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ObjectiveTo evaluate the clinical significance of deep learning-derived brain age prediction in neuromyelitis optica spectrum disorder (NMOSD) relative to relapsing-remitting multiple sclerosis (RRMS).MethodsThis cohort study used data retrospectively collected from 6 tertiary neurological centres in China between 2009 and 2018. In total, 199 patients with NMOSD and 200 patients with RRMS were studied alongside 269 healthy controls. Clinical follow-up was available in 85 patients with NMOSD and 124 patients with RRMS (mean duration NMOSD=5.8±1.9 (1.9–9.9) years, RRMS=5.2±1.7 (1.5–9.2) years). Deep learning was used to learn ‘brain age’ from MRI scans in the healthy controls and estimate the brain age gap (BAG) in patients.ResultsA significantly higher BAG was found in the NMOSD (5.4±8.2 years) and RRMS (13.0±14.7 years) groups compared with healthy controls. A higher baseline disability score and advanced brain volume loss were associated with increased BAG in both patient groups. A longer disease duration was associated with increased BAG in RRMS. BAG significantly predicted Expanded Disability Status Scale worsening in patients with NMOSD and RRMS.ConclusionsThere is a clear BAG in NMOSD, although smaller than in RRMS. The BAG is a clinically relevant MRI marker in NMOSD and RRMS.

There is extensive grey matter volume (GMV) reduction in multiple sclerosis (MS), which may account for cognitive impairment in this disabling disorder. Although genome-wide association studies (GWASs) have identified hundreds of genes associated with MS, we know little about which genes associated with GMV reduction and cognitive decline in MS. In the present study, we aimed to uncover genes associated with GMV reduction in MS by performing cross-sample (1473 brain tissue samples) partial least squares regression between gene expression from 6 postmortem brains and case-control GMV difference of MS from a meta-analysis of 1391 patients and 1189 controls (discovery phase) and from the intergroup comparison between 69 patients and 70 controls (replication phase). We identified 623 genes whose brain spatial expression profiles were significantly associated with GMV reduction in MS. These genes showed significant enrichment for MS-related genes identified by GWAS; were functionally associated with ion channel, synaptic transmission, axon and neuron projection; and showed more significant cell type-specific expression in neurons than other cell types. More importantly, the identified genes showed significant enrichment for those genes with downregulated rather than upregulated expression in MS. The spatial distribution patterns of the expression of the identified genes showed more significant correlations with brain activation patterns of memory and language tasks. These findings indicate that grey matter atrophy in MS may be resulted from the joint effects of multiple genes that are associated with this disorder, especially genes with downregulated expression in MS.

Background and purpose: Subtyping relapsing–remitting multiple sclerosis (RRMS) patients may help predict disease progression and triage patients for treatment. We aimed to subtype RRMS patients by structural MRI and investigate their clinical significances. Methods: 155 relapse-remitting MS (RRMS) and 210 healthy controls (HC) were retrospectively enrolled with structural 3DT1, diffusion tensor imaging (DTI) and resting-state functional MRI. Z scores of cortical and deep gray matter volumes (CGMV and DGMV) and white matter fractional anisotropy (WM-FA) in RRMS patients were calculated based on means and standard deviations of HC. We defined RRMS as “normal” (− 2 < z scores of both GMV and WM-FA), DGM (z scores of DGMV < − 2), and DGM-plus types (z scores of DGMV and [CGMV or WM-FA] < − 2) according to combinations of z scores compared to HC. Expanded disability status scale (EDSS), cognitive and functional MRI measurements, and conversion rate to secondary progressive MS (SPMS) at 5-year follow-up were compared between subtypes. Results: 77 (49.7%) patients were “normal” type, 37 (23.9%) patients were DGM type and 34 (21.9%) patients were DGM-plus type. 7 (4.5%) patients who were not categorized into the above types were excluded. DGM-plus type had the highest EDSS. Both DGM and DGM-plus types had more severe cognitive impairment than “normal” type. Only DGM-plus type showed decreased functional MRI measures compared to HC. A higher conversion ratio to SPMS in DGM-plus type (55%) was identified compared to “normal” type (14%, p < 0.001) and DGM type (20%, p = 0.005). Conclusion: Three MRI-subtypes of RRMS were identified with distinct clinical and imaging features and different prognosis.

