > 0.37). Across all regions and metrics, effect sizes were largest in the superior cerebellar peduncles (ηρ 2 > 0.46). CONCLUSIONS: Multi-compartment diffusion measures of free-water and neurite integrity distinguish FRDA from controls with large effects. Free-water magnitude in the brainstem and cerebellum provided the greatest distinction between groups. This study supports further applications of multi-compartment diffusion modeling, and investigations of free-water as a measure of disease expression and progression in FRDA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Reduced cerebello-cerebral functional connectivity correlates with disease severity and impaired white matter integrity in Friedreich ataxia.

Friedreich ataxia (FRDA) is a rare, inherited neurodegenerative disease characterised in most cases by progressive and debilitating motor dysfunction. Degeneration of cerebellar white matter pathways have been previously reported, alongside indications of cerebello-cerebral functional alterations. In this work, we examine resting-state functional connectivity changes within cerebello-cerebral circuits, and their associations with disease severity (Scale for the Assessment and Rating of Ataxia [SARA]), psychomotor function (speeded and paced finger tapping), and white matter integrity (diffusion tensor imaging) in 35 adults with FRDA and 45 age and sex-matched controls. Voxel-wise seed-based functional connectivity was assessed for three cerebellar cortical regions (anterior lobe, lobules I-V; superior posterior lobe, lobules VI-VIIB; inferior posterior lobe, lobules VIIIA-IX) and two dentate nucleus seeds (dorsal and ventral). Compared to controls, people with FRDA showed significantly reduced connectivity between the anterior cerebellum and bilateral pre/postcentral gyri, and between the superior posterior cerebellum and left dorsolateral PFC. Greater disease severity correlated with lower connectivity in these circuits. Lower anterior cerebellum-motor cortex functional connectivity also correlated with slower speeded finger tapping and less fractional anisotropy in the superior cerebellar peduncles, internal capsule, and precentral white matter in the FRDA cohort. There were no significant between-group differences in inferior posterior cerebellar or dentate nucleus connectivity. This study indicates that altered cerebello-cerebral functional connectivity is associated with functional status and white matter damage in cerebellar efferent pathways in people with FRDA, particularly in motor circuits.

Evaluation of diaphragm functions with diaphragm ultrasound and pulmonary function tests in individuals with Friedreich's ataxia.

Background/aim: It is known that the correlation of pulmonary function tests (PFT) with muscle dysfunction is insufficient. Here, we aimed to evaluate the diaphragm functions in individuals with Friedreich's ataxia (FRDA) and to examine its relationship with respiratory parameters and disease severity. Materials and methods: This prospective study, conducted between November and December 2022, at Erciyes University, included 14 individuals with genetically confirmed FRDA and an age- and gender-matched healthy control group of eight individuals. We examined pulmonary functions with spirometric methods and evaluated diaphragm excursion, and diaphragm thickness-expiratory (Tde) and - end of inspiration (Tdi) with ultrasonography during calm breathing. Thickening fraction (TF) calculated. Also, we examined PaCO2 at rest. The neurological status of individuals was assessed using the Scale for the Assessment and Rating of Ataxia (SARA). Results: The mean values of FEV1(lt), FEV1(%), FVC (lt), and FVC (%) were higher in the control group (p; <0.001, 0.013, <0.001, and 0.009, respectively). Also, mean Tdi, Tde, excursion and TF were lower in the FRDA group compared to the control group (p = 0.005, 0.294,0.005, and 0.019, respectively). The mean excursion value was 1.13 ± 0.54cm in the FRDA group and 1.71 ± 0.49cm in the control group. There is a strong, negative, and statistically significant correlation between SARA total score with excursion and TF (r = -0.7432, p = 0.002; r = -0.697, p = 0.008). There is no statistically significant relationship between excursion and BMI, standing-to-supine decrease in FVC, FEV1, and PaCO2. Also, the relationship between maximal inspiratory pressure (PImax) and excursion was moderate. Conclusion: Diaphragm ultrasound may reveal respiratory dysfunction better than PFT. Diaphragm excursion and TF are associated with disease scores in individuals with FDRA. Further studies are needed regarding the detection of alveolar hypoventilation.

Importance of an echocardiogram in the evaluation of ataxia.

