Clinical and radiological correlates of apathy in multiple sclerosis.

BACKGROUND: Although apathy has been associated with fronto-striatal dysfunction in several neurological disorders, its clinical and magnetic resonance imaging (MRI) correlates have been poorly investigated in people with multiple sclerosis (PwMS). OBJECTIVES: To evaluate clinical variables and investigate microstructural integrity of fronto-striatal grey matter (GM) and white matter (WM) structures using diffusion tensor imaging (DTI). METHODS: A total of 123 PwMS (age: 40.25 ± 11.5; female: 60.9%; relapsing-remitting multiple sclerosis: 75.6%) were prospectively enrolled and underwent neurological and neuropsychological evaluation, including Expanded Disability Status Scale (EDSS), Apathy Evaluation Scale (AES-S), Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS) and brain 3T-MRI volumes of whole brain, frontal/prefrontal cortex (PFC) and subcortical regions were calculated. DTI-derived metrics were evaluated in the same GM regions and in connecting WM tracts. RESULTS: Apathetic PwMS (32.5%) showed lower education levels, higher HADS, MFIS scores and WM lesions volume than nonapathetic PwMS. Significant differences in DTI metrics were found in middle frontal, anterior cingulate and superior frontal PFC subregions and in caudate nuclei. Significant alterations were found in the right cingulum and left striatal-frontorbital tracts. CONCLUSIONS: Apathy in PwMS is associated with higher levels of physical disability, depression, anxiety and fatigue together with lower educational backgrounds. Microstructural damage within frontal cortex, caudate and fronto-striatal WM bundles is a significant pathological substrate of apathy in multiple sclerosis (MS).

Mapping tissue microstructure across the human brain on a clinical scanner with soma and neurite density image metrics.

Soma and neurite density image (SANDI) is an advanced diffusion magnetic resonance imaging biophysical signal model devised to probe in vivo microstructural information in the gray matter (GM). This model requires acquisitions that include b values that are at least six times higher than those used in clinical practice. Such high b values are required to disentangle the signal contribution of water diffusing in soma from that diffusing in neurites and extracellular space, while keeping the diffusion time as short as possible to minimize potential bias due to water exchange. These requirements have limited the use of SANDI only to preclinical or cutting-edge human scanners. Here, we investigate the potential impact of neglecting water exchange in the SANDI model and present a 10-min acquisition protocol that enables to characterize both GM and white matter (WM) on 3 T scanners. We implemented analytical simulations to (i) evaluate the stability of the fitting of SANDI parameters when diminishing the number of shells; (ii) estimate the bias due to potential exchange between neurites and extracellular space in such reduced acquisition scheme, comparing it with the bias due to experimental noise. Then, we demonstrated the feasibility and assessed the repeatability and reproducibility of our approach by computing microstructural metrics of SANDI with AMICO toolbox and other state-of-the-art models on five healthy subjects. Finally, we applied our protocol to five multiple sclerosis patients. Results suggest that SANDI is a practical method to characterize WM and GM tissues in vivo on performant clinical scanners.

Multicenter Evaluation of AI-generated DIR and PSIR for Cortical and Juxtacortical Multiple Sclerosis Lesion Detection.

