Publications by authors named "Filippo Arrigoni"

71 Publications

DBB - A Distorted Brain Benchmark for Automatic Tissue Segmentation in Paediatric Patients.

Neuroimage 2022 Oct 16;260:119486. Epub 2022 Jul 16.

NeuroInformatics Laboratory (NILab), Bruno Kessler Foundation (FBK), Trento, Italy; Center for Mind and Brain Sciences (CIMeC), University of Trento, Italy.

T1-weighted magnetic resonance images provide a comprehensive view of the morphology of the human brain at the macro scale. These images are usually the input of a segmentation process that aims detecting the anatomical structures labeling them according to a predefined set of target tissues. Automated methods for brain tissue segmentation rely on anatomical priors of the human brain structures. This is the reason why their performance is quite accurate on healthy individuals. Nevertheless model-based tools become less accurate in clinical practice, specifically in the cases of severe lesions or highly distorted cerebral anatomy. More recently there are empirical evidences that a data-driven approach can be more robust in presence of alterations of brain structures, even though the learning model is trained on healthy brains. Our contribution is a benchmark to support an open investigation on how the tissue segmentation of distorted brains can be improved by adopting a supervised learning approach. We formulate a precise definition of the task and propose an evaluation metric for a fair and quantitative comparison. The training sample is composed of almost one thousand healthy individuals. Data include both T1-weighted MR images and their labeling of brain tissues. The test sample is a collection of several tens of individuals with severe brain distortions. Data and code are openly published on BrainLife, an open science platform for reproducible neuroscience data analysis.
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http://dx.doi.org/10.1016/j.neuroimage.2022.119486DOI Listing
October 2022

Superior Cerebellar Atrophy: An Imaging Clue to Diagnose -Related Disorders.

Int J Mol Sci 2022 Jun 16;23(12). Epub 2022 Jun 16.

Radiology and Neuroradiology Department, Children's Hospital V. Buzzi, 20154 Milan, Italy.

The inositol 1,4,5-triphosphate receptor type 1 () gene encodes an InsP-gated calcium channel that modulates intracellular Ca release and is particularly expressed in cerebellar Purkinje cells. Pathogenic variants in the gene are associated with different types of autosomal dominant spinocerebellar ataxia: SCA15 (adult onset), SCA29 (early-onset), and Gillespie syndrome. Cerebellar atrophy/hypoplasia is invariably detected, but a recognizable neuroradiological pattern has not been identified yet. With the aim of describing -related neuroimaging findings, the brain MRI of 14 patients with variants (11 SCA29, 1 SCA15, and 2 Gillespie) were reviewed by expert neuroradiologists. To further evaluate the role of superior vermian and hemispheric cerebellar atrophy as a clue for the diagnosis of -related conditions, the gene was sequenced in 5 patients with similar MRI pattern, detecting pathogenic variants in 4 of them. Considering the whole cohort, a distinctive neuroradiological pattern consisting in superior vermian and hemispheric cerebellar atrophy was identified in 83% patients with causative variants, suggesting this MRI finding could represent a hallmark for -related disorders.
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http://dx.doi.org/10.3390/ijms23126723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223788PMC
June 2022

Biallelic loss of EMC10 leads to mild to severe intellectual disability.

Ann Clin Transl Neurol 2022 07 9;9(7):1080-1089. Epub 2022 Jun 9.

Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK.

The endoplasmic reticulum membrane protein complex subunit 10 (EMC10) is a highly conserved protein responsible for the post-translational insertion of tail-anchored membrane proteins into the endoplasmic reticulum in a defined topology. Two biallelic variants in EMC10 have previously been associated with a neurodevelopmental disorder. Utilizing exome sequencing and international data sharing we have identified 10 affected individuals from six independent families with five new biallelic loss-of-function and one previously reported recurrent EMC10 variants. This report expands the molecular and clinical spectrum of EMC10 deficiency, provides a comprehensive dysmorphological assessment and highlights an overlap between the clinical features of EMC10-and EMC1-related disease.
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http://dx.doi.org/10.1002/acn3.51602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268894PMC
July 2022

Effects of age and gender on neural correlates of emotion imagery.

Hum Brain Mapp 2022 Sep 12;43(13):4116-4127. Epub 2022 May 12.

Department of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Mental imagery is part of people's own internal processing and plays an important role in everyday life, cognition and pathology. The neural network supporting mental imagery is bottom-up modulated by the imagery content. Here, we examined the complex associations of gender and age with the neural mechanisms underlying emotion imagery. We assessed the brain circuits involved in emotion mental imagery (vs. action imagery), controlled by a letter detection task on the same stimuli, chosen to ensure attention to the stimuli and to discourage imagery, in 91 men and women aged 14-65 years using fMRI. In women, compared with men, emotion imagery significantly increased activation within the right putamen, which is involved in emotional processing. Increasing age, significantly decreased mental imagery-related activation in the left insula and cingulate cortex, areas involved in awareness of ones' internal states, and it significantly decreased emotion verbs-related activation in the left putamen, which is part of the limbic system. This finding suggests a top-down mechanism by which gender and age, in interaction with bottom-up effect of type of stimulus, or directly, can modulate the brain mechanisms underlying mental imagery.
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http://dx.doi.org/10.1002/hbm.25906DOI Listing
September 2022

Quantitative MRI Harmonization to Maximize Clinical Impact: The RIN-Neuroimaging Network.

Front Neurol 2022 14;13:855125. Epub 2022 Apr 14.

Istituto di Radiologia, UOC Radiologia e Neuroradiologia, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy.