Ischemic vasculopathy, particularly small-vessel disease, may mimic multiple sclerosis (MS) located in the periventricular or subcortical region on magnetic resonance (MR) examinations and should be included in the differential diagnosis of MS-like lesions.To evaluate the performance of a T2-weighted imaging (T2WI)-based radiomic signature to distinguish MS lesions from lesions corresponding to ischemic demyelination, which often mimics MS on MRI.A retrospective study was conducted in 38 patients (627 lesions) with MS and 914 patients (2466 lesions) with lesions mimicking ischemic demyelination in the periventricular or subcortical region. All patients underwent 3 T MRI. A total of 472 radiomic features were extracted from the T2WI data of each patient. Intraclass correlation coefficients were used to select the features with excellent stability and repeatability. Then, we used the minimum-redundancy maximum-relevance (mRMR) and least absolute shrinkage and selection operator (LASSO) algorithms for feature selection. After feature selection, various classifiers (including logistic regression, decision tree, AdaBoost, random forest (RF), or support vector machine (SVM)) were trained. The performance of each classifier was validated in the test set by determining the area under the curve (AUC).Nine features were selected to distinguish MS lesions from the similar lesions of ischemic demyelination. The radiomic signature showed a significant difference between the MS and ischemic demyelination patients (p0.01). RF and SVM were overfitted. The LASSO logistic regression model was the best-performing radiomic model,with an AUC, accuracy, sensitivity, and specificity of 0.900 (95% CI: 0.883-0.918), 87.0%, 58.9% and 95.2%, respectively, in the training set and 0.828 (95% CI: 0.791-0.864), 87.7%, 53.6% and 94.4%, respectively, in the validation set.The T2WI-based radiomic signature can effectively differentiate MS patients from patients with MS-like lesions due to ischemic demyelination.

Background: Hippocampal involvement may differ between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Objective: To investigate the morphometric, diffusion and functional alterations in hippocampus in MS and NMOSD and the clinical significance. Methods: A total of 752 participants including 236 MS, 236 NMOSD and 280 healthy controls (HC) were included in this retrospective multi-center study. The hippocampus and subfield volumes, fractional anisotropy (FA) and mean diffusivity (MD), amplitude of low frequency fluctuation (ALFF) and degree centrality (DC) were analyzed, and their associations with clinical variables were investigated. Results: The hippocampus showed significantly lower volume, FA and greater MD in MS compared to NMOSD and HC ( p < 0.05), while no abnormal ALFF or DC was identified in any group. Hippocampal subfields were affected in both diseases, though subiculum, presubiculum and fimbria showed significantly lower volume only in MS ( p < 0.05). Significant correlations between diffusion alterations, several subfield volumes and clinical variables were observed in both diseases, especially in MS ( R = −0.444 to 0.498, p < 0.05). FA and MD showed fair discriminative power between MS and HC, NMOSD and HC (AUC > 0.7). Conclusions: Hippocampal atrophy and diffusion abnormalities were identified in MS and NMOSD, partly explaining how clinical disability and cognitive impairment are differentially affected.

Subtyping relapsing-remitting multiple sclerosis (RRMS) patients may help predict disease progression and triage patients for treatment. We aimed to subtype RRMS patients by structural MRI and investigate their clinical significances.155 relapse-remitting MS (RRMS) and 210 healthy controls (HC) were retrospectively enrolled with structural 3DT1, diffusion tensor imaging (DTI) and resting-state functional MRI. Z scores of cortical and deep gray matter volumes (CGMV and DGMV) and white matter fractional anisotropy (WM-FA) in RRMS patients were calculated based on means and standard deviations of HC. We defined RRMS as "normal" (- 2 z scores of both GMV and WM-FA), DGM (z scores of DGMV - 2), and DGM-plus types (z scores of DGMV and [CGMV or WM-FA] - 2) according to combinations of z scores compared to HC. Expanded disability status scale (EDSS), cognitive and functional MRI measurements, and conversion rate to secondary progressive MS (SPMS) at 5-year follow-up were compared between subtypes.77 (49.7%) patients were "normal" type, 37 (23.9%) patients were DGM type and 34 (21.9%) patients were DGM-plus type. 7 (4.5%) patients who were not categorized into the above types were excluded. DGM-plus type had the highest EDSS. Both DGM and DGM-plus types had more severe cognitive impairment than "normal" type. Only DGM-plus type showed decreased functional MRI measures compared to HC. A higher conversion ratio to SPMS in DGM-plus type (55%) was identified compared to "normal" type (14%, p 0.001) and DGM type (20%, p = 0.005).Three MRI-subtypes of RRMS were identified with distinct clinical and imaging features and different prognosis.

