Search

Background: Family history of Parkinson's disease (PD) is a common finding in PD patients. However, a few studies have systematically examined this aspect., Objectives: We investigated the family history of PD patients, comparing demographic and clinical features between familial PD (fPD) and sporadic PD (sPD)., Methods: A cross-sectional study enrolling 2035 PD patients was conducted in 28 Italian centers. Clinical data and family history up to the third degree of kinship were collected., Results: Family history of PD was determined in 21.9% of patients. fPD patients had earlier age at onset than sporadic patients. No relevant differences in the prevalence of motor and nonmotor symptoms were detected. Family history of mood disorders resulted more prevalently in the fPD group., Conclusions: fPD was found to recur more frequently than previously reported. Family history collection beyond the core family is essential to discover disease clusters and identify novel risk factors for PD., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: To evaluate: (1) the distribution of gray matter (GM) atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and relapsing-remitting multiple sclerosis (RRMS); and (2) the relationship between GM volumes and white matter lesions in various brain regions within each disease., Methods: A retrospective, multicenter analysis of magnetic resonance imaging data included patients with MOGAD/AQP4+NMOSD/RRMS in non-acute disease stage. Voxel-wise analyses and general linear models were used to evaluate the relevance of regional GM atrophy. For significant results (p < 0.05), volumes of atrophic areas are reported., Results: We studied 135 MOGAD patients, 135 AQP4+NMOSD, 175 RRMS, and 144 healthy controls (HC). Compared with HC, MOGAD showed lower GM volumes in the temporal lobes, deep GM, insula, and cingulate cortex (75.79 cm 3 ); AQP4+NMOSD in the occipital cortex (32.83 cm 3 ); and RRMS diffusely in the GM (260.61 cm 3 ). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm 3 ), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm 3 ). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm 3 ) and AQP4+NMOSD (47.04 cm 3 ). In MOGAD, higher periventricular and cortical/juxtacortical lesions were linked to reduced temporal cortex, deep GM, and insula volumes. In RRMS, the diffuse GM atrophy was associated with lesions in all locations. AQP4+NMOSD showed no lesion/GM volume correlation., Interpretation: GM atrophy is more widespread in RRMS compared with the other two conditions. MOGAD primarily affects the temporal cortex, whereas AQP4+NMOSD mainly involves the occipital cortex. In MOGAD and RRMS, lesion-related tract degeneration is associated with atrophy, but this link is absent in AQP4+NMOSD. ANN NEUROL 2024;96:276-288., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Nonspecific clinical manifestations and unclear radiological features may delay treatment initiation in pediatric patients with Herpes simplex encephalitis (HSE). The aim of this study is to analyze the clinical and radiological features of the disease., Methods: Clinical, laboratory, and magnetic resonance imaging (MRI) data were obtained retrospectively from a group of 37 hospitalized pediatric patients older than two months and with a polymerase chain reaction-confirmed HSE diagnosis. Clinical severity (i.e., mechanical ventilatory support) and outcome at discharge (i.e., pediatric modified Rankin Scale [ped-mRS]) were also assessed., Results: Median age was 14 months (interquartile range: 10-36). All patients survived, 15 (41%) had complete recovery (i.e., ped-mRS = 0), and 10 (27%) had significant residual disability at discharge (i.e., ped-mRS ≥3). Brain MRI was obtained in 31 patients. T2-hyperintense lesions were usually bilateral (28, 90%) and multifocal (30, 97%). Hemorrhage and mass effect were observed in 13 (42%) and 15 (48%) patients, respectively. Parenchymal lesions involved the temporal lobes (94%), insula (90%), parietal lobes (84%), and frontal lobes (61%). Occipital lesions were rare. In multivariable binary logistic regression models the presence of altered consciousness was associated with mechanical ventilation (odds ratio [OR] = 8.2, Nagelkerke R 2  = 0.22), whereas the involvement of the occipital lobes (OR = 7.8) and the administration of vasopressors (OR = 12.1) were independent predictors of poor outcome (Nagelkerke R 2  = 0.41)., Conclusions: Brain MRI is useful for diagnosis and outcome assessment in pediatric HSE. Radiological patterns with common frontotemporal involvement overlap adults, but multifocal and parietal lobe abnormalities are observed as well., Competing Interests: Declaration of competing interest Thai Son Pham, Federico Montini, Hoang Nhat Pham, Minh-Thu Nguyen Tran, and Tien Huy Nguyen report no disclosures. Laura Cacciaguerra received speaker and consultant honoraria from ACCMED, Biomedia, Roche, BMS Celgene, and Sanofi and travel support for conferences by Merck Serono. Massimo Filippi is Editor-in-Chief of the Journal of Neurology, is Associate Editor of Human Brain Mapping, Neurological Sciences, and is Associate Editor of Radiology. He received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, and Sanofi; for speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; for participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, and Takeda; and for scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, and Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to assess the diagnostic utility of cerebrospinal fluid (CSF) myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) testing., Methods: We retrospectively identified patients for CSF MOG-IgG testing from January 1, 1996, to May 1, 2023, at Mayo Clinic and other medical centers that sent CSF MOG-IgG for testing including: controls, 282; serum MOG-IgG positive MOG antibody-associated disease (MOGAD), 74; serum MOG-IgG negative high-risk phenotypes, 73; serum false positive MOG-IgG with alternative diagnoses, 18. A live cell-based assay assessed CSF MOG-IgG positivity (IgG-binding-index [IBI], ≥2.5) using multiple anti-human secondary antibodies and end-titers were calculated if sufficient sample volume. Correlation of CSF MOG-IgG IBI and titer was assessed., Results: The pan-IgG Fc-specific secondary was optimal, yielding CSF MOG-IgG sensitivity of 90% and specificity of 98% (Youden's index 0.88). CSF MOG-IgG was positive in: 4/282 (1.4%) controls; 66/74 (89%) serum MOG-IgG positive MOGAD patients; and 9/73 (12%) serum MOG-IgG negative patients with high-risk phenotypes. Serum negative but CSF positive MOG-IgG accounted for 9/83 (11%) MOGAD patients, and all fulfilled 2023 MOGAD diagnostic criteria. Subgroup analysis of serum MOG-IgG low-positives revealed CSF MOG-IgG positivity more in MOGAD (13/16[81%]) than other diseases with false positive serum MOG-IgG (3/15[20%]) (p = 0.01). CSF MOG-IgG IBI and CSF MOG-IgG titer (both available in 29 samples) were correlated (Spearman's r = 0.64, p < 0.001)., Interpretation: CSF MOG-IgG testing has diagnostic utility in patients with a suspicious phenotype but negative serum MOG-IgG, and those with low positive serum MOG-IgG results and diagnostic uncertainty. These findings support a role for CSF MOG-IgG testing in the appropriate clinical setting. ANN NEUROL 2024;96:34-45., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Objectives: Knowledge of the evolution of CNS demyelinating lesions within attacks could assist diagnosis. We evaluated intra-attack lesion dynamics in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) vs multiple sclerosis (MS) and aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (AQP4+NMOSD)., Methods: This retrospective observational multicenter study included consecutive patients from Mayo Clinic (USA) and Great Ormond Street Hospital for Children (UK). Inclusion criteria were as follows: (1) MOGAD, MS, or AQP4+NMOSD diagnosis; (2) availability of ≥2 brain MRIs (within 30 days of attack onset); and (3) brain involvement (i.e., ≥1 T2 lesion) on ≥1 brain MRI. The initial and subsequent brain MRIs within a single attack were evaluated for the following: new T2 lesions(s); resolved T2 lesion(s); both; or no change. This was compared between MOGAD, MS, and AQP4+NMOSD attacks. We used the Mann-Whitney U test and χ 2 /Fisher exact test for statistical analysis., Results: Our cohort included 55 patients with MOGAD (median age, 14 years; interquartile range [IQR] 5-34; female sex, 29 [53%]) for a total of 58 attacks. The comparison groups included 38 patients with MS, and 19 with AQP4+NMOSD. In MOGAD, the initial brain MRI (median of 5 days from onset [IQR 3-9]) was normal in 6/58 (10%) attacks despite cerebral symptoms (i.e., radiologic lag). The commonest reason for repeat MRI was clinical worsening or no improvement (33/56 [59%] attacks with details available). When compared with the first MRI, the second intra-attack MRI (median of 8 days from initial scan [IQR 5-13]) showed the following: new T2 lesion(s) 27/58 (47%); stability 24/58 (41%); resolution of T2 lesion(s) 4/58 (7%); or both new and resolved T2 lesions 3/58 (5%). Findings were similar between children and adults. Steroid treatment was associated with resolution of ≥1 T2 lesion (6/28 [21%] vs 1/30 [3%], p = 0.048) and reduced the likelihood of new T2 lesions (9/28 vs 18/30, p = 0.03). Intra-attack MRI changes favored MOGAD (34/58 [59%]) over MS (10/38 [26%], p = 0.002) and AQP4+NMOSD (4/19 [21%], p = 0.007). Resolution of ≥1 T2 lesions was exclusive to MOGAD (7/58 [12%])., Discussion: Radiologic lag is common within MOGAD attacks. Dynamic imaging with frequent appearance and occasional disappearance of lesions within a single attack suggest MOGAD diagnosis over MS and AQP4+NMOSD. These findings have implications for clinical practice, clinical trial attack adjudication, and understanding of MOGAD pathogenesis.

