In vivo demonstration of globotriaosylceramide brain accumulation in Fabry Disease using MR Relaxometry.

PURPOSE: How to measure brain globotriaosylceramide (Gb3) accumulation in Fabry Disease (FD) patients in-vivo is still an open challenge. The objective of this study is to provide a quantitative, non-invasive demonstration of this phenomenon using quantitative MRI (qMRI). METHODS: In this retrospective, monocentric cross-sectional study conducted from November 2015 to July 2018, FD patients and healthy controls (HC) underwent an MRI scan with a relaxometry protocol to compute longitudinal relaxation rate (R1) maps to evaluate gray (GM) and white matter (WM) lipid accumulation. In a subgroup of 22 FD patients, clinical (FAbry STabilization indEX -FASTEX- score) and biochemical (residual α-galactosidase activity) variables were correlated with MRI data. Quantitative maps were analyzed at both global ("bulk" analysis) and regional ("voxel-wise" analysis) levels. RESULTS: Data were obtained from 42 FD patients (mean age = 42.4 ± 12.9, M/F = 16/26) and 49 HC (mean age = 42.3 ± 16.3, M/F = 28/21). Compared to HC, FD patients showed a widespread increase in R1 values encompassing both GM (pFWE = 0.02) and WM (pFWE = 0.02) structures. While no correlations were found between increased R1 values and FASTEX score, a significant negative correlation emerged between residual enzymatic activity levels and R1 values in GM (r = -0.57, p = 0.008) and WM (r = -0.49, p = 0.03). CONCLUSIONS: We demonstrated the feasibility and clinical relevance of non-invasively assessing cerebral Gb3 accumulation in FD using MRI. R1 mapping might be used as an in-vivo quantitative neuroimaging biomarker in FD patients.

Assessing brain involvement in Fabry disease with deep learning and the brain-age paradigm.

While neurological manifestations are core features of Fabry disease (FD), quantitative neuroimaging biomarkers allowing to measure brain involvement are lacking. We used deep learning and the brain-age paradigm to assess whether FD patients' brains appear older than normal and to validate brain-predicted age difference (brain-PAD) as a possible disease severity biomarker. MRI scans of FD patients and healthy controls (HCs) from a single Institution were, retrospectively, studied. The Fabry stabilization index (FASTEX) was recorded as a measure of disease severity. Using minimally preprocessed 3D T1-weighted brain scans of healthy subjects from eight publicly available sources (N = 2160; mean age = 33 years [range 4-86]), we trained a model predicting chronological age based on a DenseNet architecture and used it to generate brain-age predictions in the internal cohort. Within a linear modeling framework, brain-PAD was tested for age/sex-adjusted associations with diagnostic group (FD vs. HC), FASTEX score, and both global and voxel-level neuroimaging measures. We studied 52 FD patients (40.6 ± 12.6 years; 28F) and 58 HC (38.4 ± 13.4 years; 28F). The brain-age model achieved accurate out-of-sample performance (mean absolute error = 4.01 years, R2 = .90). FD patients had significantly higher brain-PAD than HC (estimated marginal means: 3.1 vs. -0.1, p = .01). Brain-PAD was associated with FASTEX score (B = 0.10, p = .02), brain parenchymal fraction (B = -153.50, p = .001), white matter hyperintensities load (B = 0.85, p = .01), and tissue volume reduction throughout the brain. We demonstrated that FD patients' brains appear older than normal. Brain-PAD correlates with FD-related multi-organ damage and is influenced by both global brain volume and white matter hyperintensities, offering a comprehensive biomarker of (neurological) disease severity.

Clinical correlates of R1 relaxometry and magnetic susceptibility changes in multiple sclerosis: a multi-parameter quantitative MRI study of brain iron and myelin.