Purpose To investigate the brain MRI features in neuromyelitis optica spectrum disorders (NMOSD) and its clinical relevance in a large multi-center cohort in China. Methods 270 NMOSD patients were recruited from seven centers. The brain MRI were classified as normal, NMOSD-specific lesions, multiple sclerosis-like, nonspecific white matter changes. Brain volumes including whole brain, white, gray matter, cortex and subcortex gray matter volume were measured. The relationship between MRI measures, clinical disability and cognitive impairment were investigated. Results 98 patients (36.3%) had normal brain MRI; 48 patients (17.7%) had NMOSD-specific lesions located in dorsal brainstem, corticospinal tract corpus, callosum and periependymal lesions surrounding the ventricular system; 16 patients (6%) had multiple sclerosis-like lesions; and 108 patients (40%) had nonspecific white matter changes. NMOSD patients with brain lesions had a trend of lower subcortex gray matter volume compared to patients without lesions. 52.5% patients with normal brain MRI and 50.8% patients with abnormal brain MRI showed cognitive impairment. No significant differences were identified in brain volume between cognitive impairment and cognitive preserved groups. Conclusion In this large multicenter NMOSD cohort, nonspecific white matter changes were the most common findings (40%). NMOSD patients with brain lesions demonstrated a trend of having lower brain volume than patients without lesions. Approximately 50% NMOSD patients presented cognitive impairment independent of brain lesions.

Neurovascular coupling reflects the close relationship between neuronal activity and cerebral blood flow (CBF), providing a new mechanistic insight into health and disease. Neuromyelitis optica (NMO) is an autoimmune inflammatory demyelinating disease of the central nervous system and shows cognitive decline-related brain gray matter abnormalities besides the damage of optic nerve and spinal cord. We aimed to investigate neurovascular coupling alteration and its clinical significance in NMO by using regional homogeneity (ReHo) to measure neuronal activity and CBF to measure vascular response. ReHo was calculated from functional MRI and CBF was computed from arterial spin labeling (ASL) in 56 patients with NMO and 63 healthy controls. Global neurovascular coupling was assessed by across-voxel CBF-ReHo correlations and regional neurovascular coupling was evaluated by CBF/ReHo ratio. Correlations between CBF/ReHo ratio and clinical variables were explored in patients with NMO. Global CBF-ReHo coupling was decreased in patients with NMO relative to healthy controls (p = .009). Patients with NMO showed decreased CBF/ReHo ratio (10.9%-17.3% reduction) in the parietal and occipital regions and increased CBF/ReHo ratio (8.0%-13.3% increase) in the insular, sensorimotor, temporal and prefrontal regions. Some of these abnormalities cannot be identified by a single CBF or ReHo analysis. Both abnormally decreased and increased CBF/ReHo ratios were correlated with more severe clinical impairments and cognitive decline in patients with NMO. These findings suggested that patients with NMO show abnormal neurovascular coupling, which is associated with disease severity and cognitive impairments.

Summary Aims We evaluate safety and efficacy of autologous bone marrow-derived mesenchymal stem cells (MSCs) as a potential treatment for neuromyelitis optica spectrum disorder (NMOSD). Methods Fifteen patients with NMOSD were recruited. All patients received a single intravenous infusion of 1.0 × 108 autologous MSC within 3–4 generations derived from bone marrow. The primary endpoints of the study were efficacy as reflected by reduction in annualized relapse rates (ARRs) and inflammatory lesions observed by MRI. Results At 12 months after MSC infusion, the mean ARR was reduced (1.1 vs. 0.3, P = 0.002), and the T2 or gadolinium-enhancing T1 lesions decreased in the optic nerve and spinal cord. Disability in these patients was reduced (EDSS, 4.3 vs. 4.9, P = 0.021; visual acuity, 0.4 vs. 0.5, P = 0.007). The patients had an increase in retinal nerve fiber layer thickness, optic nerve diameters and upper cervical cord area. We did not identify any serious MSC-related adverse events. At 24 months of MSC infusion, of 15 patients, 13 patients (87%) remained relapse-free, the mean ARR decreased to 0.1; the disability of 6 patients (40%) was improved, and the mean EDSS decreased to 4.0. Conclusions This pilot trial demonstrates that MSC infusion is safe, reduces the relapse frequency, and mitigates neurological disability with neural structures in the optic nerve and spinal cord recover in patients with NMOSD. The beneficial effect of MSC infusion on NMOSD was maintained, at least to some degree, throughout a 2-year observational period.

