Non-invasive neuromodulation of cerebello-hippocampal volume-behavior relationships.

The study here explores the link between transcranial direct current stimulation (tDCS) and brain-behavior relationships. We propose that tDCS may indirectly influence the complex relationships between brain volume and behavior. We focused on the dynamics between the hippocampus (HPC) and cerebellum (CB) in cognitive processes, a relationship with significant implications for understanding memory and motor skills. Seventy-four young adults (mean age: 22±0.42 years, mean education: 14.7±0.25 years) were randomly assigned to receive either anodal, cathodal, or sham stimulation. Following stimulation, participants completed computerized tasks assessing working memory and sequence learning in a magnetic resonance imaging (MRI) environment. We investigated the statistical interaction between CB and HPC volumes. Our findings showed that individuals with larger cerebellar volumes had shorter reaction times (RT) on a high-load working memory task in the sham stimulation group. In contrast, the anodal stimulation group exhibited faster RTs during the low-load working memory condition. These RT differences were associated with the cortical volumetric interaction between CB-HPC. Literature suggests that anodal stimulation down-regulates the CB and here, those with larger volumes perform more quickly, suggesting the potential need for additional cognitive resources to compensate for cerebellar downregulation. This new insight suggests that tDCS can aid in revealing structure-function relationships, due to greater performance variability, especially in young adults. It may also reveal new targets of interest in the study of aging or in diseases where there is also greater behavioral variability.

Prevalence and Diagnostic Journey of Friedreich's Ataxia in the State of São Paulo, Brazil.

Friedreich's Ataxia (FRDA) is the leading cause of ataxia worldwide, but data on epidemiology and diagnostic journey are scarce, particularly in Latin America. Herein we estimated the prevalence of FRDA in the most populous Brazilian state and characterized the diagnostic odyssey of the disease. We received anonymized data of patients with FRDA from advocacy groups and physicians. Prevalence was estimated dividing the number of patients by the population of the state as reported in the last census. Patients were invited to answer an online survey to describe clinical data and diagnostic journey of the disease. FRDA estimated prevalence was 0.367:100,000, with a slight predominance of women (58.2% vs 41.7%). One hundred and four patients answered the survey (mean age of 37.3 ± 13.8 years; 75.9% classical and 24.0% late onset). On average, 6.2 ± 4.1 physicians were visited before reaching the diagnosis. Mean diagnostic delay was 7.8 ± 6.7 years; no difference between classical and LOFA groups was found. Most of the patients reported unsteadiness and gait abnormalities as the first symptom. Neurologists and orthopedical surgeons were the main specialties first sought by patients. We found a prevalence of 0.36:100,000 for FRDA in the state of São Paulo, Brazil. The disease is characterized by remarkable diagnostic delay, with no relevant differences between classical and LOFA patients.

Cranial Nerve Thinning Distinguishes RFC1-Related Disorder from Other Late-Onset Ataxias.

BACKGROUND: RFC1-related disorder (RFC1/CANVAS) shares clinical features with other late-onset ataxias, such as spinocerebellar ataxias (SCA) and multiple system atrophy cerebellar type (MSA-C). Thinning of cranial nerves V (CNV) and VIII (CNVIII) has been reported in magnetic resonance imaging (MRI) scans of RFC1/CANVAS, but its specificity remains unclear. OBJECTIVES: To assess the usefulness of CNV and CNVIII thinning to differentiate RFC1/CANVAS from SCA and MSA-C. METHODS: Seventeen individuals with RFC1/CANVAS, 57 with SCA (types 2, 3 and 6), 11 with MSA-C and 15 healthy controls were enrolled. The Balanced Fast Field Echo sequence was used for assessment of cranial nerves. Images were reviewed by a neuroradiologist, who classified these nerves as atrophic or normal, and subsequently the CNV was segmented manually by an experienced neurologist. Both assessments were blinded to patient and clinical data. Non-parametric tests were used to assess between-group comparisons. RESULTS: Atrophy of CNV and CNVIII, both alone and in combination, was significantly more frequent in the RFC1/CANVAS group than in healthy controls and all other ataxia groups. Atrophy of CNV had the highest sensitivity (82%) and combined CNV and CNVIII atrophy had the best specificity (92%) for diagnosing RFC1/CANVAS. In the quantitative analyses, CNV was significantly thinner in the RFC1/CANVAS group relative to all other groups. The cutoff CNV diameter that best identified RFC1/CANVAS was ≤2.2 mm (AUC = 0.91; sensitivity 88.2%, specificity 95.6%). CONCLUSION: MRI evaluation of CNV and CNVIII using a dedicated sequence is an easy-to-use tool that helps to distinguish RFC1/CANVAS from SCA and MSA-C.