Background Cortical multiple sclerosis lesions are clinically relevant but inconspicuous at conventional clinical MRI. Double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) are more sensitive but often unavailable. In the past 2 years, artificial intelligence (AI) was used to generate DIR and PSIR from standard clinical sequences (eg, T1-weighted, T2-weighted, and fluid-attenuated inversion-recovery sequences), but multicenter validation is crucial for further implementation. Purpose To evaluate cortical and juxtacortical multiple sclerosis lesion detection for diagnostic and disease monitoring purposes on AI-generated DIR and PSIR images compared with MRI-acquired DIR and PSIR images in a multicenter setting. Materials and Methods Generative adversarial networks were used to generate AI-based DIR (n = 50) and PSIR (n = 43) images. The number of detected lesions between AI-generated images and MRI-acquired (reference) images was compared by randomized blinded scoring by seven readers (all with >10 years of experience in lesion assessment). Reliability was expressed as the intraclass correlation coefficient (ICC). Differences in lesion subtype were determined using Wilcoxon signed-rank tests. Results MRI scans of 202 patients with multiple sclerosis (mean age, 46 years ± 11 [SD]; 127 women) were retrospectively collected from seven centers (February 2020 to January 2021). In total, 1154 lesions were detected on AI-generated DIR images versus 855 on MRI-acquired DIR images (mean difference per reader, 35.0% ± 22.8; P < .001). On AI-generated PSIR images, 803 lesions were detected versus 814 on MRI-acquired PSIR images (98.9% ± 19.4; P = .87). Reliability was good for both DIR (ICC, 0.81) and PSIR (ICC, 0.75) across centers. Regionally, more juxtacortical lesions were detected on AI-generated DIR images than on MRI-acquired DIR images (495 [42.9%] vs 338 [39.5%]; P < .001). On AI-generated PSIR images, fewer juxtacortical lesions were detected than on MRI-acquired PSIR images (232 [28.9%] vs 282 [34.6%]; P = .02). Conclusion Artificial intelligence-generated double inversion-recovery and phase-sensitive inversion-recovery images performed well compared with their MRI-acquired counterparts and can be considered reliable in a multicenter setting, with good between-reader and between-center interpretative agreement. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Zivadinov and Dwyer in this issue.

Safety of anti-varicella zoster virus vaccination in patients with multiple sclerosis treated with natalizumab: A case series.

The vaccination with live attenuated vaccines is generally not recommended during natalizumab (NTZ), as it is included among immunosuppressive/immunomodulating therapies. Nevertheless, considering the lack of evidence of a non-Central Nervous System (CNS) immunosuppressive effect of NTZ, after a risk/benefit evaluation, we decided to vaccinate four multiple sclerosis (MS) patients (three with an indication to switch to ocrelizumab for high-risk Progressive Multifocal Leukoencephalopathy (PML) and one for pregnancy planning). No vaccine-related adverse events of any type nor varicella zoster virus (VZV) infections were observed. To the best of our knowledge, these case series represent the first description of the good safety profile of anti-VZV vaccination in MS patients during NTZ treatment.

Evaluating the central vein sign in paediatric-onset multiple sclerosis: A case series study.

The central vein sign (CVS) has been proposed as a biomarker of multiple sclerosis (MS). In adult-onset MS (AOMS), 40%-threshold of CVS positive (+) lesions demonstrated high accuracy for MS diagnosis. However, CVS+ lesions' performance has not been characterized in paediatric-onset (POMS) yet. We compared the CVS contribution to MS diagnosis in 10 POMS and 12 disease-duration-matched AOMS patients. Three POMS patients did not meet the 40%-threshold, while all AOMS patients were correctly diagnosed as having MS. The high proportion of periventricular confluent lesions, excluded from the CVS assessment, seemed to impair CVS sensitivity in POMS diagnosis.

A real-world study of alemtuzumab in a cohort of Italian patients.

