Autoimmune encephalitis: what the radiologist needs to know.

Autoimmune encephalitis is a relatively novel nosological entity characterized by an immune-mediated damage of the central nervous system. While originally described as a paraneoplastic inflammatory phenomenon affecting limbic structures, numerous instances of non-paraneoplastic pathogenesis, as well as extra-limbic involvement, have been characterized. Given the wide spectrum of insidious clinical presentations ranging from cognitive impairment to psychiatric symptoms or seizures, it is crucial to raise awareness about this disease category. In fact, an early diagnosis can be dramatically beneficial for the prognosis both to achieve an early therapeutic intervention and to detect a potential underlying malignancy. In this scenario, the radiologist can be the first to pose the hypothesis of autoimmune encephalitis and refer the patient to a comprehensive diagnostic work-up - including clinical, serological, and neurophysiological assessments.In this article, we illustrate the main radiological characteristics of autoimmune encephalitis and its subtypes, including the typical limbic presentation, the features of extra-limbic involvement, and also peculiar imaging findings. In addition, we review the most relevant alternative diagnoses that should be considered, ranging from other encephalitides to neoplasms, vascular conditions, and post-seizure alterations. Finally, we discuss the most appropriate imaging diagnostic work-up, also proposing a suggested MRI protocol.

Short-term mild hyperventilation on intracranial pressure, cerebral autoregulation, and oxygenation in acute brain injury patients: a prospective observational study.

Current guidelines suggest a target of partial pressure of carbon dioxide (PaCO2) of 32-35 mmHg (mild hypocapnia) as tier 2 for the management of intracranial hypertension. However, the effects of mild hyperventilation on cerebrovascular dynamics are not completely elucidated. The aim of this study is to evaluate the changes of intracranial pressure (ICP), cerebral autoregulation (measured through pressure reactivity index, PRx), and regional cerebral oxygenation (rSO2) parameters before and after induction of mild hyperventilation. Single center, observational study including patients with acute brain injury (ABI) admitted to the intensive care unit undergoing multimodal neuromonitoring and requiring titration of PaCO2 values to mild hypocapnia as tier 2 for the management of intracranial hypertension. Twenty-five patients were included in this study (40% female), median age 64.7 years (Interquartile Range, IQR = 45.9-73.2). Median Glasgow Coma Scale was 6 (IQR = 3-11). After mild hyperventilation, PaCO2 values decreased (from 42 (39-44) to 34 (32-34) mmHg, p < 0.0001), ICP and PRx significantly decreased (from 25.4 (24.1-26.4) to 17.5 (16-21.2) mmHg, p < 0.0001, and from 0.32 (0.1-0.52) to 0.12 (-0.03-0.23), p < 0.0001). rSO2 was statistically but not clinically significantly reduced (from 60% (56-64) to 59% (54-61), p < 0.0001), but the arterial component of rSO2 (ΔO2Hbi, changes in concentration of oxygenated hemoglobin of the total rSO2) decreased from 3.83 (3-6.2) µM.cm to 1.6 (0.5-3.1) µM.cm, p = 0.0001. Mild hyperventilation can reduce ICP and improve cerebral autoregulation, with minimal clinical effects on cerebral oxygenation. However, the arterial component of rSO2 was importantly reduced. Multimodal neuromonitoring is essential when titrating PaCO2 values for ICP management.

Biometry extraction and probabilistic anatomical atlas of the anterior Visual Pathway using dedicated high-resolution 3-D MRI.