Advanced Structural Magnetic Resonance Imaging of the Spinal Cord: Technical Aspects and Clinical Use.

For a long time, technical obstacles have hampered the acquisition of high-resolution images and the development of reliable processing protocols for spinal cord (SC) MRI. Fortunately, this scenario has changed in the past 5-10 years, due to hardware and software improvements. Nowadays, with advanced protocols, SC MRI is considered a useful tool for several inherited and acquired neurologic diseases, not only for diagnosis approach but also for pathophysiological unraveling and as a biomarker for disease monitoring and clinical trials. In this review, we address advanced SC MRI sequences for macrostructural and microstructural evaluation, useful semiautomatic and automatic processing tools and clinical applications on several neurologic conditions such as hereditary cerebellar ataxia, hereditary spastic paraplegia, motor neuron diseases and multiple sclerosis.

Progressive Spinal Cord Degeneration in Friedreich's Ataxia: Results from ENIGMA-Ataxia.

BACKGROUND: Spinal cord damage is a hallmark of Friedreich's ataxia (FRDA), but its progression and clinical correlates remain unclear. OBJECTIVE: The objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort. METHODS: We performed a cross-sectional analysis of cervical spinal cord (C1-C4) cross-sectional area (CSA) and eccentricity using magnetic resonance imaging data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched control subjects. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age. RESULTS: Individuals with FRDA, relative to control subjects, had significantly reduced CSA at all examined levels, with large effect sizes (d > 2.1) and significant correlations with disease severity (r < -0.4). Similarly, we found significantly increased eccentricity (d > 1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, although CSA appears to decrease progressively, eccentricity remains stable over time. CONCLUSIONS: Previous research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage, or both. Hence our data support the hypothesis that damage to the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol.

INTRODUCTION: Drug development for neurodegenerative diseases such as Friedreich's ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers of pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been limited by their small sample sizes and limited follow up. TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to address these shortcomings by enabling better understanding of underlying pathology and identifying sensitive, clinical trial ready, neuroimaging biomarkers for FRDA. METHODS: 200 individuals with FRDA and 104 control participants will be recruited across seven international study sites. Inclusion criteria for participants with genetically confirmed FRDA involves, age of disease onset ≤ 25 years, Friedreich's Ataxia Rating Scale (FARS) functional staging score of ≤ 5, and a total modified FARS (mFARS) score of ≤ 65 upon enrolment. The control cohort is matched to the FRDA cohort for age, sex, handedness, and years of education. Participants will be evaluated at three study visits over two years. Each visit comprises of a harmonized multimodal Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) scan of the brain and spinal cord; clinical, cognitive, mood and speech assessments and collection of a blood sample. Primary outcome measures, informed by previous neuroimaging studies, include measures of: spinal cord and brain morphometry, spinal cord and brain microstructure (measured using diffusion MRI), brain iron accumulation (using Quantitative Susceptibility Mapping) and spinal cord biochemistry (using MRS). Secondary and exploratory outcome measures include clinical, cognitive assessments and blood biomarkers. DISCUSSION: Prioritising immediate areas of need, TRACK-FA aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease trajectory. Once validated, these potential pharmacodynamic biomarkers can be used to measure the efficacy of new therapeutics in forestalling disease progression. CLINICAL TRIAL REGISTRATION: ClinicalTrails.gov Identifier: NCT04349514.

RFC1-Related Disorder: In Vivo Evaluation of Spinal Cord Damage.