BACKGROUND AND PURPOSE: Real-world data on alemtuzumab are limited and do not provide evidence of its effectiveness after various disease-modifying therapies (DMTs). Our aim was to provide real-world data on the impact of clinical variables and previous DMTs on clinical response to alemtuzumab. METHODS: Sixteen Italian multiple sclerosis centers retrospectively included patients who started alemtuzumab from January 2015 to December 2018, and recorded demographics, previous therapies, washout duration, relapses, Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging data. Negative binomial regression models were used to assess the effect of factors on annualized relapse (ARR) after alemtuzumab initiation. RESULTS: We studied 322 patients (mean age 36.8 years, median EDSS score 3, median follow-up 1.94 years). Previous treatments were: fingolimod (106), natalizumab (80), first-line oral agents (56), first-line injectables (interferon/glatiramer acetate; 30), and other drugs (15). Thirty-five patients were treatment-naïve. The pre-alemtuzumab ARR was 0.99 and decreased to 0.13 during alemtuzumab treatment (p < 0.001). The number of previous-year relapses was associated with alemtuzumab ARR (adjusted risk ratio [RR] 1.38, p = 0.009). Progression-free survival was 94.5% after 1 year, and 89.2% after 2 years of alemtuzumab treatment. EDSS score improvement occurred in 13.5% after 1 year, and 20.6% after 2 years. Re-baselining patients after 6 months of alemtuzumab treatment, led to no evidence of disease activity status in 71.6% after 1 year and 58.9% after 2 years. CONCLUSIONS: Alemtuzumab decreases ARR independent of previous therapy, including patients with disease activity during natalizumab treatment. Overall, 90% of patients showed no disease progression, and 20% an improvement after 2 years of alemtuzumab.

Embracing resilience in multiple sclerosis: a new perspective from COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19) resulted in several psychological consequences. Past epidemiological experiences already showed the deep albeit heterogeneous psychological repercussions of pandemics. Nevertheless, little is known about COVID-19 outbreak and the possible strategies for boosting resilience in patients with chronic diseases such as Multiple Sclerosis (MS). Therefore, we designed a study aiming to assess the changes in mental distress during COVID-19 outbreak in patients with MS and to identifyfactors contributing to resilience's development.We enrolled 106 patients (69 relapsing-remitting, 20 secondary-progressive, and 17 primary-progressive) whose neuropsychological assessment before the COVID-19 pandemic (1 January 2019-1 March 2020) was available. It consisted of Brief International Cognitive Assessment for MS (BICAMS), Hospital Anxiety and Depression Scale (HADS) and patient-reported MS Neuropsychological Screening Questionnaire (MSNQ-P). All patients were re-tested during Italian lockdown through an online survey, comprehensive of sociodemographic information, HADS self-rating Scale, MSNQ-P Questionnaire and finally Connor-Davidson Resilience self-rating Scale (CD-RISC 25), in order to evaluate resilience.No significant changes in HADS and MSNQ-P scores were detected during COVID-19 pandemic in our population. Though, pre-existing lower HADS and MSNQ-P scores but not demographic, disease- and treatment-related elements were found significantly (p < 0.0001) and independently associated with a better resilience attitude.

Neuromuscular complications following targeted therapy in cancer patients: beyond the immune checkpoint inhibitors. Case reports and review of the literature.

INTRODUCTION: In the last years, many new drugs have been developed targeting different oncology pathways, overall improving both quality of life and survival in several malignancies. However, the increase of those therapies is associated with novel toxicities, mainly immune-related adverse events (irAEs), never observed before. Different irAEs are now well characterized, and, among them, neuromuscular complications, following immune checkpoint inhibitor (ICPi) therapy, are increasingly studied and described. However, there are also neurological complications related to the use of other targeted therapies, less known and probably underestimated. Herein we describe two oncological patients who developed neuromuscular diseases after administration of targeted therapies, different from ICPi. CASE REPORTS: The first patient was treated with the combination of Vemurafenib and Cobimetinib, BRAF and MEK inhibitors, respectively, for a cutaneous melanoma. One year after the beginning of the combined treatment, she developed a sub-acute motor neuropathy with predominant cranial nerve involvement. She was successfully treated with methylprednisolone. The second patient received therapy with Imatinib, tyrosine kinase inhibitor and precursor of the targeted therapy, for a gastrointestinal stromal tumour. Few days after the first administration, he developed generalized myasthenia gravis with respiratory failure. Clinical remission was obtained with plasma-exchange, intravenous immunoglobulins and steroids. DISCUSSION AND CONCLUSION: We strengthen the relevance of neuromuscular complications which may occur long after treatment start or in patients receiving not only the latest ICPi but also "older" and apparently better-known targeted therapies. Also in the latter cases, an immune-mediated "off-target" pathogenic mechanism can be hypothesized, and consequences can be life threatening, if not promptly diagnosed and appropriately managed.