Neuroimaging studies often lack reproducibility, one of the cardinal features of the scientific method. Multisite collaboration initiatives increase sample size and limit methodological flexibility, therefore providing the foundation for increased statistical power and generalizable results. However, multisite collaborative initiatives are inherently limited by hardware, software, and pulse and sequence design heterogeneities of both clinical and preclinical MRI scanners and the lack of benchmark for acquisition protocols, data analysis, and data sharing. We present the overarching vision that yielded to the constitution of , a national consortium dedicated to identifying disease and subject-specific neuroimaging biomarkers of diverse neurological and neuropsychiatric conditions. This ambitious goal needs efforts toward increasing the diagnostic and prognostic power of advanced MRI data. To this aim, 23 Italian Scientific Institutes of Hospitalization and Care (IRCCS), with technological and clinical specialization in the neurological and neuroimaging field, have gathered together. Each IRCCS is equipped with high- or ultra-high field MRI scanners (i.e., ≥3T) for clinical or preclinical research or has established expertise in MRI data analysis and infrastructure. The actions of this Network were defined across several work packages (WP). A clinical work package (WP1) defined the guidelines for a minimum standard clinical qualitative MRI assessment for the main neurological diseases. Two neuroimaging technical work packages (WP2 and WP3, for clinical and preclinical scanners) established for quality controls on phantoms as well as advanced harmonized quantitative MRI protocols for studying the brain of healthy human participants and wild type mice. Under FAIR principles, a web-based e-infrastructure to store and share data across sites was also implemented (WP4). Finally, the RIN translated all these efforts into a large-scale multimodal data collection in patients and animal models with dementia (i.e., case study). The can maximize the impact of public investments in research and clinical practice acquiring data across institutes and pathologies with high-quality and highly-consistent acquisition protocols, optimizing the analysis pipeline and data sharing procedures.
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http://dx.doi.org/10.3389/fneur.2022.855125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9047871PMC
April 2022

Functional MRI Studies in Friedreich's Ataxia: A Systematic Review.

Front Neurol 2021 10;12:802496. Epub 2022 Mar 10.

Department of Neurorehabilitation, Pieve di Soligo, Scientific Institute, IRCCS E. Medea, Pieve di Soligo, Italy.

Friedreich's ataxia (FRDA) is an inherited neurodegenerative movement disorder with early onset, widespread cerebral and cerebellar pathology, and no cure still available. Functional MRI (fMRI) studies, although currently limited in number, have provided a better understanding of brain changes in people with FRDA. This systematic review aimed to provide a critical overview of the findings and methodologies of all fMRI studies conducted in genetically confirmed FRDA so far, and to offer recommendations for future study designs. About 12 cross-sectional and longitudinal fMRI studies, included 198 FRDA children and young adult patients and, 205 healthy controls (HCs), according to the inclusion criteria. Details regarding GAA triplet expansion and demographic and clinical severity measures were widely reported. fMRI designs included motor and cognitive task paradigms, and resting-state studies, with widespread changes in functionally activated areas and extensive variability in study methodologies. These studies highlight a mixed picture of both hypoactivation and hyperactivation in different cerebral and cerebellar brain regions depending on fMRI design and cohort characteristics. Functional changes often correlate with clinical variables. In aggregate, the findings provide support for cerebro-cerebellar loop damage and the compensatory mechanism hypothesis. Current literature indicates that fMRI is a valuable tool for gaining insights into FRDA pathology, but addressing that its limitations would be a key to improving the design, interpretation, and generalizability of studies in the future.
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http://dx.doi.org/10.3389/fneur.2021.802496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8960250PMC
March 2022

Long-term follow-up in a cohort of children with isolated corpus callosum agenesis at fetal MRI.

Ann Clin Transl Neurol 2021 12 1;8(12):2280-2288. Epub 2021 Dec 1.

Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy.

Objective: This long-term retrospective follow-up study aimed to address the knowledge gap between prenatal diagnosis of complete isolated Agenesis of Corpus Callosum (cACC) at fetal MRI and postnatal neurodevelopmental outcome to improve prenatal counseling for parents.

Methods: Data on fetuses with isolated cACC from a single-center MRI database built up in two decades were considered. Detailed postnatal clinical, neuropsychological evaluations were performed and descriptions of available neuroradiological and genetic data were provided.

Results: Following a detailed neuropsychological evaluation and a long-term follow-up, the subsequent results emerged: 38 school-aged children (older than 6 years) of 50 (aged 2.5-15 years) showed normal intellectual functions (50%), intellectual disability (21%), and borderline intelligence quotient (29%). Deficits in motor functions (58%), executive functions (37%), language (61%), memory abilities (58%), and academic performances (53%) were found. Twenty-one percent of participants showed behavioral difficulties. Almost half of the participants underwent rehabilitation. Additional findings (21%) were detected at postnatal brain MRI, and a significant association between additional findings at postnatal imaging and abnormal neurodevelopmental outcome was observed.

Interpretations: This study supports the view that children with prenatal diagnosis of isolated cACC may present with several degrees of neurologic and neuropsychological impairment which become more evident only in their second decade of life. Postnatal MRI and detailed genetic analysis may add crucial information to prenatal data and substantially influence final judgment on the outcome and orient clinical management and counseling.
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http://dx.doi.org/10.1002/acn3.51484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8670314PMC
December 2021

Get Your Molar Tooth Right: Joubert Syndrome Misdiagnosis Unmasked by Whole-Exome Sequencing.

Cerebellum 2021 Nov 30. Epub 2021 Nov 30.

Deparment of Molecular Medicine, University of Pavia, via Forlanini 14, 27100, Pavia, Italy.

Joubert syndrome (JS) is a recessively inherited ciliopathy, characterized by a specific cerebellar and brainstem malformation recognizable on brain imaging as the "molar tooth sign" (MTS). Clinical signs include hypotonia, developmental delay, breathing abnormalities, and ocular motor apraxia. Older patients develop ataxia, intellectual impairment, and variable organ involvement. JS is genetically heterogeneous, with over 40 ciliary genes overall accounting for 65-75% cases. Thus, in recent years, the genetic diagnosis of JS has been based on the analysis of next-generation sequencing targeted gene panels. Since clinical features are unspecific and undistinguishable from other neurodevelopmental syndromes, the recognition of the MTS is crucial to address the patient to the appropriate genetic testing. However, the MTS is not always properly diagnosed, resulting either in false negative diagnoses (patients with the MTS not addressed to JS genetic testing) or in false positive diagnoses (patients with a different brain malformation wrongly addressed to JS genetic testing). Here, we present six cases referred for JS genetic testing based on inappropriate recognition of MTS. While the analysis of JS-related genes was negative, whole-exome sequencing (WES) disclosed pathogenic variants in other genes causative of distinct brain malformative conditions with partial clinical and neuroradiological overlap with JS. Reassessment of brain MRIs from five patients by a panel of expert pediatric neuroradiologists blinded to the genetic diagnosis excluded the MTS in all cases but one, which raised conflicting interpretations. This study highlights that the diagnostic yield of NGS-based targeted panels is strictly related to the accuracy of the diagnostic referral based on clinical and imaging assessment and that WES has an advantage over targeted panel analysis when the diagnostic suspicion is not straightforward.
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http://dx.doi.org/10.1007/s12311-021-01350-8DOI Listing
November 2021

haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum.