BACKGROUND: RFC1-related disorder is a novel heredodegenerative condition with a broad phenotypic spectrum. Its neuropathological bases are not yet fully understood, particularly regarding the pattern, extent, and clinical relevance of spinal cord (SC) damage. OBJECTIVES: The objectives were to determine the SC structural signature in RFC1-related disorder in vivo and to identify potential clinical correlates for these imaging abnormalities. METHODS: We enrolled 17 subjects with biallelic RFC1 (AAGGG)n expansions and 11 age- and sex-matched healthy controls that underwent multimodal magnetic resonance imaging SC acquisitions in a 3T Philips Achieva scanner. Both global morphometry and tract-specific analyses were then performed across all cervical levels. Between-group comparisons were assessed using nonparametric tests. RESULTS: In the patient group, mean age and disease duration were 62.9 ± 9.3 and 9.3 ± 4.0, respectively. Compared to controls, patients had remarkable SC cross-sectional area reduction along all cervical levels but anteroposterior flattening only in the lower cervical levels. There was also prominent SC gray matter atrophy. Diffusivity abnormalities were identified in the dorsal columns but not in the lateral corticospinal tracts. Disease severity did not correlate with these imaging parameters. CONCLUSION: SC damage is a hallmark of RFC1-related disorder and characterized by gray as well as white matter involvement. In particular, dorsal columns are severely and diffusely affected. The clinical correlates of these imaging abnormalities still deserve additional investigations. © 2022 International Parkinson and Movement Disorder Society.

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.

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.

Brain Structural Signature of RFC1-Related Disorder.

BACKGROUND: The cerebellar ataxia, neuropathy, and vestibular areflexia syndrome was initially described in the early 1990s as a late-onset slowly progressive condition. Its underlying genetic cause was recently mapped to the RFC1 gene, and additional reports have expanded on the phenotypic manifestations related to RFC1, although little is known about the pattern and extent of structural brain abnormalities in this condition. OBJECTIVE: The aim is to characterize the structural signature of brain damage in RFC1-related disorder, correlating the findings with clinical symptoms and normal brain RFC1 expression. METHODS: We recruited 22 individuals with molecular confirmation of RFC1 expansions and submitted them to high-resolution 3T magnetic resonance imaging scans. We performed multimodal analyses to assess separately cerebral and cerebellar abnormalities within gray and white matter (WM). The results were compared with a group of 22 age- and sex-matched controls. RESULTS: The mean age and disease duration of patients were 62.8 and 10.9 years, respectively. Ataxia, sensory neuronopathy, and vestibular areflexia were the most frequent manifestations, but parkinsonism and pyramidal signs were also noticed. We found that RFC1-related disorder is characterized by widespread and relatively symmetric cerebellar and basal ganglia atrophy. There is brainstem volumetric reduction along all its segments. Cerebral WM is also involved-mostly the corpus callosum and deep tracts, but cerebral cortical damage is rather restricted. CONCLUSION: This study adds new relevant insights into the pathophysiological mechanisms of RFC1-related disorder. It should no longer be considered a purely cerebellar and sensory pathway disorder. Basal ganglia and deep cerebral WM are additional targets of damage. © 2021 International Parkinson and Movement Disorder Society.

Measurement of retina/choroid complex perfusion with magnetic resonance imaging in eyes with acute primary angle-closure.

PURPOSE: To measure retina/choroid complex perfusion with magnetic resonance imaging in eyes with acute primary angle-closure (APAC). METHODS: Three sequences of magnetic resonance imaging, two anatomical and one perfusional using gadolinium, were acquired in patients who were diagnosed with acute primary angle-closure. Regions of interest were drawn on the perfusional sequence and overlaid to the anatomical sequence. The relative blood volume measured during the first 2 s was considered as the baseline value and the change during the subsequent 28 s was analyzed. RESULTS: Five eyes of 5 patients with acute primary angle-closure were included (3 with unilateral and 2 with bilateral acute primary angle-closure). Three contralateral eyes and 2 eyes of 2 healthy patients, paired for age and sex, were included in the control group. Acute primary angle-closure patients included 4 (80%) women, with an average age of 65.8 ± 12.37 y, mean intraocular pressure of 56.2 ± 14.67 mmHg, mean arterial pressure of 113.4 ± 8.17 mmHg, and average ocular perfusion pressure of 57.2 ± 13.46 mmHg. In the control group, the mean intraocular pressure was 15.6 ± 2.61 mmHg (p=0.0625), the mean arterial pressure was 107.4 ± 6.57 mmHg (p=1.00), and the average ocular perfusion pressure was 91.8 ± 6.72 mmHg (p=0.0625). The relative blood volume of the retina/choroid complex was -0.127 ± 0.048 in acute primary angle-closure patients and -0.213 ± 0.116 in the controls (p=0.3125). CONCLUSION: The magnetic resonance imaging sequence with gadolinium did not show a change in the retina/choroid complex perfusion in the eyes of patients with acute primary angle-closure.

Behavioral manifestations in a Brazilian non-demented C9orf72-negative ALS population.