Neurogenesis decline with aging may be associated with brain atrophy. Subventricular zone neuron precursor cells possibly modulate striatal neuronal activity via the release of soluble molecules. Neurogenesis decay in the subventricular zone may result in structural alterations of brain regions connected to the caudate, particularly to its medial component. The aim of this study was to investigate how the functional organization of caudate networks relates to structural brain changes with aging. One hundred and fifty-two normal subjects were recruited: 52 young healthy adults (≤35 years old), 42 middle-aged (36 ≤ 60 years old) and 58 elderly subjects (≥60 years old). In young adults, stepwise functional connectivity was used to characterize regions that connect to the medial and lateral caudate at different levels of link-step distances. A statistical comparison between the connectivity of medial and lateral caudate in young subjects was useful to define medial and lateral caudate connected regions. Atrophy of medial and lateral caudate connected regions was estimated in young, middle-aged and elderly subjects using T 1 -weighted images. Results showed that middle-aged and elderly adults exhibited decreased stepwise functional connectivity at one-link step from the caudate, particularly in the frontal, parietal, temporal and occipital brain regions, compared to young subjects. Elderly individuals showed increased stepwise functional connectivity in frontal, parietal, temporal and occipital lobes compared to both young and middle-aged adults. Additionally, elderly adults displayed decreased stepwise functional connectivity compared to middle-aged subjects in specific parietal and subcortical areas. Moreover, in young adults, the medial caudate showed higher direct connectivity to the basal ganglia (left thalamus), superior, middle and inferior frontal and inferior parietal gyri (medial caudate connected region) relative to the lateral caudate. Considering the opposite contrast, lateral caudate showed stronger connectivity to the basal ganglia (right pallidum), orbitofrontal, rostral anterior cingulate and insula cortices (lateral caudate connected region) compared to medial caudate. In elderly subjects, the medial caudate connected region showed greater atrophy relative to the lateral caudate connected region. Brain regions linked to the medial caudate appear to be more vulnerable to aging than lateral caudate connected areas. The adjacency to the subventricular zone may, at least partially, explain these findings. Stepwise functional connectivity analysis can be useful to evaluate the role of the subventricular zone in network disruptions in age-related neurodegenerative disorders., Competing Interests: S.B. and E.C. receive or have received research supports from the Italian Ministry of Health. M.Z., G.R., G.S., C.C., L.C., M.B. and G.M. report no disclosures. M.F. is Editor-in-Chief of the Journal of Neurology and Associate Editor of Human Brain Mapping, Neurological Sciences and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. F.A. is Associate Editor of NeuroImage: Clinical, has received speaker honoraria from Biogen Idec, Italfarmaco, Roche, Zambon and Eli Lilly, and receives or has received research supports from the Italian Ministry of Health, the Italian Ministry of University and Research, AriSLA (Fondazione Italiana di Ricerca per la SLA), the European Research Council, the EU Joint Programme – Neurodegenerative Disease Research (JPND), and Foundation Research on Alzheimer Disease (France)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Pediatric multiple sclerosis (PedMS) can hamper brain maturation. Aim of this study was to assess the neuropsychological profile of PedMS patients and their resting-state functional connectivity (RS FC)., Methods: We assessed intelligence quotient (IQ), executive speed, and language in 76 PedMS patients. On a 3.0T scanner RS FC of brain networks was estimated with a seed-based analysis (subset of 58 right-handed PedMS patients and 22 matched healthy controls). Comparisons were run between controls and PedMS (whole cohort and by age)., Results: Ninety-five% of patients had normal IQ. The highest rate of failure was observed in executive speed. PedMS showed reduced RS FC in all networks than controls, especially in the basal ganglia. In younger patients (<16-year-old, n = 32) reduced RS FC in the basal ganglia, language, and sensorimotor networks associated with poorer cognitive performance (p < 0.05; r range: 0.39; 0.56). Older patients (≥16-year-old, n = 26) showed increased RS FC in the basal ganglia, default-mode, sensorimotor, executive, and language networks, associated with poorer performance in executive speed and language abilities (p < 0.05; r range: -0.40; -0.59). In both groups, lower RS FC of the caudate nucleus associated with poorer executive speed., Conclusions: The effect of PedMS on RS FC is clinically relevant and differs according to patients' age., Competing Interests: Declaration of Competing Interest L. Cacciaguerra received speaker and consultant honoraria from ACCMED, Roche, BMS Celgene, and Sanofi; C. Curatoli has nothing to disclose; C. Vizzino has nothing to disclose; P. Valsasina received speaker honoraria from Biogen Idec; M. Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology, received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi, speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA, participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda, scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme, he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla; M.A. Rocca received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche, and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva, she receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aquaporin-4-IgG positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) and myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are antibody-associated diseases targeting astrocytes and oligodendrocytes, respectively. Their recognition as distinct entities has led to each having its own diagnostic criteria that require a combination of clinical, serologic, and MRI features. The therapeutic approach to acute attacks in AQP4+NMOSD and MOGAD is similar. There is now class 1 evidence to support attack-prevention medications for AQP4+NMOSD. MOGAD lacks proven treatments although clinical trials are now underway. In this review, we will outline similarities and differences between AQP4+NMOSD and MOGAD in terms of diagnosis and treatment., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Limited data exist on brain MRI enhancement in myelin-oligodendrocyte-glycoprotein (MOG) antibody-associated disease (MOGAD) and differences from aquaporin-4-IgG-positive-neuromyelitis-optica-spectrum-disorder (AQP4+NMOSD), and multiple sclerosis (MS)., Methods: In this retrospective observational study, we identified 122 Mayo Clinic MOGAD patients (1 January 1996-1 July 2020) with cerebral attacks. We explored enhancement patterns using a discovery set (n=41). We assessed enhancement frequency and Expanded Disability Status Scale scores at nadir and follow-up in the remainder (n=81). Two raters assessed T1-weighted-postgadolinium MRIs (1.5T/3T) for enhancement patterns in MOGAD, AQP4+NMOSD (n=14) and MS (n=26). Inter-rater agreement was assessed. Leptomeningeal enhancement clinical correlates were analysed., Results: Enhancement occurred in 59/81 (73%) MOGAD cerebral attacks but did not influence outcome. Enhancement was often patchy/heterogeneous in MOGAD (33/59 (56%)), AQP4+NMOSD (9/14 (64%); p=0.57) and MS (16/26 (62%); p=0.63). Leptomeningeal enhancement favoured MOGAD (27/59 (46%)) over AQP4+NMOSD (1/14 (7%); p=0.01) and MS (1/26 (4%); p<0.001) with headache, fever and seizures frequent clinical correlates. Ring enhancement favoured MS (8/26 (31%); p=0.006) over MOGAD (4/59 (7%)). Linear ependymal enhancement was unique to AQP4+NMOSD (2/14 (14%)) and persistent enhancement (>3 months) was rare (0%-8%) across all groups. Inter-rater agreement for enhancement patterns was moderate., Conclusions: Enhancement is common with MOGAD cerebral attacks and often has a non-specific patchy appearance and rarely persists beyond 3 months. Leptomeningeal enhancement favours MOGAD over AQP4+NMOSD and MS., Competing Interests: Competing interests: PE has no conflicts of interests or financial disclosures to declare regarding this submission. LC received speaker and consultant honoraria from Biomedia, ACCMED, Roche, BMS Celgene and Sanofi. KNK and DG reports no disclosures. JJC has received consulting fees from Roche, UCB and Horizon. ASL-C has served on advisory boards for Genentech and Horizon Therapeutics. ES, VR and PPM reports no disclosures. JLC has received research support from Roche and Genentech for an MS clinical trial, and serves as chair of the DMSC for several migraine clinical trials. DMW has received consulting fees from Alexion, Roche, Genentech, Horizon Therapeutics, Imcyse, Bristol Myers Squibb and Reistone, serves on an attack adjudication committee for a MOGAD clinical trial funded by UCB Pharma and is co-editor in chief of the neurologist. J-MT is associate editor for Journal of Child Neurology. CV-S and ST no disclosures. SJP reports grants, personal fees and non-financial support from Alexion Pharmaceuticals; grants, personal fees, non-financial support and other support from MedImmune, Inc/Viela Bio.; personal fees for consulting from Genentech/Roche. He has a patent, Patent# 8889102 (application#12-678350, Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia)—issued; a patent, Patent# 9891219B2 (application#12-573942, Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive)—issued. EPF has served on advisory boards for Alexion, Genentech, Horizon Therapeutics and UCB. He has received research support from UCB. He has received speaker honoraria from Pharmacy Times. He received royalties from UpToDate. EPF was a site primary investigator in a randomised clinical trial on Inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics. EPF has received funding from the NIH (R01NS113828). EPF is a member of the medical advisory board of the MOG project. EPF is an editorial board member of the Journal of the Neurological Sciences and Neuroimmunology Reports. A patent has been submitted on DACH1-IgG as a biomarker of paraneoplastic autoimmunity., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Magnetic resonance imaging (MRI) has been extensively applied in the study of multiple sclerosis (MS), substantially contributing to diagnosis, differential diagnosis, and disease monitoring. MRI studies have significantly contributed to the understanding of MS through the characterization of typical radiological features and their clinical or prognostic implications using conventional MRI pulse sequences and further with the application of advanced imaging techniques sensitive to microstructural damage. Interpretation of results has often been validated by MRI-pathology studies. However, the application of MRI techniques in the study of neuromyelitis optica spectrum disorders (NMOSD) remains an emerging field, and MRI studies have focused on radiological correlates of NMOSD and its pathophysiology to aid in diagnosis, improve monitoring, and identify relevant prognostic factors. In this review, we discuss the main contributions of MRI to the understanding of MS and NMOSD, focusing on the most novel discoveries to clarify differences in the pathophysiology of focal inflammation initiation and perpetuation, involvement of normal-appearing tissue, potential entry routes of pathogenic elements into the CNS, and existence of primary or secondary mechanisms of neurodegeneration., Competing Interests: Laura Cacciaguerra received speaker and consultant honoraria from ACCMED, Roche, BMS Celgene, and Sanofi. Maria A. Rocca received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche, and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva, she receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders., (Copyright © 2023 The Korean Society of Radiology.)