It is clinically essential to distinguish aquaporin-4 antibody (AQP4-Ab) negative neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) because of different therapeutic strategies. Since clinical and lesion features may not allow the distinction, we aimed to identify advanced imaging features that could improve the distinction between two disorders.Multimodal imaging measures included fractional anisotropy, mean, axial, radial diffusivity (MD, AD, RD) and kurtosis (MK, AK, RK) from diffusion kurtosis imaging; functional connectivity strength (FCS) and density, regional homogeneity, amplitude of low frequency fluctuations from resting-state functional MRI; gray matter volume from structural MRI; and cerebral blood flow from arterial spin labeling imaging. Voxel-wise comparisons were performed to identify inter-group differences in imaging measures, and the performance of differentiating these two disorders was estimated by receiver operating characteristic curves.Compared to MS, patients with AQP4-Ab negative NMOSD showed decreased MD and AD but increased MK and AK in white matter regions; and reduced FCS in the occipital cortex (P 0.05, FWE corrected). The joint-use of these five imaging measures distinguished the two disorders with an accuracy of 94% (P 0.001, 95%CI = 0.84-0.98). Other imaging measures showed no significant differences between the two patient groups.The study showed less white matter damage and a more severe functional disconnection of the occipital cortex in patients with AQP4-Ab negative NMOSD compared to MS. The combined use of diffusion and functional connectivity could facilitate a better distinction between NMO and MS with seronegative AQP4-Ab in clinical management.

Olfactory dysfunction (ODF) has been reported in patients with neuromyelitis optica (NMO) and multiple sclerosis (MS). However, the comparison of olfactory function and olfactory-related gray matter (GM) between patients with NMO and MS needed to be further elucidated.Thirty-seven patients with NMO and 37 with MS were enrolled. Olfactory function was evaluated with a Japanese TT olfactometer test kit, and the neuroanatomical features of olfactory-related GM were assessed using voxel-based morphometry.Olfactory deficits were found in 51.4% of patients with NMO and 40.5% of patients with MS. Patients with NMO with ODF had significantly smaller olfactory bulbs than patients with MS with ODF (p = 0.031). Olfactory-related GM atrophy was found in patients with NMO in several regions of the right orbitofrontal cortex and right superior frontal gyrus; in patients with MS, reduced GM volume was found in the right parahippocampal gyrus and piriform cortex (p0.05, cluster size200 voxels).Olfactory deficits are common in both NMO and MS. However, the neuroanatomical features related to olfactory deficits differ greatly between the two diseases.

Few data were available for the understanding of olfactory function in neuromyelitis optica spectrum disorders (NMOSDs). The aims of our study were to investigate the incidence of olfactory dysfunction and characterize olfactory structures, using MRI, in patients with NMOSDs. Olfactory function was evaluated by olfactometer in 49 patients with NMOSDs and 26 matched healthy controls. MRI parameters such as olfactory bulb (OB) and the olfactory-related gray matter volume changes were assessed. The frequency of olfactory dysfunction was 53% in patients with NMOSDs. Olfactory detection thresholds were positively correlated with serum aquaporin-4 antibodies (fluorescent units) tested by fluorescent immunoprecipitation assay (FIPA) in NMOSDs (p = 0.009). Patients with olfactory dysfunction had smaller OB volume than did patients without olfactory dysfunction or controls (p0.01). Both detection and recognition thresholds for olfaction were negatively correlated with OB volume (p = 0.018, p0.01). The significant gray matter volume reduction in NMOSDs was found in the bilateral piriform cortex, orbitofrontal cortex, and parahippocampal gyri (FDR correction, p0.05, cluster size200 voxels). Our data suggested that olfactory function deficits are prevalent in patients with NMOSDs. Reduced OB and olfactory-related cortex volume may be responsible for the olfactory dysfunction.