Cognitive decline and behavioral changes are common features in amyotrophic lateral sclerosis (ALS) and imply worse prognosis as well as increased disease burden for patients and caregivers. Currently, there is a lack of studies regarding behavioral profile in Brazilian ALS cohorts. We assessed the prevalence and profile of behavioral impairment (ALSbi) in a Brazilian non-demented C9orf72-negative ALS cohort according to broad behavioral assessment and the latest consensus. Among 76 initially recruited consecutive ALS patients, 70 were included, including seven ALS type 8 (VAPB-related ALS) individuals. Patients with Frontotemporal Dementia (FTD) diagnosis were excluded. Sixteen ALS patients (23%) were diagnosed as ALSbi. Among ALS type 8 individuals, 2 (28.6%) were diagnosed as ALSbi. Neuropsychiatric Inventory Questionnaire (NPI) total scores did positively correlate with age, but not with other demographic or clinical data. Apathy was the most prevalent finding in the ALSbi subgroup, although the prevalence (20%) was smaller than reported in previous literature. Dysphoria and anxiety were also prevalent findings in the whole ALS cohort. Future studies with larger cohorts and validated ALS-specific tools are needed in order to expand our knowledge.

Test-retest reproducibility of a multi-atlas automated segmentation tool on multimodality brain MRI.

INTRODUCTION: The increasing use of large sample sizes for population and personalized medicine requires high-throughput tools for imaging processing that can handle large amounts of data with diverse image modalities, perform a biologically meaningful information reduction, and result in comprehensive quantification. Exploring the reproducibility of these tools reveals the specific strengths and weaknesses that heavily influence the interpretation of results, contributing to transparence in science. METHODS: We tested-retested the reproducibility of MRICloud, a free automated method for whole-brain, multimodal MRI segmentation and quantification, on two public, independent datasets of healthy adults. RESULTS: The reproducibility was extremely high for T1-volumetric analysis, high for diffusion tensor images (DTI) (however, regionally variable), and low for resting-state fMRI. CONCLUSION: In general, the reproducibility of the different modalities was slightly superior to that of widely used software. This analysis serves as a normative reference for planning samples and for the interpretation of structure-based MRI studies.

Sensory ataxia rating scale: Development and validation of a functional scale for patients with sensory neuronopathies.

Sensory neuronopathies (SN) result from dorsal root ganglia damage and manifest with a combination of sensory deficits and proprioceptive ataxia. Characterization of the natural history and development of therapeutic trials are hampered by the lack of clinical scales that capture the whole spectrum of SN-related manifestations. We propose and validate a rating instrument for SN. Three experienced neuromuscular specialists developed items to rate SN. The resultant instrument was later validated by the assessment of the intra-class correlation coefficient, for inter-rater validity in 48 SN patients, and later in a smaller subset of 16 patients to assess its intra-rater validity. Standardized Crombach's alpha and Oblimin rotation analysis were performed to verify internal consistency and items' relationship, respectively. Evaluation of Sensory Ataxia Rating Scale (SEARS)'s external validity was performed by comparison to: scale for the assessment and rating of ataxia (SARA), Beck balance scale (BBS), and INCAT sensory sum score (ISS). A 10-item scale with an intra-class correlation coefficient >0.95 for intra- and inter-rating measurements with a good internal consistency (standardized Cronbach's alpha of 0.83) were observed. There was a normal distribution of the scores without a floor or ceiling effect. A moderate to good correlation between SEARS and SARA, BBS, and ISS was observed. SEARS is a reliable, easy-to-perform and consistent instrument to rate SN. Larger cohorts and multicenter studies are needed to validate its usefulness towards possible treatment trials.

Is Diffusion Tensor Imaging a Good Biomarker for Early Parkinson's Disease?