J Med Genet 2021 Oct 21. Epub 2021 Oct 21.

Unit of Neurorehabilitation, Department of Neurosciences, IRCCS Bambino Gesù Children's Hospital, Roma, Italy.

Background: Joubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%-75%.In 2018, we reported homozygous hypomorphic missense variants of the gene in two families with mild JS. Recently, heterozygous truncating variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies.

Methods: We reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes.

Results: Heterozygous truncating and splice-site variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents.

Conclusion: Heterozygous truncating or splice-site variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.
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http://dx.doi.org/10.1136/jmedgenet-2021-108114DOI Listing
October 2021

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

Ann Neurol 2021 10 17;90(4):570-583. Epub 2021 Sep 17.

NSRO Department, University of Naples Federico II, Naples, Italy.

Objective: Friedreich ataxia (FRDA) is an inherited neurological disease defined by progressive movement incoordination. We undertook a comprehensive characterization of the spatial profile and progressive evolution of structural brain abnormalities in people with FRDA.

Methods: A coordinated international analysis of regional brain volume using magnetic resonance imaging data charted the whole-brain profile, interindividual variability, and temporal staging of structural brain differences in 248 individuals with FRDA and 262 healthy controls.

Results: The brainstem, dentate nucleus region, and superior and inferior cerebellar peduncles showed the greatest reductions in volume relative to controls (Cohen d = 1.5-2.6). Cerebellar gray matter alterations were most pronounced in lobules I-VI (d = 0.8), whereas cerebral differences occurred most prominently in precentral gyri (d = 0.6) and corticospinal tracts (d = 1.4). Earlier onset age predicted less volume in the motor cerebellum (r  = 0.35) and peduncles (r  = 0.36). Disease duration and severity correlated with volume deficits in the dentate nucleus region, brainstem, and superior/inferior cerebellar peduncles (r  = -0.49); subgrouping showed these to be robust and early features of FRDA, and strong candidates for further biomarker validation. Cerebral white matter abnormalities, particularly in corticospinal pathways, emerge as intermediate disease features. Cerebellar and cerebral gray matter loss, principally targeting motor and sensory systems, preferentially manifests later in the disease course.

Interpretation: FRDA is defined by an evolving spatial profile of neuroanatomical changes beyond primary pathology in the cerebellum and spinal cord, in line with its progressive clinical course. The design, interpretation, and generalization of research studies and clinical trials must consider neuroanatomical staging and associated interindividual variability in brain measures. ANN NEUROL 2021;90:570-583.
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http://dx.doi.org/10.1002/ana.26200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9292360PMC
October 2021

The Paternal Brain in Action: A Review of Human Fathers' fMRI Brain Responses to Child-Related Stimuli.

Brain Sci 2021 Jun 20;11(6). Epub 2021 Jun 20.

Department of Psychology and Speech-Language Pathology, University of Turku, 20500 Turku, Finland.

As fathers are increasingly involved in childcare, understanding the neurological underpinnings of fathering has become a key research issue in developmental psychobiology research. This systematic review specifically focused on (1) highlighting methodological issues of paternal brain research using functional magnetic resonance imaging (fMRI) and (2) summarizing findings related to paternal brain responses to auditory and visual infant stimuli. Sixteen papers were included from 157 retrieved records. Sample characteristics (e.g., fathers' and infant's age, number of kids, and time spent caregiving), neuroimaging information (e.g., technique, task, stimuli, and processing), and main findings were synthesized by two independent authors. Most of the reviewed works used different stimuli and tasks to test fathers' responses to child visual and/or auditory stimuli. Pre-processing and first-level analyses were performed with standard pipelines. Greater heterogeneity emerged in second-level analyses. Three main cortical networks (mentalization, embodied simulation, and emotion regulation) and a subcortical network emerged linked with fathers' responses to infants' stimuli, but additional areas (e.g., frontal gyrus, posterior cingulate cortex) were also responsive to infants' visual or auditory stimuli. This review suggests that a distributed and complex brain network may be involved in facilitating fathers' sensitivity and responses to infant-related stimuli. Nonetheless, specific methodological caveats, the exploratory nature of large parts of the literature to date, and the presence of heterogeneous tasks and measures also demonstrate that systematic improvements in study designs are needed to further advance the field.
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http://dx.doi.org/10.3390/brainsci11060816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233834PMC
June 2021

Refining the mutational spectrum and gene-phenotype correlates in pontocerebellar hypoplasia: results of a multicentric study.

J Med Genet 2022 04 5;59(4):399-409. Epub 2021 Mar 5.

Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Roma, Italy.

Background: Pontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorders characterised by concurrent hypoplasia of the pons and the cerebellum and variable clinical and imaging features. The current classification includes 13 subtypes, with ~20 known causative genes. Attempts have been made to delineate the phenotypic spectrum associated to specific PCH genes, yet clinical and neuroradiological features are not consistent across studies, making it difficult to define gene-specific outcomes.

Methods: We performed deep clinical and imaging phenotyping in 56 probands with a neuroradiological diagnosis of PCH, who underwent NGS-based panel sequencing of PCH genes and MLPA for rearrangements. Next, we conducted a phenotype-based unsupervised hierarchical cluster analysis to investigate associations between genes and specific phenotypic clusters.

Results: A genetic diagnosis was obtained in 43 probands (77%). The most common causative gene was , which accounted for nearly half cases (45%) and was mutated in females and occasionally in males. The European founder mutation p.Ala307Ser in and pathogenic variants in accounted for 18% and 9% of cases, respectively. , and were mutated in single patients. We were able to confirm only few previously reported associations, including jitteriness and clonus with and lower motor neuron signs with . When considering multiple features simultaneously, a clear association with a phenotypic cluster only emerged for .

