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Cocozza S, Bosticardo S, Battocchio M, Corben L, Delatycki M, Egan G, Georgiou‐Karistianis N, Monti S, Palma G, Pane C, Saccà F, Schiavi S, Selvadurai L, Tranfa M, Daducci A, Brunetti A, Harding IH. Gradient of microstructural damage along the dentato-thalamo-cortical tract in Friedreich ataxia. Ann Clin Transl Neurol 2024; 11:1691-1702. [PMID: 38952134 PMCID: PMC11251475 DOI: 10.1002/acn3.52048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 02/02/2024] [Accepted: 02/29/2024] [Indexed: 07/03/2024] Open
Abstract
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.
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Affiliation(s)
- Sirio Cocozza
- Department of Advanced Biomedical SciencesUniversity of Naples “Federico II”NaplesItaly
| | - Sara Bosticardo
- Department of Computer Science, Diffusion Imaging and Connectivity Estimation (DICE) LabUniversity of VeronaVeronaItaly
| | - Matteo Battocchio
- Department of Computer Science, Diffusion Imaging and Connectivity Estimation (DICE) LabUniversity of VeronaVeronaItaly
| | - Louise Corben
- Bruce Lefroy Centre for Genetic Health ResearchMurdoch Children's Research InstituteParkvilleVictoriaAustralia
- Department of PediatricsUniversity of MelbourneParkvilleVictoriaAustralia
- School of Psychological Sciences, The Turner Institute for Brain and Mental HealthMonash UniversityClaytonVictoriaAustralia
| | - Martin Delatycki
- Bruce Lefroy Centre for Genetic Health ResearchMurdoch Children's Research InstituteParkvilleVictoriaAustralia
- Department of PediatricsUniversity of MelbourneParkvilleVictoriaAustralia
- School of Psychological Sciences, The Turner Institute for Brain and Mental HealthMonash UniversityClaytonVictoriaAustralia
| | - Gary Egan
- Turner Institute for Brain and Mental Health, School of Psychological SciencesMonash UniversityClaytonVictoriaAustralia
- Monash Biomedical ImagingMonash UniversityClaytonVictoriaAustralia
| | - Nellie Georgiou‐Karistianis
- School of Psychological Sciences, The Turner Institute for Brain and Mental HealthMonash UniversityClaytonVictoriaAustralia
| | - Serena Monti
- Institute of Biostructures and BioimagingNational Research CouncilNapoliItaly
| | - Giuseppe Palma
- Institute of NanotechnologyNational Research CouncilLecceItaly
| | - Chiara Pane
- Department of Neurosciences Reproductive and Odontostomatological SciencesUniversity of Naples “Federico II”NaplesItaly
| | - Francesco Saccà
- Department of Neurosciences Reproductive and Odontostomatological SciencesUniversity of Naples “Federico II”NaplesItaly
| | - Simona Schiavi
- Department of Computer Science, Diffusion Imaging and Connectivity Estimation (DICE) LabUniversity of VeronaVeronaItaly
- ASG Superconductors SpAGenoaItaly
| | - Louisa Selvadurai
- School of Psychological Sciences, The Turner Institute for Brain and Mental HealthMonash UniversityClaytonVictoriaAustralia
| | - Mario Tranfa
- Department of Advanced Biomedical SciencesUniversity of Naples “Federico II”NaplesItaly
| | - Alessandro Daducci
- Department of Computer Science, Diffusion Imaging and Connectivity Estimation (DICE) LabUniversity of VeronaVeronaItaly
| | - Arturo Brunetti
- Department of Advanced Biomedical SciencesUniversity of Naples “Federico II”NaplesItaly
| | - Ian H. Harding
- Monash Biomedical ImagingMonash UniversityClaytonVictoriaAustralia
- Department of Neuroscience, Central Clinical SchoolMonash UniversityMelbourneVictoriaAustralia
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Yang G, Xu M, Chen W, Qiao X, Shi H, Hu Y. A brain CT-based approach for predicting and analyzing stroke-associated pneumonia from intracerebral hemorrhage. Front Neurol 2023; 14:1139048. [PMID: 37332986 PMCID: PMC10272424 DOI: 10.3389/fneur.2023.1139048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 05/08/2023] [Indexed: 06/20/2023] Open
Abstract
Introduction Stroke-associated pneumonia (SAP) is a common complication of stroke that can increase the mortality rate of patients and the burden on their families. In contrast to prior clinical scoring models that rely on baseline data, we propose constructing models based on brain CT scans due to their accessibility and clinical universality. Methods Our study aims to explore the mechanism behind the distribution and lesion areas of intracerebral hemorrhage (ICH) in relation to pneumonia, we utilized an MRI atlas that could present brain structures and a registration method in our program to extract features that may represent this relationship. We developed three machine learning models to predict the occurrence of SAP using these features. Ten-fold cross-validation was applied to evaluate the performance of models. Additionally, we constructed a probability map through statistical analysis that could display which brain regions are more frequently impacted by hematoma in patients with SAP based on four types of pneumonia. Results Our study included a cohort of 244 patients, and we extracted 35 features that captured the invasion of ICH to different brain regions for model development. We evaluated the performance of three machine learning models, namely, logistic regression, support vector machine, and random forest, in predicting SAP, and the AUCs for these models ranged from 0.77 to 0.82. The probability map revealed that the distribution of ICH varied between the left and right brain hemispheres in patients with moderate and severe SAP, and we identified several brain structures, including the left-choroid-plexus, right-choroid-plexus, right-hippocampus, and left-hippocampus, that were more closely related to SAP based on feature selection. Additionally, we observed that some statistical indicators of ICH volume, such as mean and maximum values, were proportional to the severity of SAP. Discussion Our findings suggest that our method is effective in classifying the development of pneumonia based on brain CT scans. Furthermore, we identified distinct characteristics, such as volume and distribution, of ICH in four different types of SAP.
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Affiliation(s)
- Guangtong Yang
- School of Control Science and Engineering, Shandong University, Jinan, China
| | - Min Xu
- Neurointensive Care Unit, Shengli Oilfield Central Hospital, Dongying, China
| | - Wei Chen
- Department of Radiology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Xu Qiao
- School of Control Science and Engineering, Shandong University, Jinan, China
| | - Hongfeng Shi
- Neurointensive Care Unit, Shengli Oilfield Central Hospital, Dongying, China
| | - Yongmei Hu
- School of Control Science and Engineering, Shandong University, Jinan, China
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Kerestes R, Cummins H, Georgiou-Karistianis N, Selvadurai LP, Corben LA, Delatycki MB, Egan GF, Harding IH. Reduced cerebello-cerebral functional connectivity correlates with disease severity and impaired white matter integrity in Friedreich ataxia. J Neurol 2023; 270:2360-2369. [PMID: 36859626 PMCID: PMC10130106 DOI: 10.1007/s00415-023-11637-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 02/07/2023] [Accepted: 02/19/2023] [Indexed: 03/03/2023]
Abstract
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.
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Affiliation(s)
- Rebecca Kerestes
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
| | - Hannah Cummins
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
| | - Nellie Georgiou-Karistianis
- Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Melbourne, Australia
| | - Louisa P Selvadurai
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
| | - Louise A Corben
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Melbourne, Australia
| | - Martin B Delatycki
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Melbourne, Australia
| | - Gary F Egan
- Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Melbourne, Australia.,Monash Biomedical Imaging, Monash University, Melbourne, VIC, 3800, Australia
| | - Ian H Harding
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia. .,Monash Biomedical Imaging, Monash University, Melbourne, VIC, 3800, Australia.
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Phenotype and management of neurologic intronic repeat disorders (NIRDs). Rev Neurol (Paris) 2023; 179:173-182. [PMID: 36371266 DOI: 10.1016/j.neurol.2022.09.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 11/11/2022]
Abstract
During recent years an increasing number of neurologic disorders due to expanded tri-, tetra-, penta-, or hexa-nucleotide repeat motifs in introns of various genes have been described (neurologic intronic repeat disorders (NIRDs)). The repeat may be pathogenic in the heterozygous or homozygous form. Repeat lengths vary considerably and can be stable or unstable during transmission to the next generation. The most well-known NIRDs are Friedreich ataxia, spinocerebellar ataxia types-10, -31, and -36, CANVAS, C9Orf72 familial amyotrophic lateral sclerosis (fALS), and myotonic dystrophy-2 (MD2). Phenotypically, NIRDs manifest as mono-organ (e.g. spinocerebellar ataxia type 31) or multi-organ disease (e.g. Friedreich ataxia, myotonic dystrophy-2). A number of other more rare NIRDs have been recently detected. This review aims at summarising and discussing previous findings and recent advances concerning the etiology, pathophysiology, clinical presentation, and therapeutic management of the most common NIRDs.
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Georgiou-Karistianis N, Corben LA, Reetz K, Adanyeguh IM, Corti M, Deelchand DK, Delatycki MB, Dogan I, Evans R, Farmer J, França MC, Gaetz W, Harding IH, Harris KS, Hersch S, Joules R, Joers JJ, Krishnan ML, Lax M, Lock EF, Lynch D, Mareci T, Muthuhetti Gamage S, Pandolfo M, Papoutsi M, Rezende TJR, Roberts TPL, Rosenberg JT, Romanzetti S, Schulz JB, Schilling T, Schwarz AJ, Subramony S, Yao B, Zicha S, Lenglet C, Henry PG. A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol. PLoS One 2022; 17:e0269649. [PMID: 36410013 PMCID: PMC9678384 DOI: 10.1371/journal.pone.0269649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 05/25/2022] [Indexed: 11/23/2022] Open
Abstract
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.
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Affiliation(s)
- Nellie Georgiou-Karistianis
- School of Psychological Sciences, The Turner Institute for Brain and Mental Health, Monash University, Clayton, Victoria, Australia
| | - Louise A. Corben
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Kathrin Reetz
- Department of Neurology, RWTH Aachen University, Aachen, Germany
- JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany
| | - Isaac M. Adanyeguh
- Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Manuela Corti
- Powell Gene Therapy Centre, University of Florida, Gainesville, Florida, United States of America
| | - Dinesh K. Deelchand
- Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Martin B. Delatycki
- School of Psychological Sciences, The Turner Institute for Brain and Mental Health, Monash University, Clayton, Victoria, Australia
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Imis Dogan
- Department of Neurology, RWTH Aachen University, Aachen, Germany
- JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany
| | - Rebecca Evans
- Takeda Pharmaceutical Company Ltd, Cambridge, Massachusetts, United States of America
| | - Jennifer Farmer
- Friedreich’s Ataxia Research Alliance (FARA), Downingtown, Pennsylvania, United States of America
| | - Marcondes C. França
- Department of Neurology, University of Campinas, Campinas, Sao Paulo, Brazil
| | - William Gaetz
- Department of Radiology, Lurie Family Foundations MEG Imaging Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Ian H. Harding
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
| | - Karen S. Harris
- School of Psychological Sciences, The Turner Institute for Brain and Mental Health, Monash University, Clayton, Victoria, Australia
| | - Steven Hersch
- Neurology Business Group, Eisai Inc., Nutley, New Jersey, United States of America
| | | | - James J. Joers
- Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Michelle L. Krishnan
- Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America
| | | | - Eric F. Lock
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, United States of America
| | - David Lynch
- Department of Neurology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Thomas Mareci
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States of America
| | - Sahan Muthuhetti Gamage
- School of Psychological Sciences, The Turner Institute for Brain and Mental Health, Monash University, Clayton, Victoria, Australia
| | - Massimo Pandolfo
- Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
| | | | | | - Timothy P. L. Roberts
- Department of Radiology, Lurie Family Foundations MEG Imaging Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Jens T. Rosenberg
- McKnight Brain Institute, Department of Neurology, University of Florida, Gainesville, Florida, United States of America
| | - Sandro Romanzetti
- Department of Neurology, RWTH Aachen University, Aachen, Germany
- JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany
| | - Jörg B. Schulz
- Department of Neurology, RWTH Aachen University, Aachen, Germany
- JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany
| | - Traci Schilling
- PTC Therapeutics, Inc, South Plainfield, New Jersey, United States of America
| | - Adam J. Schwarz
- Takeda Pharmaceutical Company Ltd, Cambridge, Massachusetts, United States of America
| | - Sub Subramony
- McKnight Brain Institute, Department of Neurology, University of Florida, Gainesville, Florida, United States of America
| | - Bert Yao
- PTC Therapeutics, Inc, South Plainfield, New Jersey, United States of America
| | - Stephen Zicha
- Takeda Pharmaceutical Company Ltd, Cambridge, Massachusetts, United States of America
| | - Christophe Lenglet
- Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Pierre-Gilles Henry
- Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota, Minneapolis, Minnesota, United States of America
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MRI CNS Atrophy Pattern and the Etiologies of Progressive Ataxias. Tomography 2022; 8:423-437. [PMID: 35202200 PMCID: PMC8877967 DOI: 10.3390/tomography8010035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/16/2022] [Accepted: 02/02/2022] [Indexed: 11/18/2022] Open
Abstract
MRI shows the three archetypal patterns of CNS volume loss underlying progressive ataxias in vivo, namely spinal atrophy (SA), cortical cerebellar atrophy (CCA) and olivopontocerebellar atrophy (OPCA). The MRI-based CNS atrophy pattern was reviewed in 128 progressive ataxias. A CNS atrophy pattern was identified in 91 conditions: SA in Friedreich’s ataxia, CCA in 5 acquired and 72 (24 dominant, 47 recessive,1 X-linked) inherited ataxias, OPCA in Multi-System Atrophy and 12 (9 dominant, 2 recessive,1 X-linked) inherited ataxias. The MRI-based CNS atrophy pattern may be useful for genetic assessment, identification of shared cellular targets, repurposing therapies or the enlargement of drug indications in progressive ataxias.
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Selvadurai LP, Georgiou-Karistianis N, Shishegar R, Sheridan C, Egan GF, Delatycki MB, Harding IH, Corben LA. Longitudinal structural brain changes in Friedreich ataxia depend on disease severity: the IMAGE-FRDA study. J Neurol 2021; 268:4178-4189. [PMID: 33860369 DOI: 10.1007/s00415-021-10512-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 11/29/2022]
Abstract
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.