OBJECTIVES: The clinical impact of brain microstructural abnormalities in multiple sclerosis (MS) remains elusive. We aimed to characterize the topography of longitudinal relaxation rate (R1) and quantitative susceptibility (χ) changes, as indices of iron and myelin, together with brain atrophy, and to clarify their contribution to cognitive and motor disability in MS. METHODS: In this cross-sectional study, voxel-based morphometry, and voxel-based quantification analyses of R1 and χ maps were conducted in gray matter (GM) and white matter (WM) of 117 MS patients and 53 healthy controls. Voxel-wise between-group differences were assessed with nonparametric permutation tests, while correlations between MRI metrics and clinical variables (global disability, cognitive and motor performance) were assessed both globally and voxel-wise within clusters emerging from the between-group comparisons. RESULTS: MS patients showed widespread R1 decrease associated with more limited modifications of χ, with atrophy mainly involving deep GM, posterior and infratentorial regions (p < 0.02). While R1 and χ showed a parallel reduction in several WM tracts (p < 0.001), reduced GM R1 values (p < 0.001) were associated with decreased thalamic χ (p < 0.001) and small clusters of increased χ in the caudate nucleus and prefrontal cortex (p < 0.02). In addition to the atrophy, χ values in the cingulum and corona radiata correlated with global disability and motor performance, while focal demyelination correlated with cognitive performance (p < 0.04). CONCLUSIONS: We confirmed the presence of widespread R1 changes, involving both GM and WM, and atrophy in MS, with less extensive modifications of tissue χ. While atrophy and χ changes are related to global and motor disability, R1 changes are meaningful correlates of cognition. KEY POINTS: • Compared to healthy controls, multiple sclerosis patients showed R1 and χ changes suggestive of iron increase within the basal ganglia and reduced iron and myelin content within (subnuclei of) the thalamus. • Thalamic volume and χ changes significantly predicted clinical disability, as well as pulvinar R1 and χ changes, independently from atrophy. • Atrophy-independent R1 and χ changes, suggestive of thalamic iron and myelin depletion, may represent a sensitive marker of subclinical inflammation.

The central vein sign helps in differentiating multiple sclerosis from its mimickers: lessons from Fabry disease.

OBJECTIVES: Although the use of specific MRI criteria has significantly increased the diagnostic accuracy of multiple sclerosis (MS), reaching a correct neuroradiological diagnosis remains a challenging task, and therefore the search for new imaging biomarkers is crucial. This study aims to evaluate the incidence of one of the emerging neuroradiological signs highly suggestive of MS, the central vein sign (CVS), using data from Fabry disease (FD) patients as an index of microvascular disorder that could mimic MS. METHODS: In this retrospective study, after the application of inclusion and exclusion criteria, MRI scans of 36 FD patients and 73 relapsing-remitting (RR) MS patients were evaluated. Among the RRMS participants, 32 subjects with a disease duration inferior to 5 years (early MS) were also analyzed. For all subjects, a Fazekas score (FS) was recorded, excluding patients with FS = 0. Different neuroradiological signs, including CVS, were evaluated on FLAIR T2-weighted and spoiled gradient recalled echo sequences. RESULTS: Among all the recorded neuroradiological signs, the most striking difference was found for the CVS, with a detectable prevalence of 78.1% (57/73) in RRMS and of 71.4% (25/32) in early MS patients, while this sign was absent in FD (0/36). CONCLUSIONS: Our results confirm the high incidence of CVS in MS, also in the early phases of the disease, while it seems to be absent in conditions with a different etiology. These results corroborate the possible role of CVS as a useful neuroradiological sign highly suggestive of MS. KEY POINTS: • The search for new imaging biomarkers is crucial to achieve a correct neuroradiological diagnosis of MS. • The CVS shows an incidence superior to 70% in MS patients, even in the early phases of the disease, while it appears to be absent in FD. • These findings further corroborate the possible future central role of CVS in distinguishing between MS and its mimickers.

State of the Art in Artificial Intelligence and Radiomics in Hepatocellular Carcinoma.

The most common liver malignancy is hepatocellular carcinoma (HCC), which is also associated with high mortality. Often HCC develops in a chronic liver disease setting, and early diagnosis as well as accurate screening of high-risk patients is crucial for appropriate and effective management of these patients. While imaging characteristics of HCC are well-defined in the diagnostic phase, challenging cases still occur, and current prognostic and predictive models are limited in their accuracy. Radiomics and machine learning (ML) offer new tools to address these issues and may lead to scientific breakthroughs with the potential to impact clinical practice and improve patient outcomes. In this review, we will present an overview of these technologies in the setting of HCC imaging across different modalities and a range of applications. These include lesion segmentation, diagnosis, prognostic modeling and prediction of treatment response. Finally, limitations preventing clinical application of radiomics and ML at the present time are discussed, together with necessary future developments to bring the field forward and outside of a purely academic endeavor.