We present the case of a boy in his middle childhood with gait ataxia and loss of reflexes with a 1-year onset. He had a background of an autism spectrum disorder but was otherwise healthy. A paediatric cardiology assessment was requested to investigate possible cardiac involvement associated to his neurological symptoms. Even though he had no cardiac symptoms and a normal electrocardiography, the echocardiogram revealed severe asymmetric left ventricle hypertrophy consistent with hypertrophic cardiomyopathy. This prompted genetic testing and the diagnosis of Friedreich's ataxia was confirmed.

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.

In vivo assessment of OXPHOS capacity using 3 T CrCEST MRI in Friedreich's ataxia.

BACKGROUND: Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by decreased expression of frataxin, a protein involved in many cellular metabolic processes, including mitochondrial oxidative phosphorylation (OXPHOS). Our objective was to assess skeletal muscle oxidative metabolism in vivo in adults with FRDA as compared to adults without FRDA using chemical exchange saturation transfer (CrCEST) MRI, which measures free creatine (Cr) over time following an in-magnet plantar flexion exercise. METHODS: Participants included adults with FRDA (n = 11) and healthy adults (n = 25). All underwent 3-Tesla CrCEST MRI of the calf before and after in-scanner plantar flexion exercise. Participants also underwent whole-body dual-energy X-ray absorptiometry (DXA) scans to measure body composition and completed questionnaires to assess physical activity. RESULTS: We found prolonged post-exercise exponential decline in CrCEST (τCr) in the lateral gastrocnemius (LG, 274 s vs. 138 s, p = 0.01) in adults with FRDA (vs. healthy adults), likely reflecting decreased OXPHOS capacity. Adults with FRDA (vs. healthy adults) also engaged different muscle groups during exercise, as indicated by muscle group-specific changes in creatine with exercise (∆CrCEST), possibly reflecting decreased coordination. Across all participants, increased adiposity and decreased usual physical activity were associated with smaller ∆CrCEST. CONCLUSION: In FRDA, CrCEST MRI may be a useful biomarker of muscle-group-specific decline in OXPHOS capacity that can be leveraged to track within-participant changes over time. Appropriate participant selection and further optimization of the exercise stimulus will enhance the utility of this technique.

Tract-Specific Spinal Cord Diffusion Tensor Imaging in Friedreich's Ataxia.

BACKGROUND: Spinal cord (SC) damage is a hallmark in Friedreich's ataxia (FRDA). Neuroimaging has been able to capture some SC macroscopic changes, but no study has evaluated microstructural SC white matter (WM) damage in vivo. OBJECTIVES: We designed a cross-sectional study to evaluate microstructural integrity in SC WM tracts of FRDA patients using diffusion tensor imaging (DTI) with an automated analysis pipeline. METHODS: Thirty patients and 30 matched healthy controls underwent 3 Tesla (T) magnetic resonance imaging (MRI). We obtained cervical SC T2 and diffusion-weighted imaging (DWI) acquisitions. Images were processed using the Spinal Cord Toolbox v.4.3.0. For levels C2-C5, we measured cross-sectional area (CSA) and WM DTI parameters (axial diffusivity [AD], fractional anisotropy [FA], radial diffusivity [RD], and mean diffusivity [MD]). Age, duration, and FARS scores were also obtained. RESULTS: Mean age and disease duration of patients were 31 ± 10 and 11 ± 9 years, respectively. There was CSA reduction in FRDA amongst all levels. Between-group differences in FA, MD, and RD in total white matter (TWM), dorsal columns (DC), fasciculus gracilis (FG), fasciculus cuneatus (FC), and corticospinal tracts (CST) were present in all levels. FA and RD from TWM, DC, FC, and CST correlated with FARS scores, and in CST they also correlated with disease duration. CONCLUSION: DTI uncovered abnormalities in SC WM tracts, which correlated with clinical features in FRDA. CSA and CST FA in C2 correlated best with disease severity, whereas DC FA showed the largest effect size to differentiate patients and healthy controls. SC WM microstructure is a potential neuroimaging biomarker to be explored in the disease. © 2021 International Parkinson and Movement Disorder Society.

Neuroinflammation in the Cerebellum and Brainstem in Friedreich Ataxia: An [18F]-FEMPA PET Study.