Conclusion: represents the major PCH causative gene in Italy. Phenotypic variability associated with the most common genetic causes of PCH is wider than previously thought, with marked overlap between and -associated disorders.
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http://dx.doi.org/10.1136/jmedgenet-2020-107497DOI Listing
April 2022

Selecting the Most Relevant Brain Regions to Classify Children with Developmental Dyslexia and Typical Readers by Using Complex Magnocellular Stimuli and Multiple Kernel Learning.

Brain Sci 2021 May 28;11(6). Epub 2021 May 28.

Neuroimaging Lab, Scientific Institute, IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy.

Increasing evidence supports the presence of deficits in the visual magnocellular (M) system in developmental dyslexia (DD). The M system is related to the fronto-parietal attentional network. Previous neuroimaging studies have revealed reduced/absent activation within the visual M pathway in DD, but they have failed to characterize the extensive brain network activated by M stimuli. We performed a multivariate pattern analysis on a Region of Interest (ROI) level to differentiate between children with DD and age-matched typical readers (TRs) by combining full-field sinusoidal gratings, controlled for spatial and temporal frequencies and luminance contrast, and a coherent motion (CM) sensitivity task at 6%-CML6, 15%-CML15 and 40%-CML40. ROIs spanning the entire visual dorsal stream and ventral attention network (VAN) had higher discriminative weights and showed higher act1ivation in TRs than in children with DD. Of the two tasks, CM had the greatest weight when classifying TRs and children with DD in most of the ROIs spanning these streams. For the CML6, activation within the right superior parietal cortex positively correlated with reading skills. Our approach highlighted the dorsal stream and the VAN as highly discriminative areas between children with DD and TRs and allowed for a better characterization of the "dorsal stream vulnerability" underlying DD.
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http://dx.doi.org/10.3390/brainsci11060722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228080PMC
May 2021

Novel SPTBN2 gene mutation and first intragenic deletion in early onset spinocerebellar ataxia type 5.

Ann Clin Transl Neurol 2021 04 23;8(4):956-963. Epub 2021 Mar 23.

Laboratory of Molecular Biology, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Italy.

In the present study, we describe two novel cases of SCA5 with early onset. The first one, carrying a novel heterozygous de novo missense mutation in SPTBN2 gene, showed a striking very severe cerebellar atrophy and reduction of volume of the pons at a very young age (16 months). The latter, carrying the first de novo intragenic deletion so far reported in SPTBN2 gene, showed a mild cerebellar atrophy involving the hemispheres and a later onset. In both cases, for the first time, a hyperintense signal of the dentate nuclei was observed.
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http://dx.doi.org/10.1002/acn3.51345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045899PMC
April 2021

Retrospective study of late radiation-induced damages after focal radiotherapy for childhood brain tumors.

PLoS One 2021 26;16(2):e0247748. Epub 2021 Feb 26.

Pediatric Radiotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Purpose: To study a robust and reproducible procedure to investigate a relation between focal brain radiotherapy (RT) low doses, neurocognitive impairment and late White Matter and Gray Matter alterations, as shown by Diffusion Tensor Imaging (DTI), in children.

Methods And Materials: Forty-five patients (23 males and 22 females, median age at RT 6.2 years, median age at evaluations 11.1 years) who had received focal RT for brain tumors were recruited for DTI exams and neurocognitive tests. Patients' brains were parceled in 116 regions of interest (ROIs) using an available segmented atlas. After the development of an ad hoc, home-made, multimodal and highly deformable registration framework, we collected mean RT doses and DTI metrics values for each ROI. The pattern of association between cognitive scores or domains and dose or DTI values was assessed in each ROI through both considering and excluding ROIs with mean doses higher than 75% of the prescription. Subsequently, a preliminary threshold value of dose discriminating patients with and without neurocognitive impairment was selected for the most relevant associations.

Results: The workflow allowed us to identify 10 ROIs where RT dose and DTI metrics were significantly associated with cognitive tests results (p<0.05). In 5/10 ROIs, RT dose and cognitive tests were associated with p<0.01 and preliminary RT threshold dose values, implying a possible cognitive or neuropsychological damage, were calculated. The analysis of domains showed that the most involved one was the "school-related activities".

Conclusion: This analysis, despite being conducted on a retrospective cohort of children, shows that the identification of critical brain structures and respective radiation dose thresholds is achievable by combining, with appropriate methodological tools, the large amount of data arising from different sources. This supported the design of a prospective study to gain stronger evidence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247748PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909688PMC
August 2021

Basal Ganglia Dysmorphism in Patients With Aicardi Syndrome.

Neurology 2021 03 4;96(9):e1319-e1333. Epub 2020 Dec 4.