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Affiliation(s)
- Louisa P Selvadurai
- School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Clayton Campus, Clayton, VIC, 3800, Australia
| | - Nellie Georgiou-Karistianis
- School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Clayton Campus, Clayton, VIC, 3800, Australia.
| | - Rosita Shishegar
- School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Clayton Campus, Clayton, VIC, 3800, Australia.,The Australian E-Health Research Centre, CSIRO, Melbourne, Australia
| | - Cathlin Sheridan
- School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Clayton Campus, Clayton, VIC, 3800, Australia
| | - Gary F Egan
- School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Clayton Campus, Clayton, VIC, 3800, Australia.,Monash Biomedical Imaging, Monash University, Clayton, Australia
| | - Martin B Delatycki
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Australia.,Department of Paediatrics, The University of Melbourne, Parkville, Australia.,Victorian Clinical Genetics Services, Parkville, Australia
| | - Ian H Harding
- Monash Biomedical Imaging, Monash University, Clayton, Australia.,Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
| | - Louise A Corben
- School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Clayton Campus, Clayton, VIC, 3800, Australia.,Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Australia.,Department of Paediatrics, The University of Melbourne, Parkville, Australia
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Hui CK, Dedkova EN, Montgomery C, Cortopassi G. Dimethyl fumarate dose-dependently increases mitochondrial gene expression and function in muscle and brain of Friedreich's ataxia model mice. Hum Mol Genet 2021; 29:3954-3965. [PMID: 33432356 DOI: 10.1093/hmg/ddaa282] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 12/16/2020] [Accepted: 12/23/2020] [Indexed: 01/03/2023] Open
Abstract
Previously we showed that dimethyl fumarate (DMF) dose-dependently increased mitochondrial gene expression and function in cells and might be considered as a therapeutic for inherited mitochondrial disease, including Friedreich's ataxia (FA). Here we tested DMF's ability to dose-dependently increase mitochondrial function, mitochondrial gene expression (frataxin and cytochrome oxidase protein) and mitochondrial copy number in C57BL6 wild-type mice and the FXNKD mouse model of FA. We first dosed DMF at 0-320 mg/kg in C57BL6 mice and observed significant toxicity above 160 mg/kg orally, defining the maximum tolerated dose. Oral dosing of C57BL6 mice in the range 0-160 mg/kg identified a maximum increase in aconitase activity and mitochondrial gene expression in brain and quadriceps at 110 mg/kg DMF, thus defining the maximum effective dose (MED). The MED of DMF in mice overlaps the currently approved human-equivalent doses of DMF prescribed for multiple sclerosis (480 mg/day) and psoriasis (720 mg/day). In the FXNKD mouse model of FA, which has a doxycycline-induced deficit of frataxin protein, we observed significant decreases of multiple mitochondrial parameters, including deficits in brain mitochondrial Complex 2, Complex 4 and aconitase activity, supporting the idea that frataxin deficiency reduces mitochondrial gene expression, mitochondrial functions and biogenesis. About 110 mg/kg of oral DMF rescued these enzyme activities in brain and rescued frataxin and cytochrome oxidase expression in brain, cerebellum and quadriceps muscle of the FXNKD mouse model. Taken together, these results support the idea of using fumarate-based molecules to treat FA or other mitochondrial diseases.
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Affiliation(s)
- Chun Kiu Hui
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Elena N Dedkova
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Claire Montgomery
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Gino Cortopassi
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
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Straub S, Mangesius S, Emmerich J, Indelicato E, Nachbauer W, Degenhardt KS, Ladd ME, Boesch S, Gizewski ER. Toward quantitative neuroimaging biomarkers for Friedreich's ataxia at 7 Tesla: Susceptibility mapping, diffusion imaging, R 2 and R 1 relaxometry. J Neurosci Res 2020; 98:2219-2231. [PMID: 32731306 PMCID: PMC7590084 DOI: 10.1002/jnr.24701] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 06/12/2020] [Accepted: 07/08/2020] [Indexed: 01/21/2023]
Abstract
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.
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Affiliation(s)
- Sina Straub
- Division of Medical Physics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stephanie Mangesius
- Department of Neuroradiology, Medical University of Innsbruck, Innsbruck, Austria.,Neuroimaging Core Facility, Medical University of Innsbruck, Innsbruck, Austria
| | - Julian Emmerich
- Division of Medical Physics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Physics and Astronomy, Heidelberg University, Heidelberg, Germany
| | | | - Wolfgang Nachbauer
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Katja S Degenhardt
- Division of Medical Physics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Physics and Astronomy, Heidelberg University, Heidelberg, Germany
| | - Mark E Ladd
- Division of Medical Physics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Physics and Astronomy, Heidelberg University, Heidelberg, Germany.,Faculty of Medicine, Heidelberg University, Heidelberg, Germany
| | - Sylvia Boesch
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Elke R Gizewski
- Department of Neuroradiology, Medical University of Innsbruck, Innsbruck, Austria.,Neuroimaging Core Facility, Medical University of Innsbruck, Innsbruck, Austria
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10
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Selvadurai LP, Corben LA, Delatycki MB, Storey E, Egan GF, Georgiou‐Karistianis N, Harding IH. Multiple mechanisms underpin cerebral and cerebellar white matter deficits in Friedreich ataxia: The IMAGE-FRDA study. Hum Brain Mapp 2020; 41:1920-1933. [PMID: 31904895 PMCID: PMC7267947 DOI: 10.1002/hbm.24921] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Revised: 12/20/2019] [Accepted: 12/29/2019] [Indexed: 01/16/2023] Open
Abstract
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.
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Affiliation(s)
- Louisa P. Selvadurai
- School of Psychological Sciences and Turner Institute for Brain and Mental HealthMonash UniversityMelbourneVictoriaAustralia
| | - Louise A. Corben
- School of Psychological Sciences and Turner Institute for Brain and Mental HealthMonash UniversityMelbourneVictoriaAustralia
- Bruce Lefroy Centre for Genetic Health ResearchMurdoch Children's Research InstituteParkvilleVictoriaAustralia
- Department of PaediatricsThe University of MelbourneParkvilleVictoriaAustralia
| | - Martin B. Delatycki
- Bruce Lefroy Centre for Genetic Health ResearchMurdoch Children's Research InstituteParkvilleVictoriaAustralia
- Department of PaediatricsThe University of MelbourneParkvilleVictoriaAustralia
- Victorian Clinical Genetics ServicesParkvilleVictoriaAustralia
| | - Elsdon Storey
- Department of MedicineMonash UniversityPrahranVictoriaAustralia
| | - Gary F. Egan
- School of Psychological Sciences and Turner Institute for Brain and Mental HealthMonash UniversityMelbourneVictoriaAustralia
- Monash Biomedical ImagingMonash UniversityClaytonVictoriaAustralia
| | - Nellie Georgiou‐Karistianis
- School of Psychological Sciences and Turner Institute for Brain and Mental HealthMonash UniversityMelbourneVictoriaAustralia
| | - Ian H. Harding
- School of Psychological Sciences and Turner Institute for Brain and Mental HealthMonash UniversityMelbourneVictoriaAustralia
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11
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Pattern of Cerebellar Atrophy in Friedreich's Ataxia-Using the SUIT Template. THE CEREBELLUM 2019; 18:435-447. [PMID: 30771164 DOI: 10.1007/s12311-019-1008-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Whole-brain voxel-based morphometry (VBM) studies revealed patterns of patchy atrophy within the cerebellum of Friedreich's ataxia patients, missing clear clinico-anatomic correlations. Studies so far are lacking an appropriate registration to the infratentorial space. To circumvent these limitations, we applied a high-resolution atlas template of the human cerebellum and brainstem (SUIT template) to characterize regional cerebellar atrophy in Friedreich's ataxia (FRDA) on 3-T MRI data. We used a spatially unbiased voxel-based morphometry approach together with T2-based manual segmentation, T2 histogram analysis, and atlas generation of the dentate nuclei in a representative cohort of 18 FRDA patients and matched healthy controls. We demonstrate that the cerebellar volume in FRDA is generally not significantly different from healthy controls but mild lobular atrophy develops beyond normal aging. The medial parts of lobule VI, housing the somatotopic representation of tongue and lips, are the major site of this lobular atrophy, which possibly reflects speech impairment. Extended white matter affection correlates with disease severity across and beyond the cerebellar inflow and outflow tracts. The dentate nucleus, as a major site of cerebellar degeneration, shows a mean volume loss of about 30%. Remarkably, not the atrophy but the T2 signal decrease of the dentate nuclei highly correlates with disease duration and severity.
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12
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Cerebellum and cognition in Friedreich ataxia: a voxel-based morphometry and volumetric MRI study. J Neurol 2019; 267:350-358. [PMID: 31641877 DOI: 10.1007/s00415-019-09582-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 09/25/2019] [Accepted: 10/14/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Recent studies have suggested the presence of a significant atrophy affecting the cerebellar cortex in Friedreich ataxia (FRDA) patients, an area of the brain long considered to be relatively spared by neurodegenerative phenomena. Cognitive deficits, which occur in FRDA patients, have been associated with cerebellar volume loss in other conditions. The aim of this study was to investigate the correlation between cerebellar volume and cognition in FRDA. METHODS Nineteen FRDA patients and 20 healthy controls (HC) were included in this study and evaluated via a neuropsychological examination. Cerebellar global and lobular volumes were computed using the Spatially Unbiased Infratentorial Toolbox (SUIT). Furthermore, a cerebellar voxel-based morphometry (VBM) analysis was also carried out. Correlations between MRI metrics and clinical data were tested via partial correlation analysis. RESULTS FRDA patients showed a significant reduction of the total cerebellar volume (p = 0.004), significantly affecting the Lobule IX (p = 0.001). At the VBM analysis, we found a cluster of significant reduced GM density encompassing the entire lobule IX (p = 0.003). When correlations were probed, we found a direct correlation between Lobule IX volume and impaired visuo-spatial functions (r = 0.58, p = 0.02), with a similar correlation that was found between the same altered function and results obtained at the VBM (r = 0.52; p = 0.03). CONCLUSIONS With two different image analysis techniques, we confirmed the presence of cerebellar volume loss in FRDA, mainly affecting the posterior lobe. In particular, Lobule IX atrophy correlated with worse visuo-spatial abilities, further expanding our knowledge about the physiopathology of cognitive impairment in FRDA.
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13
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Vedantam A, Stormes KM, Gadgil N, Kralik SF, Aldave G, Lam SK. Association between postoperative DTI metrics and neurological deficits after posterior fossa tumor resection in children. J Neurosurg Pediatr 2019; 24:364-370. [PMID: 31323626 DOI: 10.3171/2019.5.peds1912] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Accepted: 05/09/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Resection of posterior fossa tumors in children may be associated with persistent neurological deficits. It is unclear if these neurological deficits are associated with persistent structural damage to the cerebellar pathways. The purpose of this research was to define longitudinal changes in diffusion tensor imaging (DTI) metrics in white matter cerebellar tracts and the clinical correlates of these metrics in children undergoing resection of posterior fossa tumors. METHODS Longitudinal brain DTI was performed in a cohort of pediatric patients who underwent resection of posterior fossa tumors. Fractional anisotropy (FA) of the superior cerebellar peduncles (SCPs) and middle cerebellar peduncles (MCPs) was measured on preoperative, postoperative, and follow-up DTI. Early postoperative (< 48 hours) and longer-term follow-up neurological deficits (mutism, ataxia, and extraocular movement dysfunction) were documented. Statistical analysis was performed to determine differences in FA values based on presence or absence of neurological deficits. Statistical significance was set at p < 0.05. RESULTS Twenty children (mean age 6.1 ± 4.1 years [SD], 12 males and 8 females) were included in this study. Follow-up DTI was performed at a median duration of 14.3 months after surgery, and the median duration of follow-up was 19.7 months. FA of the left SCP was significantly reduced on postoperative DTI in comparison with preoperative DTI (0.44 ± 0.07 vs 0.53 ± 0.1, p = 0.003). Presence of ataxia at follow-up was associated with a persistent reduction in the left SCP FA on follow-up DTI (0.43 ± 0.1 vs 0.55 ± 0.1, p = 0.016). Patients with early postoperative mutism who did not recover at follow-up had significantly decreased FA of the left SCP on early postoperative DTI in comparison with those who recovered (0.38 ± 0.05 vs 0.48 ± 0.06, p = 0.04). CONCLUSIONS DTI after resection of posterior fossa tumors in children shows that persistent reduction of SCP FA is associated with ataxia at follow-up.
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Affiliation(s)
- Aditya Vedantam
- 1Division of Pediatric Neurosurgery, Texas Children's Hospital, Department of Neurosurgery, Baylor College of Medicine, Houston, Texas; and
| | - Katie M Stormes
- 1Division of Pediatric Neurosurgery, Texas Children's Hospital, Department of Neurosurgery, Baylor College of Medicine, Houston, Texas; and
| | - Nisha Gadgil
- 1Division of Pediatric Neurosurgery, Texas Children's Hospital, Department of Neurosurgery, Baylor College of Medicine, Houston, Texas; and
| | - Stephen F Kralik
- 2Department of Radiology, Texas Children's Hospital, Houston, Texas
| | - Guillermo Aldave
- 1Division of Pediatric Neurosurgery, Texas Children's Hospital, Department of Neurosurgery, Baylor College of Medicine, Houston, Texas; and
| | - Sandi K Lam
- 1Division of Pediatric Neurosurgery, Texas Children's Hospital, Department of Neurosurgery, Baylor College of Medicine, Houston, Texas; and
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14
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Rodriguez C, Jagadish AK, Meskaldji DE, Haller S, Herrmann F, Van De Ville D, Giannakopoulos P. Structural Correlates of Personality Dimensions in Healthy Aging and MCI. Front Psychol 2019; 9:2652. [PMID: 30670999 PMCID: PMC6331460 DOI: 10.3389/fpsyg.2018.02652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 12/10/2018] [Indexed: 12/21/2022] Open
Abstract
The revised NEO Personality Inventory (NEOPI-R), popularly known as the five-factor model, defines five personality factors: Neuroticism, Extraversion, Openness to Experience, Agreeableness, and Conscientiousness. The structural correlates of these personality factors are still a matter of debate. In this work, we examine the impact of subtle cognitive deficits on structural substrates of personality in the elderly using DTI derived white matter (WM) integrity measure, Fractional Anisotropy (FA). We employed canonical correlation analysis (CCA) to study the relationship between personality factors of the NEOPI-R and FA measures in two population groups: healthy controls and MCI. Agreeableness was the only personality factor to be associated with FA patterns in both groups. Openness was significantly related to FA data in the MCI group and the inverse was true for Conscientiousness. Furthermore, we generated saliency maps using bootstrapping strategy which revealed a larger number of positive correlations in healthy aging in contrast to the MCI status. The MCI group was found to be associated with a predominance of negative correlations indicating that higher Agreeableness and Openness scores were mostly related to lower FA values in interhemispheric and cortico-spinal tracts and a limited number of higher FA values in cortico-cortical and cortico-subcortical connection. Altogether these findings support the idea that WM microstructure may represent a valid correlate of personality dimensions and also indicate that the presence of early cognitive deficits led to substantial changes in the associations between WM integrity and personality factors.