Objectives: To determine the timing and predictors of T2-lesion resolution in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD)., Methods: This retrospective observational study using standard-of-care data had inclusion criteria of MOGAD diagnosis, ≥2 MRIs 12 months apart, and ≥1 brain/spinal cord T2-lesion. The median (interquartile range [IQR]) number of MRIs (82% at disease onset) per-patient were: brain, 5 (2-8); spine, 4 (2-8). Predictors of T2-lesion resolution were assessed with age- and sex-adjusted generalized estimating equations and stratified by T2-lesion size (small <1 cm; large ≥1 cm)., Results: We studied 583 T2-lesions (brain, 512 [88%]; spinal cord, 71 [12%]) from 55 patients. At last MRI (median follow-up 54 months [IQR 7-74]) 455 T2-lesions (78%) resolved. The median (IQR) time to resolution was 3 months (1.4-7.0). Small T2-lesions resolved more frequently and faster than large T2-lesions. Acute T1-hypointensity decreased the likelihood (odds ratio [95% CI]) of T2-lesion resolution independent of size (small: 0.23 [0.09-0.60], p = 0.002; large: 0.30 [0.16-0.55], p < 0.001), whereas acute steroids favored resolution of large T2-lesions (1.75 [1.01-3.03], p = 0.046). Notably, 32/55 (58%) T2-lesions resolved without treatment., Discussion: The high frequency of spontaneous T2-lesion resolution suggests that this represents MOGAD's natural history. The speed of T2-lesion resolution and influence of size, corticosteroids, and T1-hypointensity on this phenomenon gives insight into MOGAD pathogenesis., (© 2023 American Academy of Neurology.)

Background and Purpose: The differences in cognitive function between primary progressive and secondary progressive multiple sclerosis (MS) remain unclear. We compared cognitive performance between primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS), and explored the structural and functional magnetic resonance imaging (MRI) correlates of their cognitive functions., Methods: Seventy-five healthy controls and 183 MS patients (60 PPMS and 123 SPMS) underwent 3.0-T MRI. MS patients were administered the Brief Repeatable Battery of Neuropsychological Tests; cognitive domain z-scores were calculated and then averaged to obtain a measure of global cognition. Using hierarchical linear regression analysis, the contribution of lesion volumes, normalized brain volumes, white matter (WM) fractional anisotropy (FA) and mean diffusivity abnormalities, and resting state (RS) functional connectivity (FC) alterations to global cognition in PPMS and SPMS was investigated., Results: PPMS and SPMS had similar z-scores in all investigated cognitive domains. Poor global cognitive function was associated with decreased FA of the medial lemniscus (ΔR 2  = 0.11, p = 0.011) and lower normalized gray matter volume (ΔR 2  = 0.29, p < 0.001) in PPMS, and with decreased FA of the fornix (ΔR 2  = 0.35, p < 0.001) and lower normalized WM volume (ΔR 2  = 0.05; p = 0.034) in SPMS., Conclusions: PPMS and SPMS had similar neuropsychological performance. Cognitive dysfunction in PPMS and SPMS was related to distinct patterns of structural MRI abnormalities and involvement of different WM tracts, whereas RS FC alterations did not contribute to explaining their global cognitive functioning., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: To assess marked central canal T2-hyperintensity in patients with myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) myelitis compared to myelitis patients with aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD) and multiple sclerosis (MS)., Material/methods: Two blinded raters evaluated spinal cord magnetic resonance imaging (MRIs) of myelitis patients with MOGAD (n = 63), AQP4 + NMOSD (n = 37), and MS (n = 26), assessing for marked central canal T2-hyperintensity and its evolution. If there were conflicting results, a third neurologist assessed the MRI., Results: Marked central canal T2-hyperintensity was more frequent in patients with MOGAD (18/63[29%]) than MS (1/26[4%]; p = 0.01) myelitis but did not differ from AQP4 + NMOSD (13/37[35%]; p = 0.49). Marked central canal T2-hyperintensity had completely resolved on follow-up axial MRI for most MOGAD (12/14[86%]) and AQP4 + NMOSD (10/10[100%]; p = 0.49) patients., Conclusions: Marked central canal T2-hyperintensity is a common transient radiologic accompaniment of MOGAD and AQP4 + NMOSD myelitis, but not MS myelitis., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Magnetic resonance imaging (MRI) T2-lesions resolve more often in myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) than aquaporin-4 IgG-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD) and multiple sclerosis (MS) in adults but few studies analyzed children., Objective: The main objective of this study is to investigate MRI T2-lesion evolution in pediatric MOGAD, AQP4 + NMOSD, and MS., Methods: Inclusion criteria were as follows: (1) first clinical attack; (2) abnormal MRI (⩽6 weeks); (3) follow-up MRI beyond 6 months without relapses in that region; and (4) age < 18 years. An index T2-lesion (symptomatic/largest) was identified, and T2-lesion resolution or persistence on follow-up MRI was determined., Results: We included 56 patients (MOGAD, 21; AQP4 + NMOSD, 8; MS, 27) with 69 attacks. Index T2-lesion resolution was more frequent in MOGAD (brain 9 of 15 [60%]; spine 8 of 12 [67%]) than AQP4 + NMOSD (brain 1 of 4 [25%]; spine 0 of 7 [0%]) and MS (brain 0 of 18 [0%]; spine 1 of 13 [8%]), p < 0.01. Resolution of all T2-lesions occurred more often in MOGAD (brain 6 of 15 [40%]; spine 7 of 12 [58%]) than AQP4 + NMOSD (brain 1 of 4 [25%]; spine 0 of 7 [0%]), and MS (brain 0 of 18 [0%]; spine 1 of 13 [8%]), p < 0.01. Reductions in median index T2-lesion area were greater in MOGAD (brain, 305 mm; spine, 23 mm) than MS (brain, 42 mm [ p <0.001]; spine, 10 mm [ p <0.001]) without differing from AQP4 + NMOSD (brain, 133 mm [ p =0.42]; spine, 19.5 mm [ p =0.69])., Conclusion: In children, MRI T2-lesions resolved more often in MOGAD than AQP4 + NMOSD and MS which is similar to adults suggesting these differences are related to pathogenesis rather than age.