Anterior Visual Pathway (aVP) damage may be linked to diverse inflammatory, degenerative and/or vascular conditions. Currently however, a standardized methodological framework for extracting MRI biomarkers of the aVP is not available. We used high-resolution, 3-D MRI data to generate a probabilistic anatomical atlas of the normal aVP and its intraorbital (iOrb), intracanalicular (iCan), intracranial (iCran), optic chiasm (OC), and tract (OT) subdivisions. We acquired 0.6 mm3 steady-state free-precession images from 24 healthy participants using a 3 T scanner. aVP masks were obtained by manual segmentation of each aVP subdivision. Mask straightening and normalization with cross-sectional area (CSA) preservation were obtained using scripts developed in-house. A probabilistic atlas ("aVP-24") was generated by averaging left and right sides of all subjects. Leave-one-out cross-validation with respect to interindividual variability was performed employing the Dice Similarity Index (DSI). Spatially normalized representations of the aVP subdivisions were generated. Overlapping CSA values before and after normalization demonstrate preservation of the aVP cross-section. Volume, length, CSA, and ellipticity index (ε) biometrics were extracted. The aVP-24 morphology followed previous descriptions from the gross anatomy. Atlas spatial validation DSI scores of 0.85 in 50% and 0.77 in 95% of participants indicated good generalizability across the subjects. The proposed MRI standardization framework allows for previously unavailable, geometrically unbiased biometric data of the entire aVP and provides the base for future spatial-resolved, group-level investigations.

Incident anti-LGI1 autoimmune encephalitis during dementia with Lewy bodies: when Occam razor is a double-edged sword.

In Dementia with Lewy bodies (DLB), rapid cognitive decline and seizures seldom complicate the typical clinical course. Nevertheless, concurrent, treatable conditions may be responsible. We report a case of DLB with superimposed anti-LGI1 encephalitis, emphasizing the importance of thorough diagnostic reasoning beyond the simplest explanation amid distinct clinical cues.

Central vein sign and diffusion MRI differentiate microstructural features within white matter lesions of multiple sclerosis patients with comorbidities.

Introduction: The Central Vein Sign (CVS) has been suggested as a potential biomarker to improve diagnostic specificity in multiple sclerosis (MS). Nevertheless, the impact of comorbidities on CVS performance has been poorly investigated so far. Despite the similar features shared by MS, migraine and Small Vessel Disease (SVD) at T2-weighted conventional MRI sequences, ex-vivo studies demonstrated their heterogeneous histopathological substrates. If in MS, inflammation, primitive demyelination and axonal loss coexist, in SVD demyelination is secondary to ischemic microangiopathy, while the contemporary presence of inflammatory and ischemic processes has been suggested in migraine. The aims of this study were to investigate the impact of comorbidities (risk factors for SVD and migraine) on the global and subregional assessment of the CVS in a large cohort of MS patients and to apply the Spherical Mean Technique (SMT) diffusion model to evaluate whether perivenular and non-perivenular lesions show distinctive microstructural features. Methods: 120 MS patients stratified into 4 Age Groups performed 3T brain MRI. WM lesions were classified in "perivenular" and "non-perivenular" by visual inspection of FLAIR* images; mean values of SMT metrics, indirect estimators of inflammation, demyelination and fiber disruption (EXTRAMD: extraneurite mean diffusivity, EXTRATRANS: extraneurite transverse diffusivity and INTRA: intraneurite signal fraction, respectively) were extracted. Results: Of the 5303 lesions selected for the CVS assessment, 68.7% were perivenular. Significant differences were found between perivenular and non-perivenular lesion volume in the whole brain (p < 0.001) and between perivenular and non-perivenular lesion volume and number in all the four subregions (p < 0.001 for all). The percentage of perivenular lesions decreased from youngest to oldest patients (79.7%-57.7%), with the deep/subcortical WM of oldest patients as the only subregion where the number of non-perivenular was higher than the number of perivenular lesions. Older age and migraine were independent predictors of a higher percentage of non-perivenular lesions (p < 0.001 and p = 0.013 respectively). Whole brain perivenular lesions showed higher inflammation, demyelination and fiber disruption than non perivenular lesions (p = 0.001, p = 0.001 and p = 0.02 for EXTRAMD, EXTRATRANS and INTRA respectively). Similar findings were found in the deep/subcortical WM (p = 0.001 for all). Compared to non-perivenular lesions, (i) perivenular lesions located in periventricular areas showed a more severe fiber disruption (p = 0.001), (ii) perivenular lesions located in juxtacortical and infratentorial regions exhibited a higher degree of inflammation (p = 0.01 and p = 0.05 respectively) and (iii) perivenular lesions located in infratentorial areas showed a higher degree of demyelination (p = 0.04). Discussion: Age and migraine have a relevant impact in reducing the percentage of perivenular lesions, particularly in the deep/subcortical WM. SMT may differentiate perivenular lesions, characterized by higher inflammation, demyelination and fiber disruption, from non perivenular lesions, where these pathological processes seemed to be less pronounced. The development of new non-perivenular lesions, especially in the deep/subcortical WM of older patients, should be considered a "red flag" for a different -other than MS- pathophysiology.