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Affiliation(s)
- Cristelle Rodriguez
- Division of Institutional Measures, Medical Direction, University Hospitals of Geneva, Geneva, Switzerland
| | - Akshay Kumar Jagadish
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- Department of Electrical and Electronics Engineering, National Institute of Technology Karnataka, Surathkal, India
| | - Djalel-Eddine Meskaldji
- Institute of Mathematics, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- Department of Radiology and Medical Informatics, University of Geneva, Geneva, Switzerland
| | - Sven Haller
- Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden
- CIRD – Centre d’Imagerie Rive Droite, Geneva, Switzerland
| | - Francois Herrmann
- Division of Geriatrics, Department of Internal Medicine, Rehabilitation and Geriatrics, University of Geneva, Geneva, Switzerland
| | - Dimitri Van De Ville
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- Department of Radiology and Medical Informatics, University of Geneva, Geneva, Switzerland
| | - Panteleimon Giannakopoulos
- Division of Institutional Measures, Medical Direction, University Hospitals of Geneva, Geneva, Switzerland
- Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland
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15
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Mascalchi M, Vella A. Neuroimaging Applications in Chronic Ataxias. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2018; 143:109-162. [PMID: 30473193 DOI: 10.1016/bs.irn.2018.09.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) are the main instruments for neuroimaging investigation of patients with chronic ataxia. MRI has a predominant diagnostic role in the single patient, based on the visual detection of three patterns of atrophy, namely, spinal atrophy, cortical cerebellar atrophy and olivopontocerebellar atrophy, which correlate with the aetiologies of inherited or sporadic ataxia. In fact spinal atrophy is observed in Friedreich ataxia, cortical cerebellar atrophy in Ataxia Telangectasia, gluten ataxia and Sporadic Adult Onset Ataxia and olivopontocerebellar atrophy in Multiple System Atrophy cerebellar type. The 39 types of dominantly inherited spinocerebellar ataxias show either cortical cerebellar atrophy or olivopontocerebellar atrophy. T2 or T2* weighted MR images can contribute to the diagnosis by revealing abnormally increased or decreased signal with a characteristic distribution. These include symmetric T2 hyperintensity of the posterior and lateral columns of the cervical spinal cord in Friedreich ataxia, diffuse and symmetric hyperintensity of the cerebellar cortex in Infantile Neuro-Axonal Dystrophy, symmetric hyperintensity of the peridentate white matter in Cerebrotendineous Xanthomatosis, and symmetric hyperintensity of the middle cerebellar peduncles and peridentate white matter, cerebral white matter and corpus callosum in Fragile X Tremor Ataxia Syndrome. Abnormally decreased T2 or T2* signal can be observed with a multifocal distribution in Ataxia Telangectasia and with a symmetric distribution in the basal ganglia in Multiple System Atrophy. T2 signal hypointensity lining diffusely the outer surfaces of the brainstem, cerebellum and cerebrum enables diagnosis of superficial siderosis of the central nervous system. The diagnostic role of nuclear medicine techniques is smaller. SPECT and PET show decreased uptake of radiotracers investigating the nigrostriatal system in Multiple System Atrophy and in patients with Fragile X Tremor Ataxia Syndrome. Semiquantitative or quantitative MRI, SPECT and PET data describing structural, microstructural and functional changes of the cerebellum, brainstem, and spinal cord have been widely applied to investigate physiopathological changes in patients with chronic ataxias. Moreover they can track diseases progression with a greater sensitivity than clinical scales. So far, a few small-size and single center studies employed neuroimaging techniques as surrogate markers of treatment effects in chronic ataxias.
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Affiliation(s)
- Mario Mascalchi
- Meyer Children Hospital, Florence, Italy; Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
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16
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Vavla M, Arrigoni F, Nordio A, De Luca A, Pizzighello S, Petacchi E, Paparella G, D'Angelo MG, Brighina E, Russo E, Fantin M, Colombo P, Martinuzzi A. Functional and Structural Brain Damage in Friedreich's Ataxia. Front Neurol 2018; 9:747. [PMID: 30237783 PMCID: PMC6135889 DOI: 10.3389/fneur.2018.00747] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 08/17/2018] [Indexed: 11/13/2022] Open
Abstract
Friedreich's ataxia (FRDA) is a rare hereditary neurodegenerative disorder caused by a GAA repeat expansion in the FXN gene. There is still no cure or quantitative biomarkers reliaby correlating with the progression rate and disease severity. Investigation of functional and structural alterations characterizing white (WM) and gray matter (GM) in FRDA are needed prerequisite to monitor progression and response to treatment. Here we report the results of a multimodal cross-sectional MRI study of FRDA including Voxel-Based Morphometry (VBM), diffusion-tensor imaging (DTI), functional MRI (fMRI), and a correlation analysis with clinical severity scores. Twenty-one early-onset FRDA patients and 18 age-matched healthy controls (HCs) were imaged at 3T. All patients underwent a complete cognitive and clinical assessment with ataxia scales. VBM analysis showed GM volume reduction in FRDA compared to HCs bilaterally in lobules V, VI, VIII (L>R), as well as in the crus of cerebellum, posterior lobe of the vermis, in the flocculi and in the left tonsil. Voxel-wise DTI analysis showed a diffuse fractional anisotropy reduction and mean, radial, axial (AD) diffusivity increase in both infratentorial and supratentorial WM. ROI-based analysis confirmed the results showing differences of the same DTI metrics in cortico-spinal-tracts, forceps major, corpus callosum, posterior thalamic radiations, cerebellar penduncles. Additionally, we observed increased AD in superior (SCP) and middle cerebellar peduncles. The WM findings correlated with age at onset (AAO), short-allelle GAA, and disease severity. The intragroup analysis of fMRI data from right-handed 14 FRDA and 15 HCs showed similar findings in both groups, including activation in M1, insula and superior cerebellar hemisphere (lobules V-VIII). Significant differences emerged only during the non-dominant hand movement, with HCs showing a stronger activation in the left superior cerebellar hemisphere compared to FRDA. Significant correlations were found between AAO and the fMRI activation in cerebellar anterior and posterior lobes, insula and temporal lobe. Our multimodal neuroimaging protocol suggests that MRI is a useful tool to document the extension of the neurological impairment in FRDA.
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Affiliation(s)
- Marinela Vavla
- Severe Developmental Disabilities Unit, Scientific Institute, IRCCS "Eugenio Medea", Conegliano, Italy
| | - Filippo Arrigoni
- Neuroimaging Lab, Scientific Institute IRCCS "Eugenio Medea", Bosisio Parini, Italy
| | - Andrea Nordio
- Neuroimaging Lab, Scientific Institute IRCCS "Eugenio Medea", Bosisio Parini, Italy.,Department of Information Engineering, University of Padova, Padova, Italy
| | - Alberto De Luca
- Neuroimaging Lab, Scientific Institute IRCCS "Eugenio Medea", Bosisio Parini, Italy
| | - Silvia Pizzighello
- Severe Developmental Disabilities Unit, Scientific Institute, IRCCS "Eugenio Medea", Conegliano, Italy
| | - Elisa Petacchi
- Severe Developmental Disabilities Unit, Scientific Institute, IRCCS "Eugenio Medea", Conegliano, Italy
| | - Gabriella Paparella
- Severe Developmental Disabilities Unit, Scientific Institute, IRCCS "Eugenio Medea", Conegliano, Italy
| | - Maria Grazia D'Angelo
- NeuroMuscular Unit, Department of NeuroRehabilitation, IRCCS "Eugenio Medea", Bosisio Parini, Italy
| | - Erika Brighina
- NeuroMuscular Unit, Department of NeuroRehabilitation, IRCCS "Eugenio Medea", Bosisio Parini, Italy
| | - Emanuela Russo
- Severe Developmental Disabilities Unit, Scientific Institute, IRCCS "Eugenio Medea", Conegliano, Italy
| | - Marianna Fantin
- Severe Developmental Disabilities Unit, Scientific Institute, IRCCS "Eugenio Medea", Conegliano, Italy
| | - Paola Colombo
- Neuroimaging Lab, Scientific Institute IRCCS "Eugenio Medea", Bosisio Parini, Italy
| | - Andrea Martinuzzi
- Severe Developmental Disabilities Unit, Scientific Institute, IRCCS "Eugenio Medea", Conegliano, Italy
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17
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Cocozza S, Costabile T, Tedeschi E, Abate F, Russo C, Liguori A, Del Vecchio W, Paciello F, Quarantelli M, Filla A, Brunetti A, Saccà F. Cognitive and functional connectivity alterations in Friedreich's ataxia. Ann Clin Transl Neurol 2018; 5:677-686. [PMID: 29928651 PMCID: PMC5989773 DOI: 10.1002/acn3.555] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 02/14/2018] [Accepted: 02/22/2018] [Indexed: 01/26/2023] Open
Abstract
Objective The aim of this study was to perform the first resting-state functional MRI (RS-fMRI) analysis in Friedreich's ataxia (FRDA) patients to assess possible brain functional connectivity (FC) differences in these patients, and test their correlations with neuropsychological performances. Methods In total, 24 FRDA patients (M/F: 15/9, mean age 31.3 ± 15.0) and 24 healthy controls (HC; M/F: 15/9, mean age 30.7 ± 15.5) were enrolled in this cross-sectional study. All patients underwent a thorough neuropsychological battery, investigating different cognitive domains. RS-fMRI data were analyzed using a seed-based approach, probing the FC of cortical areas potentially referable to specific executive and cognitive functions compromised in FRDA. Results Compared to HC, FRDA patients showed overall worse neuropsychological scores in several domains, including global cognitive assessment, spatial memory, visuoperception and visuospatial functions, and executive functions. Analysis of RS-fMRI data showed a higher FC in FRDA patients compared to HC between paracingulate gyri and the medial frontal gryrus, between the superior frontal gyrus and bilateral angular gyri, and between the middle temporal gyrus and the cingulate gyrus, with a reduced FC between the medial frontal gryrus and the cerebellum. Interpretation We found a reduction in FC between frontal areas and the contralateral cerebellar cortex in FRDA, in line with the known alteration in cerebello-cortical pathway in this condition. On the other hand, a higher FC between different cortical areas was shown, possibly reflecting a compensatory phenomenon. These results, in conjunction with clinical findings, may shed new light on the pattern of supratentorial and infratentorial involvement, and on dynamics of brain plasticity in this disease.
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Affiliation(s)
- Sirio Cocozza
- Department of Advanced Biomedical Sciences University "Federico II" Naples Italy
| | - Teresa Costabile
- Department of Neurosciences and Reproductive and Odontostomatological Sciences University "Federico II" Naples Italy
| | - Enrico Tedeschi
- Department of Advanced Biomedical Sciences University "Federico II" Naples Italy
| | - Filomena Abate
- Department of Neurosciences and Reproductive and Odontostomatological Sciences University "Federico II" Naples Italy
| | - Camilla Russo
- Department of Advanced Biomedical Sciences University "Federico II" Naples Italy
| | - Agnese Liguori
- Department of Neurosciences and Reproductive and Odontostomatological Sciences University "Federico II" Naples Italy
| | - Walter Del Vecchio
- Institute of Biostructure and Bioimaging National Research Council Naples Italy
| | - Francesca Paciello
- Department of Neurosciences and Reproductive and Odontostomatological Sciences University "Federico II" Naples Italy
| | - Mario Quarantelli
- Institute of Biostructure and Bioimaging National Research Council Naples Italy
| | - Alessandro Filla
- Department of Neurosciences and Reproductive and Odontostomatological Sciences University "Federico II" Naples Italy
| | - Arturo Brunetti
- Department of Advanced Biomedical Sciences University "Federico II" Naples Italy
| | - Francesco Saccà
- Department of Neurosciences and Reproductive and Odontostomatological Sciences University "Federico II" Naples Italy
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18
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Moscufo N, Wakefield DB, Meier DS, Cavallari M, Guttmann CRG, White WB, Wolfson L. Longitudinal microstructural changes of cerebral white matter and their association with mobility performance in older persons. PLoS One 2018; 13:e0194051. [PMID: 29554115 PMCID: PMC5858767 DOI: 10.1371/journal.pone.0194051] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 02/25/2018] [Indexed: 11/18/2022] Open
Abstract
Mobility impairment in older persons is associated with brain white matter hyperintensities (WMH), a common finding in magnetic resonance images and one established imaging biomarker of small vessel disease. The contribution of possible microstructural abnormalities within normal-appearing white matter (NAWM) to mobility, however, remains unclear. We used diffusion tensor imaging (DTI) measures, i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), to assess microstructural changes within supratentorial NAWM and WMH sub-compartments, and to investigate their association with changes in mobility performance, i.e. Tinetti assessment and the 2.5-meters walk time test. We analyzed baseline (N = 86, age ≥75 years) and 4-year (N = 41) follow-up data. Results from cross-sectional analysis on baseline data showed significant correlation between WMH volume and NAWM-FA (r = -0.33, p = 0.002), NAWM-AD (r = 0.32, p = 0.003) and NAWM-RD (r = 0.39, p = 0.0002). Our longitudinal analysis showed that after 4-years, FA and AD decreased and RD increased within NAWM. In regional tract-based analysis decrease in NAWM-FA and increase in NAWM-RD within the genu of the corpus callosum correlated with slower walk time independent of age, gender and WMH burden. In conclusion, global DTI indices of microstructural integrity indicate that significant changes occur in the supratentorial NAWM over four years. The observed changes likely reflect white matter deterioration resulting from aging as well as accrual of cerebrovascular injury associated with small vessel disease. The observed association between mobility scores and regional measures of NAWM microstructural integrity within the corpus callosum suggests that subtle changes within this structure may contribute to mobility impairment.