Relationship Between Retinal Layer Thickness and Disability Worsening in Relapsing-Remitting and Progressive Multiple Sclerosis.

BACKGROUND: Data regarding the predictive value of optical coherence tomography (OCT)-derived measures are lacking, especially in progressive multiple sclerosis (PMS). Accordingly, we aimed at investigating whether a single OCT assessment can predict a disability risk in both relapsing-remitting MS (RRMS) and PMS. METHODS: One hundred one patients with RRMS and 79 patients with PMS underwent Spectral-Domain OCT, including intraretinal layer segmentation. All patients had at least 1 Expanded Disability Status Scale (EDSS) measurement during the subsequent follow-up (FU). Differences in terms of OCT metrics and their association with FU disability were assessed by analysis of covariance and linear regression models, respectively. RESULTS: The median FU was 2 years (range 1-5.5 years). The baseline peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell + inner plexiform layer (GCIPL) were thinner in PMS compared with RRMS (P = 0.02 and P = 0.003, respectively). In the RRMS population, multivariable models showed that the GCIPL significantly correlated with FU disability (0.04 increase in the EDSS for each 1-µm decrease in the baseline GCIPL, 95% confidence interval: 0.006-0.08; P = 0.02). The baseline GCIPL was thinner in patients with RRMS with FU-EDSS >4 compared with those with FU-EDSS ≤4, and individuals in the highest baseline GCIPL tertile had a significantly lower FU-EDSS score than those in the middle and lowest tertile (P = 0.01 and P = 0.001, respectively). These findings were not confirmed in analyses restricted to patients with PMS. CONCLUSIONS: Among OCT-derived metrics, GCIPL thickness had the strongest association with short-medium term disability in patients with RRMS. The predictive value of OCT metrics in the longer term will have to be further investigated, especially in PMS.

Degree of microstructural changes within T1-SE versus T1-GE hypointense lesions in multiple sclerosis: relevance for the definition of "black holes".

OBJECTIVES: To retrospectively evaluate the different performances of T1-SE and T1-GE sequences in detecting hypointense lesions in multiple sclerosis (MS), to quantify the degree of microstructural damage within lesions and to correlate them with patient clinical status. METHODS: Sixty clinically isolated syndrome (CIS) and MS patients underwent brain magnetic resonance imaging (MRI) on 1.5-T and 3-T scanners. We identified T2 fluid-attenuated inversion recovery hyperintense lesions with no hypointense signal on T1-SE/T1-GE (a), hypointense lesions only on T1-GE (b), and hypointense lesions on both T1-SE and T1-GE sequences (c). We compared mean lesion number (LN) and volume (LV) identified on T1-SE and T1-GE sequences, correlating them with Expanded Disability Status Scale (EDSS); fractional anisotropy (FA) and mean diffusivity (MD) values inside each lesion type were extracted and normal-appearing white matter (NAWM). RESULTS: Thirty-five patients were female. Mean age was 39.2 (± 7.8); median EDSS was 3 (± 2). There were 23 CIS, 21 relapsing-remitting (RR), and 16 progressive MS. T1-GE and T1-SE LN and LV were significantly different (p < 0.001), both correlating with EDSS. Both FA and MD metrics resulted significantly different among the three lesion groups and NAWM (p < 0.001). FA and MD values extracted from (b) and (c) showed statistically significant differences (p < 0.001), while for (a) and (b), the differences were not significant (p = 0.31 for FA and p = 0.62 for MD). CONCLUSION: T1-SE hypointense lesions demonstrated a more pronounced degree of microstructural damage. T1-weighted sequence type must be more carefully evaluated in clinical and research settings. KEY POINTS: • T1-weighted spin-echo (T1-SE) images detect chronic hypointense lesions (so called black holes) associated with more severe microstructural changes. • In the last years, three-dimensional (3D) T1-weighted gradient-echo (T1-GE) sequences are often utilized in lieu of T1-SE acquisition, more so at 3 T or higher fields. • T1-weighted sequence type must be more carefully evaluated in clinical and research settings in the definition of "black holes" in MS, in order to avoid the overestimation of the effective severe tissue damage.