Exit Strategies in Natalizumab-Treated RRMS at High Risk of Progressive Multifocal Leukoencephalopathy: a Multicentre Comparison Study.

The main aim of the study is to evaluate the efficacy and safety profile of ocrelizumab (OCR), rituximab (RTX), and cladribine (CLA), employed as natalizumab (NTZ) exit strategies in relapsing-remitting multiple sclerosis (RRMS) patients at high-risk for progressive multifocal leukoencephalopathy (PML). This is a multicentre, retrospective, real-world study on consecutive RRMS patients from eleven tertiary Italian MS centres, who switched from NTZ to OCR, RTX, and CLA from January 1st, 2019, to December 31st, 2019. The primary study outcomes were the annualized relapse rate (ARR) and magnetic resonance imaging (MRI) outcome. Treatment effects were estimated by the inverse probability treatment weighting (IPTW), based on propensity-score (PS) approach. Additional endpoint included confirmed disability progression (CDP) as measured by Expanded Disability Status Scale and adverse events (AEs). Patients satisfying predefined inclusion and exclusion criteria were 120; 64 switched to OCR, 36 to RTX, and 20 to CLA. Patients from the 3 groups did not show differences for baseline characteristics, also after post hoc analysis. The IPTW PS-adjusted models revealed that patients on OCR had a lower risk for ARR than patients on CLA (ExpBOCR 0.485, CI 95% 0.264-0.893, p = 0.020). This result was confirmed also for 12-month MRI activity (ExpBOCR 0.248 CI 95% 0.065-0.948, p = 0.042). No differences were found in other pairwise comparisons (OCR vs RTX and RTX vs CLA) for the investigated outcomes. AEs were similar among the 3 groups. Anti-CD20 drugs were revealed to be effective and safe options as NTZ exit strategies. All investigated DMTs showed a good safety profile.

Possible progressive multifocal leukoencephalopathy and active multiple sclerosis under dimethyl fumarate: the central role of MRI in informing therapeutic decisions.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) can rarely occur in Multiple Sclerosis (MS) patients undergoing dimethyl fumarate (DMF) treatment. Our case stresses the limits of current diagnostic and stratification risk criteria, highlighting the potential role of Magnetic Resonance Imaging (MRI) in advising clinical choices. CASE PRESENTATION: A 54 years old MS male patient treated with DMF, after 3 years of clinical stability developed a subacute clinical worsening. He had no severe lymphopenia but MRI signs suggestive of a coexistence of PML and MS activity. Although his viral title was negative, DMF was discontinued, with clinical and radiological improvement. CONCLUSIONS: This case highlights the challenges behind PML diagnosis, especially in patients not fulfilling the risk stratification criteria and that might present with concurrent disease activity, stressing the potential role of MRI in informing therapeutic decisions.

Microstructural damage of the cortico-striatal and thalamo-cortical fibers in Fabry disease: a diffusion MRI tractometry study.

PURPOSE: Recent evidences have suggested the possible presence of an involvement of the extrapyramidal system in Fabry disease (FD), a rare X-linked lysosomal storage disorder. We aimed to investigate the microstructural integrity of the main tracts of the cortico-striatal-thalamo-cortical loop in FD patients. METHODS: Forty-seven FD patients (mean age = 42.3 ± 16.3 years, M/F = 28/21) and 49 healthy controls (mean age = 42.3 ± 13.1 years, M/F = 19/28) were enrolled in this study. Fractional anisotropy (FA), axial (AD), radial (RD), and mean diffusivity (MD) maps were computed for each subject, and connectomes were built using a standard atlas. Diffusion metrics and connectomes were then combined to carry on a diffusion MRI tractometry analysis. The main afferent and efferent pathways of the cortico-striatal-thalamo-cortical loop (namely, bundles connecting the precentral gyrus (PreCG) with the striatum and the thalamus) were evaluated. RESULTS: We found the presence of a microstructural involvement of cortico-striatal-thalamo-cortical loop in FD patients, predominantly affecting the left side. In particular, we found significant lower mean FA values of the left cortico-striatal fibers (p = 0.001), coupled to higher MD (p = 0.001) and RD (p < 0.001) values, as well as higher MD (p = 0.01) and RD (p = 0.01) values at the level of the thalamo-cortical fibers. CONCLUSION: We confirmed the presence of an alteration of the extrapyramidal system in FD patients, in line with recent evidences suggesting the presence of brain changes as a possible reflection of the subtle motor symptoms present in this condition. Our results suggest that, along with functional changes, microstructural damage of this pathway is also present in FD patients.