Mild behavioral impairment as a potential marker of predementia risk states in motor neuron diseases.

BACKGROUND AND PURPOSE: Mild behavioral impairment (MBI) has been increasingly regarded as the neurobehavioral axis of predementia risk states, but a specific investigation of its detection as a potential marker of prodromal dementia in motor neuron diseases (MNDs) is still lacking. The aims of our study were therefore to explore MBI in MNDs both at onset and over the disease course, and to evaluate its relationship with baseline and longitudinal cognitive features. METHODS: Sixty MND patients with cognitive/behavioral, mood, and motor examinations were recruited and followed longitudinally for up to 15 months. Associations between baseline MBI symptoms and clinical features were tested using the Spearman correlation coefficient. Based on longitudinal data, relative deltas of variation for each cognitive measure were generated, and linear regression models were then used to evaluate the role of baseline MBI symptoms in predicting longitudinal rates of cognitive decline. RESULTS: At disease onset, the most impaired MBI domain was affective/emotional dysregulation, followed by impulse dyscontrol, apathy, and social inappropriateness. Greater MBI symptoms correlated with more severe baseline motor, cognitive/behavioral, and mood disturbances (p values from <0.001 to 0.05). Longitudinally, the greatest decline was observed in the affective/emotional dysregulation domain, followed by impulse dyscontrol, apathy, and social inappropriateness. Greater MBI symptoms at onset were significant predictors of more severe longitudinal cognitive decline in both amyotrophic lateral sclerosis (ALS)-specific and ALS-nonspecific functions (p values from <0.001 to 0.03). CONCLUSIONS: MBI represents a valuable clinical marker of incident cognitive decline in MNDs, and its evaluation has good potential for detecting dementia in its preclinical/prodromal phase.

Compressed sensing (CS) MP2RAGE versus standard MPRAGE: A comparison of derived brain volume measurements.

PURPOSE: T1 Magnetization Prepared Two Rapid Acquisition Gradient Echo (MP2RAGE) with compress sensing (CS) has been proposed as an improvement of the standard MPRAGE sequence with multiple advantages including reduced acquisition time needed to provide a quantitative 3D anatomical image coupled with T1-map. Here we investigated the agreement between FreeSurfer-derived volume measurements obtained from MPRAGE and CS MP2RAGE acquisitions. METHODS: MPRAGE and CS MP2RAGE images of 37 subjects (14 patients with neurodegenerative disorders and 23 healthy controls) were acquired on a 3 T MR scanner and grey matter volumes were extracted using standard FreeSurfer parcellation. Lin's concordance correlation coefficient (Lin's CCC), Bland-Altman analysis, Passing-Bablok regression and DICE similarity coefficient were calculated to assess the agreement between the two. RESULTS: We found a good correspondence for most of the regions examined, with 93.5 % of them showing a mean DICE index >0.70. Poorer results were found with Lin's CCC especially for subcortical labels across patients. The Bland-Altman analysis showed CS MP2RAGE tended to measure lower cortical volumes compared to MPRAGE but in most cases the difference wasn't statistically relevant. The Passing-Bablock regression indicated overall an absence of systematic constant and proportional bias when CS MP2RAGE was used instead of MPRAGE. CONCLUSIONS: We found a good concordance for volumes obtained from MPRAGE and CS MP2RAGE images using FreeSurfer, suggesting a possible role of CS MP2RAGE for structural analysis with significant advantages like shorter acquisition time and the possibility to simultaneously obtain quantitative T1-maps of the brain enriching the diagnostic power of this technique.