Alzheimer's disease (AD) affects several important molecules in brain metabolism. The resulting neurochemical changes can be quantified non-invasively in localized brain regions using in vivo single-voxel proton magnetic resonance spectroscopy (SV 1H MRS). Although the often heralded diagnostic potential of MRS in AD largely remains unfulfilled, more recent use of high magnetic fields has led to significantly improved signal-to-noise ratios and spectral resolutions, thereby allowing clinical applications with increased measurement reliability. The present article provides a comprehensive review of SV 1H MRS studies on AD at high magnetic fields (3.0 Tesla and above). This review suggests that patterned regional differences and longitudinal alterations in several neurometabolites are associated with clinically established AD. Changes in multiple metabolites are identifiable even at early stages of AD development. By combining information of neurochemicals in different brain regions revealing either pathological or compensatory changes, high field MRS can be evaluated in AD diagnosis and in the detection of treatment effects. To achieve this, standardization of data acquisition and analytical approaches is needed.

Genetic variations of APOE and KIBRA have been associated with human memory and Alzheimer's disease. APOE and KIBRA can jointly modulate glutamate receptor to influence long-term potentiation; however, their interactions on brain functional connectivity remain unknown. Here, we investigated additive and epistatic interactions between APOE and KIBRA (rs17070145) on brain functional connectivity density (FCD) in 267 healthy young adults. A voxel-based FCD analysis was performed to identify brain regions with significant APOE-KIBRA interaction. Additive effects showed decreased FCD in the left parahippocampal gyrus and the right middle temporal gyrus and increased FCD in the bilateral middle occipital gyri, with the increase of the number of the risk-alleles of APOE and KIBRA. Epistatic effects showed APOE x KIBRA interaction in the FCD of the dorsolateral prefrontal cortex (DLPFC). The FCD of the DLPFC showed APOE risk-allele-dependent reduction (epsilon 2 > epsilon 3 > epsilon 4) in KIBRA TT homozygotes, but APOE risk-allele-dependent increase (epsilon 2 < epsilon 3 < epsilon 4) in KIBRA C-carriers. FCD differences were only significant between the 2 extreme subgroups in both additive and epistatic analyses. These findings suggest that APOE and KIBRA have region-dependent additive and epistatic interactions on brain connectivity in healthy young adults.

Objectives According to aquaporin-4 antibody (AQP4-Ab), neuromyelitis optica (NMO) can be divided into seropositive and seronegative subgroups. The purpose of this study was to a) compare the distribution of spinal cord and brain magnetic resonance imaging (MRI) lesions between seropositive and seronegative NMO patients; b) explore occult brain damage in seropositive and seronegative NMO patients; and c) explore the contribution of visible lesions to occult grey and white matter damage in seropositive and seronegative NMO patients. Materials and methods Twenty-two AQP4-Ab seropositive and 14 seronegative NMO patients and 30 healthy controls were included in the study. Two neuroradiologists independently measured the brain lesion volume (BLV) and the length of spinal cord lesion (LSCL) and recorded the region of brain lesions. The normal-appearing grey matter volume (NAGM-GMV) and white matter fractional anisotropy (NAWM-FA) were calculated for each subject to evaluate occult brain damage. Results The seropositive patients displayed more extensive damage in the spinal cord than the seronegative patients, and the seronegative group had a higher proportion of patients with brainstem lesions (28.57%) than the seropositive group (4.55%, P = 0.064). Both NMO subgroups exhibited reduced NAGM-GMV and NAWM-FA compared with the healthy controls. NAGM-GMV was negatively correlated with LSCL in the seropositive group (r s = −0.444, P = 0.044) and with BLV in the seronegative group (r s = −0.768, P = 0.002). NAWM-FA was also negatively correlated with BLV in the seropositive group (r s = −0.682, P Conclusion Our findings suggest that the occult brain damage in these two NMO subgroups may be due to different mechanisms, which need to be further clarified.

Patients with neuromyelitis optica (NMO) have shown structural and functional impairments in the visual cortex. We aimed to characterize subregional grey matter volume (GMV) and resting-state functional connectivity (rsFC) changes in the visual cortex in NMO. Thirty-seven NMO patients and forty-two controls underwent structural and functional MRI scans. The GMV and rsFC of each visual subregion were compared between the groups. Compared with controls, NMO patients had GMV reductions in the bilateral V1, V2, V3d, VP, and LO and in the left V3A. In canonical visual pathways, the relatively low-level subregions showed more significant GMV reductions than did the high-level ones. Regardless of GMV correction, NMO patients showed reduced rsFC in the bilateral LO and V4v and in the left V2. The GMVs of the bilateral V1 and LO and of the left V2 and V3d were negatively correlated with clinical disability in NMO patients; these correlation coefficients were associated with hierarchical positions in the visual pathways. These findings suggest that in NMO, the low-level visual subregions have more severe structural damage; structural damage is not the only factor affecting rsFC alterations of visual subregions; GMV reduction in the low-level visual subregions has the highest predictive value for clinical disability.