Prevalence of GLA gene mutations and polymorphisms in patients with multiple sclerosis: A cross-sectional study.

PURPOSE: Fabry Disease (FD) has been frequently proposed as possible underestimated differential diagnosis of Multiple Sclerosis (MS), but no study has been performed to test prevalence of GLA gene mutations in a population fulfilling diagnostic criteria of MS. Aim of this study is to determine the prevalence of GLA gene mutations in a large and representative population diagnosed with MS, simultaneously providing a critical revision of current literature reports of coexistence or misdiagnosis between these two conditions. METHODS: In this mono-centric cross-sectional study, 927 patients fulfilling McDonald diagnostic criteria and encompassing all MS phenotypes were enrolled. Patients underwent evaluation of α-GalA activity and genotyping. Both genetic variants annotated as pathogenic and GVUS were considered. Estimated alleles frequencies were then compared to the ones reported in the gnomAD database. RESULTS: GLA gene variants were found in seven individuals. Five patients carried variants previously described having controversial impact on FD phenotype, and the analysis of exome database revealed that they are not rare among healthy individuals. One patient showed a new variant never described before, and another one carried a late-onset FD cardiac variant. CONCLUSIONS: The overall prevalence of GLA gene variants in MS patients is comparable to the one estimated in healthy population. This result is further supported by critical revision of current literature evidences of misdiagnosis between MS and FD, arguing in favour of independence between these disorders.

Upper Eyelid Isolated Arterio-Venous Malformation Treated With Embolization in a Patient With Keloid-Prone Skin.

Ocular adnexal aterio-venous malformations (AVMs) are rare congenital disabling anomalies, which may enlarge causing disfiguring deformity and rarely severe hemorrhage. These lesions are generally treated by preliminary endovascular embolization to shrink the arterio-venous malformation, followed by surgical gross total resection. The authors report a case of eyelid arterio-venous malformation in a 12-year-old girl, which progressively increased in size in few months. The patient complained mild itching, blurring of the vision, and mild tenderness. Magnetic resonance imaging showed an expansive mass with multiple arterial vessels at the left superior eyelid and left forehead. The diagnosis of arterio-venous malformation was then confirmed by digital subtraction angiography. Primary surgical excision was excluded because of the high risk of intrasurgical bleeding. Embolization through superselective cannulation of the left external carotid feeder vessels was performed resulting in flow exclusion up to the 80% of the nidus. Subsequent surgical resection was not recommended due to clinical evidence of keloid-prone skin.

Is This Truly A "Leave-Me-Alone" Lesion? An Unusual Case of Multiple Ring-shaped Lateral Ventricular Nodules.

BACKGROUND: Ring-shaped lateral ventricular nodules (RSLVNs) are commonly considered as benign asymptomatic lesions, which are sporadically detected as incidental findings on routine brain magnetic resonance imaging scans. Despite their not irrelevant frequency, the exact biological nature of these lesions remains largely unknown due to the lack of histopathologic studies. Here we present the clinical, neuroradiologic, and histopathologic findings of an unusual case of symptomatic multiple RSLVNs. CASE DESCRIPTION: A 44-year-old otherwise healthy man presented with a recent history of headache and retching. Neuroradiologic imaging revealed the presence of multiple RSLVNs, the largest of which, located in the cella media of the right lateral ventricle, exerted a mild to moderate mass effect on adjacent brain parenchyma. This latter nodule was successfully removed, with complete resolution of the symptoms. Histopathology revealed glial differentiation, and the specimen was diagnosed as subependymoma. CONCLUSIONS: This report provides novel evidence characterizing RSLVNs as possible variants of subependymoma with a peculiar imaging appearance, also suggesting that, like subependymomas, they may occasionally grow large enough to cause mass effect-related symptoms, thus requiring neurosurgical intervention.