MND Phenotypes Differentiation: The Role of Multimodal Characterization at the Time of Diagnosis.

Pure/predominant upper motor neuron (pUMN) and lower motor neuron (pLMN) diseases have significantly better prognosis compared to amyotrophic lateral sclerosis (ALS), but their early differentiation is often challenging. We therefore tested whether a multimodal characterization approach embedding clinical, cognitive/behavioral, genetic, and neurophysiological data may improve the differentiation of pUMN and pLMN from ALS already by the time of diagnosis. Dunn's and chi-squared tests were used to compare data from 41 ALS, 34 pLMN, and 19 pUMN cases with diagnoses confirmed throughout a 2-year observation period. Area under the curve (AUC) analyses were implemented to identify the finest tools for phenotypes discrimination. Relative to ALS, pLMN showed greater lower limbs weakness, lower UMN burden, and progression rate (p < 0.001−0.04). PUMN showed a greater frequency of lower limbs onset, higher UMN burden, lower ALSFRS-r and MRC progression rates (p < 0.001−0.03), and greater ulnar compound muscle action potential (CMAP) amplitude and tibial central motor conduction time (CMCT) (p = 0.05−0.03). The UMN progression rate was the finest measure to identify pLMN cases (AUC = 90%), while the MRC progression rate was the finest tool to identify pUMN (AUC = 82%). Detailed clinical and neurophysiological examinations may significantly improve MNDs differentiation, facilitating prognosis estimation and ameliorating stratification strategies for clinical trials enrollment.

Intravenous immunoglobulin bridging to rituximab in NMDAR encephalitis patients non-responders to first-line treatments.

BACKGROUND: The immunotherapy strategy for autoimmune encephalitis is based on several types and schedules of both first- and second-line drugs. Failing to respond to the latter prompts the use of non-conventional rescue therapies, with higher risks of severe adverse effects. We report on a protocol that entails the use of intravenous immunoglobulin cycles to bridge the 4-month period that the second-line drug rituximab needs to exert its full therapeutic effects. METHODS: Three patients with NMDAR encephalitis who were non-responders to first-line treatments entered the study. The protocol consisted of six monthly cycles of intravenous immunoglobulins (IVIG, 0.4 mg/kg/die for 5 days), starting 1 month after the last rituximab infusion (1000 mg at days 0 and 15). Brain MRI and [18F]-FDG-PET were performed at onset and at six and 18 months after onset. RESULTS: In the three patients, substantial improvements of disability or complete recovery were achieved, without modifications over the 30-to-50-month follow-up. No adverse events nor laboratory test abnormalities were recorded. Imaging findings paralleled the favorable disease courses. Brain [18F]-FDG-PET was more sensitive than MRI in detecting abnormalities. DISCUSSION: Our observations suggest that the herein-described protocol might be used in patients with NMDAR encephalitis at risk for poor prognosis in the mid-term when they need to shift to rituximab. [18F]-FDG-PET confirmed to be a sensitive tool to detect the minimal brain lesions that can underlie isolated cognitive and psychiatric symptoms.

Improved detection of multiple sclerosis lesions with T2-prepared double inversion recovery at 3T.

BACKGROUND AND PURPOSE: Double inversion recovery (DIR) imaging is used in multiple sclerosis (MS) clinical protocols to improve the detection of cortical and juxtacortical gray matter lesions by nulling confounding signals originating from the cerebrospinal fluid and white matter. Achieving a high isotropic spatial resolution, to depict the neocortex and its typically small lesions, is challenged by the reduced signal-to-noise ratio (SNR) determined by multiple tissue signal nulling. Here, we evaluate both conventional and optimized DIR implementations to improve tissue contrast (TC), SNR, and MS lesion conspicuity. METHODS: DIR images were obtained from MS patients and healthy controls using both conventional and prototype implementations featuring a T2-preparation module (T2P), to improve SNR and TC, as well as an image reconstruction routine with iterative denoising (ID). We obtained quantitative measures of SNR and TC, and evaluated the visibility of MS cortical, cervical cord, and optic nerve lesions in the different DIR images. RESULTS: DIR implementations adopting T2P and ID enabled improving the SNR and TC of conventional DIR. In MS patients, 34% of cortical, optic nerve, and cervical cord lesions were visible only in DIR images acquired with T2P, and not in conventional DIR images. In the studied cases, image reconstruction with ID did not improve lesion conspicuity. CONCLUSIONS: DIR with T2P should be preferred to conventional DIR imaging in protocols studying MS patients, as it improves SNR and TC and determines an improvement in cortical, optic nerve, and cervical cord lesion conspicuity.