BACKGROUND: Neuroinflammation is proposed to accompany, or even contribute to, neuropathology in Friedreich ataxia (FRDA), with implications for disease treatment and tracking. OBJECTIVES: To examine brain glial activation and systemic immune dysfunction in people with FRDA and quantify their relationship with symptom severity, duration, and onset age. METHODS: Fifteen individuals with FRDA and 13 healthy controls underwent brain positron emission tomography using the translocator protein (TSPO) radioligand [18 F]-FEMPA, a marker of glial activation, together with the quantification of blood plasma inflammatory cytokines. RESULTS: [18 F]-FEMPA binding was significantly increased in the dentate nuclei (d = 0.67), superior cerebellar peduncles (d = 0.74), and midbrain (d = 0.87), alongside increased plasma interleukin-6 (IL-6) (d = 0.73), in individuals with FRDA compared to controls. Increased [18 F]-FEMPA binding in the dentate nuclei, brainstem, and cerebellar anterior lobe correlated with earlier age of symptom onset (controlling for the genetic triplet repeat expansion length; all r part < -0.6), and in the pons and anterior lobe with shorter disease duration (r = -0.66; -0.73). CONCLUSIONS: Neuroinflammation is evident in brain regions implicated in FRDA neuropathology. Increased neuroimmune activity may be related to earlier disease onset and attenuate over the course of the illness. © 2021 International Parkinson and Movement Disorder Society.

Longitudinal Assessment Using Optical Coherence Tomography in Patients with Friedreich's Ataxia.

Ocular abnormalities occur frequently in Friedreich's ataxia (FRDA), although visual symptoms are not always reported. We evaluated a cohort of patients with FRDA to characterise the clinical phenotype and optic nerve findings as detected with optical coherence tomography (OCT). A total of 48 patients from 42 unrelated families were recruited. Mean age at onset was 13.8 years (range 4-40), mean disease duration 19.5 years (range 5-43), mean disease severity as quantified with the Scale for the Assessment and Rating of Ataxia 22/40 (range 4.5-38). All patients displayed variable ataxia and two-thirds had ocular abnormalities. Statistically significant thinning of average retinal nerve fibre layer (RNFL) and thinning in all but the temporal quadrant compared to controls was demonstrated on OCT. Significant RNFL and macular thinning was documented over time in 20 individuals. Disease severity and visual acuity were correlated with RNFL and macular thickness, but no association was found with disease duration. Our results highlight that FDRA is associated with subclinical optic neuropathy. This is the largest longitudinal study of OCT findings in FRDA to date, demonstrating progressive RNFL thickness decline, suggesting that RNFL thickness as measured by OCT has the potential to become a quantifiable biomarker for the evaluation of disease progression in FRDA.

Age of onset modulates resting-state brain network dynamics in Friedreich Ataxia.

This magnetoencephalography (MEG) study addresses (i) how Friedreich ataxia (FRDA) affects the sub-second dynamics of resting-state brain networks, (ii) the main determinants of their dynamic alterations, and (iii) how these alterations are linked with FRDA-related changes in resting-state functional brain connectivity (rsFC) over long timescales. For that purpose, 5 min of resting-state MEG activity were recorded in 16 FRDA patients (mean age: 27 years, range: 12-51 years; 10 females) and matched healthy subjects. Transient brain network dynamics was assessed using hidden Markov modeling (HMM). Post hoc median-split, nonparametric permutations and Spearman rank correlations were used for statistics. In FRDA patients, a positive correlation was found between the age of symptoms onset (ASO) and the temporal dynamics of two HMM states involving the posterior default mode network (DMN) and the temporo-parietal junctions (TPJ). FRDA patients with an ASO <11 years presented altered temporal dynamics of those two HMM states compared with FRDA patients with an ASO > 11 years or healthy subjects. The temporal dynamics of the DMN state also correlated with minute-long DMN rsFC. This study demonstrates that ASO is the main determinant of alterations in the sub-second dynamics of posterior associative neocortices in FRDA patients and substantiates a direct link between sub-second network activity and functional brain integration over long timescales.

Brain Structure and Degeneration Staging in Friedreich Ataxia: Magnetic Resonance Imaging Volumetrics from the ENIGMA-Ataxia Working Group.