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Affiliation(s)
- Nicola Moscufo
- Center for Neurological Imaging, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail:
| | - Dorothy B. Wakefield
- Department of Neurology, University of Connecticut School of Medicine, Farmington, Connecticut, United States of America
| | - Dominik S. Meier
- Center for Neurological Imaging, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Michele Cavallari
- Center for Neurological Imaging, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Charles R. G. Guttmann
- Center for Neurological Imaging, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - William B. White
- Division of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center (WBW), University of Connecticut School of Medicine, Farmington, Connecticut, United States of America
| | - Leslie Wolfson
- Department of Neurology, University of Connecticut School of Medicine, Farmington, Connecticut, United States of America
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19
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Zhou H, Tang Y, Yuan Z. White matter asymmetries in patients with cerebral small vessel disease. J Integr Neurosci 2018. [DOI: 10.3233/jin-170037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
- Hua Zhou
- School of Information Science and Engineering, Central South University, Changsha, Hunan 410083, P. R. China
- South China Institute of Software Engineering, Guangzhou, 510990, P. R. China
- School of Basic Medical Science Central South University, Changsha, Hunan 410083, P. R. China
| | - Yan Tang
- School of Information Science and Engineering, Central South University, Changsha, Hunan 410083, P. R. China
| | - Zhi Yuan
- South China Institute of Software Engineering, Guangzhou, 510990, P. R. China
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20
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Reetz K, Rodríguez-Labrada R, Dogan I, Mirzazade S, Romanzetti S, Schulz JB, Cruz-Rivas EM, Alvarez-Cuesta JA, Aguilera Rodríguez R, Gonzalez Zaldivar Y, Auburger G, Velázquez-Pérez L. Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2. Ann Clin Transl Neurol 2018; 5:128-137. [PMID: 29468174 PMCID: PMC5817824 DOI: 10.1002/acn3.504] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 10/06/2017] [Accepted: 10/21/2017] [Indexed: 01/11/2023] Open
Abstract
Objective Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disease mainly affecting the cerebellum and brainstem. In this Cuban-German research collaboration, we aimed to characterize atrophy patterns and associations with clinical measures in preclinical and manifest SCA2. Methods In this study, 16 nonmanifest SCA2 mutation carriers, 26 manifest patients with SCA2, and 18 healthy control subjects underwent magnetic resonance imaging, as well as genetic and clinical characterization including assessment of ataxia (Scale for the Assessment and Rating of Ataxia) and saccade velocity in Cuba were enrolled. Semiautomated quantitative volumetry of the cerebellum and brainstem, subdivided into the medulla oblongata, the pontine brainstem, and mesencephalon was performed. Additionally, the anteroposterior diameter of the pontine brainstem was measured. Results Analysis of volumetric data revealed degeneration of the cerebellum and brainstem, in particular of pontine volumes and the anteroposterior diameter of the pons, in both manifest SCA2 patients and individuals at risk for SCA2 compared to controls. Comparing patients with nonataxic preclinical SCA2 mutation carriers, we found more pronounced reductions of the pontine brainstem and cerebellum in manifest SCA2. Volumetric data further showed associations with CAG repeat length and predicted age of onset in preclinical SCA2 individuals, and by trend with ataxia signs in patients. Although saccade velocity was associated with reduction in the pontine brainstem in preclinical and manifest SCA2, reduced ability to suppress interfering stimuli measured by the Stroop task was related to cerebellar volume loss in patients. Interpretation Preclinical SCA2 mutation carriers exhibit brain abnormalities, which could be targeted as surrogate parameters for disease progression and in future preventive trials.
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Affiliation(s)
- Kathrin Reetz
- Department of Neurology RWTH Aachen University Pauwelsstr. 3052074 Aachen Germany.,JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging Forschungszentrum Jülich GmbH and RWTH Aachen University 52074 Aachen Germany
| | - Roberto Rodríguez-Labrada
- Department Clinical Neurophysiology Centre for the Research and Rehabilitation of Hereditary Ataxias Calle Libertad 26 Holguín 80100 Cuba
| | - Imis Dogan
- Department of Neurology RWTH Aachen University Pauwelsstr. 3052074 Aachen Germany.,JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging Forschungszentrum Jülich GmbH and RWTH Aachen University 52074 Aachen Germany
| | - Shahram Mirzazade
- Department of Neurology RWTH Aachen University Pauwelsstr. 3052074 Aachen Germany.,JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging Forschungszentrum Jülich GmbH and RWTH Aachen University 52074 Aachen Germany
| | - Sandro Romanzetti
- Department of Neurology RWTH Aachen University Pauwelsstr. 3052074 Aachen Germany.,JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging Forschungszentrum Jülich GmbH and RWTH Aachen University 52074 Aachen Germany
| | - Jörg B Schulz
- Department of Neurology RWTH Aachen University Pauwelsstr. 3052074 Aachen Germany.,JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging Forschungszentrum Jülich GmbH and RWTH Aachen University 52074 Aachen Germany
| | - Edilia M Cruz-Rivas
- Department of Imaging Clinical-Surgical Hospital "Lucía Iñiguez". Avenue "Celia Sanchez 1 Holguín Cuba
| | - Jose A Alvarez-Cuesta
- Department of Imaging Clinical-Surgical Hospital "Lucía Iñiguez". Avenue "Celia Sanchez 1 Holguín Cuba
| | - Raul Aguilera Rodríguez
- Department Clinical Neurophysiology Centre for the Research and Rehabilitation of Hereditary Ataxias Calle Libertad 26 Holguín 80100 Cuba
| | - Yanetza Gonzalez Zaldivar
- Department Molecular Genetics Centre for the Research and Rehabilitation of Hereditary Ataxias Calle Libertad 26 Holguín 80100 Cuba
| | - Georg Auburger
- Experimental Neurology Goethe University Medical School 60590 Frankfurt/Main Germany
| | - Luis Velázquez-Pérez
- Department Clinical Neurophysiology Centre for the Research and Rehabilitation of Hereditary Ataxias Calle Libertad 26 Holguín 80100 Cuba
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21
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22
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Selvadurai LP, Harding IH, Corben LA, Georgiou-Karistianis N. Cerebral abnormalities in Friedreich ataxia: A review. Neurosci Biobehav Rev 2018; 84:394-406. [DOI: 10.1016/j.neubiorev.2017.08.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Revised: 06/06/2017] [Accepted: 08/10/2017] [Indexed: 12/31/2022]
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Abstract
Diffusion tensor imaging (DTI) is a noninvasive neuroimaging tool assessing the organization of white-matter tracts and brain microstructure in vivo. The technique takes into account the three-dimensional (3D) direction of diffusion of water in space, the brownian movements of water being constrained by the brain microstructure. The main direction of diffusion in the brain is extracted to obtain the principal direction of axonal projection within a given voxel. Overall, the diffusion tensor is a mathematic analysis of the magnitude/directionality (anisotropy) of the movement of water molecules in 3D space. Tracts running in the white matter are subsequently reconstructed graphically with fiber tractography. Tractography can be applied to myelinated and unmyelinated fibers or axonopathy. Decreased fractional anisotropy in white-matter tracts occurs in cases of injury with disorganized or disrupted myelin sheaths. Furthermore, high angular resolution methods enable detection of fiber crossings or convergence. DTI is a modern tool which complements conventional magnetic resonance techniques and is particularly relevant to assess the organization of cerebellar tracts. Indeed, both the afferent and efferent pathways of the cerebellar circuitry passing through the inferior, middle, and superior cerebellar peduncles can be visualized in vivo, including in children. The microanatomy of the cerebellar cortex and cerebellar nuclei is also emerging as a future assessment. Applications in the field of cerebellar disorders are multiple, ranging from developmental disorders to adult-onset cerebellar ataxias.
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24
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Mormina E, Petracca M, Bommarito G, Piaggio N, Cocozza S, Inglese M. Cerebellum and neurodegenerative diseases: Beyond conventional magnetic resonance imaging. World J Radiol 2017; 9:371-388. [PMID: 29104740 PMCID: PMC5661166 DOI: 10.4329/wjr.v9.i10.371] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 07/18/2017] [Accepted: 08/02/2017] [Indexed: 02/06/2023] Open
Abstract
The cerebellum plays a key role in movement control and in cognition and cerebellar involvement is described in several neurodegenerative diseases. While conventional magnetic resonance imaging (MRI) is widely used for brain and cerebellar morphologic evaluation, advanced MRI techniques allow the investigation of cerebellar microstructural and functional characteristics. Volumetry, voxel-based morphometry, diffusion MRI based fiber tractography, resting state and task related functional MRI, perfusion, and proton MR spectroscopy are among the most common techniques applied to the study of cerebellum. In the present review, after providing a brief description of each technique’s advantages and limitations, we focus on their application to the study of cerebellar injury in major neurodegenerative diseases, such as multiple sclerosis, Parkinson’s and Alzheimer’s disease and hereditary ataxia. A brief introduction to the pathological substrate of cerebellar involvement is provided for each disease, followed by the review of MRI studies exploring structural and functional cerebellar abnormalities and by a discussion of the clinical relevance of MRI measures of cerebellar damage in terms of both clinical status and cognitive performance.
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Affiliation(s)
- Enricomaria Mormina
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
- Neuroradiology Unit, Department of Biomedical Sciences and Morphological and Functional Images, University of Messina, 98100 Messina, Italy
| | - Maria Petracca
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
- Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples Federico II, 80138 Naples, Italy
| | - Giulia Bommarito
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI), University of Genoa, 16132 Genoa, Italy
| | - Niccolò Piaggio
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI), University of Genoa, 16132 Genoa, Italy
- Department of Neuroradiology, San Martino Hospital, 16132 Genoa, Italy
| | - Sirio Cocozza
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
- Department of Advanced Biomedical Sciences, University of Naples Federico II, 80138 Naples, Italy
| | - Matilde Inglese
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI), University of Genoa, 16132 Genoa, Italy
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25
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Corben LA, Klopper F, Stagnitti M, Georgiou-Karistianis N, Bradshaw JL, Rance G, Delatycki MB. Measuring Inhibition and Cognitive Flexibility in Friedreich Ataxia. CEREBELLUM (LONDON, ENGLAND) 2017; 16:757-763. [PMID: 28229372 DOI: 10.1007/s12311-017-0848-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with subtle impact on cognition. Inhibitory processes and cognitive flexibility were examined in FRDA by assessing the ability to suppress a predictable verbal response. We administered the Hayling Sentence Completion Test (HSCT), the Trail Making Test, and the Stroop Test to 43 individuals with FRDA and 42 gender- and age-matched control participants. There were no significant group differences in performance on the Stroop or Trail Making Test whereas significant impairment in cognitive flexibility including the ability to predict and inhibit a pre-potent response as measured in the HSCT was evident in individuals with FRDA. These deficits did not correlate with clinical characteristics of FRDA (age of disease onset, disease duration, number of guanine-adenine-adenine repeats on the shorter or larger FXN allele, or Friedreich Ataxia Rating Scale score), suggesting that such impairment may not be related to the disease process in a straightforward way. The observed specific impairment of inhibition and predictive capacity in individuals with FRDA on the HSCT task, in the absence of impairment in associated executive functions, supports cerebellar dysfunction in conjunction with disturbance to cortico-thalamo-cerebellar connectivity, perhaps via inability to access frontal areas necessary for successful task completion.
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Affiliation(s)
- Louise A Corben
- Experimental Neuropsychology Research Unit, School of Psychological Sciences, Monash University, Clayton, Victoria, Australia.
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Flemington Road, Parkville, Victoria, Australia.
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
| | - Felicity Klopper
- Experimental Neuropsychology Research Unit, School of Psychological Sciences, Monash University, Clayton, Victoria, Australia
| | - Monique Stagnitti
- Experimental Neuropsychology Research Unit, School of Psychological Sciences, Monash University, Clayton, Victoria, Australia
| | - Nellie Georgiou-Karistianis
- Experimental Neuropsychology Research Unit, School of Psychological Sciences, Monash University, Clayton, Victoria, Australia
| | - John L Bradshaw
- Experimental Neuropsychology Research Unit, School of Psychological Sciences, Monash University, Clayton, Victoria, Australia
| | - Gary Rance
- Department of Otolaryngology, University of Melbourne, Parkville, Victoria, Australia
| | - Martin B Delatycki
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Flemington Road, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
- Victorian Clinical Genetics Services, Parkville, Victoria, Australia
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26
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Olivito G, Dayan M, Battistoni V, Clausi S, Cercignani M, Molinari M, Leggio M, Bozzali M. Bilateral effects of unilateral cerebellar lesions as detected by voxel based morphometry and diffusion imaging. PLoS One 2017; 12:e0180439. [PMID: 28692678 PMCID: PMC5503258 DOI: 10.1371/journal.pone.0180439] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 06/15/2017] [Indexed: 11/18/2022] Open
Abstract
Over the last decades, the importance of cerebellar processing for cortical functions has been acknowledged and consensus was reached on the strict functional and structural cortico-cerebellar interrelations. From an anatomical point of view strictly contralateral interconnections link the cerebellum to the cerebral cortex mainly through the middle and superior cerebellar peduncle. Diffusion MRI (dMRI) based tractography has already been applied to address cortico-cerebellar-cortical loops in healthy subjects and to detect diffusivity alteration patterns in patients with neurodegenerative pathologies of the cerebellum. In the present study we used dMRI-based tractography to determine the degree and pattern of pathological changes of cerebellar white matter microstructure in patients with focal cerebellar lesions. Diffusion imaging and high-resolution volumes were obtained in patients with left cerebellar lesions and in normal controls. Middle cerebellar peduncles and superior cerebellar peduncles were reconstructed by multi fiber diffusion tractography. From each tract, measures of microscopic damage were assessed, and despite the presence of unilateral lesions, bilateral diffusivity differences in white matter tracts were found comparing patients with normal controls. Consistently, bilateral alterations were also evidenced in specific brain regions linked to the cerebellum and involved in higher-level functions. This could be in line with the evidence that in the presence of unilateral cerebellar lesions, different cognitive functions can be affected and they are not strictly linked to the side of the cerebellar lesion.