MRI and clinical features of myelin oligodendrocyte glycoprotein (MOG)-antibody disease may overlap with those of other inflammatory demyelinating conditions posing diagnostic challenges, especially in non-acute phases and when serologic testing for MOG antibodies is unavailable or shows uncertain results. We aimed to identify MRI and clinical markers that differentiate non-acute MOG-antibody disease from aquaporin 4 (AQP4)-antibody neuromyelitis optica spectrum disorder and relapsing remitting multiple sclerosis, guiding in the identification of patients with MOG-antibody disease in clinical practice. In this cross-sectional retrospective study, data from 16 MAGNIMS centres were included. Data collection and analyses were conducted from 2019 to 2021. Inclusion criteria were: diagnosis of MOG-antibody disease; AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis; brain and cord MRI at least 6 months from relapse; and Expanded Disability Status Scale (EDSS) score on the day of MRI. Brain white matter T2 lesions, T1-hypointense lesions, cortical and cord lesions were identified. Random forest models were constructed to classify patients as MOG-antibody disease/AQP4-neuromyelitis optica spectrum disorder/multiple sclerosis; a leave one out cross-validation procedure assessed the performance of the models. Based on the best discriminators between diseases, we proposed a guide to target investigations for MOG-antibody disease. One hundred and sixty-two patients with MOG-antibody disease [99 females, mean age: 41 (±14) years, median EDSS: 2 (0-7.5)], 162 with AQP4-neuromyelitis optica spectrum disorder [132 females, mean age: 51 (±14) years, median EDSS: 3.5 (0-8)], 189 with multiple sclerosis (132 females, mean age: 40 (±10) years, median EDSS: 2 (0-8)] and 152 healthy controls (91 females) were studied. In young patients (<34 years), with low disability (EDSS < 3), the absence of Dawson's fingers, temporal lobe lesions and longitudinally extensive lesions in the cervical cord pointed towards a diagnosis of MOG-antibody disease instead of the other two diseases (accuracy: 76%, sensitivity: 81%, specificity: 84%, P < 0.001). In these non-acute patients, the number of brain lesions < 6 predicted MOG-antibody disease versus multiple sclerosis (accuracy: 83%, sensitivity: 82%, specificity: 83%, P < 0.001). An EDSS < 3 and the absence of longitudinally extensive lesions in the cervical cord predicted MOG-antibody disease versus AQP4-neuromyelitis optica spectrum disorder (accuracy: 76%, sensitivity: 89%, specificity: 62%, P < 0.001). A workflow with sequential tests and supporting features is proposed to guide better identification of patients with MOG-antibody disease. Adult patients with non-acute MOG-antibody disease showed distinctive clinical and MRI features when compared to AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis. A careful inspection of the morphology of brain and cord lesions together with clinical information can guide further analyses towards the diagnosis of MOG-antibody disease in clinical practice., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Studies on tumefactive brain lesions in myelin oligodendrocyte glycoprotein-immunoglobulin G (IgG)-associated disease (MOGAD) are lacking. We sought to characterize the frequency clinical, laboratory, and MRI features of these lesions in MOGAD and compare them with those in multiple sclerosis (MS) and aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD)., Methods: We retrospectively searched 194 patients with MOGAD and 359 patients with AQP4+NMOSD with clinical/MRI details available from the Mayo Clinic databases and included those with ≥1 tumefactive brain lesion (maximum transverse diameter ≥2 cm) on MRI. Patients with tumefactive MS were identified using the Mayo Clinic medical record linkage system. Binary multivariable stepwise logistic regression identified independent predictors of MOGAD diagnosis; Cox proportional regression models were used to assess the risk of relapsing disease and gait aid in patients with tumefactive MOGAD vs those with nontumefactive MOGAD., Results: We included 108 patients with tumefactive demyelination (MOGAD = 43; AQP4+NMOSD = 16; and MS = 49). Tumefactive lesions were more frequent among those with MOGAD (43/194 [22%]) than among those with AQP4+NMOSD (16/359 [5%], p < 0.001). Risk of relapse and need for gait aid were similar in tumefactive and nontumefactive MOGAD. Clinical features more frequent in MOGAD than in MS included headache (18/43 [42%] vs 10/49 [20%]; p = 0.03) and somnolence (12/43 [28%] vs 2/49 [4%]; p = 0.003), the latter also more frequent than in AQP4+NMOSD (0/16 [0%]; p = 0.02). The presence of peripheral T2-hypointense rim, T1-hypointensity, diffusion restriction (particularly an arc pattern), ring enhancement, and Baló-like or cystic appearance favored MS over MOGAD ( p ≤ 0.001). MRI features were broadly similar in MOGAD and AQP4+NMOSD, except for more frequent diffusion restriction in AQP4+NMOSD (10/15 [67%]) than in MOGAD (11/42 [26%], p = 0.005). CSF analysis revealed less frequent positive oligoclonal bands in MOGAD (2/37 [5%]) than in MS (30/43 [70%], p < 0.001) and higher median white cell count in MOGAD than in MS (33 vs 6 cells/μL, p < 0.001). At baseline, independent predictors of MOGAD diagnosis were the presence of somnolence/headache, absence of T2-hypointense rim, lack of T1-hypointensity, and no diffusion restriction (Nagelkerke R 2 = 0.67). Tumefactive lesion resolution was more common in MOGAD than in MS or AQP4+NMOSD and improved model performance., Discussion: Tumefactive lesions are frequent in MOGAD but not associated with a worse prognosis. The clinical, MRI, and CSF attributes of tumefactive MOGAD differ from those of tumefactive MS and are more similar to those of tumefactive AQP4+NMOSD with the exception of lesion resolution, which favors MOGAD., (© 2023 American Academy of Neurology.)

The adult brain retains over life endogenous neural stem/precursor cells (eNPCs) within the subventricular zone (SVZ). Whether or not these cells exert physiological functions is still unclear. In the present work, we provide evidence that SVZ-eNPCs tune structural, electrophysiological, and behavioural aspects of striatal function via secretion of insulin-like growth factor binding protein-like 1 (IGFBPL1). In mice, selective ablation of SVZ-eNPCs or selective abrogation of IGFBPL1 determined an impairment of striatal medium spiny neuron morphology, a higher failure rate in GABAergic transmission mediated by fast-spiking interneurons, and striatum-related behavioural dysfunctions. We also found IGFBPL1 expression in the human SVZ, foetal and induced-pluripotent stem cell-derived NPCs. Finally, we found a significant correlation between SVZ damage, reduction of striatum volume, and impairment of information processing speed in neurological patients. Our results highlight the physiological role of adult SVZ-eNPCs in supporting cognitive functions by regulating striatal neuronal activity., (© 2022. The Author(s).)