Two-way crossed cerebellar diaschisis in a clinically isolated syndrome suggestive of multiple sclerosis.

The term diaschisis refers to a neural dysfunction manifesting in anatomically intact, but functionally related, brain regions distant from a primary lesion. Here we report the diaschisis phenomenon as a consequence of a first demyelinating event in the middle and superior cerebellar peduncles in both the ipsilateral cerebellar hemisphere and in the contralateral thalamus and cerebral cortex (two-way crossed cerebellar diaschisis), resulting in the simultaneous disruption of the afferent cortico-ponto-cerebellar pathway and the efferent cerebellar-thalamo-cortical pathway. The use of 18F-FDG-PET could help clarifying in vivo the distant pathophysiological effect of focal lesions in inflammatory diseases such as multiple sclerosis.

Multiparametric Characterization and Spatial Distribution of Different MS Lesion Phenotypes.

BACKGROUND AND PURPOSE: MS lesions exhibit varying degrees of axonal and myelin damage. A comprehensive description of lesion phenotypes could contribute to an improved radiologic evaluation of smoldering inflammation and remyelination processes. This study aimed to identify in vivo distinct MS lesion types using quantitative susceptibility mapping and susceptibility mapping-weighted imaging and to characterize them through T1-relaxometry, myelin mapping, and diffusion MR imaging. The spatial distribution of lesion phenotypes in relation to ventricular CSF was investigated. MATERIALS AND METHODS: MS lesions of 53 individuals were categorized into iso- or hypointense lesions, hyperintense lesions, and paramagnetic rim lesions, on the basis of their appearance on quantitative susceptibility mapping alone, according to published criteria, and with the additional support of susceptibility mapping-weighted imaging. Susceptibility values, T1-relaxation times, myelin and free water fractions, intracellular volume fraction, and the orientation dispersion index were compared among lesion phenotypes. The distance of the geometric center of each lesion from the ventricular CSF was calculated. RESULTS: Eight hundred ninety-six MS lesions underwent the categorization process using quantitative susceptibility mapping and susceptibility mapping-weighted imaging. The novel use of susceptibility mapping-weighted images, which revealed additional microvasculature details, led us to re-allocate several lesions to different categories, resulting in a 35.6% decrease in the number of paramagnetic rim lesions, a 22.5% decrease in hyperintense lesions, and a 17.2% increase in iso- or hypointense lesions, with respect to the categorization based on quantitative susceptibility mapping only. The outcome of the categorization based on the joint use of quantitative susceptibility mapping and susceptibility mapping-weighted imaging was that 44.4% of lesions were iso- or hypointense lesions, 47.9% were hyperintense lesions, and 7.7% were paramagnetic rim lesions. A worsening gradient was observed from iso- or hypointense lesions to hyperintense lesions to paramagnetic rim lesions in T1-relaxation times, myelin water fraction, free water faction, and intracellular volume fraction. Paramagnetic rim lesions were located closer to ventricular CSF than iso- or hypointense lesions. The volume of hyperintense lesions was associated with a more severe disease course. CONCLUSIONS: Quantitative susceptibility mapping and susceptibility mapping-weighted imaging allow in vivo classification of MS lesions into different phenotypes, characterized by different levels of axonal and myelin loss and spatial distribution. Hyperintense lesions and paramagnetic rim lesions, which have the most severe microstructural damage, were more often observed in the periventricular WM and were associated with a more severe disease course.

Lesion phenotyping based on magnetic susceptibility in pediatric multiple sclerosis.