The role of disconnection in explaining disability in multiple sclerosis.

BACKGROUND: In multiple sclerosis, the correlation between white matter lesion volumes (LV) and expanded disability status scale (EDSS) is at best moderate, leading to the "clinico-radiological paradox", influenced by many factors, including the lack of information on the spatial localisation of each lesion on synthetic metrics such as LV. We used a probabilistic approach to provide the volume of WM tracts that may be disconnected by lesions and to evaluate its correlation with EDSS. METHODS: Forty-five patients (aged 37.4 ± 6.8 years, mean ± standard deviation; 30 females; 29 relapsing-remitting, 16 progressive) underwent 3-T magnetic resonance imaging. Both LV and the volume of the tracts crossing the lesioned regions (disconnectome volume, DV) were calculated using BCBtoolkit and correlated with EDSS. RESULTS: T1-weighted LV and DV significantly correlated with EDSS (p ≤ 0.006 r ≥ 0.413) as it was for T2-weighted LV and T2-weighted DV (p ≤ 0.004 r ≥ 0.430), but only T1-weighetd and T2-weighted DVs were EDSS significant predictors (p ≤ 0.001). The correlations of T1-weighted and T2-weighted LV with EDSS were significantly mediated by DV, while no effect of LV on the EDSS-DV correlation was observed. CONCLUSION: The volume of disconnected WM bundles mediates the LV-EDSS correlation, representing the lonely EDSS predictor.

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

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 RIN-Neuroimaging Network, a national consortium dedicated to identifying disease and subject-specific in-vivo 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 Standard Operative Procedures 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 RIN-Neuroimaging Network 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.

18F-FDG-PET correlates of aging and disease course in ALS as revealed by distinct PVC approaches.

PURPOSE: The partial volume effect (PVE) complicates PET studies of neurodegenerative diseases, since a decreased 18F-FDG retention might be influenced by atrophy-related changes of cortical regions. Multiple partial volume correction (PVC) methods have been therefore developed, but their application in amyotrophic lateral sclerosis (ALS) is still rare. Additionally, even if metabolic changes have been established in ALS, no study yet has investigated how these may be influenced by aging and disease course. The aim of the present study was therefore to apply and compare multiple PVC approaches to explore aging and disease course-related hypometabolism in ALS. METHODS: PET and MRI data from 15 ALS patients were analyzed using PETSurfer to implement 4 distinct PVC methods: noPVC, Meltzer (MZ), Müller-Gärtner (MG) and Symmetric Geometric Transfer Matrix (SGTM). For each method and Region of Interest (ROI), the 18F-FDG value was regressed against subject age and disease duration. RESULTS: MG/SGTM application almost halved the number of regions showing a significant age-related hypometabolism, while the same effect was not observed for disease course, where only the distribution of identified regions varied. Three distinct patterns emerged: regions showing a significant age/disease course-related effect across all the different methods, regions yielding significance only with MG/SGTM application, and regions maintaining significance only with noPVC/MZ application. CONCLUSIONS: Significant changes in the distribution of aging and disease course-related hypometabolism were observed when the effect of the underlying structural status was considered, supporting the need for investigate the impact of PVE on PET-assessed metabolic changes in clinical and research settings.

An eleven-year history of Vanishing White Matter Disease in an adult patient with no cognitive decline and EIF2B5 mutations. A case report.