Objectives: To assess white matter abnormalities in Parkinson's disease (PD). Methods: A hundred and thirty-two patients with PD (mean age 60.93 years; average disease duration 7.8 years) and 137 healthy controls (HC; mean age 57.8 years) underwent the same MRI protocol. Patients were assessed by clinical scales and a complete neurological evaluation. We performed a TBSS analysis to compare patients and controls, and we divided patients into early PD, moderate PD, and severe PD and performed an ROI analysis using tractography. Results: With TBSS we found lower FA in patients in corpus callosum, internal and external capsule, corona radiata, thalamic radiation, sagittal stratum, cingulum and superior longitudinal fasciculus. Increased AD was found in the corpus callosum, fornix, corticospinal tract, superior cerebellar peduncle, cerebral peduncle, internal and external capsules, corona radiata, thalamic radiation and sagittal stratum and increased RD were seen in the corpus callosum, internal and external capsules, corona radiata, sagittal stratum, fornix, and cingulum. Regarding the ROIs, a GLM analysis showed abnormalities in all tracts, mainly in the severe group, when compared to HC, mild PD and moderate PD. Conclusions: Since major abnormalities were found in the severe PD group, we believe DTI analysis might not be the best tool to assess early alterations in PD, and probably, functional and other structural analysis might suit this purpose better. However it can be used to differentiate disease stages, and as a surrogate marker to assess disease progression, being an important measure that could be used in clinical trials. HIGHLIGHTS DTI is not the best tool to identify early PDDTI can differentiate disease stagesDTI analysis may be a useful marker for disease progression.

Differences in Cortical Structure and Functional MRI Connectivity in High Functioning Autism.

Autism spectrum disorders (ASD) represent a complex group of neurodevelopmental conditions characterized by deficits in communication and social behaviors. We examined the functional connectivity (FC) of the default mode network (DMN) and its relation to multimodal morphometry to investigate superregional, system-level alterations in a group of 22 adolescents and young adults with high-functioning autism compared to age-, and intelligence quotient-matched 29 healthy controls. The main findings were that ASD patients had gray matter (GM) reduction, decreased cortical thickness and larger cortical surface areas in several brain regions, including the cingulate, temporal lobes, and amygdala, as well as increased gyrification in regions associated with encoding visual memories and areas of the sensorimotor component of the DMN, more pronounced in the left hemisphere. Moreover, patients with ASD had decreased connectivity between the posterior cingulate cortex, and areas of the executive control component of the DMN and increased FC between the anteromedial prefrontal cortex and areas of the sensorimotor component of the DMN. Reduced cortical thickness in the right inferior frontal lobe correlated with higher social impairment according to the scores of the Autism Diagnostic Interview-Revised (ADI-R). Reduced cortical thickness in left frontal regions, as well as an increased cortical thickness in the right temporal pole and posterior cingulate, were associated with worse scores on the communication domain of the ADI-R. We found no association between scores on the restrictive and repetitive behaviors domain of ADI-R with structural measures or FC. The combination of these structural and connectivity abnormalities may help to explain some of the core behaviors in high-functioning ASD and need to be investigated further.

Multimodal neuroimaging analysis in patients with SYNE1 Ataxia.

BACKGROUND: The gene SYNE1 is highly expressed in the cerebellum and its dysfunction is related to an autosomal recessive ataxia (SYNE1-ataxia). The disease was firstly considered a pure cerebellar ataxia however, recent studies have described a broader clinical presentation, including motor neuron disease symptoms. OBJECTIVES: To investigate cerebellar and potential extra-cerebellar changes in SYNE1-ataxia using multimodal neuroimaging analyses. METHODS: Six patients completed clinical and imaging exams, and were compared to age-gender-matched healthy controls. Gray matter was analyzed using FreeSurfer and CERES for brain and cerebellum, respectively. White matter was analyzed with DTI-TBSS while we used SpineSeg for spinal cord analysis. RESULTS: We found significantly reduced cortical thickness (p < 0.05, FDR-corrected) in primary and association cortices, and volume reduction in subcortical structures, brainstem and cerebellum. White matter was found disrupted in both brain and cerebellum (p < 0.05, FWE-corrected). These results are consistent with the expression of the SYNE1 mRNA and its encoded protein in the brain. We failed to demonstrate spinal cord changes. CONCLUSIONS: SYNE1-ataxia is, therefore, a relatively common cause of recessive ataxia characterized by complex multisystemic neurostructural changes consistent with the phenotypic heterogeneity and neuroimaging configures a potential marker of the disease.

Brain signature of mild stages of cognitive and behavioral impairment in amyotrophic lateral sclerosis.