BACKGROUND AND PURPOSE: Pediatric multiple sclerosis (MS) displays different pathological features compared to adult MS, which can be studied in vivo by assessing tissue magnetic susceptibility with 3T-MRI. We aimed to assess different white matter lesions (WMLs) phenotypes in pediatric MS patients using quantitative susceptibility mapping (QSM) and susceptibility mapping weighted imaging (SMWI) over 12 months. METHODS: Eleven pediatric MS patients [female: 63.6%; mean ± standard deviation (SD) age and disease duration: 16.3 ± 2.2 and 2.4 ± 1.5; median (range) Expanded Disability Status Scale (EDSS) 1 (0-2)] underwent 3 Tesla-MRI exams and EDSS assessments at baseline and after 1 year. QSM and SMWI were obtained using 3-dimensional (3D)-segmented echo-planar-imaging with submillimetric spatial resolution. WMLs were classified according to their QSM appearance and SMWI was used to identify QSM hyperintensities ascribable to veins. Total brain volumes at baseline and follow-up were computed using high-resolution 3D T1-weighted images. RESULTS: Mean ± SD paramagnetic rim lesions (PRLs) prevalence was 7.0% ± 9.0. Fifty-four percent (6/11) of patients exhibited at least one PRL, with one patient exhibiting ≥ 4 PRLs. All patients showed QSM-iso-/hypo-intense lesions, which represented a mean ± SD of 65.8% ± 22.7 of total WMLs. QSM-hyperintense WMLs showed a positive correlation with total brain volume reduction at follow-up (r = 0.705; p =  .02). No lesion was classified as different between baseline and follow-up. CONCLUSION: Chronic compartmentalized inflammation seems to occur early in pediatric MS patients with short disease duration. A high prevalence of iso-/hypo-intense lesions was found, which could account for the higher remyelination potential in pediatric MS.

Brain lesion microstructure in neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein disease.

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) diagnosis are based on the presence of serological and magnetic resonance imaging (MRI) biomarkers. Diffusion tensor imaging (DTI), neurites orientation dispersion and density imaging (NODDI), and the Spherical Mean Technique (SMT) may be helpful to provide a microstructural characterization of the different types of white matter lesions and give an insight about their different pathological mechanisms. The aim of the study was to characterize microstructural differences between brain typical lesions (TLs) and nontypical lesions (nTLs). METHODS: A total of 17 NMOSD and MOGAD patients [9 Aquaporin4 (AQP4) + NMO, 2 seronegative-NMO, 6 MOGAD] underwent MRI scans on a 3 Tesla MAGNETON PRISMA. Diffusion parameters (fractional anisotropy; mean diffusivity [MD]; intracellular volume fraction [ICVF]; extra-neurite transverse diffusivity; and extra-neurite MD; neurite signal fraction) were obtained using DTI, NODDI, and SMT. Microstructural parameters within lesions were compared through a generalized linear model using age, sex, and total lesion volume as covariates. RESULTS: In NMOSD/MOGAD whole cohort (total lesions = 477), TLs showed increased MD and decreased ICVF compared to nTLs (p < .05), indicating higher inflammation and axonal loss. Similar results were found also in the AQP4 + NMO subgroup (decreased ICVF, p < .05). Furthermore, in NMOSD/MOGAD whole cohort and in AQP4 + NMO subgroup, TLs showed a trend toward higher EXRATRANS than nTLs, suggesting a more severe degree of demyelination within TLs. CONCLUSIONS: TLs and nTLs in NMOSD/MOGAD showed different diffusion MRI-derived microstructural features, with TLs showing a more severe degree of inflammation and fiber disruption with respect to nTLs.

CD19+ B cell values predict the increase of anti-SARS CoV2 antibodies in fingolimod-treated and COVID-19-vaccinated patients with multiple sclerosis.