OBJECTIVE: Friedreich ataxia (FRDA) is an inherited neurological disease defined by progressive movement incoordination. We undertook a comprehensive characterization of the spatial profile and progressive evolution of structural brain abnormalities in people with FRDA. METHODS: A coordinated international analysis of regional brain volume using magnetic resonance imaging data charted the whole-brain profile, interindividual variability, and temporal staging of structural brain differences in 248 individuals with FRDA and 262 healthy controls. RESULTS: The brainstem, dentate nucleus region, and superior and inferior cerebellar peduncles showed the greatest reductions in volume relative to controls (Cohen d = 1.5-2.6). Cerebellar gray matter alterations were most pronounced in lobules I-VI (d = 0.8), whereas cerebral differences occurred most prominently in precentral gyri (d = 0.6) and corticospinal tracts (d = 1.4). Earlier onset age predicted less volume in the motor cerebellum (rmax  = 0.35) and peduncles (rmax  = 0.36). Disease duration and severity correlated with volume deficits in the dentate nucleus region, brainstem, and superior/inferior cerebellar peduncles (rmax  = -0.49); subgrouping showed these to be robust and early features of FRDA, and strong candidates for further biomarker validation. Cerebral white matter abnormalities, particularly in corticospinal pathways, emerge as intermediate disease features. Cerebellar and cerebral gray matter loss, principally targeting motor and sensory systems, preferentially manifests later in the disease course. INTERPRETATION: FRDA is defined by an evolving spatial profile of neuroanatomical changes beyond primary pathology in the cerebellum and spinal cord, in line with its progressive clinical course. The design, interpretation, and generalization of research studies and clinical trials must consider neuroanatomical staging and associated interindividual variability in brain measures. ANN NEUROL 2021;90:570-583.

Longitudinal structural brain changes in Friedreich ataxia depend on disease severity: the IMAGE-FRDA study.

BACKGROUND: Friedreich ataxia is an inherited neurodegenerative disease, with cerebral and cerebellar pathology evident. Despite an increased understanding of its neuropathology, disease progression in this disease remains poorly understood. This study aimed to characterise longitudinal change in brain structure using a multi-modal approach across cerebral and cerebellar grey and white matter. METHODS: T1-weighted, diffusion-tensor, and magnetisation transfer magnetic resonance images were obtained from 28 individuals with Friedreich ataxia and 29 age- and gender-matched controls at two time-points, 2 years apart. Region-of-interest and exploratory between-group comparisons assessed changes in brain macrostructure (cerebellar lobule volume, cerebral cortical thickness/gyrification, brain white matter volume) and microstructure (white matter fractional anisotropy, mean/axial/radial diffusivity, magnetisation transfer ratio). Rates of change were correlated against change in neurological severity, Time 1 severity, and onset age. RESULTS: Individuals with Friedreich ataxia had a greater rate of white matter volume loss than controls in the superior cerebellar peduncles and right peri-thalamic/posterior cerebral regions, and greater reduction in left primary motor cortex gyrification. Greater cerebellar/brainstem white matter volume loss and right dorsal premotor gyrification loss was observed amongst individuals with less severe neurological symptoms at Time 1. Conversely, cerebral atrophy and changes in axial diffusivity were observed in individuals with more severe Time 1 symptoms. Progression in radial diffusivity was more pronounced amongst individuals with earlier disease onset. Greater right ventral premotor gyrification loss correlated with greater neurological progression. CONCLUSION: Heterogeneity in Friedreich ataxia progression is observed at the neurobiological level, with evidence of earlier cerebellar and later cerebral degeneration.

Toward quantitative neuroimaging biomarkers for Friedreich's ataxia at 7 Tesla: Susceptibility mapping, diffusion imaging, R2 and R1 relaxometry.

Friedreich's ataxia (FRDA) is a rare genetic disorder leading to degenerative processes. So far, no effective treatment has been found. Therefore, it is important to assist the development of medication with imaging biomarkers reflecting disease status and progress. Ten FRDA patients (mean age 37 ± 14 years; four female) and 10 age- and sex-matched controls were included. Acquisition of magnetic resonance imaging (MRI) data for quantitative susceptibility mapping, R1 , R2 relaxometry and diffusion imaging was performed at 7 Tesla. Results of volume of interest (VOI)-based analyses of the quantitative data were compared with a voxel-based morphometry (VBM) evaluation. Differences between patients and controls were assessed using the analysis of covariance (ANCOVA; p < 0.01) with age and sex as covariates, effect size of group differences, and correlations with disease characteristics with Spearman correlation coefficient. For the VBM analysis, a statistical threshold of 0.001 for uncorrected and 0.05 for corrected p-values was used. Statistically significant differences between FRDA patients and controls were found in five out of twelve investigated structures, and statistically significant correlations with disease characteristics were revealed. Moreover, VBM revealed significant white matter atrophy within regions of the brainstem, and the cerebellum. These regions overlapped partially with brain regions for which significant differences between healthy controls and patients were found in the VOI-based quantitative MRI evaluation. It was shown that two independent analyses provided overlapping results. Moreover, positive results on correlations with disease characteristics were found, indicating that these quantitative MRI parameters could provide more detailed information and assist the search for effective treatments.