Inflammatory myelopathies can manifest with a combination of motor, sensory and autonomic dysfunction of variable severity. Depending on the underlying etiology, the episodes of myelitis can recur, often leading to irreversible spinal cord damage and major long-term disability. Three main demyelinating disorders of the central nervous system, namely multiple sclerosis (MS), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders (AQP4+NMOSD) and myelin oligodendrocyte glycoprotein-IgG associated disease (MOGAD), can induce spinal cord inflammation through different pathogenic mechanisms, resulting in a more or less profound disruption of spinal cord integrity. This ultimately translates into distinctive clinical-MRI features, as well as distinct patterns of disability accrual, with a step-wise worsening of neurological function in MOGAD and AQP4+NMOSD, and progressive disability accrual in MS. Early recognition of the specific etiologies of demyelinating myelitis and initiation of the appropriate treatment is crucial to improve outcome. In this review article we summarize and compare the clinical and imaging features of spinal cord involvement in these three demyelinating disorders, both during the acute phase and over time, and outline the current knowledge on the expected patterns of disability accrual and outcomes. We also discuss the potential implications of these observations for patient management and counseling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fadda, Flanagan, Cacciaguerra, Jitprapaikulsan, Solla, Zara and Sechi.)

Background: The precuneus is involved in cognition and depression; static functional connectivity (SFC) abnormalities of this region have been observed in neuromyelitis optica spectrum disorders (NMOSD). Time-varying functional connectivity (TVC) underpins dynamic variations of brain connectivity., Objective: The aim of this study was to explore precuneus SFC and TVC in NMOSD patients and their associations with neuropsychological features., Methods: This retrospective study includes 27 NMOSD patients and 30 matched healthy controls undergoing resting state functional magnetic resonance imaging (MRI) and a neuropsychological evaluation of cognitive performance and depressive symptoms. A sliding-window correlation analysis using bilateral precuneus as seed region assessed TVC, which was quantified by the standard deviation of connectivity across windows. Mean connectivity indicated SFC., Results: Compared to controls, patients had reduced SFC between precuneus, temporal lobe, putamen and cerebellum, and reduced TVC between precuneus and prefronto-parietal-temporo-occipital cortices and caudate. Patients also had increased intra-precuneal TVC and increased TVC between the precuneus and the temporal cortex. More severe depressive symptoms correlated with increased TVC between the precuneus and the temporal lobe; worse cognitive performance mainly correlated with higher TVC between the precuneus and the parietal lobe., Conclusion: TVC rather than SFC of the precuneus correlates with NMOSD neuropsychological features; different TVC abnormalities underlie depressive symptoms and cognitive impairment.

Background and Objective: To determine the frequency of new or enlarging T2-hyperintense or enhancing lesions outside of clinical attacks in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) vs multiple sclerosis (MS) and aquaporin-4 antibody positive neuromyelitis optica spectrum disorder (AQP4+NMOSD)., Methods: We retrospectively included Mayo Clinic patients with MOGAD with: (1) MOG-Immunoglobulin-G positivity by live cell-based assay, (2) fulfilling proposed MOGAD diagnostic criteria, and (3) baseline and follow-up paired MRIs without interval attacks. A neurologist and neuroradiologist reviewed MRIs (T2-fluid attenuated inversion recovery brain, T2 spine, and T1-postgadolinium brain and spine) to identify new or enlarging lesions. A MOGAD subset was then compared to patients with MS and AQP4+NMOSD, based on broadly similar interscan intervals., Results: We included 105 patients with MOGAD (median age, 31 years [range, 2-80]; 60% female) with 373 paired MRIs. In total, 10/105 (9.5%) patients and 13/373 (3%) scans had one or more new T2 lesions (brain, 12/213 [6%]; spine, 1/160 [0.6%]); and 8/367 (2%) had enhancing lesions. New brain lesions were less in MOGAD (1/25 [4%]) than MS (14/26 [54%], p < 0.0001) but did not differ from AQP4+NMOSD (1/13 [8%], p = 1.0) in subgroup analysis. New spinal lesions were rare across groups (0%-4%)., Discussion: New or enlarging MRI lesions rarely develop outside of clinical attacks in MOGAD differing from MS. Surveillance MRIs in MOGAD have limited utility with implications for clinical practice and trial design., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Spinal cord involvement can be observed in the course of immune-mediated disorders. Although multiple sclerosis (MS) represents the leading cause of inflammatory myelopathy, an increasing number of alternative etiologies must be now considered in the diagnostic work-up of patients presenting with myelitis. These include antibody-mediated disorders and cytotoxic T cell-mediated diseases targeting central nervous system (CNS) antigens, and systemic autoimmune conditions with secondary CNS involvement. Even though clinical features are helpful to orient the diagnostic suspicion (e.g., timing and severity of myelopathy symptoms), the differential diagnosis of inflammatory myelopathies is often challenging due to overlapping features. Moreover, noninflammatory etiologies can sometimes mimic an inflammatory process. In this setting, magnetic resonance imaging (MRI) is becoming a fundamental tool for the characterization of spinal cord damage, revealing a pictorial scenario which is wider than the clinical manifestations. The characterization of spinal cord lesions in terms of longitudinal extension, location on axial plane, involvement of the white matter and/or gray matter, and specific patterns of contrast enhancement, often allows a proper differentiation of these diseases. For instance, besides classical features, such as the presence of longitudinally extensive spinal cord lesions in patients with aquaporin-4-IgG positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), novel radiological signs (e.g., H sign, trident sign) have been recently proposed and successfully applied for the differential diagnosis of inflammatory myelopathies. In this review article, we will discuss the radiological features of spinal cord involvement in autoimmune disorders such as MS, AQP4+NMOSD, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and other recently characterized immune-mediated diseases. The identification of imaging pitfalls and mimics that can lead to misdiagnosis will also be examined. Since spinal cord damage is a major cause of irreversible clinical disability, the recognition of these radiological aspects will help clinicians achieve a correct and prompt diagnosis, treat early with disease-specific treatment and improve patient outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cacciaguerra, Sechi, Rocca, Filippi, Pittock and Flanagan.)