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Affiliation(s)
- Giusy Olivito
- Ataxia Laboratory, Santa Lucia Foundation, Rome, Rome, Italy
- Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy
| | - Michael Dayan
- Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy
- Pattern Analysis and Computer Vision, Istituto Italiano di Tecnologia, Genova, Italy
| | | | - Silvia Clausi
- Ataxia Laboratory, Santa Lucia Foundation, Rome, Rome, Italy
- Department of Psychology, "Sapienza" University of Rome, Rome, Italy
| | - Mara Cercignani
- Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy
- Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, Falmer, United Kingdom
| | - Marco Molinari
- Neurological and Spinal Cord Injury Rehabilitation, Department A, Santa Lucia Foundation, Rome, Italy
| | - Maria Leggio
- Ataxia Laboratory, Santa Lucia Foundation, Rome, Rome, Italy
- Department of Psychology, "Sapienza" University of Rome, Rome, Italy
| | - Marco Bozzali
- Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy
- Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Falmer, United Kingdom
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27
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Vogel AP, Wardrop MI, Folker JE, Synofzik M, Corben LA, Delatycki MB, Awan SN. Voice in Friedreich Ataxia. J Voice 2017; 31:243.e9-243.e19. [DOI: 10.1016/j.jvoice.2016.04.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 04/26/2016] [Accepted: 04/27/2016] [Indexed: 10/21/2022]
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28
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Selvadurai LP, Harding IH, Corben LA, Stagnitti MR, Storey E, Egan GF, Delatycki MB, Georgiou-Karistianis N. Cerebral and cerebellar grey matter atrophy in Friedreich ataxia: the IMAGE-FRDA study. J Neurol 2016; 263:2215-2223. [PMID: 27522354 DOI: 10.1007/s00415-016-8252-7] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 07/30/2016] [Accepted: 07/30/2016] [Indexed: 12/22/2022]
Abstract
Friedreich ataxia (FRDA) is traditionally associated with neuropathology in the cerebellar dentate nucleus and spinal cord. Growing evidence also suggests involvement of the cerebral and cerebellar cortices, although reports of structural abnormalities remain mixed. This study assessed the structural integrity of cortical grey matter in FRDA, focussing on regions in which pathology may underlie the motor deficits characteristic of this disorder. T1-weighted anatomical magnetic resonance imaging scans were acquired from 31 individuals with FRDA and 37 healthy controls. Cortical thickness (FreeSurfer) and cortical volume (SPM-VBM) were measured in cerebral motor regions-of-interest (primary motor, dorsal and ventral premotor, and supplementary motor areas) alongside unconstrained exploratory analyses of the cerebral and cerebellar cortices. Correlations were assessed between cortical thickness/volume measures and each of disease severity, length of the causative genetic triplet-repeat expansion, and finger-tapping behavioural measures. Individuals with FRDA had significantly reduced cortical thickness, relative to controls, in the premotor and supplementary motor areas. Reduced cortical thickness and/or volume were also observed in the cuneus and precuneus, posterior aspects of the medial and lateral prefrontal cortices, insula, temporal poles, and cerebellar lobules V, VI, and VII. Measures of clinical severity, genetic abnormality, and motor dysfunction correlated with volume loss in the lateral cerebellar hemispheres. These results suggest that atrophy preferentially affects premotor relative to primary areas of the cortical motor system, and also extends to a range of non-motor brain regions. Furthermore, cortical thickness and cortical volume findings were largely divergent, suggesting that each is sensitive to different aspects of neuropathology in FRDA. Overall, this study supports a disease model involving neural aberrations within the cerebral and cerebellar cortices, beyond those traditionally associated with this disorder.
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Affiliation(s)
- Louisa P Selvadurai
- School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, 18 Innovation Walk, Melbourne, VIC, 3800, Australia
| | - Ian H Harding
- School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, 18 Innovation Walk, Melbourne, VIC, 3800, Australia.
| | - Louise A Corben
- School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, 18 Innovation Walk, Melbourne, VIC, 3800, Australia.,Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.,Department of Paediatrics, The University of Melbourne, Melbourne, Australia
| | - Monique R Stagnitti
- School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, 18 Innovation Walk, Melbourne, VIC, 3800, Australia
| | - Elsdon Storey
- Department of Medicine, Monash University, Melbourne, Australia
| | - Gary F Egan
- School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, 18 Innovation Walk, Melbourne, VIC, 3800, Australia.,Monash Biomedical Imaging, Monash University, Melbourne, Australia
| | - Martin B Delatycki
- School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, 18 Innovation Walk, Melbourne, VIC, 3800, Australia.,Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.,Department of Paediatrics, The University of Melbourne, Melbourne, Australia.,Clinical Genetics, Austin Health, Melbourne, Australia
| | - Nellie Georgiou-Karistianis
- School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, 18 Innovation Walk, Melbourne, VIC, 3800, Australia
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29
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Dogan I, Tinnemann E, Romanzetti S, Mirzazade S, Costa AS, Werner CJ, Heim S, Fedosov K, Schulz S, Timmann D, Giordano IA, Klockgether T, Schulz JB, Reetz K. Cognition in Friedreich's ataxia: a behavioral and multimodal imaging study. Ann Clin Transl Neurol 2016; 3:572-87. [PMID: 27606341 PMCID: PMC4999591 DOI: 10.1002/acn3.315] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 04/06/2016] [Accepted: 04/07/2016] [Indexed: 02/02/2023] Open
Abstract
Objective Friedreich's ataxia (FRDA) is a spinocerebellar degenerative disorder, in which cognitive deficits are sparsely explored. In this behavioral and multimodal magnetic resonance imaging (MRI) study, we investigated the neurocognitive profile and cortico‐cerebellar dysfunctions underlying executive functioning in individuals with FRDA. Methods 22 FRDA patients and 22 controls were clinically and neuropsychologically examined. Fifteen of each underwent structural and functional MRI using a verbal‐fluency task with phonemic and semantic conditions. Gray (GM) and white matter (WM) alterations were assessed by means of voxel‐based morphometry and diffusion‐tensor imaging. Results The neuropsychological profile demonstrated deficits in verbal fluency, working memory and social cognition. Functional MRI data showed most pronounced group‐differences in phonemic fluency with patients exhibiting enhanced activity in the cerebellum (VI, Crus I), fronto‐insular, premotor and temporo‐occipital regions. The semantic condition only revealed reduced activity in the anterior cerebellum; for overt speech, we found increased activity in the motor cortex. Functional connectivity‐analysis showed higher co‐activation within cerebellar and cortical regions, respectively, and impaired interregional coupling between the cerebellum and fronto‐insular cortex for phonemic processing, which was also related to poorer task performance. GM reduction in FRDA was mainly found in lobule VI, whereas WM degeneration was more pronounced including brainstem, cerebellum, and cortex. Decreased cerebellar GM was associated with enhanced activity in the fronto‐insular cortex, while loss of WM integrity may translate cortico‐cerebellar pathway disruptions. Interpretation The pattern of increased neural response with both cerebellar and cortical involvement underlying executive functioning indicates functional reorganization driven by disease‐related structural damage in FRDA.
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Affiliation(s)
- Imis Dogan
- Department of Neurology RWTH Aachen University Aachen Germany; JARA - Translational Brain Medicine Aachen and Jülich Germany
| | | | - Sandro Romanzetti
- Department of Neurology RWTH Aachen University Aachen Germany; JARA - Translational Brain Medicine Aachen and Jülich Germany
| | - Shahram Mirzazade
- Department of Neurology RWTH Aachen University Aachen Germany; JARA - Translational Brain Medicine Aachen and Jülich Germany
| | - Ana S Costa
- Department of Neurology RWTH Aachen University Aachen Germany; JARA - Translational Brain Medicine Aachen and Jülich Germany; Neurocognition Unit Department of Neurology Hospital de Braga Braga Portugal
| | - Cornelius J Werner
- Department of Neurology RWTH Aachen University Aachen Germany; JARA - Translational Brain Medicine Aachen and Jülich Germany
| | - Stefan Heim
- JARA - Translational Brain Medicine Aachen and Jülich Germany; JARA BRAIN Institute IIInstitute of Neuroscience and Medicine (INM-1) Research Center Jülich GmbH Jülich Germany; Department of Psychiatry, Psychotherapy and Psychosomatics RWTH Aachen Aachen
Germany
| | - Kathrin Fedosov
- Department of Neurology RWTH Aachen University Aachen Germany
| | - Stefanie Schulz
- Department of Neurology RWTH Aachen University Aachen Germany
| | - Dagmar Timmann
- Department of Neurology Essen University Hospital Essen Germany
| | - Ilaria A Giordano
- Department of Neurology University Hospital of Bonn Bonn Germany; German Center for Neurodegenerative Diseases (DZNE) Bonn Germany
| | - Thomas Klockgether
- Department of Neurology University Hospital of Bonn Bonn Germany; German Center for Neurodegenerative Diseases (DZNE) Bonn Germany
| | - Jörg B Schulz
- Department of Neurology RWTH Aachen University Aachen Germany; JARA - Translational Brain Medicine Aachen and Jülich Germany; JARA BRAIN Institute IIInstitute of Neuroscience and Medicine (INM-1)Research Center Jülich GmbH Jülich Germany
| | - Kathrin Reetz
- Department of Neurology RWTH Aachen University Aachen Germany; JARA - Translational Brain Medicine Aachen and Jülich Germany; JARA BRAIN Institute IIInstitute of Neuroscience and Medicine (INM-1)Research Center Jülich GmbH Jülich Germany
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Gramegna LL, Tonon C, Manners DN, Pini A, Rinaldi R, Zanigni S, Bianchini C, Evangelisti S, Fortuna F, Carelli V, Testa C, Lodi R. Combined Cerebellar Proton MR Spectroscopy and DWI Study of Patients with Friedreich’s Ataxia. THE CEREBELLUM 2016; 16:82-88. [DOI: 10.1007/s12311-016-0767-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Rezende TJR, Silva CB, Yassuda CL, Campos BM, D'Abreu A, Cendes F, Lopes-Cendes I, França MC. Longitudinal magnetic resonance imaging study shows progressive pyramidal and callosal damage in Friedreich's ataxia. Mov Disord 2015; 31:70-8. [PMID: 26688047 DOI: 10.1002/mds.26436] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Revised: 08/21/2015] [Accepted: 08/30/2015] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Spinal cord and peripheral nerves are classically known to be damaged in Friedreich's ataxia, but the extent of cerebral involvement in the disease and its progression over time are not yet characterized. The aim of this study was to evaluate longitudinally cerebral damage in Friedreich's ataxia. METHODS We enrolled 31 patients and 40 controls, which were evaluated at baseline and after 1 and 2 years. To assess gray matter, we employed voxel-based morphometry and cortical thickness measurements. White matter was evaluated using diffusion tensor imaging. Statistical analyses were both cross-sectional and longitudinal (corrected for multiple comparisons). RESULTS Group comparison between patients and controls revealed widespread macrostructural differences at baseline: gray matter atrophy in the dentate nuclei, brainstem, and precentral gyri; and white matter atrophy in the cerebellum and superior cerebellar peduncles, brainstem, and periventricular areas. We did not identify any longitudinal volumetric change over time. There were extensive microstructural alterations, including superior cerebellar peduncles, corpus callosum, and pyramidal tracts. Longitudinal analyses identified progressive microstructural abnormalities at the corpus callosum, pyramidal tracts, and superior cerebellar peduncles after 1 year of follow-up. CONCLUSION Patients with Friedreich's ataxia present more widespread gray and white matter damage than previously reported, including not only infratentorial areas, but also supratentorial structures. Furthermore, patients with Friedreich's ataxia have progressive microstructural abnormalities amenable to detection in a short-term follow-up.
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Affiliation(s)
- Thiago J R Rezende
- Department of Neurology and Neuroimaging Laboratory, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil
| | - Cynthia B Silva
- Department of Neurology and Neuroimaging Laboratory, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil
| | - Clarissa L Yassuda
- Department of Neurology and Neuroimaging Laboratory, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil
| | - Brunno M Campos
- Department of Neurology and Neuroimaging Laboratory, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil
| | - Anelyssa D'Abreu
- Department of Neurology and Neuroimaging Laboratory, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil
| | - Fernando Cendes
- Department of Neurology and Neuroimaging Laboratory, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil
| | - Iscia Lopes-Cendes
- Medical Genetics, School of Medical Sciences, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil
| | - Marcondes C França
- Department of Neurology and Neuroimaging Laboratory, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil
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Baldarçara L, Currie S, Hadjivassiliou M, Hoggard N, Jack A, Jackowski AP, Mascalchi M, Parazzini C, Reetz K, Righini A, Schulz JB, Vella A, Webb SJ, Habas C. Consensus paper: radiological biomarkers of cerebellar diseases. THE CEREBELLUM 2015; 14:175-96. [PMID: 25382714 DOI: 10.1007/s12311-014-0610-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine.