Paediatric neck ultrasonography: a pictorial essay.

The neck structures are located very superficially and are therefore easy to explore by ultrasound examination. Ultrasonography is crucial for the detection of neck pathologies in children. High-frequency probes (10-15 MHz) are used for the ultrasound examination on the patient lying in supine decubitus and with their neck stretched out. The outcome of the exam depends mainly on the child's cooperation-hence the need for warm sonographic gel and a comfortable cushion to place under the patient's shoulders. The complete scan of the neck includes the evaluation of the thyroid and salivary glands and the vascular structures as well as the lymph node analysis. In children and adolescents, the thymus is often visualised in the supraclavicular and jugular scans. It appears as a structure, usually hypoechoic, with thin hyperechoic straps, though echogenicity increases with age. In this pictorial essay, the main pathological conditions of the neck in paediatric age will be examined, such as thyroid dysgenesis, thyroiditis, thyroid nodules, lymphadenopathies, cystic lesions, haemangiomas and vascular malformation, cervical thymus, fibromatosis colli and pilomatrixoma.

Absence of infratentorial lesions in Fabry disease contributes to differential diagnosis with multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple Sclerosis (MS) has been proposed as a possible differential diagnosis with Fabry Disease (FD). We evaluated the incidence of infratentorial lesions in FD patients, investigating whether their presence could help in differentiating these two conditions. We explored the diagnostic accuracy of this sign alone and in combination to the involvement of corpus callosum (CC). METHODS: White Matter lesions were retrospectively evaluated on FLAIR images available from 136 MS and 144 FD patients. Infratentorial involvement was assessed considering the whole cerebellum, and the part of the brainstem included between the occipital foramen and the upper edge of the red nucleus. Furthermore, the presence of callosal lesions was also recorded, evaluating the portion of CC included between the two external walls of the lateral ventricles. RESULTS: Infratentorial involvement was detectable in 119/136 (87.5%) MS patients, while it was present in only 17/144 (11.8%) FD patients. When the diagnostic performance of a positive infratentorial involvement was evaluated in combination with the presence of CC lesions, a specificity of 97%, with a positive predictive value of 96% was reached. CONCLUSIONS: We concluded that the absence of infratentorial lesions, especially when combined to the evaluation of other typical imaging features, can help in the differential diagnosis between MS and FD.

Multiple sclerosis and fabry Disease, two sides of the coin? The case of an Italian family.

BACKGROUND: Multiple Sclerosis (MS) is considered among possible differential diagnosis of Fabry Disease (FD), especially in early stages when findings are suggestive but not diagnostic for MS. We report the case of a family in which FD and MS coexist, offering an overview on clues for differential diagnosis and speculating on shared etiopathogenic mechanisms for these conditions. METHODS: Taking as starting point the diagnosis of FD in a dialysis patient during a screening programme, we retrospectively rebuilt his family history and revised clinical and imaging examinations of his five siblings, two of which with previous diagnosis of MS. RESULTS: After genetic testing, two subjects were found positive to a new α-galactosidase A mutation, probably causative for FD classical variant. The two subjects meeting diagnostic criteria for MS were found negative to any GLA gene mutation, therefore initial diagnosis was confirmed. The remaining two siblings resulted unaffected, with neither clinical nor instrumental evidence of FD and MS. CONCLUSIONS: Differential diagnosis between FD and MS may be challenging, especially in early clinical stages when only extensive clinical evaluation and correct MRI interpretation may reduce the risk of misdiagnosis. Moreover this report allows speculating on potential etiological and pathogenic mechanisms, common both to FD and MS.

Striatonigral involvement in Fabry Disease: A quantitative and volumetric Magnetic Resonance Imaging study.