Recent evidence has shown the existence of a CNS 'waste clearance' system, defined as the glymphatic system. Glymphatic abnormalities have been described in several neurodegenerative conditions, including Alzheimer's and Parkinson's disease. Glymphatic function has not been thoroughly explored in multiple sclerosis, where neurodegenerative processes are intermingled with inflammatory processes. We aimed to investigate glymphatic system function in multiple sclerosis and to evaluate its association with clinical disability, disease course, demyelination and neurodegeneration, quantified using different MRI techniques. In this retrospective study, we enrolled 71 multiple sclerosis patients (49 relapsing-remitting and 22 progressive multiple sclerosis) and 32 age- and sex-matched healthy control subjects. All subjects underwent neurological and MRI assessment including high-resolution T1, T2 and double inversion recovery sequences, diffusion and susceptibility weighted imaging. We calculated the diffusion along perivascular space index, a proxy for glymphatic function, cortical and deep grey matter volume, white and cortical grey matter lesion volume and normal-appearing white matter microstructural damage. Multiple sclerosis patients showed an overall lower diffusion along perivascular space index versus healthy controls (estimated mean difference: -0.09, P = 0.01). Both relapsing-remitting and progressive multiple sclerosis patients had lower diffusion along perivascular space index versus healthy controls (estimated mean difference: -0.06, P = 0.04 for relapsing-remitting and -0.19, P = 0.001 for progressive multiple sclerosis patients). Progressive multiple sclerosis patients showed lower diffusion along perivascular space index versus relapsing-remitting multiple sclerosis patients (estimated mean difference: -0.09, P = 0.03). In multiple sclerosis patients, lower diffusion along perivascular space index was associated with more severe clinical disability (r = -0.45, P = 0.001) and longer disease duration (r = -0.37, P = 0.002). Interestingly, we detected a negative association between diffusion along perivascular space index and disease duration in the first 4.13 years of the disease course (r = -0.38, P = 0.04) without any association thereafter (up to 34 years of disease duration). Lower diffusion along perivascular space index was associated with higher white (r = -0.36, P = 0.003) and cortical (r = -0.41, P = 0.001) lesion volume, more severe cortical (r = 0.30, P = 0.007) and deep (r = 0.42, P = 0.001) grey matter atrophy, reduced fractional anisotropy (r = 0.42, P = 0.001) and increased mean diffusivity (r = -0.45, P = 0.001) in the normal-appearing white matter. Our results suggest that the glymphatic system is impaired in multiple sclerosis, especially in progressive stages. Impaired glymphatic function was associated with measures of both demyelination and neurodegeneration and reflects a more severe clinical disability. These findings suggest that glymphatic impairment may be a pathological mechanism underpinning multiple sclerosis. The dynamic interplay with other pathological substrates of the disease deserves further investigation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Previous studies demonstrated an association between motor and cognitive performance in multiple sclerosis (MS). However, disease-related brain damage might represent a common substrate to both phenomena, which was not considered before., Objective: Aim of this study is to investigate whether the association between cognition and motor function is beyond structural damage in patients with MS., Methods: Eighty-one healthy controls and 106 relapsing-remitting (RR) MS patients underwent a 3.0 T MRI with quantification of T2-lesion volumes, T1-lesion volumes and normalized brain volumes. A functional examination [Nine-Hole Peg Test (9-HPT), Timed 25-Foot Walk test (T25FW) and Expanded Disability Status Scale] and a neuropsychological evaluation (Brief Repeatable Battery of Neuropsychological Tests) were also administered. Association between demographic, clinical, cognitive, MRI and functional measures were analysed with univariate analyses and hierarchical linear regression., Results: In RRMS patients, Spatial Recall Test and Symbol Digit Modalities Test were positively correlated with 9-HPT (p < 0.001) and T25FW (p ≤ 0.035); Paced Auditory Serial Addition Test (PASAT) correlated with 9-HPT (p ≤ 0.009). 9-HPT and T25FW were significantly associated with normalized brain volumes (p ≤ 0.016), T2- and T1-lesion volumes (p ≤ 0.009). Hierarchical regression models selected age and normalized deep gray matter volume as predictors of T25FW (adjusted-R 2  = 0.109). Younger age, female sex, higher normalized gray matter volume and higher PASAT 2″ scores predicted higher 9-HPT scores (adjusted-R 2  = 0.337)., Conclusions: In RRMS patients, deficit in information processing speed and executive function may contribute to hand motor dysfunction beyond the effect of structural disease-related burden, supporting the integration of motor and cognitive assessment in clinical settings., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: Astrocytes outline the perivascular space (PVS) and regulate fluid exchange through the aquaporin-4 water channel. As neuromyelitis optica is an autoimmune astrocytopathy targeting aquaporin-4, we hypothesized that it could be associatied with PVS abnormalities., Methods: A total of 34 patients, and 46 age- and sex-matched healthy controls from two independent cohorts (exploratory and validation dataset) underwent a standardized 3.0-T magnetic resonance imaging protocol including conventional and diffusion tensor imaging. Susceptibility-weighted imaging was also acquired in the exploratory dataset. We evaluated macroscopic and microstructural abnormalities of PVS in terms of enlargement and water diffusivity (DTI-ALPS index). In the exploration dataset, a susceptibility-weighted sequence was used to draw the regions of interest for the DTI-ALPS index calculation in areas having veins perpendicular to lateral ventricles. Between-group comparisons, correlations, and regression models were run to assess associations between PVS abnormalities, and clinical and magnetic resonance imaging variables., Results: Patients had a higher frequency of severe PVS enlargement in the centrum semiovale (29.4% vs 8.7%), which correlated with brain atrophy, deep grey matter atrophy, and poorer cognitive performance (r-values range: -0.44, -0.36; p values: 0.01-0.046). In both datasets, patients had reduced DTI-ALPS index compared with controls (p values 0.004-0.038). Lower DTI-ALPS index, deep gray matter volume, and cortical volume could discriminate between patients and controls (R 2  = 0.62), whereas lower DTI-ALPS index, higher number of myelitis, and higher T2-lesion volume were associated with worse disability (R 2  = 0.55)., Interpretation: Patients with neuromyelitis optica spectrum disorder are characterized by abnormal enlargement and impaired water diffusion along the PVS, whose clinical implications suggest a direct correlation with disease pathogenesis and severity. ANN NEUROL 2022;92:173-183., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is the most recently defined inflammatory demyelinating disease of the central nervous system (CNS). Over the last decade, several studies have helped delineate the characteristic clinical-MRI phenotypes of the disease, allowing distinction from aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) and multiple sclerosis (MS). The clinical manifestations of MOGAD are heterogeneous, ranging from isolated optic neuritis or myelitis to multifocal CNS demyelination often in the form of acute disseminated encephalomyelitis (ADEM), or cortical encephalitis. A relapsing course is observed in approximately 50% of patients. Characteristic MRI features have been described that increase the diagnostic suspicion (e.g., perineural optic nerve enhancement, spinal cord H-sign, T2-lesion resolution over time) and help discriminate from MS and AQP4+NMOSD, despite some overlap. The detection of MOG-IgG in the serum (and sometimes CSF) confirms the diagnosis in patients with compatible clinical-MRI phenotypes, but false positive results are occasionally encountered, especially with indiscriminate testing of large unselected populations. The type of cell-based assay used to evaluate for MOG-IgG (fixed vs. live) and antibody end-titer (low vs. high) can influence the likelihood of MOGAD diagnosis. International consensus diagnostic criteria for MOGAD are currently being compiled and will assist in clinical diagnosis and be useful for enrolment in clinical trials. Although randomized controlled trials are lacking, MOGAD acute attacks appear to be very responsive to high dose steroids and plasma exchange may be considered in refractory cases. Attack-prevention treatments also lack class-I data and empiric maintenance treatment is generally reserved for relapsing cases or patients with severe residual disability after the presenting attack. A variety of empiric steroid-sparing immunosuppressants can be considered and may be efficacious based on retrospective or prospective observational studies but prospective randomized placebo-controlled trials are needed to better guide treatment. In summary, this article will review our rapidly evolving understanding of MOGAD diagnosis and management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sechi, Cacciaguerra, Chen, Mariotto, Fadda, Dinoto, Lopez-Chiriboga, Pittock and Flanagan.)