We aimed to assess the brain signature of cognitive and behavioral impairment in C9orf72-negative non-demented ALS patients. The study included 50 amyotrophic lateral sclerosis (ALS) patients (out of 75 initially recruited) and 38 healthy controls. High-resolution T1-weighted and spin-echo diffusion tensor images were acquired in a 3T MRI scanner. The multi atlas-based analysis protocol and the FreeSurfer tool were employed for gray matter assessment, and fiber tractography for white matter evaluation. Cognitively impaired ALS patients (n = 12) had bilateral amygdalae and left thalamic volumetric reduction compared to non-impaired ALS patients. Behaviorally impaired ALS patients (n = 14) had lower fractional anisotropy (FA) at the fornix in comparison with healthy subjects. These parameters did correlate with cognitive/behavioral scores, but not with motor-functional parameters in the ALS cohort. We believe that basal ganglia and fornix damage might be related to cognitive and behavioral impairment across ALS-frontotemporal dementia continuum. Also, distinct anatomical areas seem to influence the behavioral and cognitive status of these individuals.

Exploratory structural assessment in craniocervical dystonia: Global and differential analyses.

INTRODUCTION: Our goal was to investigate the cortical thickness and subcortical volume in subjects with craniocervical dystonia and its subgroups. METHODS: We studied 49 subjects, 17 with cervical dystonia, 18 with blepharospasm or oromandibular dystonia, and 79 healthy controls. We performed a whole group analysis, followed by a subgroup analysis. We used Freesurfer software to measure cortical thickness, subcortical volume and to perform a primary exploratory analysis in the craniocervical dystonia group, complemented by a region of interest analysis. We also performed a secondary analysis, with data generated from Freesurfer for subgroups, corrected by false discovery rate. We then performed an exploratory generalized linear model with significant areas for the previous steps using clinical features as independent variables. RESULTS: The primary exploratory analysis demonstrated atrophy in visual processing regions in craniocervical dystonia. The secondary analysis demonstrated atrophy in motor, sensory, and visual regions in blepharospasm or oromandibular dystonia, as well as in limbic regions in cervical dystonia. Cervical dystonia patients also had greater cortical thickness than blepharospasm or oromandibular dystonia patients in frontal pole and medial orbitofrontal regions. Finally, we observed an association between precuneus, age of onset of dystonia and age at the MRI exam, in craniocervical dystonia; between motor and limbic regions and age at the exam, clinical score and time on botulinum toxin in cervical dystonia and sensory regions and age of onset and time on botulinum toxin in blepharospasm or oromandibular dystonia. CONCLUSIONS: We detected involvement of visual processing regions in craniocervical dystonia, and a pattern of involvement in cervical dystonia and blepharospasm or oromandibular dystonia, including motor, sensory and limbic areas. We also showed an association of cortical thickness atrophy and younger onset age, older age at the MRI exam, higher clinical score and an uncertain association with longer time on botulinum toxin.

Nonneurological Involvement in Late-Onset Friedreich Ataxia (LOFA): Exploring the Phenotypes.

Friedreich's ataxia (FDRA) is the most common inherited ataxia worldwide, caused by homozygous GAA expansions in the FXN gene. Patients usually have early onset ataxia, areflexia, Babinski sign, scoliosis and pes cavus, but at least 25 % of cases have atypical phenotypes. Disease begins after the age of 25 in occasional patients (late-onset Friedreich ataxia (LOFA)). Little is known about the frequency and clinical profile of LOFA patients. One hundred six patients with molecular confirmation of FDRA and followed in three Brazilian outpatient centers were enrolled. General demographics, GAA expansion size, age at onset, cardiac, endocrine, and skeletal manifestations were evaluated and compared between LOFA and classic FDRA (cFDRA) groups. We used Mann-Whitney and Fisher tests to compare means and proportions between groups; p values <0.05 were considered significant. LOFA accounted for 17 % (18/106) and cFDRA for 83 % (88/106) of the patients. There were 13 and 48 women in each group, respectively. LOFA patients were significantly older and had smaller GAA expansions. Clinically, LOFA group had a tendency toward lower frequency of diabetes/impaired glucose tolerance (5.8 vs. 17 %, p = 0.29) and cardiomyopathy (16.6 vs. 28.4 %, p = 0.38). Skeletal abnormalities were significantly less frequent in LOFA (scoliosis 22 vs. 61 %, p = 0.003, and pes cavus 22 vs.75 %, p < 0.001) as were spasticity and sustained reflexes, found in 22 % of LOFA patients but in none of the cFDRA patients (p = 0.001). LOFA accounts for 17 % of Brazilian FDRA patients evaluated herein. Clinically, orthopedic features and spasticity with retained reflexes are helpful tips to differentiate LOFA from cFDRA patients.