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Harding IH, Corben LA, Storey E, Egan GF, Stagnitti MR, Poudel GR, Delatycki MB, Georgiou-Karistianis N. Fronto-cerebellar dysfunction and dysconnectivity underlying cognition in friedreich ataxia: The IMAGE-FRDA study. Hum Brain Mapp 2015; 37:338-50. [PMID: 26502936 DOI: 10.1002/hbm.23034] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 09/16/2015] [Accepted: 10/12/2015] [Indexed: 12/22/2022] Open
Abstract
Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder defined by pathology within the cerebellum and spinal tracts. Although FRDA is most readily linked to motor and sensory dysfunctions, reported impairments in working memory and executive functions indicate that abnormalities may also extend to associations regions of the cerebral cortex and/or cerebello-cerebral interactions. To test this hypothesis, 29 individuals with genetically confirmed FRDA and 34 healthy controls performed a verbal n-back working memory task while undergoing functional magnetic resonance imaging. No significant group differences were evident in task performance. However, individuals with FRDA had deficits in brain activations both in the lateral cerebellar hemispheres, principally encompassing lobule VI, and the prefrontal cortex, including regions of the anterior insular and rostrolateral prefrontal cortices. Functional connectivity between these brain regions was also impaired, supporting a putative link between primary cerebellar dysfunction and subsequent cerebral abnormalities. Disease severity and genetic markers of disease liability were correlated specifically with cerebellar dysfunction, while correlations between behavioural performance and both cerebral activations and cerebello-cerebral connectivity were observed in controls, but not in the FRDA cohort. Taken together, these findings support a diaschisis model of brain dysfunction, whereby primary disease effects in the cerebellum result in functional changes in downstream fronto-cerebellar networks. These fronto-cerebellar disturbances provide a putative biological basis for the nonmotor symptoms observed in FRDA, and reflect the consequence of localized cerebellar pathology to distributed brain function underlying higher-order cognition.
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Affiliation(s)
- Ian H Harding
- School of Psychological Sciences, Monash University, Melbourne, Australia
| | - Louise A Corben
- School of Psychological Sciences, Monash University, Melbourne, Australia.,Bruce Lefroy Centre, Murdoch Childrens Research Institute, Melbourne, Australia.,Friedreich Ataxia Clinic, Monash Medical Centre, Monash Health, Melbourne, Australia
| | - Elsdon Storey
- Department of Medicine, Monash University, Melbourne, Australia
| | - Gary F Egan
- Monash Biomedical Imaging, Monash University, Melbourne, Australia
| | | | - Govinda R Poudel
- School of Psychological Sciences, Monash University, Melbourne, Australia
| | - Martin B Delatycki
- School of Psychological Sciences, Monash University, Melbourne, Australia.,Bruce Lefroy Centre, Murdoch Childrens Research Institute, Melbourne, Australia.,Department of Clinical Genetics, Austin Health, Melbourne, Australia
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Hernandez-Castillo CR, Galvez V, Mercadillo R, Diaz R, Campos-Romo A, Fernandez-Ruiz J. Extensive White Matter Alterations and Its Correlations with Ataxia Severity in SCA 2 Patients. PLoS One 2015; 10:e0135449. [PMID: 26263162 PMCID: PMC4532454 DOI: 10.1371/journal.pone.0135449] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 07/22/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Previous studies of SCA2 have revealed significant degeneration of white matter tracts in cerebellar and cerebral regions. The motor deficit in these patients may be attributable to the degradation of projection fibers associated with the underlying neurodegenerative process. However, this relationship remains unclear. Statistical analysis of diffusion tensor imaging enables an unbiased whole-brain quantitative comparison of the diffusion proprieties of white matter tracts in vivo. METHODS Fourteen genetically confirmed SCA2 patients and aged-matched healthy controls participated in the study. Tract-based spatial statistics were performed to analyze structural white matter damage using two different measurements: fractional anisotropy (FA) and mean diffusivity (MD). Significant diffusion differences were correlated with the patient's ataxia impairment. RESULTS Our analysis revealed decreased FA mainly in the inferior/middle/superior cerebellar peduncles, the bilateral posterior limb of the internal capsule and the bilateral superior corona radiata. Increases in MD were found mainly in cerebellar white matter, medial lemniscus, and middle cerebellar peduncle, among other regions. Clinical impairment measured with the SARA score correlated with FA in superior parietal white matter and bilateral anterior corona radiata. Correlations with MD were found in cerebellar white matter and the middle cerebellar peduncle. CONCLUSION Our findings show significant correlations between diffusion measurements in key areas affected in SCA2 and measures of motor impairment, suggesting a disruption of information flow between motor and sensory-integration areas. These findings result in a more comprehensive view of the clinical impact of the white matter degeneration in SCA2.
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Affiliation(s)
- Carlos R. Hernandez-Castillo
- Consejo Nacional de Ciencia y Tecnología—Cátedras—Instituto de Neuroetologia, Universidad Veracruzana, Mexico DF, Mexico
| | - Victor Galvez
- Instituto de Neuroetologia, Universidad Veracruzana, Xalapa, Mexico
| | - Roberto Mercadillo
- Cátedras Consejo Nacional de Ciencia y Tecnología, Área de Neurociencias, Departamento de Biología de la Reproducción, Universidad Autónoma Metropolitana, Mexico DF, Mexico
| | - Rosalinda Diaz
- Laboratorio de Neuropsicología, Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico DF, Mexico
| | - Aurelio Campos-Romo
- Unidad Periferica de Neurociencias, Facultad de Medicina Universidad Nacional Autonoma de Mexico/Instituto Nacional de Neurología y Neurocirugía, Mexico DF, Mexico
| | - Juan Fernandez-Ruiz
- Laboratorio de Neuropsicología, Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico DF, Mexico
- * E-mail:
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Mascalchi M, Toschi N, Giannelli M, Ginestroni A, Della Nave R, Tessa C, Piacentini S, Dotti MT, Aiello M, Nicolai E, Soricelli A, Salvi F, Diciotti S. Regional Cerebral Disease Progression in Friedreich's Ataxia: A Longitudinal Diffusion Tensor Imaging Study. J Neuroimaging 2015; 26:197-200. [PMID: 26175281 DOI: 10.1111/jon.12270] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 05/17/2015] [Accepted: 05/19/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND PURPOSE Imaging biomarkers of disease progression are desirable in inherited ataxias. MRI has demonstrated brain damage in Friedreich ataxia (FRDA) in form of regional atrophy of the medulla, peridentate cerebellar white matter (WM) and superior cerebellar peduncles (visible in T1-weighted images) and of change of microstructural characteristics of WM tracts of the brainstem, cerebellar peduncles, cerebellum, and supratentorial structures (visible through diffusion-weighted imaging). We explored the potential of brain MR morphometry and diffusion tensor imaging (DTI) to track the progression of neurodegeneration in FRDA. METHODS Eight patients (5F, 3M; age 13.4-41.2 years) and 8 healthy controls (2F, 6M; age 26.2-48.3 years) underwent 2 MRI examinations (mean 3.9 and 4.1 years apart, respectively) on the same 1.5T scanner. The protocol included 3D T1-weighted images and axial diffusion-weighted images (b-value 1,000 s/mm(2)) for calculating maps of fractional anisotropy, mean, axial and radial diffusivity, and mode of anisotropy. Tensor-based morphometry was used to investigate regional volume changes and tract-based spatial statistics was used to investigate microstructural changes in WM tracts. RESULTS Longitudinal analyses showed no differences in regional volume changes but a significant difference in axial diffusivity changes in cerebral and corpus callosum WM of patients as compared to controls (mean longitudinal rate of change for axial diffusivity: -.02 × 10(-3) mm(2)/s/year in patients vs. .01 × 10(-3) mm(2)/s/year in controls). No correlation with number of triplets, disease duration, and worsening of the clinical deficit was observed. CONCLUSION DTI can track brain microstructural changes in FRDA and can be considered a potential biomarker of disease progression.
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Affiliation(s)
- Mario Mascalchi
- Quantitative and Functional Neuroradiology Research Unit at Meyer Children and Careggi Hospitals of Florence, Florence, Italy.,"Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Nicola Toschi
- Medical Physics Section, Department of Biomedicine and Prevention, University of Rome "Tor Vergata,", Rome, Italy.,Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Boston, MA.,Harvard Medical School, Boston, MA
| | - Marco Giannelli
- Unit of Medical Physics, Pisa University Hospital "Azienda Ospedaliero-Universitaria Pisana,", Pisa, Italy
| | | | | | - Carlo Tessa
- Unit of Radiology, Versilia Hospital, Azienda USL 12 Viareggio, Lido di Camaiore (Lu), Italy
| | | | | | | | | | - Andrea Soricelli
- IRCSS SDN Foundation, Naples, Italy.,University of Naples Parthenope, Naples, Italy
| | - Fabrizio Salvi
- "Il Bene" Centre for Immunological and Rare Diseases, Bellaria Hospital, IRCSS Neurologia Città di Bologna, Bologna, Italy
| | - Stefano Diciotti
- Department of Electrical, Electronic, and Information Engineering "Guglielmo Marconi,", University of Bologna, Cesena, Italy
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Abrahão A, Pedroso JL, Braga-Neto P, Bor-Seng-Shu E, de Carvalho Aguiar P, Barsottini OGP. Milestones in Friedreich ataxia: more than a century and still learning. Neurogenetics 2015; 16:151-60. [PMID: 25662948 DOI: 10.1007/s10048-015-0439-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 01/20/2015] [Indexed: 10/24/2022]
Abstract
Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia worldwide. This review highlights the main clinical features, pathophysiological mechanisms, and therapeutic approaches for FRDA patients. The disease is characterized by a combination of neurological involvement (ataxia and neuropathy), cardiomyopathy, skeletal abnormalities, and glucose metabolism disturbances. FRDA is caused by expanded guanine-adenine-adenine (GAA) triplet repeats in the first intron of the frataxin gene (FXN), resulting in reduction of messenger RNA and protein levels of frataxin in different tissues. The molecular and metabolic disturbances, including iron accumulation, lead to pathological changes characterized by spinal cord and dorsal root ganglia atrophy, dentate nucleus atrophy without global cerebellar volume reduction, and hypertrophic cardiomyopathy. DNA analysis is the hallmark for the diagnosis of FRDA. There is no specific treatment to stop the disease progression in FRDA patients. However, a number of drugs are under investigation. Therapeutic approaches intend to improve mitochondrial functioning and to increase FXN expression.
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Affiliation(s)
- Agessandro Abrahão
- Division of General Neurology and Ataxia Unit, Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, Rua Pedro de Toledo 650 Vila Clementino, São Paulo, 04039-002, SP, Brazil,
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Cocozza S, Saccà F, Cervo A, Marsili A, Russo CV, Giorgio SMDA, De Michele G, Filla A, Brunetti A, Quarantelli M. Modifications of resting state networks in spinocerebellar ataxia type 2. Mov Disord 2015; 30:1382-90. [PMID: 26094751 DOI: 10.1002/mds.26284] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Revised: 04/13/2015] [Accepted: 05/11/2015] [Indexed: 12/29/2022] Open
Abstract
PURPOSE We aimed to investigate the integrity of the Resting State Networks in spinocerebellar ataxia type 2 (SCA2) and the correlations between the modification of these networks and clinical variables. METHODS Resting-state functional magnetic resonance imaging (RS-fMRI) data from 19 SCA2 patients and 29 healthy controls were analyzed using an independent component analysis and dual regression, controlling at voxel level for the effect of atrophy by co-varying for gray matter volume. Correlations between the resting state networks alterations and disease duration, age at onset, number of triplets, and clinical score were assessed by Spearman's coefficient, for each cluster which was significantly different in SCA2 patients compared with healthy controls. RESULTS In SCA2 patients, disruption of the cerebellar components of all major resting state networks was present, with supratentorial involvement only for the default mode network. When controlling at voxel level for gray matter volume, the reduction in functional connectivity in supratentorial regions of the default mode network, and in cerebellar regions within the default mode, executive and right fronto-parietal networks, was still significant. No correlations with clinical variables were found for any of the investigated resting state networks. CONCLUSIONS The SCA2 patients show significant alterations of the resting state networks, only partly explained by the atrophy. The default mode network is the only resting state network that shows also supratentorial changes, which appear unrelated to the cortical gray matter volume. Further studies are needed to assess the clinical significance of these changes.
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Affiliation(s)
- Sirio Cocozza
- Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy
| | - Francesco Saccà
- Department of Neurosciences and Reproductive and Odontostomatological Sciences, University "Federico II", Naples, Italy
| | - Amedeo Cervo
- Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy
| | - Angela Marsili
- Department of Neurosciences and Reproductive and Odontostomatological Sciences, University "Federico II", Naples, Italy
| | - Cinzia Valeria Russo
- Department of Neurosciences and Reproductive and Odontostomatological Sciences, University "Federico II", Naples, Italy
| | | | - Giuseppe De Michele
- Department of Neurosciences and Reproductive and Odontostomatological Sciences, University "Federico II", Naples, Italy
| | - Alessandro Filla
- Department of Neurosciences and Reproductive and Odontostomatological Sciences, University "Federico II", Naples, Italy
| | - Arturo Brunetti
- Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy
| | - Mario Quarantelli
- Biostructure and Bioimaging Institute, National Research Council, Naples, Italy
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Mascalchi M, Toschi N, Giannelli M, Ginestroni A, Della Nave R, Nicolai E, Bianchi A, Tessa C, Salvatore E, Aiello M, Soricelli A, Diciotti S. Progression of microstructural damage in spinocerebellar ataxia type 2: a longitudinal DTI study. AJNR Am J Neuroradiol 2015; 36:1096-101. [PMID: 25882284 DOI: 10.3174/ajnr.a4343] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 11/21/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND PURPOSE The ability of DTI to track the progression of microstructural damage in patients with inherited ataxias has not been explored so far. We performed a longitudinal DTI study in patients with spinocerebellar ataxia type 2. MATERIALS AND METHODS Ten patients with spinocerebellar ataxia type 2 and 16 healthy age-matched controls were examined twice with DTI (mean time between scans, 3.6 years [patients] and 3.3 years [controls]) on the same 1.5T MR scanner. Using tract-based spatial statistics, we analyzed changes in DTI-derived indices: mean diffusivity, axial diffusivity, radial diffusivity, fractional anisotropy, and mode of anisotropy. RESULTS At baseline, the patients with spinocerebellar ataxia type 2, as compared with controls, showed numerous WM tracts with significantly increased mean diffusivity, axial diffusivity, and radial diffusivity and decreased fractional anisotropy and mode of anisotropy in the brain stem, cerebellar peduncles, cerebellum, cerebral hemisphere WM, corpus callosum, and thalami. Longitudinal analysis revealed changes in axial diffusivity and mode of anisotropy in patients with spinocerebellar ataxia type 2 that were significantly different than those in the controls. In patients with spinocerebellar ataxia type 2, axial diffusivity was increased in WM tracts of the right cerebral hemisphere and the corpus callosum, and the mode of anisotropy was extensively decreased in hemispheric cerebral WM, corpus callosum, internal capsules, cerebral peduncles, pons and left cerebellar peduncles, and WM of the left paramedian vermis. There was no correlation between the progression of changes in DTI-derived indices and clinical deterioration. CONCLUSIONS DTI can reveal the progression of microstructural damage of WM fibers in the brains of patients with spinocerebellar ataxia type 2, and mode of anisotropy seems particularly sensitive to such changes. These results support the potential of DTI-derived indices as biomarkers of disease progression.