Objective: To characterise in vivo the microstructural abnormalities of multiple sclerosis (MS) normal-appearing (NA) cortex and cortical lesions (CLs) and their relations with clinical phenotypes and disability using neurite orientation dispersion and density imaging (NODDI)., Methods: One hundred and seventy-two patients with MS (101 relapsing-remitting multiple sclerosis (RRMS), 71 progressive multiple sclerosis (PMS)) and 62 healthy controls (HCs) underwent a brain 3T MRI. Brain cortex and CLs were segmented from three-dimensional T1-weighted and double inversion recovery sequences. Using NODDI on diffusion-weighted sequence, intracellular volume fraction (ICV&#95;f) and Orientation Dispersion Index (ODI) were assessed in NA cortex and CLs with default or optimised parallel diffusivity for the cortex (D//=1.7 or 1.2 µm 2 /ms, respectively)., Results: The NA cortex of patients with MS had significantly lower ICV&#95;f versus HCs' cortex with both D// values (false discovery rate (FDR)-p <0.001). CLs showed significantly decreased ICV&#95;f and ODI versus NA cortex of both HCs and patients with MS with both D// values (FDR-p ≤0.008). Patients with PMS versus RRMS had significantly decreased NA cortex ICV&#95;f and ODI (FDR-p=0.050 and FDR-p=0.032) with only D//=1.7 µm 2 /ms. No CL microstructural differences were found between MS clinical phenotypes. MS NA cortex ICV&#95;f and ODI were significantly correlated with disease duration, clinical disability, lesion burden and global and regional brain atrophy (r from -0.51 to 0.71, FDR-p from <0.001 to 0.045)., Conclusions: A significant neurite loss occurs in MS NA cortex. CLs show a further neurite density reduction and a reduced ODI suggesting a simplification of neurite complexity. NODDI is relevant to investigate in vivo the heterogeneous pathology affecting the MS cortex., Competing Interests: Competing interests: Potential conflicts of interest outside the submitted work are as follows: PP received speaker honoraria from Biogen, Novartis, Merck Serono, Bristol Myers Squibb and ExceMED. EP received speaker honoraria from Biogen. RB and AF report no conflicts of interest. LC received speaker and consultant honoraria from ACCMED, Roche, BMS Celgene and Sanofi. MAR received speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche and Teva, and received research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla. MF is editor-in-chief of the Journal of Neurology, associate editor of Human Brain Mapping, associate editor of Radiology and associate editor of Neurological Sciences; received compensation for consulting services and/or speaking activities from Alexion, Almirall, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda and Teva Pharmaceutical Industries; and received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla and ARiSLA (Fondazione Italiana di Ricerca per la SLA)., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The "1/3″ brain magnetic resonance imaging (MRI) criteria including 1) a lesion adjacent to the lateral ventricle and in the inferior temporal lobe, or 2) a juxtacortical lesion, or 3) a Dawson finger-type lesion were shown to distinguish multiple sclerosis (MS) from antibody-mediated conditions. In this large multicentre study, we aimed to assess how the criteria perform 1) in different onset phenotypes, 2) distinct ethnic groups, 3) when the absence of myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated disease (MOGAD)-typical fluffy infratentorial (FIT) lesions and longitudinally extensive transverse myelitis (LETM) lesions are added as features ("2/4″ and 3/5″ criteria, respectively)., Methods: 577 patients with MS (n = 332), aquaporin-4 antibody (AQP4-Ab) neuromyelitis optica spectrum disorder (NMOSD) (n = 196) and MOGAD (n = 49) were recruited from 6 international centres (Buenos Aires, Sao Paolo, Maracaibo, Goyang, Oxford and Milan). Imaging scans were obtained at disease onset or relapse., Results: Adding the absence of FIT lesions increased the specificity of the "1/3″ criteria vs. AQP4-Ab NMOSD from 84.7% to 87.2% and vs. MOGAD from 85.7% to 93.9% without compromising their sensitivity (86%). In particular, for those presenting with brain/brainstem attacks "2/4″ had significantly higher specificity than "1/3″ (85% vs. 80% against AQP4-Ab NMOSD, 88.9% vs. 72.2% against MOGAD). Positive predictive values of the "1/3″ criteria for MS were lowest for Asian patients (84.8 vs. 99.1% for White) but were significantly increased by adding further criteria (94.1% for "3/5″)., Conclusion: The "1/3″ criteria perform well in discriminating MS from NMOSD and MOGAD regardless of ethnic background and clinical scenario. Adding the absence of FIT lesions increases the specificity in those presenting with brain/brainstem symptoms., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Since astrocytes at the blood-brain barrier are targeted by neuromyelitis optica spectrum disorder (NMOSD), this study aims to assess whether patients with NMOSD have a subclinical accumulation of brain water and if it differs according to disease activity., Methods: Seventy-seven aquaporin-4-positive patients with NMOSD and 105 healthy controls were enrolled at two European centres. Brain dual-echo turbo spin-echo MR images were evaluated and maps of T2 relaxation time (T2rt) in the normal-appearing white matter (NAWM), grey matter and basal ganglia were obtained. Patients with a clinical relapse within 1 month before or after MRI acquisition were defined 'active'. Differences between patients and controls were assessed using z-scores of T2rt obtained with age-adjusted and sex-adjusted linear models from each site. A stepwise binary logistic regression was run on clinical and MRI variables to identify independent predictors of disease activity., Results: Patients had increased T2rt in both white and grey matter structures (p range: 0.014 to <0.0001). Twenty patients with NMOSD were defined active. Despite similar clinical and MRI features, active patients had a significantly increased T2rt in the NAWM and grey matter compared with those clinically stable (p range: 0.010-0.002). The stepwise binary logistic regression selected the NAWM as independently associated with disease activity (beta=2.06, SE=0.58, Nagelkerke R 2 =0.46, p<0.001)., Conclusions: In line with the research hypothesis, patients with NMOSD have increased brain T2rt. The magnitude of this alteration might be useful for identifying those patients with active disease., Competing Interests: Competing interests: LC received speaker and consultant honoraria from ACCMED, Roche, BMS Celgene, and Sanofi. EP received speaker honoraria from Biogen Idec. MR reports no disclosures. SM has received grants or contracts from the Ministry of Education and Science, Republic of Serbia (Project 175031); and payment or honoraria for lectures, presentations, manuscript writing, or educational events from Merck Serono and Novartis; and support for attending meetings from Bayer, Genzyme Sanofi, Medis, Merck, and Schering. VM received honoraria for consulting services or speaking activity from Biogen, Merck, Novartis, TEVA, Almirall, and Sanofi. JI has nothing to report. JD has received travel support and/or research grants and/or lecture fees and/or advisory services from Novartis, Bayer, Merck, Sanofi Genzyme, Roche, Teva, Medis, Hemofarm, and Medtronic. MF is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Associate Editor of Radiology, and Associate Editor of Neurological Sciences; received compensation for consulting services and/or speaking activities from Almiral, Alexion, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). MAR received speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche and Teva, and receives research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Executive dysfunctions, including difficulties in attention, working memory, planning, and inhibition affect 15%-28% of multiple sclerosis (MS) patients., Objectives: To investigate structural and functional magnetic resonance imaging (MRI) abnormalities underlying executive function (EF) in MS patients., Methods: A total 116 MS patients and 65 controls underwent resting-state (RS) and diffusion-weighted sequences and neuropsychological examination, including Wisconsin Card Sorting Test (WCST) to test EF. Brain RS cognitive networks and fractional anisotropy (FA) from a priori selected white matter tracts were derived. Associations of WCST scores with RS functional connectivity (FC) and FA abnormalities were investigated., Results: In MS patients, predictors of working memory/updating were: lower corpus callosum (CC) FA, lower left working-memory network (WMN), right WMN RS FC for worse performance; lower executive control network (ECN), higher default-mode network (DMN), and salience network (SN) RS FC for better performance ( R 2  = 0.35). Predictors of attention were lower CC genu FA, lower left WMN, and DMN RS FC for worse performance; higher left WMN and ECN RS FC for better performance ( R 2  = 0.24). Predictors of worse shifting/inhibition were lower CC genu and superior cerebellar peduncle (SCP) FA, lower left WMN RS FC for worse performance; and higher ECN RS FC for better performance ( R 2  = 0.24)., Conclusions: CC and SCP microstructural damage and RS FC abnormalities in cognitive networks underlie EF frailty in MS.