From the Department of Brain and Behavioural Neurosciences (S.M., A.P., M. Formica, S.O.) and Department of Public Health Experimental and Forensic Medicine, Biostatistic and Clinical Epidemiology Unit (P. Borrelli), University of Pavia; Pediatric Neurology Unit (S.M., M. Mastrangelo, P.V.), V. Buzzi Children's Hospital, Milan; Department of Neuroradiology (A.P.), Child Neurology and Psychiatry Unit (R.B., V.D.G., S.O.), and Department of Internal Medicine and Therapeutics, Member of the ERN EpiCARE, University of Pavia and Clinical Trial Center (E.P.), IRCCS Mondino Foundation Pavia; Neuroimaging Lab (F.A.) and Neuropsychiatry and Neurorehabilitation Unit (R.R.), Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco; Child Neuropsychiatric Unit (P.A., L.G.), Civilian Hospital, Brescia; Scientific Institute (P. Bonanni, A.D., E.O.), IRCCS E. Medea, Epilepsy and Clinical Neurophysiology Unit, Conegliano, Treviso; UOC Child Neuropsychiatry (B.D.B., F.D.), Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Italy; Département de Neurologie Pédiatrique (N.D.), Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Belgium; AdPueriVitam (O.D.), Antony; Service d'Explorations Fonctionnelles (S.G.), Centre de Médecine du Sommeil, l'Hôpital Àntoine Béclère, AP-HP, Clamart; Pediatrics Departement (S.G.), André-Grégoire Hospital, Centre Hospitalier Inter Communal, Montreuil, France; Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department (R.G., M. Montomoli, M.C.) and Radiology (M. Mortilla), A. Meyer Children's Hospital, Member of the ERN EpiCARE, University of Florence; IRCCS Stella Maris Foundation (R.G.), Pisa; Child Neuropsychiatry Unit, Epilepsy Center (F.L.B., A.V.), San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan; Child Neurology, NESMOS Department (P.P.), Faculty of Medicine & Psychology, Sant'Andrea Hospital, Sapienza University, Rome; Department of Neuroradiology (L.P.), Pediatric Neuroradiology Section, ASST Spedali Civili, Brescia; Pediatric Neuroradiology Unit (M.S.), IRCCS Istituto Giannina Gaslini, Genova; Neurology Unit, Department of Neuroscience, Member of the ERN EpiCARE (F.V.), Oncological Neuroradiology Unit, Department of Imaging, IRCCS (G.C.), and Department of Neuroscience and Neurorehabilitation (A.F.), Bambino Gesù Children's Hospital, Rome, Italy; Institut Imagine (N.B.-B.), Université Paris Descartes-Sorbonne Paris Cités; Pediatric Neurology (N.B.-B., I.D.), Necker Enfants Malades Hospital, Member of the ERN EpiCARE, Assistance Publique-Hôpitaux de Paris; INSERM UMR-1163 (N.B.-B., A. Arzimanoglou), Embryology and Genetics of Congenital Malformations, France; UOC Neurochirurgia (A. Accogli, V.C.), Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa (F.Z.), and Laboratory of Neurogenetics and Neuroscience, IRCCS (F.Z.), Istituto Giannina Gaslini, Genoa, Italy; Neurochirurgie Pédiatrique (M.B.), Hôpital NEM, Paris, France; Centre Médico-Chirurgical des Eaux-Vives (V.C.-V.), Swiss Medical Network, Genève, Switzerland; Neuroradiology Unit (L.C.) and Developmental Neurology Unit (S.D.), Foundation IRCCS C. Besta Neurological Institute, Milan; Service de Génétique (M.D.-F.), AMH2, CHU Reims, UFR de Médecine, Reims, France; Epilepsy Centre-Clinic of Nervous System Diseases (G.d.), Riuniti Hospital, Foggia, Italy; MediClubGeorgia Co Ltd (N.E.), Tbilisi, Georgia; Epilepsy Center (N.E.), Medical Center, Faculty of Medicine, University of Freiburg, Germany; Child and Adolescence Neurology and Psychiatry Unit (E. Fazzi), ASST Civil Hospital, Department of Clinical and Experimental Sciences, University of Brescia; Child Neurology Department (E. Fiorini), Verona, Italy; Service de Genetique Clinique (M. Fradin, P.L., C.Q.), CLAD-Ouest, Hospital Sud, Rennes, France; Child Neurology Unit, Pediatric Department (C.F., C.S.), Azienda USL-IRCCS di Reggio Emilia; Department of Pediatric Neuroscience (T.G., R.S.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Member of the ERN EpiCARE, Milan, Italy; Department of Epilepsy Genetics and Personalized Treatment (K.M.J., R.S.M.), The Danish Epilepsy Centre, Dianalund; Institute for Regional Health Services (K.M.J., R.S.M.), University of Southern Denmark, Odense; Unit of Pediatric Neurology and Pediatric Neurorehabilitation (S.L.), Woman-Mother-Child Department, Lausanne University Hospital CHUV, Switzerland; Unit of Neuroradiology (D.M.), Fondazione CNR/Regione Toscana G. Monasterio, Pisa; Pediatric Neurology Unit and Epilepsy Center (E.R., A.R.), Fatebenefratelli Hospital, Milan, Italy; KJF Klinik Josefinum GmbH (C.U.), Klinik für Kinder und Jugendliche, Neuropädiatrie, Augsburg, Germany; Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology (A. Arzimanoglou), University Hospitals of Lyon, Coordinator of the ERN EpiCARE, France; and Pediatric Epilepsy Unit, Child Neurology Department (P.V.), Hospital San Juan de Dios, Member of the ERN EpiCARE and Universitat de Barcelona, Spain.

Objective: Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed.

Methods: Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed.

Results: Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported).

Conclusion: The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome.

Classification Of Evidence: This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.
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http://dx.doi.org/10.1212/WNL.0000000000011237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055324PMC
March 2021

Sensitivity of Neuroimaging Indicators in Monitoring the Effects of Interferon Gamma Treatment in Friedreich's Ataxia.

Front Neurosci 2020 9;14:872. Epub 2020 Oct 9.

Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) E. Medea Scientific Institute, Bosisio Parini, Italy.

The identification of efficient markers of disease progression and response to possibly effective treatments is a key priority for slowly progressive, rare and neurodegenerative diseases, such as Friedreich's ataxia. Various imaging modalities have documented specific abnormalities in Friedreich's ataxia that could be tracked to provide useful indicators of efficacy in clinical trials. Advanced MRI imaging (diffusion tensor imaging, DTI; functional MRI, fMRI; and resting-state fMRI, rs-fMRI) and retinal imaging (optical coherence tomography, OCT) were tested longitudinally in a small group of Friedreich's ataxia patients participating in an open-label clinical trial testing the safety and the efficacy of 6-month treatment with interferon gamma. While the DTI indices documented the slow progression of fractional anisotropy loss, fMRI and rs-fMRI were significantly modified during and after treatment. The fMRI changes significantly correlated with the Scale for the Assessment and Rating of Ataxia, which is used to monitor clinical response. OCT documented the known thickness reduction of the retinal nerve fiber layer thickness, but there was no change over time. This pilot study provides indications for the potential utility of fMRI and rs-fMRI as ancillary measures in clinical trials for Friedreich's ataxia.
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http://dx.doi.org/10.3389/fnins.2020.00872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583645PMC
October 2020

Definitions and classification of malformations of cortical development: practical guidelines.