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Affiliation(s)
- M Mascalchi
- From the Quantitative and Functional Neuroradiology Research Unit (M.M.), Meyer Children and Careggi Hospitals of Florence, Florence, Italy "Mario Serio" Department of Experimental and Clinical Biomedical Sciences (M.M., A.B.), University of Florence, Florence, Italy
| | - N Toschi
- Medical Physics Section (N.T.), Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Rome, Italy Department of Radiology (N.T.), Athinoula A. Martinos Center for Biomedical Imaging, Boston, Massachusetts Harvard Medical School (N.T.), Boston, Massachusetts
| | - M Giannelli
- Unit of Medical Physics (M.G.), Pisa University Hospital "Azienda Ospedaliero-Universitaria Pisana," Pisa, Italy
| | - A Ginestroni
- Neuroradiology Unit (A.G.), Careggi General Hospital, Florence, Italy
| | | | - E Nicolai
- IRCSS SDN Foundation (E.N., M.A., A.S.), Naples, Italy
| | - A Bianchi
- From the Quantitative and Functional Neuroradiology Research Unit (M.M.), Meyer Children and Careggi Hospitals of Florence, Florence, Italy
| | - C Tessa
- Unit of Radiology (C.T.), Versilia Hospital, Lido di Camaiore, Italy
| | - E Salvatore
- Department of Neurological Sciences (E.S.), University of Naples Federico II, Naples, Italy
| | - M Aiello
- IRCSS SDN Foundation (E.N., M.A., A.S.), Naples, Italy
| | - A Soricelli
- IRCSS SDN Foundation (E.N., M.A., A.S.), Naples, Italy University of Naples Parthenope (A.S.), Naples, Italy
| | - S Diciotti
- Department of Electrical, Electronic, and Information Engineering "Guglielmo Marconi" (S.D.), University of Bologna, Cesena, Italy
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Vieira Karuta SC, Raskin S, de Carvalho Neto A, Gasparetto EL, Doring T, Teive HAG. Diffusion tensor imaging and tract-based spatial statistics analysis in Friedreich's ataxia patients. Parkinsonism Relat Disord 2015; 21:504-8. [PMID: 25801908 DOI: 10.1016/j.parkreldis.2015.02.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Revised: 01/28/2015] [Accepted: 02/20/2015] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Friedreich's ataxia (FRDA) is the most common hereditary ataxia and thinning of the cervical spinal cord is a consistent observation in Magnetic resonance imaging (MRI), although neuropathological examination in FRDA reveals neuronal loss in gray matter (GM) nuclei and degeneration of white matter (WM) tracts in the spinal cord, brainstem and cerebellum. Using diffusion-tensor (DTI) imaging and tract-based spatial statistics (TBSS) we tested the hypothesis that WM damage in FRDA is more extensive than previously described and probably involves normal-appearing WM. METHODS This transversal study included 21 genetically confirmed FRDA patients and seventeen healthy controls that underwent structural MRI of the brain on a 1.5 T scanner. We quantify the severity of ataxia using SARA scale. DTI was performed and diffusion data were analyzed using FMRIB's Diffusion Toolbox in FSL 4.1 in order to identify Fractional anisotropy (FA) decreases in specific brain regions and also the mean, radial and axial diffusivities (MD, RD, AD). RESULTS The greatest decreases in FA were in the left superior cerebellar peduncle, left posterior thalamic radiation, major forceps, left inferior fronto-occipital fasciculus and corpus callosum and had a significance level of p < 0.01. No significant correlation between FA, AD, MD and RD values and the clinical findings, SARA scores and genetic expansion was found. CONCLUSION DTI and TBSS techniques clearly demonstrate the extensive cerebral and cerebellar involvement in FRDA, partially explaining the clinical phenotype of the disease. Further studies are needed with larger samples to correlate clinical, genetic findings and ataxia scores.
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Affiliation(s)
| | - Salmo Raskin
- Pontificia Universidade Catolica do Parana, Genetika Laboratorio: Rua Saldanha Marinho, 1782, Bigorrilho, Curitiba, Parana 80730-180, Brazil.
| | - Arnolfo de Carvalho Neto
- Federal University of Parana, Hospital de Clinicas: R. Gen. Carneiro, 181, Alto da Glória, Curitiba, Parana 80060-900, Brazil.
| | - Emerson Leandro Gasparetto
- Federal University of Rio de Janeiro, CDPI Clinica de Diagnostico por Imagem: Centro Medico Barra Shopping, Aveinda das Americas, 4666, terceiro andar, Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Thomas Doring
- CDPI Clinica de Diagnostico por Imagem: Centro Medico Barra Shopping, Aveinda das Americas, 4666, terceiro andar, Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Helio Afonso Ghizoni Teive
- Federal University of Parana, Hospital de Clinicas: R. Gen. Carneiro, 181, Alto da Glória, Curitiba, Parana 80060-900, Brazil.
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Training-induced improvements in postural control are accompanied by alterations in cerebellar white matter in brain injured patients. NEUROIMAGE-CLINICAL 2014; 7:240-51. [PMID: 25610786 PMCID: PMC4300016 DOI: 10.1016/j.nicl.2014.12.006] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 12/03/2014] [Accepted: 12/04/2014] [Indexed: 12/13/2022]
Abstract
We investigated whether balance control in young TBI patients can be promoted by an 8-week balance training program and whether this is associated with neuroplastic alterations in brain structure. The cerebellum and cerebellar peduncles were selected as regions of interest because of their importance in postural control as well as their vulnerability to brain injury. Young patients with moderate to severe TBI and typically developing (TD) subjects participated in balance training using PC-based portable balancers with storage of training data and real-time visual feedback. An additional control group of TD subjects did not attend balance training. Mean diffusivity and fractional anisotropy were determined with diffusion MRI scans and were acquired before, during (4 weeks) and at completion of training (8 weeks) together with balance assessments on the EquiTest® System (NeuroCom) which included the Sensory Organization Test, Rhythmic Weight Shift and Limits of Stability protocols. Following training, TBI patients showed significant improvements on all EquiTest protocols, as well as a significant increase in mean diffusivity in the inferior cerebellar peduncle. Moreover, in both training groups, diffusion metrics in the cerebellum and/or cerebellar peduncles at baseline were predictive of the amount of performance increase after training. Finally, amount of training-induced improvement on the Rhythmic Weight Shift test in TBI patients was positively correlated with amount of change in fractional anisotropy in the inferior cerebellar peduncle. This suggests that training-induced plastic changes in balance control are associated with alterations in the cerebellar white matter microstructure in TBI patients.
Brain injury patients and healthy subjects attended 8-weeks of balance training. Diffusion MRI and postural tests were acquired before, during and after training. Cerebellum and cerebellar peduncles were selected as regions of interest. Training-induced changes shown in postural control and inferior cerebellar peduncle Correlations between change in balance and change in white matter microstructure
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Key Words
- Balance control training
- Brain injury
- Cerebellum
- Diffusion tensor imaging
- ICP, inferior cerebellar peduncle
- LOS, Limits of Stability
- MCP, middle cerebellar peduncle
- Plasticity
- RWS, Rhythmic Weight Shift
- SCP, superior cerebellar peduncle
- SOT, Sensory Organization Test
- TBI, traumatic brain injury
- TBI-t, TBI group with training
- TD, typically developing
- TD-c, TD group without training
- TD-t, TD group with training
- UF, uncinate fasciculus
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Abstract
Heredoataxias are a group of genetic disorders with a cerebellar syndrome as the leading clinical manifestation. The current classification distinguishes heredoataxias according to the trait of inheritance into autosomal dominant, autosomal recessive, X-linked, and maternally inherited heredoataxias. The autosomal dominant heredoataxias are separated into spinocerebellar ataxias (SCA1-8, 10-15, 17-23, 25-30, and dentato-rubro-pallido-luysian atrophy), episodic ataxias (EA1-7), and autosomal dominant mitochondrial heredoataxias (Leigh syndrome, MIRAS, ADOAD, and AD-CPEO). The autosomal recessive ataxias are separated into Friedreich ataxia, ataxia due to vitamin E deficiency, ataxia due to Abeta-lipoproteinemia, Refsum disease, late-onset Tay-Sachs disease, cerebrotendineous xanthomatosis, spinocerebellar ataxia with axonal neuropathy, ataxia telangiectasia, ataxia telangiectasia-like disorder, ataxia with oculomotor apraxia 1 and 2, spastic ataxia of Charlevoix-Saguenay, Cayman ataxia, Marinesco-Sjögren syndrome, and autosomal recessive mitochondrial ataxias (AR-CPEO, SANDO, SCAE, AHS, IOSCA, MEMSA, LBSL CoQ-deficiency, PDC-deficiency). Only two of the heredoataxias, fragile X/tremor/ataxia syndrome, and XLSA/A are transmitted via an X-linked trait. Maternally inherited heredoataxias are due to point mutations in genes encoding for tRNAs, rRNAs, respiratory chain subunits or single large scale deletions/duplications of the mitochondrial DNA and include MELAS, MERRF, KSS, PS, MILS, NARP, and non-syndromic mitochondrial disorders. Treatment of heredoataxias is symptomatic and supportive and may have a beneficial effect in single patients.**Please see page 424 for abbreviation list.
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Jung DE, Shim WH, Yoon HM, Kim JA, Lee JS. Tract-based spatial statistics of diffusion tensor imaging after corpus callosotomy in relation to seizure recurrence. Childs Nerv Syst 2014; 30:2043-9. [PMID: 25106789 DOI: 10.1007/s00381-014-2516-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 07/25/2014] [Indexed: 11/29/2022]
Abstract
PURPOSE To delineate microstructural changes in transected white matter tracts after corpus callosotomy in relation to seizure recurrence using tract-based spatial statistics of diffusion tensor imaging (DTI-TBSS). METHODS We retrospectively included 12 total corpus callosotomy patients who had undergone serial pre- and postoperative DTI studies. The first postoperative DTI was performed within 6 months after callosotomy. The second postoperative DTI was performed in five patients with seizure recurrence (symptomatic group) and in seven patients without seizure recurrence (asymptomatic group) after 1 year following surgery. Group comparisons of fractional anisotropy (FA) with age- and sex-matched controls were performed in a whole brain voxel-wise manner using DTI-TBSS. RESULTS The first postoperative DTI-TBSS showed a significant FA decrease in the entire corpus callosum in all patients. The second postoperative DTI-TBSS showed that a significant FA decrease remained in the entire corpus callosum in the asymptomatic group. However, in the symptomatic group, no significant decrease of FA was observed in some parts of the posterior body and splenium of the corpus callosum, although there was still a significant FA decrease in the genu of the corpus callosum. CONCLUSIONS Using DTI-TBSS analysis, we characterized and visualized microstructural white matter changes over time in relation to seizure recurrence in callosotomy patients, suggesting that reorganization of some transected white matter tracts may be related to seizure recurrence. DTI-TBSS analysis can provide reliable and useful information about the state of white matter bundles affected by corpus callosotomy in a noninvasive manner.
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Affiliation(s)
- Da Eun Jung
- Department of Pediatrics, Ajou University School of Medicine, Suwon, South Korea
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Akhlaghi H, Yu J, Corben L, Georgiou-Karistianis N, Bradshaw JL, Storey E, Delatycki MB, Egan GF. Cognitive deficits in Friedreich ataxia correlate with micro-structural changes in dentatorubral tract. THE CEREBELLUM 2014; 13:187-98. [PMID: 24085646 DOI: 10.1007/s12311-013-0525-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Atrophy of the dentate nucleus is one of the major neuropathological changes in Friedreich ataxia (FRDA). Neuroimaging studies demonstrated white matter (WM) degeneration in FRDA. In this study, we used advanced tractography techniques to quantitatively measure WM changes in the dentato-thalamic and dentato-rubral tracts, and correlated these changes with cognitive profiles of FRDA. We also analysed diffusivity changes of the thalamo-cortical tract to assess whether neurological degeneration of WM extends beyond the primary site of involvement in FRDA. Twelve genetically proven individuals with FRDA and 14 controls were recruited. Sixty directions diffusion tensor images were acquired. The WM bundles from the dentate nucleus were estimated using a constrained spherical deconvolution method and the diffusivity characteristics measured. The Simon task was used to assess cognitive profile of FRDA. The dentato-rubral, dentato-thalamic and thalamo-cortical tracts manifested significantly lower fractional anisotropy, higher mean diffusivity and increased radial diffusivity in FRDA compared with controls. There was no difference in axial diffusivity between the two groups. The mean and radial diffusivity of the dentato-rubral tract was positively correlated with choice reaction time, congruent reaction time, incongruent reaction time and Simon effect reaction time and negatively with the larger GAA repeat. Significant changes in diffusivity characteristics were observed in the dentato-thalamic and thalamo-cortical tracts, suggesting extensive WM degeneration and affected WM structures in FRDA. Correlation of WM changes in the dentato-rubral tract with the cognitive assessment suggested that this tract is an important contributor to cognitive disturbances in FRDA.