We aimed to investigate abnormal time-varying functional connectivity (FC) for thalamic sub-regions in multiple sclerosis (MS) and their clinical, cognitive and MRI correlates. Eighty-nine MS patients (49 relapsing-remitting [RR] MS; 40 progressive [P] MS) and 53 matched healthy controls underwent neurological, neuropsychological and resting state fMRI assessment. Time-varying connectivity (TVC) was quantified using sliding-window seed-voxel correlation analysis. Standard deviation of FC across windows was taken as measure of TVC, while mean connectivity across windows expressed static FC. MS patients showed reduced TVC vs controls between most of thalamic sub-regions and fronto-temporo-occipital regions. At the same time, they showed increased static FC between all thalamic sub-regions and structurally connected cortico-subcortical regions. TVC reduction was mainly driven by RRMS; while PMS exhibited a variable pattern of TVC abnormalities, characterized by reduced TVC between frontal/motor thalamic seeds and default-mode network areas and increased TVC vs controls/RRMS between posterior thalamic sub-regions and occipito-temporo-insular cortices, associated with severity of clinical disability. Compared with controls, both cognitively preserved and impaired patients showed reduced TVC between anterior thalamic sub-regions and frontal cortex. Cognitively impaired patients also showed increased TVC of the right postcentral thalamic sub-region with the cingulate cortex and postcentral gyrus vs both controls and cognitively preserved patients. Divergent patterns of TVC thalamic abnormalities were found between RRMS and PMS patients. TVC reduction in RRMS may represent the attempt of thalamic network to keep with stable connections. Conversely, increased TVC of posterior thalamic sub-regions characterized PMS and cognitively impaired MS, possibly reflecting maladaptive mechanisms., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: To apply a deep-learning algorithm to brain MRIs of seronegative patients with neuromyelitis optica spectrum disorders (NMOSD) and NMOSD-like manifestations and assess whether their structural features are similar to aquaporin-4-seropositive NMOSD or multiple sclerosis (MS) patients., Patients and Methods: We analyzed 228 T2- and T1-weighted brain MRIs acquired from aquaporin-4-seropositive NMOSD (n = 85), MS (n = 95), aquaporin-4-seronegative NMOSD [n = 11, three with anti-myelin oligodendrocyte glycoprotein antibodies (MOG)], and aquaporin-4-seronegative patients with NMOSD-like manifestations (idiopathic recurrent optic neuritis and myelitis, n = 37), who were recruited from February 2010 to December 2019. Seventy-three percent of aquaporin-4-seronegative patients with NMOSD-like manifestations also had a clinical follow-up (median duration of 4 years). The deep-learning neural network architecture was based on four 3D convolutional layers. It was trained and validated on MRI scans of aquaporin-4-seropositive NMOSD and MS patients and was then applied to aquaporin-4-seronegative NMOSD and NMOSD-like manifestations. Assignment of unclassified aquaporin-4-seronegative patients was compared with their clinical follow-up., Results: The final algorithm differentiated aquaporin-4-seropositive NMOSD and MS patients with an accuracy of 0.95. All aquaporin-4-seronegative NMOSD and 36/37 aquaporin-4-seronegative patients with NMOSD-like manifestations were classified as NMOSD. Anti-MOG patients had a similar probability of being NMOSD or MS. At clinical follow-up, one unclassified aquaporin-4-seronegative patient evolved to MS, three developed NMOSD, and the others did not change phenotype., Conclusions: Our findings support the inclusion of aquaporin4-seronegative patients into NMOSD and suggest a possible expansion to aquaporin-4-seronegative unclassified patients with NMOSD-like manifestations. Anti-MOG patients are likely to have intermediate brain features between NMOSD and MS., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Aquaporin-4 (AQP4) water channel is involved in hippocampal plasticity and is the target of neuromyelitis optica spectrum disorders (NMOSD) autoimmunity. We measured volumes of hippocampal subfields and their association with cognitive performance in AQP4-seropositive NMOSD patients., Methods: Global and regional hippocampal volumes were derived from 28 AQP4-seropositive NMOSD patients and 101 healthy controls (HC) from 3D-T1-weighted images. Normalized brain volumes were also calculated. A neuropsychological evaluation, including the Brief Repeatable Battery of Neuropsychological Tests, was performed in patients. Based on HC data, we estimated mean z-scores of volumes in the whole NMOSD group and compared them according to the status of global and domain-selective cognitive impairment., Results: Global cognitive impairment was detected in 46.4% of NMOSD patients, with attentive (60.7%) and executive (21.4%) domains being the most affected. NMOSD patients had left hippocampal atrophy at global (p = 0.012) and regional level (fimbria, Cornu Ammonis [CA] 3, molecular layer, dentate gyrus [DG], and subicular complex, p values ranging between 0.033 and <0.001). On the right side the fimbria and hippocampal tail were atrophic (p = 0.024 for both). Cognitively impaired patients showed atrophy in the left CA3 and CA4 (p = 0.025-0.028), while patients presenting verbal and visual memory impairment had significant CA3 and DG atrophy. Those patients with attentive or executive impairment had preserved brain and hippocampal volumes., Conclusions: NMOSD patients showed hippocampal atrophy associated with verbal and visual memory impairment. Such damage did not explain attention and executive function alterations, which were the most common cognitive deficits in this population., (© 2021 European Academy of Neurology.)

Advances in neuromyelitis optica spectrum disorder pathogenesis have allowed the development of targeted drugs. These treatments act on core elements of the disease, including the pro-inflammatory IL-6 pathway (tocilizumab and satralizumab), B cells (rituximab and inebilizumab), and complement (eculizumab). According to recent phase II-III trials, biologics significantly reduced the risk of relapses in aquaporin-4-seropositive patients, whereas results were less striking in the small cohorts of aquaporin-4-seronegative patients. Most adverse events were mild to moderate, with systemic symptoms (headache, arthralgia) or infections (upper respiratory and urinary tracts) being most commonly reported., (© 2021. The American Society for Experimental NeuroTherapeutics, Inc.)

Background: The pathogenetic mechanisms sustaining neuroinflammatory disorders may originate from the cerebrospinal fluid., Objective: To evaluate white matter damage with diffusion tensor imaging and T1/T2-weighted ratio at progressive distances from the ventricular system in neuromyelitis optica spectrum disorders and multiple sclerosis., Methods: Fractional anisotropy, mean, axial, and radial diffusivity and T1/T2-weighted ratio maps were obtained from patients with seropositive neuromyelitis optica spectrum disorders, multiple sclerosis, and healthy controls ( n  = 20 each group). White matter damage was assessed as function of ventricular distance within progressive concentric bands., Results: Compared to healthy controls, neuromyelitis optica spectrum disorders patients had similar fractional anisotropy, radial and axial diffusivity, increased mean diffusivity ( p  = 0.009-0.013) and reduced T1/T2-weighted ratio ( p  = 0.024-0.037) in all bands. In multiple sclerosis, gradient of percentage lesion volume and intra-lesional mean and axial diffusivity were higher in periventricular bands. Compared to healthy controls, multiple sclerosis patients had reduced fractional anisotropy ( p  = 0.001-0.043) in periventricular bands, increased mean ( p  < 0.001), radial ( p  < 0.001-0.004), and axial diffusivity ( p  = 0.002-0.008) and preserved T1/T2-weighted ratio in all bands., Conclusion: White matter damage is higher at periventricular level in multiple sclerosis and diffuse in neuromyelitis optica spectrum disorders. Fractional anisotropy preservation, associated with increased mean diffusivity and reduced T1/T2-weighted ratio may reflect astrocyte damage.

Objectives: The aims of this study were to present a deep learning approach for the automated classification of multiple sclerosis and its mimics and compare model performance with that of 2 expert neuroradiologists., Materials and Methods: A total of 268 T2-weighted and T1-weighted brain magnetic resonance imagin scans were retrospectively collected from patients with migraine (n = 56), multiple sclerosis (n = 70), neuromyelitis optica spectrum disorders (n = 91), and central nervous system vasculitis (n = 51). The neural network architecture, trained on 178 scans, was based on a cascade of 4 three-dimensional convolutional layers, followed by a fully dense layer after feature extraction. The ability of the final algorithm to correctly classify the diseases in an independent test set of 90 scans was compared with that of the neuroradiologists., Results: The interrater agreement was 84.9% (Cohen κ = 0.78, P < 0.001). In the test set, deep learning and expert raters reached the highest diagnostic accuracy in multiple sclerosis (98.8% vs 72.8%, P < 0.001, for rater 1; and 81.8%, P < 0.001, for rater 2) and the lowest in neuromyelitis optica spectrum disorders (88.6% vs 4.4%, P < 0.001, for both raters), whereas they achieved intermediate values for migraine (92.2% vs 53%, P = 0.03, for rater 1; and 64.8%, P = 0.01, for rater 2) and vasculitis (92.1% vs 54.6%, P = 0.3, for rater 1; and 45.5%, P = 0.2, for rater 2). The overall performance of the automated method exceeded that of expert raters, with the worst misdiagnosis when discriminating between neuromyelitis optica spectrum disorders and vasculitis or migraine., Conclusions: A neural network performed better than expert raters in terms of accuracy in classifying white matter disorders from magnetic resonance imaging and may help in their diagnostic work-up., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)