We used functional fMRI to study the brain activation during active finger movements at different time points during the recovery phase following basal ganglia infarction. Four hemiplegic patients with basal ganglia infarction were serially evaluated at different time points spanning the acute and chronic phase using fMRI. To evaluate motor recovery, the patients were asked to perform functional tasks arranged in a block design manner with their hand. On follow-up (chronic phase), three patients achieved significant recovery of motor function of affected limbs. Activation of bilateral sensorimotor cortex (SMC) was observed in two of these patients, while activation of cerebellum was observed in all patients. No remarkable recovery of motor function was noted in one patient with left basal ganglia infarction. In this patient, the activation domain was located in SMC of both sides in acute phase and in ipsilateral SMC in chronic phase. Contralateral SMC appears to be involved in the functional rehabilitation following basal ganglia infarction. The cerebellum may act as an intermediary during functional recovery following basal ganglia infarction. The activation domain associated with active finger movement may be bilateral in acute phase; one patient was ipsilateral in the chronic stage.

Background: This study investigates how T1-weighted MRI can be used to evaluate brain anatomical changes. We investigated these changes in Alzheimer’s disease (AD) and normal aging. Methods: A semiquantitative brain atrophy and lesion index (BALI) was constructed by adapting existing visual rating scales and validated in 3 datasets. Results: The T1- and T2-weighted-imaging-based scores were highly correlated. They were both closely associated with age and with cognitive test scores. Conclusion: The T1-based BALI helps describe brain structural variability in AD, mild cognitive impairment and normal aging.

Association of changes in olfactory-related structures with olfactory function in patients with multiple sclerosis (MS) is not well understood. We used a T&T olfactometer test kit to evaluate olfactory function in 26 patients with MS and 26 age- and sex-matched healthy controls (HC). Then, Brain MRI were performed and olfactory-related structures were analyzed in these subjects. Olfactory detection and recognition threshold were significantly higher in the MS group, interestingly olfactory recognition threshold positively correlated with expanded disability status scale scores in these patients. Olfactory bulb (OB) volume reduced in patients with olfactory dysfunction (ODF). At the same time, reductions in gray matter (GM) volume were observed in the parahippocampal gyrus (PCG), amygdala, piriform cortex, and inferior frontal gyrus in patients with MS compared to HC. Atrophy of the PCG was more obvious in patients with ODF than patients without ODF and the PCG volume correlated with the olfactory recognition threshold, while no difference was found in fractional anisotropy values of tract-based spatial statistics analysis in the two groups. Olfactory function in patients with MS tends to become gradually more impaired with disability aggravation. Decreases in the volume of the OB and olfactory-related GM might provide valuable information about disease status in patients with MS with olfactory impairment.

Objective: To identify the clinical and structural MRI markers for predicting cognitive impairment (CI) in patients with neuromyelitis optica (NMO). Methods: Fifty-four patients with NMO and 27 healthy controls underwent extensive neuropsychological testing and multimodal 3.0T MRI. The patient group was classified as CI or cognitively preserved (CP), using a criterion of ≤1.5 SD on at least 2 cognitive domains. MRI measurements included white matter (WM) lesion volume, gray matter (GM), WM, and deep GM (DGM) volume, cortical thickness, and the severity and extent of WM tract diffusion metric alterations based on fractional anisotropy and mean, axial, and radial diffusivity. Groups were compared using a multivariate general linear model, and clinical and MRI measurements were related to average cognition z scores by partial correlations and a stepwise linear regression model. Results: Twenty-six patients with NMO (48.2%) were classified as CI and showed WM tract diffusion abnormalities, particularly increased radial diffusivity, and GM especially DGM atrophy compared with healthy controls. Patients classified as CP also showed alterations of WM tract diffusion but without significant GM atrophy. Compared with the CP group, patients with CI demonstrated a lower level of education and decreased hippocampal volume. In the whole patient group, average cognition z scores were best predicted by the level of education and hippocampal volume (R2 = 0.46, p Conclusion: In patients with NMO, WM tract integrity disruption was identified in both CP and CI groups. GM atrophy, particularly in the DGM, was only found in the CI group. Hippocampal volume is the main MRI predictor of cognition in NMO.