Vanishing White Matter Disease (VWMD) is a rare autosomal recessive leukoencephalopathy . The classical presentation is characterized by a severe cerebellar ataxia, spasticity, neurological deterioration with a chronic progressive course and episodes of acute neurological deterioration after stress conditions.We report a 52-year-old man with VWMD and atypical features who manifested two major events of transient aphasia eleven years apart with complete recovery in 48 hours. No cognitive decline was present. Brain MRI revealed typical aspects of VWMD including diffuse leukoencephalopathy with relative sparing of U-fibers. We identified the presence of c.592G>A (p.Glu198Lys) and c.1360 C>T (p.Pro454Ser) mutations in EIF2B5.

Walk Your Talk: Real-World Adherence to Guidelines on the Use of MRI in Multiple Sclerosis.

(1) Although guidelines about the use of MRI sequences for Multiple Sclerosis (MS) diagnosis and follow-up are available, variability in acquisition protocols is not uncommon in everyday clinical practice. The aim of this study was to evaluate the real-world application of MS imaging guidelines in different settings to clarify the level of adherence to these guidelines. (2) Via an on-line anonymous survey, neuroradiologists (NR) were asked about MRI protocols and parameters routinely acquired when MS patients are evaluated in their center, both at diagnosis and follow-up. Furthermore, data about report content and personal opinions about emerging neuroimaging markers were also retrieved. (3) A total of 46 participants were included, mostly working in a hospital or university hospital (80.4%) and with more than 10 years of experience (47.9%). We found a relatively good adherence to the suggested MRI protocols regarding the use of T2-weighted sequences, although almost 10% of the participants routinely acquired 2D sequences with a slice thickness superior to 3 mm. On the other hand, a wider degree of heterogeneity was found regarding gadolinium administration, almost routinely performed at follow-up examination (87.0% of cases) in contrast with the current guidelines, as well as a low use of a standardized reporting system (17.4% of cases). (4) Although the MS community is getting closer to a standardization of MRI protocols, there is still a relatively wide heterogeneity among NR, with particular reference to contrast administration, which must be overcome to guarantee an adequate quality of patients' care in MS.

Neuroimaging at 7 T: are we ready for clinical transition?

In the last 20 years, ultra-high field (UHF) magnetic resonance imaging (MRI) has become an outstanding research tool for the study of the human brain, with 90 of these scanners installed today, worldwide. The recent clearances from regulatory bodies in the USA and Europe to 7-T clinical systems have set the ground for a transition from pure research applications to research and clinical use of these systems. As today, UFH neuroimaging is demonstrating clinical value and, given the importance of this topic for both preclinical scientists and clinical neuroradiologists, European Radiology Experimental is launching a thematic series entitled "7-T neuro MRI: from research to clinic", consisting of peer-reviewed articles, invited or spontaneously submitted, on topics selected by the guest editors, describing the state of the art of UHF MRI neuroimaging across different pathologies, as well as related clinical applications. In this editorial, we discuss some of the challenges related to the clinical use of 7-T scanners and the strengths and weaknesses of clinical imaging at UHF.

Age at symptom onset influences cortical thinning distribution and survival in amyotrophic lateral sclerosis.

PURPOSE: The lifetime risk of developing amyotrophic lateral sclerosis (ALS) increases in the elderly, and greater age at symptom onset has been identified as a negative prognostic factor in the disease. However, the underlying neurobiological mechanisms are still poorly investigated. We hypothesized that older age at symptom onset would have been associated with greater extra-motor cortical damage contributing to worse prognosis, so we explored the relationship between age at symptom onset, cortical thinning (CT) distribution, and clinical markers of disease progression. METHODS: We included 26 ALS patients and 29 healthy controls with T1-weighted magnetic resonance imaging (MRI). FreeSurfer 6.0 was used to identify regions of cortical atrophy (CA) in ALS, and to relate age at symptom onset to CT distribution. Linear regression analyses were then used to investigate whether MRI metrics of age-related damage were predictive of clinical progression. MRI results were corrected using the Monte Carlo simulation method, and regression analyses were further corrected for disease duration. RESULTS: ALS patients exhibited significant CA mainly encompassing motor regions, but also involving the cuneus bilaterally and the right superior parietal cortex (p < 0.05). Older age at symptom onset was selectively associated with greater extra-motor (frontotemporal) CT, including pars opercularis bilaterally, left middle temporal, and parahippocampal cortices (p < 0.05), and CT of these regions was predictive of shorter survival (p = 0.004, p = 0.03). CONCLUSION: More severe frontotemporal CT contributes to shorter survival in older ALS patients. These findings have the potential to unravel the neurobiological mechanisms linking older age at symptom onset to worse prognosis in ALS.