BACKGROUND: Treatment with fingolimod for multiple sclerosis (MS) reduces the efficacy of COVID-19 vaccination. The aim of this exploratory study was to evaluate whether main lymphocyte subsets and demographic features correlated to the subsequent increase in anti-SARS-CoV2 antibodies following the third dose of COVID-19 vaccination in fingolimod-treated MS patients. METHODS: This was a prospective single-center observational exploratory study including a subgroup of adult patients with MS (pwMS) in treatment with fingolimod who underwent COVID-19 vaccination. The association of anti-SARS-CoV2 antibody levels (reported as the Log10 of the difference between the post and pre third dose levels) with the total number and percentage of CD3+ T and CD19+ B was assessed by a linear regression model adjusted for age and sex. RESULTS: We found that peripheral blood CD19+ B lymphocytes before the third dose of vaccination in pwMS treated with fingolimod predict the subsequent increase of anti-SARS-CoV2 antibodies. CONCLUSION: This work suggests that evaluating the percentage of CD19+ B cells may be important to identify patients at risk of not producing SARS-CoV-2 antibodies, with possible reduced protection from COVID-19.

Brain FDG-PET findings in chimeric antigen receptor T-cell therapy neurotoxicity for diffuse large B-cell lymphoma.

BACKGROUND AND PURPOSE: Chimeric antigen receptor (CAR) T-cell therapy is potentially associated with treatment-related toxicities mainly consisting of cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS). We evaluated brain metabolic correlates of CRS with and without ICANS in diffuse large B-cell lymphoma patients treated with CAR-T. METHODS: Twenty-one refractory DLCBLs underwent whole-body and brain [18 F]-fluorodeoxyglucose (FDG) PET before and 30 days after treatment with CAR-T. Five patients did not develop inflammatory-related side effects, 11 patients developed CRS, while in 5 patients CRS evolved in ICANS. Baseline and post-CAR-T brain FDG-PET were compared with a local controls dataset to identify hypometabolic patterns both at single-patient and group levels (p < .05 after correction for family-wise error [FWE). Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were computed on baseline FDG-PET and compared between patients' subgroups (t-test). RESULTS: ICANS showed an extended and bilateral hypometabolic pattern mainly involving the orbitofrontal cortex, frontal dorsolateral cortex, and anterior cingulate (p < .003 FWE-corrected). CRS without ICANS showed significant hypometabolism in less extended clusters mainly involving bilateral medial and lateral temporal lobes, posterior parietal lobes, anterior cingulate, and cerebellum (p < .002 FWE-corrected). When compared, ICANS showed a more prominent hypometabolism in the orbitofrontal and frontal dorsolateral cortex in both hemispheres than CRS (p < .002 FWE-corrected). Mean baseline MTV and TLG were significantly higher in ICANS than CRS (p < .02). CONCLUSIONS: Patients with ICANS are characterized by a frontolateral hypometabolic signature coherently with the hypothesis of ICANS as a predominant frontal syndrome and with the more prominent susceptibility of frontal lobes to cytokine-induced inflammation.

In-vivo characterization of macro- and microstructural injury of the subventricular zone in relapsing-remitting and progressive multiple sclerosis.