Background: Cognitive dysfunction is frequently seen in neuromyelitis optica (NMO). However, the features and influencing factors of cognitive impairment of Chinese NMO patients are unclear. Objective: To investigate the patterns of cognitive impairment in Chinese NMO patients, and correlate the neuropsychiatric scores with clinical and MRI parameters. Methods: Thirty-six Chinese NMO patients, and 30 sex and age-matched healthy controls were recruited with extensive neuropsychological assessments, using the modified Minimal Assessment of Cognitive Function in MS (MACFIMS). The demographic and clinical characteristics as well as MRI parameters were compared between cognitively impaired (CI) and cognitively preserved (CP) patients. Results: NMO patients were significantly impaired in the Paced Auditory Serial Addition Task ( PConclusions: Chinese NMO patients particularly demonstrated cognitive impairment in information processing speed, executive function and memory. Lower education level was the main factor contributing to cognitive impairment in NMO.

Peripheral lymphocytes entering brain ischemic regions orchestrate inflammatory responses, catalyze tissue death, and worsen clinical outcomes of acute ischemic stroke (AIS) in preclinical studies. However, it is not known whether modulating brain inflammation can impact the outcome of patients with AIS. In this open-label, evaluator-blinded, parallel-group clinical pilot trial, we recruited 22 patients matched for clinical and MRI characteristics, with anterior cerebral circulation occlusion and onset of stroke that had exceeded 4.5 h, who then received standard management alone (controls) or standard management plus fingolimod (FTY720, Gilenya, Novartis), 0.5 mg per day orally for 3 consecutive days. Compared with the 11 control patients, the 11 fingolimod recipients had lower circulating lymphocyte counts, milder neurological deficits, and better recovery of neurological functions. This difference was most profound in the first week when reduction of National Institutes of Health Stroke Scale was 4 vs. -1, respectively (P = 0.0001). Neurological rehabilitation was faster in the fingolimod-treated group. Enlargement of lesion size was more restrained between baseline and day 7 than in controls (9 vs. 27 mL, P = 0.0494). Furthermore, rT1%, an indicator of microvascular permeability, was lower in the fingolimod-treated group at 7 d (20.5 vs. 11.0; P = 0.005). No drug-related serious events occurred. We conclude that in patients with acute and anterior cerebral circulation occlusion stroke, oral fingolimod within 72 h of disease onset was safe, limited secondary tissue injury from baseline to 7 d, decreased microvascular permeability, attenuated neurological deficits, and promoted recovery.

Pronounced inflammatory reactions occurring shortly after intracerebral hemorrhage (ICH) contribute to the formation and progression of perihematomal edema (PHE) and secondary brain injury. We hypothesized that modulation of brain inflammation reduces edema, thus improving clinical outcomes in patients with ICH.To investigate whether oral administration of fingolimod, a Food and Drug Administration-approved sphingosine 1-phosphate receptor modulator for multiple sclerosis, is safe and effective in alleviating PHE and neurologic deficits in patients with ICH.In this 2-arm, evaluator-blinded study, we included 23 patients with primary supratentorial ICH with hematomal volume of 5 to 30 mL. Clinical and neuroimaging feature-matched patients were treated with standard care with or without oral fingolimod. The study was conducted in Tianjin Medical University General Hospital, Tianjin, China.All patients received standard management alone (control participants) or combined with fingolimod (FTY720, Gilenya), 0.5 mg, orally for 3 consecutive days. Treatment was initiated within 1 hour after the baseline computed tomographic scan and no later than 72 hours after the onset of symptoms.Neurologic status and hematomal and PHE volumes (Ev) and relative PHE, defined as Ev divided by hematomal volume, were monitored by clinical assessment and magnetic resonance imaging, respectively, for 3 months.Patients treated with fingolimod exhibited a reduction of neurologic impairment compared with control individuals, regained a Glasgow Coma Scale score of 15 by day 7 (100% vs 50%, P = .01), and had a National Institutes of Health Stroke Scale score reduction of 7.5 vs 0.5 (P .001). Neurologic functions improved in these patients in the first week coincident with a reduction of circulating lymphocyte counts. At 3 months, a greater proportion of patients receiving fingolimod achieved full recovery of neurologic functions (modified Barthel Index score range, 95-100; 63% vs 0%; P = .001; modified Rankin Scale score range, 0-1; 63% vs 0%; P = .001), and fewer reported ICH-related lung infections. Perihematomal edema volume and rPHE were significantly smaller in fingolimod-treated patients than in control individuals (Ev at day 7, 47 mL vs 108 mL, P = .04; Ev at day 14, 55 mL vs 124 mL, P = .07; rPHE at day 7, 2.5 vs 6.4, P .001; rPHE at day 14, 2.6 vs 7.7, P = .003, respectively). We recorded no differences between groups in the occurrence of adverse events.In patients with small- to moderate-sized deep primary supratentorial ICH, administration of oral fingolimod within 72 hours of disease onset was safe, reduced PHE, attenuated neurologic deficits, and promoted recovery. The efficacy of fingolimod in preventing secondary brain injury in patients with ICH warrants further investigation in late-phase trials.clinicaltrials.gov Identifier:NCT02002390.