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Affiliation(s)
- Hamed Akhlaghi
- Monash Biomedical Imaging, Monash University, Clayton, Melbourne, Victoria, 3800, Australia,
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Solbach K, Kraff O, Minnerop M, Beck A, Schöls L, Gizewski E, Ladd M, Timmann D. Cerebellar pathology in Friedreich's ataxia: atrophied dentate nuclei with normal iron content. Neuroimage Clin 2014; 6:93-9. [PMID: 25379420 PMCID: PMC4215469 DOI: 10.1016/j.nicl.2014.08.018] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 08/06/2014] [Accepted: 08/21/2014] [Indexed: 01/03/2023]
Abstract
BACKGROUND In Friedreich's ataxia (FA) the genetically decreased expression of the mitochondrial protein frataxin leads to disturbance of the mitochondrial iron metabolism. Within the cerebellum the dentate nuclei (DN) are primarily affected. Histopathological studies show atrophy and accumulation of mitochondrial iron in DN. Dentate iron content has been suggested as a biomarker to measure the effects of siderophores/antioxidant treatment of FA. We assessed the iron content and the volume of DN in FA patients and controls based on ultra-high-field MRI (7 Tesla) images. METHODS Fourteen FA patients (mean age 38.1 yrs) and 14 age- and gender-matched controls participated. Multi-echo gradient echo and susceptibility weighted imaging (SWI) sequences were acquired on a 7 T whole-body scanner. For comparison SWI images were acquired on a 1.5 T MR scanner. Volumes of the DN and cerebellum were assessed at 7 and 1.5 T, respectively. Parametric maps of T2 and T2* sequences were created and proton transverse relaxation rates were estimated as a measure of iron content. RESULTS In FA, the DN and the cerebellum were significantly smaller compared to controls. However, proton transverse relaxation rates of the DN were not significantly different between both groups. CONCLUSIONS Applying in vivo MRI methods we could demonstrate significant atrophy of the DN in the presence of normal iron content. The findings suggest that relaxation rates are not reliable biomarkers in clinical trials evaluating the potential effect of FA therapy.
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Affiliation(s)
- K. Solbach
- Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany
| | - O. Kraff
- Erwin L. Hahn Institute for Magnetic Resonance Imaging, University Duisburg-Essen, Arendahls Wiese 199, Essen 45141, Germany
| | - M. Minnerop
- Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich 52425, Germany
- Department of Neurology, University Hospital Bonn, Sigmund-Freud-straße 25, Bonn 53127, Germany
| | - A. Beck
- Department of Computer Sciences, University of Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, Germany
| | - L. Schöls
- Department of Neurology, Eberhard Karls-University, Geschwister-Scholl-platz, Tübingen, Tübingen 72074, Germany
- Hertie Institute for Clinical Brain Research, Eberhard Karls-University Tübingen, Hoppe-Seyler-straße 3, Tübingen 72076, Germany
- German Research Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-straße 27, Tübingen 72076, Germany
| | - E.R. Gizewski
- Institute of Diagnostic and Interventional Radiology and Neuroradiology, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany
| | - M.E. Ladd
- Erwin L. Hahn Institute for Magnetic Resonance Imaging, University Duisburg-Essen, Arendahls Wiese 199, Essen 45141, Germany
- Institute of Diagnostic and Interventional Radiology and Neuroradiology, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany
| | - D. Timmann
- Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany
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Sahama I, Sinclair K, Fiori S, Pannek K, Lavin M, Rose S. Altered corticomotor-cerebellar integrity in young ataxia telangiectasia patients. Mov Disord 2014; 29:1289-98. [PMID: 25042086 DOI: 10.1002/mds.25970] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 05/15/2014] [Accepted: 06/16/2014] [Indexed: 02/03/2023] Open
Abstract
Magnetic resonance imaging (MRI) research in identifying altered brain structure and function in ataxia-telangiectasia, an autosomal recessive neurodegenerative disorder, is limited. Diffusion-weighted MRI were obtained from 11 ataxia telangiectasia patients (age range, 7-22 years; mean, 12 years) and 11 typically developing age-matched participants (age range, 8-23 years; mean, 13 years). Gray matter volume alterations in patients were compared with those of healthy controls using voxel-based morphometry, whereas tract-based spatial statistics was employed to elucidate white matter microstructure differences between groups. White matter microstructure was probed using quantitative fractional anisotropy and mean diffusivity measures. Reduced gray matter volume in both cerebellar hemispheres and in the precentral-postcentral gyrus in the left cerebral hemisphere was observed in ataxia telangiectasia patients compared with controls (P < 0.05, corrected for multiple comparisons). A significant reduction in fractional anisotropy in the cerebellar hemispheres, anterior/posterior horns of the medulla, cerebral peduncles, and internal capsule white matter, particularly in the left posterior limb of the internal capsule and corona radiata in the left cerebral hemisphere, was observed in patients compared with controls (P < 0.05). Mean diffusivity differences were observed within the left cerebellar hemisphere and the white matter of the superior lobule of the right cerebellar hemisphere (P < 0.05). Cerebellum-localized gray matter changes are seen in young ataxia telangiectasia patients along with white matter tract degeneration projecting from the cerebellum into corticomotor regions. The lack of cortical involvement may reflect early-stage white matter motor pathway degeneration within young patients.
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Affiliation(s)
- Ishani Sahama
- The University of Queensland, School of Medicine, Brisbane, Australia
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46
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Myelin paucity of the superior cerebellar peduncle in individuals with Friedreich ataxia: an MRI magnetization transfer imaging study. J Neurol Sci 2014; 343:138-43. [PMID: 24930398 DOI: 10.1016/j.jns.2014.05.057] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Revised: 05/23/2014] [Accepted: 05/26/2014] [Indexed: 11/23/2022]
Abstract
The dentate nucleus (DN) is the major relay station for neural connection between the cerebellum and cerebrum via the thalamus, and is a significant component of the neuropathological profile of Friedreich ataxia (FRDA). We have previously shown that the size of the superior cerebellar peduncle (SCP), which links the DN to cortical and subcortical structures via the thalamus, is significantly reduced in individuals with FRDA compared to control participants. This study used magnetization transfer imaging (MTI) to examine and contrast the integrity of white matter (WM) in the SCP and the corpus callosum (CC) (control region) in ten individuals with FRDA and ten controls. Individuals with FRDA demonstrated a significant reduction in the magnetization transfer ratio (MTR) in the SCP compared to control participants. However, there was no significant difference between groups in MTR in the CC. When comparing regions within groups, there was a significant reduction in MTR in the SCP compared to CC in participants with FRDA only. We suggest that the reduction in MTR in the SCP may be indicative of lack of myelin secondary to axonal loss and oligodendroglial dysfunction in WM tracts in individuals with FRDA.
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47
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Silva CBD, Yasuda CL, D'Abreu A, Cendes F, Lopes-Cendes I, França MC. Neuroanatomical correlates of depression in Friedreich's ataxia: a voxel-based morphometry study. THE CEREBELLUM 2013; 12:429-36. [PMID: 23090212 DOI: 10.1007/s12311-012-0424-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Affective disorders have been increasingly recognized in neurodegenerative diseases and often result in poor quality of life. However, the frequency, clinical relevance, and anatomical substrate of depression in Friedreich's ataxia were not yet evaluated. We assessed 22 patients with Friedreich's ataxia for major depression using Beck Depression Inventory and cerebral 3 T MRI scans. We then employed whole-brain voxel-based morphometry analyses on volumetric T1 datasets to compare tissue loss between patients with and without major depression. Patients (36.3 %) fulfilled criteria for major depression (8/22). Mean Beck Depression Inventory (BDI) score was 9.63 ± 8.95 and the depressive group had significantly higher score compared to non-depressive group (18.5 ± 8.6 vs 4.4 ± 2.9, p < 0.001). There was no correlation between Beck Depression Inventory score and age of patients, ataxia severity, age at onset, or duration of the disease. The comparison between patient groups found no significant differences of white matter volumes. In contrast, we found reduction of gray matter volumes in the depressive group in medial and orbital region of frontal lobe and anterior cingulate gyri (p < 0.001). Regression analyses have shown that BDI scores were inversely correlated with gray matter volume at right superior frontal gyrus. Major depression is frequent in Friedreich's ataxia and possibly under recognized. Our results strongly suggest that this may not be a simply reactive phenomenon, but rather associated to structural abnormalities.
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Affiliation(s)
- Cynthia B da Silva
- Departments of Neurology and Neuroimaging Laboratory, University of Campinas-UNICAMP, Rua Tessália Vieira de Camargo 126, Cidade Universitaria Zeferino Vaz, Campinas, SP, Brazil
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48
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Oguz KK, Haliloglu G, Temucin C, Gocmen R, Has AC, Doerschner K, Dolgun A, Alikasifoglu M. Assessment of whole-brain white matter by DTI in autosomal recessive spastic ataxia of Charlevoix-Saguenay. AJNR Am J Neuroradiol 2013; 34:1952-7. [PMID: 23598833 DOI: 10.3174/ajnr.a3488] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND AND PURPOSE Extension and characteristics of WM involvement other than the brain stem remain inadequately investigated in ARSACS. The aim of this study was to investigate whole-brain WM alterations in patients with ARSACS. MATERIALS AND METHODS Nine Turkish unrelated patients with ARSACS and 9 sex- and age-matched healthy control participants underwent neurologic examination, molecular studies, electrophysiologic studies, and DTI of the brain. TBSS was used for whole-brain voxelwise analysis of FA, AD, RD, mean diffusivity of WM. Tractographies for the CST and TPF were also computed. RESULTS Molecular studies revealed 8 novel mutations (3 nonsense, 4 missense, and 1 frameshift insertion) and a missense variation in the SACS gene. Thick TPF displaced and compressed the CST in the pons. The TPF had increased FA, decreased RD, and increased AD, which may be attributed to hypertrophy and/or hypermyelination. Widespread decreased FA and increased RD, suggesting demyelination, was found in the limbic, commissural, and projection fibers. In addition to demyelination, CST coursing cranial and caudal to the pons also showed a marked decrease in AD, suggesting axonal degeneration. Electrophysiologic studies revealed findings that concur with demyelination and axonal involvement. CONCLUSIONS In addition to developmental changes of the TPF and their effects on the CST in the brain stem, axonal degeneration mainly along the pyramidal tracts and widespread demyelination in WM also occur in patients with ARSACS. Widespread tissue damage may be associated with extensive loss of sacsin protein in the brain and may explain a wide range of progressive neurologic abnormalities in patients with ARSACS.
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Affiliation(s)
- K K Oguz
- National Magnetic Resonance Research Center, Bilkent University, Bilkent, Ankara, Turkey
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Egger K, Clemm von Hohenberg C, Schocke MF, Guttmann CRG, Wassermann D, Wigand MC, Nachbauer W, Kremser C, Sturm B, Scheiber-Mojdehkar B, Kubicki M, Shenton ME, Boesch S. White matter changes in patients with friedreich ataxia after treatment with erythropoietin. J Neuroimaging 2013; 24:504-8. [PMID: 24015771 DOI: 10.1111/jon.12050] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 05/22/2013] [Accepted: 06/30/2013] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND AND PURPOSE Erythropoietin (EPO) has received growing attention because of its neuroregenerative properties. Preclinical and clinical evidence supports its therapeutic potential in brain conditions like stroke, multiple sclerosis, and schizophrenia. Also, in Friedreich ataxia, clinical improvement after EPO therapy was shown. The aim of this study was to assess possible therapy-associated brain white matter changes in these patients. METHODS Nine patients with Friedreich ataxia underwent Diffusion Tensor Imaging (DTI) before and after EPO treatment. Tract-based spatial statistics was used for longitudinal comparison. RESULTS We detected widespread longitudinal increase in fractional anisotropy and axial diffusivity (D||) in cerebral hemispheres bilaterally (P < .05, corrected), while no changes were observed within the cerebellum, medulla oblongata, and pons. CONCLUSIONS To the best of our knowledge, this is the first DTI study to investigate the effects of EPO in a neurodegenerative disease. Anatomically, the diffusivity changes appear disease unspecific, and their biological underpinnings deserve further study.
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Affiliation(s)
- Karl Egger
- Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Neuroradiology, University Hospital Freiburg, Germany
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50
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Clemm von Hohenberg C, Schocke MF, Wigand MC, Nachbauer W, Guttmann CRG, Kubicki M, Shenton ME, Boesch S, Egger K. Radial diffusivity in the cerebellar peduncles correlates with clinical severity in Friedreich ataxia. Neurol Sci 2013; 34:1459-62. [PMID: 23640016 DOI: 10.1007/s10072-013-1402-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Accepted: 03/13/2013] [Indexed: 01/11/2023]
Abstract
Friedreich ataxia (FRDA) is a common inherited ataxia, caused by an expanded GAA repeat sequence in the Frataxin (FXN) gene. The proprioceptive system, which enters the cerebellum through the cerebellar peduncles, is a primary focus of pathology. In this study, we investigate the relationship of clinical and genetic data with diffusion-tensor imaging (DTI) indices reflecting white matter integrity of the cerebellar peduncles. Nine FRDA patients underwent DTI. After between-subject registration using tract-based spatial statistics, a white matter atlas was used for computing average values of DTI indices in the regions of interest. These were the inferior, middle and superior cerebellar peduncles (ICP, MCP, SCP). For Bonferroni correction, significance threshold was set to p < 0.0056. We found that radial diffusivity (D(⊥)) within the ICP significantly correlated with scores on the Friedreich Ataxia Rating Scale (FARS, Spearman's ρ = 0.883, p = 0.0016, all two-sided) and, at trend level, with number of trinucleotide repeats (ρ = 0.812, p = 0.008). D(⊥) in the SCP correlated with scores on the Scale for the Assessment and Rating of Ataxia (SARA, ρ = 0.867, p = 0.0025). These findings support the role of DTI, and especially D(⊥), as an informative biomarker in FRDA.
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Affiliation(s)
- Christian Clemm von Hohenberg
- Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital and Harvard Medical School, 1249 Boylston St, Boston, Massachusetts, 02215, USA.
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