Diagnostic Utility of MOG Antibody Testing in Cerebrospinal Fluid.

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.

Grey Matter Atrophy and its Relationship with White Matter Lesions in Patients with Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease, Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder, and Multiple Sclerosis.

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 cm3); AQP4+NMOSD in the occipital cortex (32.83 cm3); and RRMS diffusely in the GM (260.61 cm3). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm3), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm3). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm3) and AQP4+NMOSD (47.04 cm3). 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.

Clinical and MRI measures to identify non-acute MOG-antibody disease in adults.

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.

Magnetic Resonance Imaging Evaluation of Perivascular Space Abnormalities in Neuromyelitis Optica.

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 (R2  = 0.62), whereas lower DTI-ALPS index, higher number of myelitis, and higher T2-lesion volume were associated with worse disability (R2  = 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.

Cerebral enhancement in MOG antibody-associated disease.

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.

Divergent time-varying connectivity of thalamic sub-regions characterizes clinical phenotypes and cognitive status in multiple sclerosis.

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.

Comparison of MRI T2-lesion evolution in pediatric MOGAD, NMOSD, and MS.

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.

Cognitive function in primary and secondary progressive multiple sclerosis: A multiparametric magnetic resonance imaging study.

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.

Glymphatic system impairment in multiple sclerosis: relation with brain damage and disability.

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.

In vivo detection of damage in multiple sclerosis cortex and cortical lesions using NODDI.

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_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 µm2/ms, respectively). RESULTS: The NA cortex of patients with MS had significantly lower ICV_f versus HCs' cortex with both D// values (false discovery rate (FDR)-p <0.001). CLs showed significantly decreased ICV_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_f and ODI (FDR-p=0.050 and FDR-p=0.032) with only D//=1.7 µm2/ms. No CL microstructural differences were found between MS clinical phenotypes. MS NA cortex ICV_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.

MR T2-relaxation time as an indirect measure of brain water content and disease activity in NMOSD.

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 R2=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.

Time-varying connectivity of the precuneus and its association with cognition and depressive symptoms in neuromyelitis optica: A pilot MRI study.

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.

Functional and structural MRI correlates of executive functions in multiple sclerosis.

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 (R2 = 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 (R2 = 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 (R2 = 0.24). CONCLUSIONS: CC and SCP microstructural damage and RS FC abnormalities in cognitive networks underlie EF frailty in MS.

Mapping white matter damage distribution in neuromyelitis optica spectrum disorders with a multimodal MRI approach.

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.

Volume of hippocampal subfields and cognitive deficits in neuromyelitis optica spectrum disorders.

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.

Spinal Cord Atrophy in Neuromyelitis Optica Spectrum Disorders Is Spatially Related to Cord Lesions and Disability.

Background The spinal cord is commonly involved in patients with neuromyelitis optica spectrum disorders (NMOSDs). However, the relationship between inflammation and atrophy remains unclear. Purpose To characterize the spatial distribution of T1-hypointense lesions in the spinal cord at MRI, its association with cord atrophy, and its correlation with disability in participants with NMOSDs. Materials and Methods This prospective study evaluated three-dimensional T1-weighted spinal cord MRI scans in seropositive participants with NMOSDs and in age-matched healthy control participants acquired between February 2010 and July 2018. Binary masks of T1-hypointense lesions and lesion probability maps were produced. Cross-sectional area of the cervical and upper thoracic cord (down to T3 level) was calculated with the active-surface method. Full factorial models were used to assess cord atrophy in participants with NMOSDs. Correlations between cord atrophy and clinical and brain MRI measures were investigated with multiple regression models. Results A total of 52 participants with NMOSDs (mean age ± standard deviation, 44 years ± 15; 45 women) and 28 age-matched healthy control participants (mean age, 44 years ± 13; 16 women) were evaluated. Thirty-eight of 52 (73%) participants with NMOSDs had T1-hypointense cord lesions. No cord lesions were detected in the healthy control participants. Lesion probability maps showed a predominant involvement of the upper cervical (C2-C4) and upper thoracic (T1-T3 level) cord. The greater involvement of C1-C4 survived Bonferroni correction (P value range, .007-.04), with a higher percentage lesion extent in the gray matter (P < .001). Atrophy colocalized with focal cord lesions and correlated with pyramidal subscore (r ranging from -0.53 to -0.40; P < .001) and sensitive subscore (r ranging from -0.48 to -0.46; P = .001) of the Expanded Disability Status Scale. Participants without cord lesions had no cord atrophy. Conclusion In participants with neuromyelitis optica spectrum disorders, focal areas of spinal cord atrophy at MRI were topographically associated with lesions and correlated to motor and sensory disability. Participants without visible cord lesions had no atrophy. © RSNA, 2020 Online supplemental material is available for this article.

Clinical Relevance of Multiparametric MRI Assessment of Cervical Cord Damage in Multiple Sclerosis.