INTRODUCTION: Aim of this study is to elucidate possible mechanisms of extrapyramidal damage in Fabry Disease (FD), a condition in which involvement of the motor system has been recently suggested, by simultaneously assessing morphometric and susceptibility changes of striatonigral pathway and their possible correlations with clinical variables. METHODS: In this cross-sectional study, we investigated possible differences in terms of Quantitative Susceptibility Mapping (QSM) values and volumes of different extrapyramidal relays, including striatum and substantia nigra (SN), in 30 FD patients (M/F = 11/19, mean age 42.6 ±â€¯12.2) and 37 healthy controls (HC) (M/F = 16/21, mean age 43.2 ±â€¯14.6). Patients underwent a clinical examination for the study of different motor functions, and the relationship between MRI and clinical variables was tested using the Spearman's coefficient. RESULTS: Compared to HC, FD patients showed an increase in susceptibility values of the SN (p < 0.001) and striatum (p = 0.001), while no difference emerged for the other tested extrapyramidal structures, suggesting their relative sparing. The increased susceptibility was coupled to a reduced volume of the SN (p < 0.001), but not of the striatum (p = 0.34). Finally, no significant correlation emerged when probing the relationship between these modifications and the clinical variables. CONCLUSION: In FD patients, susceptibility and volumetric alterations are present throughout the extrapyramidal pathway, with the SN being particularly affected by these changes. Such results are in line with the subtle extrapyramidal involvement recently suggested in FD, and could further contribute to the understanding of the physiopathological bases of cerebral involvement in FD.

Default mode network modifications in Fabry disease: A resting-state fMRI study with structural correlations.

Aim of the study was to evaluate the presence of Default Mode Network (DMN) modifications in Fabry Disease (FD), and their possible correlations with structural alterations and neuropsychological scores. Thirty-two FD patients with a genetically confirmed diagnosis of classical FD (12 males, mean age 43.3 ± 12.2) were enrolled, along with 35 healthy controls (HC) of comparable age and sex (14 males, mean age 42.1 ± 14.5). Resting-State fMRI data were analyzed using a seed-based approach, with six different seeds sampling the main hubs of the DMN. Structural modifications were assessed by means of Voxel-Based Morphometry (VBM) and Tract-Based Spatial Statistics analyses. Between-group differences and correlations with neuropsychological variables were probed voxelwise over the whole brain. Possible correlations between FC modifications and global measures of microstructural alteration were also tested in FD patients with a partial correlation analysis. In the FD group, clusters of increased functional connectivity involving both supratentorial and infratentorial regions emerged, partially correlated to the widespread white matter (WM) damage found in these patients. No gray matter volume differences were found at VBM between the two groups. The connectivity between right inferior frontal gyrus and precuneus was significantly correlated with the Corsi block-tapping test results (p = .0001). Widespread DMN changes are present in FD patients that correlate with WM alterations and cognitive performance. Our results confirm the current view of a cerebral involvement in FD patients not simply associated to major cerebrovascular events, but also related to significant and diffuse microstructural and functional changes.

Corpus callosum involvement: a useful clue for differentiating Fabry Disease from Multiple Sclerosis.

PURPOSE: Multiple sclerosis (MS) has been proposed as a possible differential diagnosis for Fabry disease (FD). The aim of this work was to evaluate the involvement of corpus callosum (CC) on MR images and its possible role as a radiological sign to differentiate between FD and MS. METHODS: In this multicentric study, we retrospectively evaluated the presence of white matter lesions (WMLs) on the FLAIR images of 104 patients with FD and 117 patients with MS. The incidence of CC-WML was assessed in the two groups and also in a subgroup of 37 FD patients showing neurological symptoms. RESULTS: WMLs were detected in 50 of 104 FD patients (48.1%) and in all MS patients. However, a lesion in the CC was detected in only 3 FD patients (2.9%) and in 106 MS patients (90.6%). In the FD subgroup with neurological symptoms, WMLs were present in 26 of 37 patients (70.3%), with two subjects (5.4%) showing a definite callosal lesion. CONCLUSION: FD patients have a very low incidence of CC involvement on conventional MR images compared to MS, independently from the clinical presentation and the overall degree of WM involvement. Evaluating the presence of CC lesions on brain MR scans can be used as a radiological sign for a differential diagnosis between MS and FD, rapidly addressing the physician toward a correct diagnosis and subsequent treatment options.