Brain 2020 10;143(10):2874-2894

Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Malformations of cortical development are a group of rare disorders commonly manifesting with developmental delay, cerebral palsy or seizures. The neurological outcome is extremely variable depending on the type, extent and severity of the malformation and the involved genetic pathways of brain development. Neuroimaging plays an essential role in the diagnosis of these malformations, but several issues regarding malformations of cortical development definitions and classification remain unclear. The purpose of this consensus statement is to provide standardized malformations of cortical development terminology and classification for neuroradiological pattern interpretation. A committee of international experts in paediatric neuroradiology prepared systematic literature reviews and formulated neuroimaging recommendations in collaboration with geneticists, paediatric neurologists and pathologists during consensus meetings in the context of the European Network Neuro-MIG initiative on Brain Malformations (https://www.neuro-mig.org/). Malformations of cortical development neuroimaging features and practical recommendations are provided to aid both expert and non-expert radiologists and neurologists who may encounter patients with malformations of cortical development in their practice, with the aim of improving malformations of cortical development diagnosis and imaging interpretation worldwide.
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http://dx.doi.org/10.1093/brain/awaa174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586092PMC
October 2020

Brain Magnetic Spectroscopy Imaging and Hereditary Spastic Paraplegia: A Focused Systematic Review on Current Landmarks and Future Perspectives.

Front Neurol 2020 14;11:515. Epub 2020 Jul 14.

SOS Neuromotor Unit, Department of Pieve di Soligo, Scientific Institute, IRCCS E. Medea, Treviso, Italy.

Magnetic resonance spectroscopy (MRS) is a non-invasive neuroimaging technique used to investigate brain metabolites. MRS could provide a sensitive tool for the study of hereditary spastic paraplegia (HSP) by helping to unveil the underlying biochemical mechanisms and monitoring response to treatment. This focused systematic review aimed to summarize the brain metabolite findings in studies performed in genetically determined HSP. The second aim was to provide a critical analysis and recommendations for well-designed protocols for future studies. Fourteen MRS studies have been analyzed with overall 61 HSP patients, falling within a wide range of age at onset, disease duration, and age at the MRS scan, including children and adults. The genetic diagnosis included several subtypes (SPG2/3/4/5/10/11/28/31/54). SPG11 and SPG54 have been more frequently investigated. The MRS methodology included different MR field strength, not easily comparable spectra areas varying from whole brain to various cortical areas, brain stem and cerebellum sampling. No consistency in disease severity and other outcome measures was observed. The main MRS findings corresponded to the white matter metabolite abnormalities in the corticospinal tracts. In summary, this focused review provides insights on the current knowledge of brain metabolites in HSP and, in particular, in SPG11 and SPG54. Despite the inhomogeneity of the studies to date reported, brain metabolites as assessed by MRS could represent potentially useful diagnostic markers and prognostic indicators of disease progression in HSP. Specific recommendations regarding the MRS technical protocol, CNS area sampling, study design, and applicability of findings are given.
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http://dx.doi.org/10.3389/fneur.2020.00515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381200PMC
July 2020

Feasibility Randomized Trial for an Intensive Memory-Focused Training Program for School-Aged Children with Acquired Brain Injury.

Brain Sci 2020 Jul 7;10(7). Epub 2020 Jul 7.

Neurophysiatric Department, Scientific Institute, I.R.C.C.S. Eugenio Medea, 23842 Bosisio Parini, Italy.

(1) Background: Memory deficits are common sequelae of pediatric Acquired Brain Injury (ABI). Only methods for non-focused cognitive remediation are available to the pediatric field. The aims of this feasibility trial are the description, implementation, and test of an intensive program specific to the training and re-adaptation of memory function in children, called Intensive Memory-Focused Training Program (IM-FTP); (2) Methods: Eleven children and adolescents with ABI (mean age at injury = 12.2 years, brain tumor survivors excluded) were clinically assessed and rehabilitated over 1-month through IM-FTP, including physio-kinesis/occupational, speech, and neuropsychology treatments. Each patient received a psychometric evaluation and a brain functional MRI at enrollment and at discharge. Ten pediatric controls with ABI (mean age at injury = 13.8 years) were clinically assessed, and rehabilitated through a standard program; (3) Results: After treatment, both groups had marked improvement in both immediate and delayed recall. IM-FTP was associated with better learning of semantically related and unrelated words, and larger improvement in immediate recall in prose memory. Imaging showed functional modification in the left frontal inferior cortex; (4) Conclusions: We described an age-independent reproducible multidisciplinary memory-focused rehabilitation protocol, which can be adapted to single patients while preserving inter-subject comparability, and is applicable up to a few months after injury. IM-FTP will now be employed in a powered clinical trial.
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http://dx.doi.org/10.3390/brainsci10070430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407971PMC
July 2020

White matter injury and neurodevelopmental disabilities: A cross-disease (dis)connection.

Prog Neurobiol 2020 10 4;193:101845. Epub 2020 Jun 4.

Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic, Vascular Sciences, and Public Health, University of Padova, Padova, Italy. Electronic address:

White matter (WM) injury, once known primarily in preterm newborns, is emerging in its non-focal (diffused), non-necrotic form as a critical component of subtle brain injuries in many early-life diseases like prematurity, intrauterine growth restriction, congenital heart defects, and hypoxic-ischemic encephalopathy. While advances in medical techniques have reduced the number of severe outcomes, the incidence of tardive impairments in complex cognitive functions or psychopathology remains high, with lifelong detrimental effects. The importance of WM in coordinating neuronal assemblies firing and neural groups synchronizing within multiple frequency bands through myelination, even mild alterations in WM structure, may interfere with the cognitive performance that increasing social and learning demands would exploit tardively during children growth. This phenomenon may contribute to explaining longitudinally the high incidence of late-appearing impairments that affect children with a history of perinatal insults. Furthermore, WM abnormalities have been highlighted in several neuropsychiatric disorders, such as autism and schizophrenia. In this review, we gather and organize evidence on how diffused WM injuries contribute to neurodevelopmental disorders through different perinatal diseases and insults. An insight into a possible common, cross-disease, mechanism, neuroimaging and monitoring, biomarkers, and neuroprotective strategies will also be presented.
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http://dx.doi.org/10.1016/j.pneurobio.2020.101845DOI Listing
October 2020

A multi-metric registration strategy for the alignment of longitudinal brain images in pediatric oncology.

Med Biol Eng Comput 2020 Apr 11;58(4):843-855. Epub 2020 Feb 11.