Predictors of self-perceived health worsening over COVID-19 emergency in ALS.

INTRODUCTION: Factors influencing self-perceived health status over Corona Virus Disease 2019 (COVID-19) emergency in vulnerable populations, such as patients with chronic neurological diseases, are still unknown. In this work, we aimed at testing whether clinical care changes imposed by the quarantine, together with certain demographic and disease-specific features, might have determined a self-perceived worsening of health status in patients with amyotrophic lateral sclerosis (ALS). METHODS: A brief web-based questionnaire investigating self-perceived anxiety, depression, and motor worsening, as well as clinical care changes over COVID-19 emergency, was administered to ALS patients currently followed at San Martino Hospital. Ordinal and logistic regression analyses were applied to identify significant predictors of health status. RESULTS: Fifty-seven ALS patients completed the questionnaire. A total of 35.08% of cases reported anxiety symptoms, 36.84% depressive symptoms, and 35.08% reported worsening of motor symptoms. Significant predictors of anxiety symptoms severity included female gender, greater motor impairment, more aggressive disease course, and rehabilitation therapy suspension. The only significant predictor of depressive symptoms severity was a more aggressive disease course. Significant predictors of motor worsening were shorter disease duration and exams/visits cancelation. DISCUSSION: COVID-19 emergency and its management exerted a significant impact on self-perceived health status in patients with ALS, particularly in those cases in the earliest disease phases and with a more aggressive disease course. These findings have potential to improve personalized medicine strategies in the next phase.

Accuracy and reproducibility of automated white matter hyperintensities segmentation with lesion segmentation tool: A European multi-site 3T study.

Brain vascular damage accumulate in aging and often manifest as white matter hyperintensities (WMHs) on MRI. Despite increased interest in automated methods to segment WMHs, a gold standard has not been achieved and their longitudinal reproducibility has been poorly investigated. The aim of present work is to evaluate accuracy and reproducibility of two freely available segmentation algorithms. A harmonized MRI protocol was implemented in 3T-scanners across 13 European sites, each scanning five volunteers twice (test-retest) using 2D-FLAIR. Automated segmentation was performed using Lesion segmentation tool algorithms (LST): the Lesion growth algorithm (LGA) in SPM8 and 12 and the Lesion prediction algorithm (LPA). To assess reproducibility, we applied the LST longitudinal pipeline to the LGA and LPA outputs for both the test and retest scans. We evaluated volumetric and spatial accuracy comparing LGA and LPA with manual tracing, and for reproducibility the test versus retest. Median volume difference between automated WMH and manual segmentations (mL) was -0.22[IQR = 0.50] for LGA-SPM8, -0.12[0.57] for LGA-SPM12, -0.09[0.53] for LPA, while the spatial accuracy (Dice Coefficient) was 0.29[0.31], 0.33[0.26] and 0.41[0.23], respectively. The reproducibility analysis showed a median reproducibility error of 20%[IQR = 41] for LGA-SPM8, 14% [31] for LGA-SPM12 and 10% [27] with the LPA cross-sectional pipeline. Applying the LST longitudinal pipeline, the reproducibility errors were considerably reduced (LGA: 0%[IQR = 0], p < 0.001; LPA: 0% [3], p < 0.001) compared to those derived using the cross-sectional algorithms. The DC using the longitudinal pipeline was excellent (median = 1) for LGA [IQR = 0] and LPA [0.02]. LST algorithms showed moderate accuracy and good reproducibility. Therefore, it can be used as a reliable cross-sectional and longitudinal tool in multi-site studies.