Background In multiple sclerosis (MS), knowledge about how spinal cord abnormalities translate into clinical manifestations is incomplete. Comprehensive, multiparametric MRI studies are useful in this perspective, but studies for the spinal cord are lacking. Purpose To identify MRI features of cervical spinal cord damage that could help predict disability and disease course in MS by using a comprehensive, multiparametric MRI approach. Materials and Methods In this retrospective hypothesis-driven analysis of longitudinally acquired data between June 2017 and April 2019, 120 patients with MS (58 with relapsing-remitting MS [RRMS] and 62 with progressive MS [PMS]) and 30 age- and sex-matched healthy control participants underwent 3.0-T MRI of the brain and cervical spinal cord. Cervical spinal cord MRI was performed with three-dimensional (3D) T1-weighted, T2-weighted, and diffusion-weighted imaging; sagittal two-dimensional (2D) short inversion time inversion-recovery imaging; and axial 2D phase-sensitive inversion-recovery imaging at the C2-C3 level. Brain MRI was performed with 3D T1-weighted, fluid-attenuated inversion-recovery and T2-weighted sequences. Associations between MRI variables and disability were explored with age-, sex- and phenotype-adjusted linear models. Results In patients with MS, multivariable analysis identified phenotype, cervical spinal cord gray matter (GM) cross-sectional area (CSA), lateral funiculi fractional anisotropy (FA), and brain GM volume as independent predictors of Expanded Disability Status Scale (EDSS) score (R2 = 0.86). The independent predictors of EDSS score in RRMS were lateral funiculi FA, normalized brain volume, and cervical spinal cord GM T2 lesion volume (R2 = 0.51). The independent predictors of EDSS score in PMS were cervical spinal cord GM CSA and brain GM volume (R2 = 0.44). Logistic regression analysis identified cervical spinal cord GM CSA and T2 lesion volume as independent predictors of phenotype (area under the receiver operating characteristic curve = 0.95). An optimal cervical spinal cord GM CSA cut-off value of 11.1 mm2 was found to enable accurate differentiation of patients with PMS, having values below the threshold, from those with RRMS (sensitivity = 90% [56 of 62], specificity = 91% [53 of 58]). Conclusion Cervical spinal cord MRI involvement has a central role in explaining disability in multiple sclerosis (MS): Lesion-induced damage in the lateral funiculi and gray matter (GM) in relapsing-remitting MS and GM atrophy in patients with progressive MS are the most relevant variables. Cervical spinal cord GM atrophy is an accurate predictor of progressive phenotype. Cervical spinal cord GM lesions may subsequently cause GM atrophy, which may contribute to evolution to PMS. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Zivadinov and Bergsland in this issue.

Brain and cord imaging features in neuromyelitis optica spectrum disorders.

OBJECTIVES: To validate imaging features able to discriminate neuromyelitis optica spectrum disorders from multiple sclerosis with conventional magnetic resonance imaging (MRI). METHODS: In this cross-sectional study, brain and spinal cord scans were evaluated from 116 neuromyelitis optica spectrum disorder patients (98 seropositive and 18 seronegative) in chronic disease phase and 65 age-, sex-, and disease duration-matched multiple sclerosis patients. To identify independent predictors of neuromyelitis optica diagnosis, after assessing the prevalence of typical/atypical findings, the original cohort was 2:1 randomized in a training sample (where a multivariate logistic regression analysis was run) and a validation sample (where the performance of the selected variables was tested and validated). RESULTS: Typical brain lesions occurred in 50.9% of neuromyelitis optica patients (18.1% brainstem periventricular/periaqueductal, 32.7% periependymal along lateral ventricles, 3.4% large hemispheric, 6.0% diencephalic, 4.3% corticospinal tract), 72.2% had spinal cord lesions (46.3% long transverse myelitis, 36.1% short transverse myelitis), 37.1% satisfied 2010 McDonald criteria, and none had cortical lesions. Fulfillment of at least 2 of 5 of absence of juxtacortical/cortical lesions, absence of periventricular lesions, absence of Dawson fingers, presence of long transverse myelitis, and presence of periependymal lesions along lateral ventricles discriminated neuromyelitis optica patients in both training (sensitivity = 0.92, 95% confidence interval [CI] = 0.84-0.97; specificity = 0.91, 95% CI = 0.78-0.97) and validation samples (sensitivity = 0.82, 95% CI = 0.66-0.92; specificity = 0.91, 95% CI = 0.71-0.99). MRI findings and criteria performance were similar irrespective of serostatus. INTERPRETATION: Although up to 50% of neuromyelitis optica patients have no typical lesions and a relatively high percentage of them satisfy multiple sclerosis criteria, several easily applicable imaging features can help to distinguish neuromyelitis optica from multiple sclerosis. ANN NEUROL 2019;85:371-384.

Dynamic volumetric changes of hippocampal subfields in clinically isolated syndrome patients: A 2-year MRI study.

BACKGROUND: Different subregional patterns of hippocampal involvement have been observed in diverse multiple sclerosis (MS) phenotypes. OBJECTIVE: To evaluate the occurrence of regional hippocampal variations in clinically isolated syndrome (CIS) patients, their relationships with focal white matter (WM) lesions, and their prognostic implications. METHODS: Brain dual-echo and three-dimensional (3D) T1-weighted scans were acquired from 14 healthy controls and 36 CIS patients within 2 months from clinical onset and after 3, 12, and 24 months. Radial distance distribution was assessed using 3D parametric surface mesh models. A cognitive screening was also performed. RESULTS: Patients showed clusters of reduced radial distance in the Cornu Ammonis 1 from month 3, progressively extending to the subiculum, negatively correlated with ipsilateral T2 and T1 lesion volume. Increased radial distance appeared in the right dentate gyrus after 3 (p < 0.05), 12, and 24 (p < 0.001) months, and in the left one after 3 and 24 months (p < 0.001), positively correlated with lesional measures. Hippocampal volume variations were more pronounced in patients converting to MS after 24 months and did not correlate with cognitive performance. CONCLUSION: Regional hippocampal changes occur in CIS, are more pronounced in patients converting to MS, and are modulated by focal WM lesions.

Functional correlates of cognitive abilities vary with age in pediatric multiple sclerosis.

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.