Department of Electronics Information and Bioengineering (DEIB), Politecnico di Milano, Milan, Italy.

Survival of pediatric patients with brain tumor has increased over the past 20 years, and increasing evidence of iatrogenic toxicities has been reported. In follow-ups, images are acquired at different time points where substantial changes of brain morphology occur, due to childhood physiological development and treatment effects. To address the image registration complexity, we propose two multi-metric approaches (M, M), combining mutual information (MI) and normalized gradient field filter (NGF). The registration performance of the proposed metrics was assessed on a simulated dataset (Brainweb) and compared with those obtained by MI and NGF separately, using mean magnitude and mean angular errors. The most promising metric (M) was then selected and tested on a retrospective dataset comprising 45 pediatric patients who underwent focal radiotherapy for brain cancer. The quality of the realignment was scored by a radiation oncologist using a perceived misalignment metric (PM). All patients but one were assessed as PM ≤ 2 (good alignment), but the remaining one, severely affected by hydrocephalus and pneumocephalus at the first MRI acquisition, scored PM = 5 (unacceptable). These preliminary findings suggest that M might improve the registration accuracy in complex applications such as pediatric oncology, when data are acquired throughout the years of follow-up, and is worth investigating. Graphical abstract Graphical abstract showing the clinical workflow of the overall registration procedure including the three rigid steps, the fourth deformable step, the reference MRI and the registered MRI as well as the contoured ROIs. The registration performance is assessed by means of the Perceived Misalignment score (PM).
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http://dx.doi.org/10.1007/s11517-019-02109-4DOI Listing
April 2020

Multi-center evaluation of stability and reproducibility of quantitative MRI measures in healthy calf muscles.

NMR Biomed 2019 09 17;32(9):e4119. Epub 2019 Jul 17.

Department of Radiology, University Medical Centre Utrecht, Utrecht, The Netherlands.

The purpose of this study was to evaluate temporal stability, multi-center reproducibility and the influence of covariates on a multimodal MR protocol for quantitative muscle imaging and to facilitate its use as a standardized protocol for evaluation of pathology in skeletal muscle. Quantitative T2, quantitative diffusion and four-point Dixon acquisitions of the calf muscles of both legs were repeated within one hour. Sixty-five healthy volunteers (31 females) were included in one of eight 3-T MR systems. Five traveling subjects were examined in six MR scanners. Average values over all slices of water-T2 relaxation time, proton density fat fraction (PDFF) and diffusion metrics were determined for seven muscles. Temporal stability was tested with repeated measured ANOVA and two-way random intraclass correlation coefficient (ICC). Multi-center reproducibility of traveling volunteers was assessed by a two-way mixed ICC. The factors age, body mass index, gender and muscle were tested for covariance. ICCs of temporal stability were between 0.963 and 0.999 for all parameters. Water-T2 relaxation decreased significantly (P < 10 ) within one hour by ~ 1 ms. Multi-center reproducibility showed ICCs within 0.879-0.917 with the lowest ICC for mean diffusivity. Different muscles showed the highest covariance, explaining 20-40% of variance for observed parameters. Standardized acquisition and processing of quantitative muscle MRI data resulted in high comparability among centers. The imaging protocol exhibited high temporal stability over one hour except for water T2 relaxation times. These results show that data pooling is feasible and enables assembling data from patients with neuromuscular diseases, paving the way towards larger studies of rare muscle disorders.
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http://dx.doi.org/10.1002/nbm.4119DOI Listing
September 2019

Diaphragm Involvement in Duchenne Muscular Dystrophy (DMD): An MRI Study.

J Magn Reson Imaging 2020 02 13;51(2):461-471. Epub 2019 Jul 13.

The Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Italy.

Background: Duchenne muscular dystrophy (DMD) is characterized by progressive weakness and wasting of skeletal, cardiac, and respiratory muscles, with consequent cardiopulmonary failure as the main cause of death. Reliable outcome measures able to demonstrate specific trends over disease progression are essential.

Purpose: To investigate MRI as a noninvasive imaging modality to assess diaphragm impairment in DMD. In particular, we sought to correlate MRI measurement of diaphragm structure and function with pulmonary function tests and with the abdominal volumes (V ) measured by optoelectronic plethysmography, being an index of the action of the diaphragm.

Study Type: Cross-sectional study.

Population: Twenty-six DMD patients (17.9 ± 6.2 years) and 12 age-matched controls (17.8 ± 5.9 years).

Field Strength/sequence: 3-Point gradient echo Dixon sequence at 3T.

Assessment: Images were acquired in breath-hold at full-expiration (EXP) and full-inspiration (INSP). INSP and EXP lung volumes were segmented and the diaphragm surface was reconstructed as the bottom surface of the left and the right lung. The inspiratory and the expiratory diaphragm surfaces were aligned by a nonrigid iterative closest point algorithm. On MRI we measured: 1) craniocaudal diaphragmatic excursion; 2) diaphragm fatty infiltration.

Statistical Tests: Three-parameter sigmoid regression, one-way analysis of variance (ANOVA), Spearman's correlation.

Results: In patients, diaphragm excursion decreased with age (r = 0.68, P < 0.0001) and fat fraction increased (r = 0.51, P = 0.0002). In healthy subjects, diaphragm excursion and fat fraction had no relationship with age. Diaphragm excursion decreased with decreasing FEV %pred (r = 0.78, P < 0.0001) and FVC %pred (r = 0.76, P < 0.0001) and correlated with V (r = 0.60, P = 0.0002). Fatty infiltration increased with decreasing FEV1 %pred (r = -0.88, P < 0.0001) and FVC %pred (r = -0.88, P < 0.0001).

Data Conclusion: The progressive structural and functional diaphragm impairment is highly related to pulmonary function tests and to V . The results suggest that MRI might represent a new and noninvasive tool for the functional and structural assessment of the diaphragm.

Level Of Evidence: 2 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2020;51:461-471.
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http://dx.doi.org/10.1002/jmri.26864DOI Listing
February 2020

Epilepsy in Tubulinopathy: Personal Series and Literature Review.

Cells 2019 07 2;8(7). Epub 2019 Jul 2.

Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, 23842 Lecco, Italy.