Multiple mechanisms underpin cerebral and cerebellar white matter deficits in Friedreich ataxia: The IMAGE-FRDA study.

Friedreich ataxia is a progressive neurodegenerative disorder with reported abnormalities in cerebellar, brainstem, and cerebral white matter. White matter structure can be measured using in vivo neuroimaging indices sensitive to different white matter features. For the first time, we examined the relative sensitivity and relationship between multiple white matter indices in Friedreich ataxia to more richly characterize disease expression and infer possible mechanisms underlying the observed white matter abnormalities. Diffusion-tensor, magnetization transfer, and T1-weighted structural images were acquired from 31 individuals with Friedreich ataxia and 36 controls. Six white matter indices were extracted: fractional anisotropy, diffusivity (mean, axial, radial), magnetization transfer ratio (microstructure), and volume (macrostructure). For each index, whole-brain voxel-wise between-group comparisons and correlations with disease severity, onset age, and gene triplet-repeat length were undertaken. Correlations between pairs of indices were assessed in the Friedreich ataxia cohort. Spatial similarities in the voxel-level pattern of between-group differences across the indices were also assessed. Microstructural abnormalities were maximal in cerebellar and brainstem regions, but evident throughout the brain, while macroscopic abnormalities were restricted to the brainstem. Poorer microstructure and reduced macrostructural volume correlated with greater disease severity and earlier onset, particularly in peri-dentate nuclei and brainstem regions. Microstructural and macrostructural abnormalities were largely independent. Reduced fractional anisotropy was most strongly associated with axial diffusivity in cerebral tracts, and magnetization transfer in cerebellar tracts. Multiple mechanisms likely underpin white matter abnormalities in Friedreich ataxia, with differential impacts in cerebellar and cerebral pathways.

Very-late-onset Friedreich's ataxia: diagnosis in a kindred with late-onset cerebellar ataxia.

Friedreich's ataxia is classically considered a disease with onset in the first or second decade. However, late-onset (age of onset 25-39 years) and very-late-onset (age of onset >40 years) forms do occur rarely. Misdiagnosis is common, particularly because the later onset forms of Friedreich's ataxia commonly do not show characteristic features of the disorder (areflexia, dysarthria, sensory neuropathy, extensor plantars, amyotrophy, cardiac involvement, diabetes mellitus, scoliosis). Also, there may be atypical features such as spasticity, brisk reflexes and laryngeal dystonia. We present the clinical, imaging and genetic findings of a kindred with very-late-onset Friedreich's ataxia and discuss the pitfalls and risk of misdiagnosis.

Neurochemical profiles in hereditary ataxias: A meta-analysis of Magnetic Resonance Spectroscopy studies.

Magnetic resonance spectroscopy (MRS) is applied to investigate the neurochemical profiles of degenerative hereditary ataxias. This meta-analysis provides a quantitative review and reappraisal of MRS findings in spinocerebellar ataxias (SCA) and Friedreich ataxia (FA) available to date. From each study, changes in N-acetyl aspartate (NAA), choline-containing compounds (Cho) and myo-Inositol (mI) ratios to total creatine (Cr) were calculated for groups of patients (1499 patients in total: SCA1 = 223, SCA2 = 298, SCA3 = 711, SCA6 = 165, and FA = 102) relative to their own control group, mostly in cerebellum and pons. SCA1, 2, 3, 6, and FA patients showed overall decreased NAA/Cr compared to controls. Decreased Cho/Cr was visible in SCA1, 2, and 3 and elevated mI/Cr in SCA2 patients in cerebellum. In SCA6 and FA Cho/Cr and mI/Cr did not differ with respect to controls but SCA6 patients indicated higher Cho/Cr compared to SCA1 patients in cerebellum. SCA2 subjects showed the lowest NAA/Cr and Cho/Cr in cerebellum and the highest mI/Cr compared to controls and other genotypes, and therefore the most promising results for a potential biomarker.