Introduction: The subventricular zone (SVZ) represents one of the main adult brain neurogenesis niche. In-vivo imaging of SVZ is very challenging and little is known about MRI correlates of SVZ macro- and micro-structural injury in multiple sclerosis (MS) patients. Methods: The aim of the present study is to evaluate differences in terms of volume and microstructural changes [as assessed with the novel Spherical Mean Technique (SMT) model, evaluating: Neurite Signal fraction (INTRA); Extra-neurite transverse (EXTRATRANS) and mean diffusivity (EXTRAMD)] in SVZ between relapsing-remitting (RR) or progressive (P) MS patients and healthy controls (HC). We are also going to explore whether SVZ microstructural injury correlate with caudate (a nucleus that is in the vicinity of the SVZ) or thalamus (another well-defined grey matter area which is further from SVZ than caudate) volume and clinical disability. Clinical and brain MRI data were prospectively acquired from 20 HC, 101 RRMS, and 50 PMS patients. Structural and diffusion metrics inside the global SVZ, normal appearing (NA-) SVZ, caudate and thalamus were collected. Results: We found a statistically significant difference between groups in terms of NA-SVZ EXTRAMD (PMS>RRMS>HC; p = 0.002), EXTRATRANS (PMS>RRMS>HC; p<0.0001), and INTRA (HC>RRMS>PMS; p = 0.009). Multivariable models showed that NA-SVZ metrics significantly predicted caudate (R 2 = 0.21, p < 0.0001), but not thalamus, atrophy. A statistically significant correlation between EXTRAMD and EXTRATRANS of the NA-SVZ and EDSS (r=0.25, p=0.003 and r=0.24, p = 0.003, respectively) was found. These findings were confirmed in analyses restricted to RRMS, but not to PMS patients. Discussion: In conclusion, the microstructural damage we observed within the NA-SVZ of MS patients - reflecting higher free water content (higher EXTRAMD), cytoarchitecture disruption and astrogliosis (higher EXTRATRANS and lower INTRA) - was more evident in the progressive as compared to the relapsing phases of MS. These abnormalities were significantly associated with a more pronounced caudate atrophy and higher clinical disability scores. Our findings may support the neuroprotective role of SVZ in MS patients.

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.

Tissue factor as a potential coagulative/vascular marker in relapsing-remitting multiple sclerosis.

Objectives: Recent studies supported coagulation involvement in multiple sclerosis, an inflammatory-demyelinating and degenerative disease of the central nervous system. The main objectives of this observational study were to identify the most specific pro-coagulative/vascular factors for multiple sclerosis pathogenesis and to correlate them with brain hemodynamic abnormalities. Methods: We compared i) serum/plasma levels of complement(C)/coagulation/vascular factors, viral/microbiological assays, fat-soluble vitamins and lymphocyte count among people with multiple sclerosis sampled in a clinical remission (n=30; 23F/7M, 40 ± 8.14 years) or a relapse (n=30; 24F/6M, age 41 ± 10.74 years) and age/sex-matched controls (n=30; 23F/7M, 40 ± 8.38 years); ii) brain hemodynamic metrics at dynamic susceptibility contrast-enhanced 3T-MRI during relapse and remission, and iii) laboratory data with MRI perfusion metrics and clinical features of people with multiple sclerosis. Two models by Partial Least Squares Discriminant Analysis were performed using two groups as input: (1) multiple sclerosis vs. controls, and (2) relapsing vs. remitting multiple sclerosis. Results: Compared to controls, multiple sclerosis patients had a higher Body-Mass-Index, Protein-C and activated-C9; and a lower activated-C4. Levels of Tissue-Factor, Tie-2 and P-Selectin/CD62P were lower in relapse compared to remission and HC, whereas Angiopoietin-I was higher in relapsing vs. remitting multiple sclerosis. A lower number of total lymphocytes was found in relapsing multiple sclerosis vs. remitting multiple sclerosis and controls. Cerebral-Blood-Volume was lower in normal-appearing white matter and left caudatum while Cerebral-Blood-Flow was inferior in bilateral putamen in relapsing versus remitting multiple sclerosis. The mean-transit-time of gadolinium-enhancing lesions negatively correlated with Tissue-Factor. The top-5 discriminating variables for model (1) were: EBV-EBNA-1 IgG, Body-Mass-Index, Protein-C, activated-C4 and Tissue-Factor whereas for model (2) were: Tissue-Factor, Angiopoietin-I, MCHC, Vitamin A and T-CD3. Conclusion: Tissue-factor was one of the top-5 variables in the models discriminating either multiple sclerosis from controls or multiple sclerosis relapse from remission and correlated with mean-transit-time of gadolinium-enhancing lesions. Tissue-factor appears a promising pro-coagulative/vascular biomarker and a possible therapeutic target in relapsing-remitting multiple sclerosis. Clinical trial registration: ClinicalTrials.gov, identifier NCT04380220.