Mutations in tubulin genes are responsible for a large spectrum of brain malformations secondary to abnormal neuronal migration, organization, differentiation and axon guidance and maintenance. Motor impairment, intellectual disability and epilepsy are the main clinical symptoms. In the present study 15 patients from a personal cohort and 75 from 21 published studies carrying mutations in , and tubulin genes were evaluated with the aim to define a clinical and electrophysiological associated pattern. Epilepsy shows a wide range of severity without a specific pattern. Mutations in (60%) and (74%) and (25%) genes are associated with epilepsy. The accurate analysis of the Electroencephalogram (EEG) pattern in wakefulness and sleep in our series allows us to detect significant abnormalities of the background activity in 100% of patients. The involvement of white matter and of the inter-hemispheric connection structures typically observed in tubulinopathies is evidenced by the high percentage of asynchronisms in the organization of sleep activity recorded. In addition to asymmetries of the background activity, excess of slowing, low amplitude and Magnetic Resonance (MR) imaging confirm the presence of extensive brain malformations involving subcortical and midline structures. In conclusion, epilepsy in tubulinopathies when present has a favorable evolution over time suggesting a not particularly aggressive therapeutic approach.
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http://dx.doi.org/10.3390/cells8070669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678821PMC
July 2019

Tubulinopathies.

Top Magn Reson Imaging 2018 Dec;27(6):395-408

Neuroimaging Lab, Scientific Institute, IRCCS E. Medea Bosisio Parini, Italy.

Mutations causing dysfunction of the tubulins and microtubule-associated proteins, otherwise known as tubulinopathies, are a group of recently described entities, that lead to complex brain malformations. An understanding of the fundamental principles of operation of the cytoskeleton and compounds in particular microtubules, actin, and microtubule-associated proteins, can assist in the interpretation of the imaging findings of tubulinopathies. Somewhat consistent morphological imaging patterns have been described in tubulinopathies such as dysmorphic basal ganglia-the hallmark (found in 75% of cases), callosal dysgenesis, cerebellar hypoplasia/dysplasia, and cortical malformations, most notably lissencephaly. Recognizing the common imaging phenotypes present in tubulinopathies can prove invaluable in directing the genetic workup for a patient with brain malformations.
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http://dx.doi.org/10.1097/RMR.0000000000000188DOI Listing
December 2018

A Different Brain: Anomalies of Functional and Structural Connections in Williams Syndrome.

Front Neurol 2018 13;9:721. Epub 2018 Sep 13.

Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, IRCCS E. Medea, Bosisio Parini, Italy.

We describe the results of a functional and structural brain connectivity analysis comparing a homogeneous group of 10 young adults with Williams Syndrome (WS; 3 females, age 20. 7 ± 3.7 years, age range 17.4-28.7 years) to a group of 18 controls of similar age (3 females, age 23.9 ± 4.4 years, age range 16.8-30.2), with the aim to increase knowledge of the structure - function relationship in WS. Subjects underwent a 3T brain MRI exam including anatomical, functional (resting state) and structural (diffusion MRI) sequences. We found convergent anomalies in structural and functional connectivity in the WS group. Altered Fractional Anisotropy (FA) values in parieto-occipital regions were associated with increased connectivity in the antero-posterior pathways linking parieto-occipital with frontal regions. The analysis of resting state data showed altered functional connectivity in the WS group in main brain networks (default mode, executive control and dorsal attention, sensori-motor, fronto-parietal, ventral stream). The combined analysis of functional and structural connectivity displayed a different pattern in the two groups: in controls the highest agreement was found in frontal and visual areas, whereas in WS patients in posterior regions (parieto-occipital and temporal areas). These preliminary findings may reflect an altered "wiring" of the brain in WS, which can be driven by hyper-connectivity of the posterior regions as opposed to disrupted connectivity in the anterior areas, supporting the hypothesis that a different brain (organization) could be associated with a different (organization of) behavior in Williams Syndrome.
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http://dx.doi.org/10.3389/fneur.2018.00721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146099PMC
September 2018

Tensor-based morphometry using scalar and directional information of diffusion tensor MRI data (DTBM): Application to hereditary spastic paraplegia.

Hum Brain Mapp 2018 12 25;39(12):4643-4651. Epub 2018 Sep 25.

Quantitative Medical Imaging, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland.

Tensor-based morphometry (TBM) performed using T1-weighted images (T1WIs) is a well-established method for analyzing local morphological changes occurring in the brain due to normal aging and disease. However, in white matter regions that appear homogeneous on T1WIs, T1W-TBM may be inadequate for detecting changes that affect specific pathways. In these regions, diffusion tensor MRI (DTI) can identify white matter pathways on the basis of their different anisotropy and orientation. In this study, we propose performing TBM using deformation fields constructed using all scalar and directional information provided by the diffusion tensor (DTBM) with the goal of increasing sensitivity in detecting morphological abnormalities of specific white matter pathways. Previously, mostly fractional anisotropy (FA) has been used to drive registration in diffusion MRI-based TBM (FA-TBM). However, FA does not have the directional information that the tensors contain, therefore, the registration based on tensors provides better alignment of brain structures and better localization of volume change. We compare our DTBM method to both T1W-TBM and FA-TBM in investigating differences in brain morphology between patients with complicated hereditary spastic paraplegia of type 11 (SPG11) and a group of healthy controls. Effect size maps of T1W-TBM of SPG11 patients showed diffuse atrophy of white matter. However, DTBM indicated that atrophy was more localized, predominantly affecting several long-range pathways. The results of our study suggest that DTBM could be a powerful tool for detecting morphological changes of specific white matter pathways in normal brain development and aging, as well as in degenerative disorders.
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http://dx.doi.org/10.1002/hbm.24278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866509PMC
December 2018

Functional and Structural Brain Damage in Friedreich's Ataxia.

Front Neurol 2018 6;9:747. Epub 2018 Sep 6.

Severe Developmental Disabilities Unit, Scientific Institute, IRCCS "Eugenio Medea", Conegliano, Italy.

Friedreich's ataxia (FRDA) is a rare hereditary neurodegenerative disorder caused by a GAA repeat expansion in the 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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http://dx.doi.org/10.3389/fneur.2018.00747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135889PMC
September 2018
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