Background On average, cognition declines as people age, but improvement can also occur. Objective To evaluate the dynamics of age-related changes in brain structure and cognitive function in patients with mild Alzheimer9s disease (AD) and mild cognitive impairment (MCI) and in healthy control (HC) older adults. Methods High-resolution 3-Tesla MRI and clinical data were obtained from the Alzheimer9s Disease Neuroimaging Initiative in 187 subjects (a cohort aged 55–91 years; AD=43, MCI=84, HC=60). At 24 months, 151 people had clinical and 128 had MRI follow-up. Brain structure was assessed using the Medial Temporal Atrophy Scale (MTAS) and the Brain Atrophy and Lesion Index (BALI). Cognition was assessed using the Mini-Mental State Examination (MMSE) and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). Responsiveness was tested. Changes were analysed using a multistate dynamic model, adjusted for age, gender, ApoE4 genotype and vascular risk factors. Results Over 2 years, decline in brain structure and cognition predominated, each showing detectable effect sizes (Cohen9s d=0.33 for MTAS, 0.32 for BALI, 0.41 for MMSE, 0.38 for ADAS-cog; standard response mean=0.71, 0.69, 0.50 and 0.47, respectively). Structural improvement was observed (10.2% in BALI and 0.8% in MTAS), as was cognitive improvement (23.2% MMSE, 27.2% ADAS-cog). Most people (66.7%) whose BALI score improved also improved in either the MMSE or ADAS-cog. No patient with MCI whose MTAS or BALI improved converted to AD. Conclusions Despite average decline in brain structure, improvement was observed and related to cognition and MCI–AD conversion. Ageing-related brain changes reflect a dynamic process.

Background: A brain atrophy and lesion index (BALI) based on high-field magnetic resonance imaging (MRI) has recently been validated to evaluate structural changes in the aging brain. The present study investigated the two-year progression of brain structural deficits in people with Alzheimer's disease (AD) and mild cognitive impairment (MCI), and in healthy control older adults (HC) using the BALI rating. Methods: T1-weighted high-resolution anatomical imaging data using 3 Tesla MRI at baseline (AD = 39, MCI = 82, HC = 58) and at 24-months were obtained from the Alzheimer's disease Neuroimaging Initiative database. Lesions in various brain structures, including the infratentorial and basal ganglia areas, and the periventricular and deep white matter and global atrophy, were evaluated and combined into the BALI scale. Results: Mean progression of brain deficits over two years was evident in all diagnostic groups (p < 0.001) and was statistically greater in MCI-AD converters than in the non-converters (p = 0.044). An increase in the BALI score was significantly associated with cognitive test scores (p = 0.008 for the Mini-Mental State Examination MMSE and p = 0.013 for the Alzheimer's Disease Assessment Scale-Cognitive Subscale ADAS-cog) in a model that adjusted for age, sex, and education. Conclusion: The BALI rating quantified the progression of brain deficits over two years, which is associated with cognitive decline. BALI ratings may be used to help summarize AD-associated structural variations. © 2011 The authors and IOS Press. All rights reserved.

Background: Several structural brain changes have been associated with Alzheimer's disease (AD). This study investigated the prediction of AD by combining multiple brain changes with the hallmark medial temporal lobe atrophy (MTA). Methods: High-resolution magnetic resonance imaging (MRI) data of people with mild AD (n = 39), mild cognitive impairment (MCI; n = 82), and of healthy controls (HC; n = 58) were obtained at baseline. Among these people, 26 AD, 53 MCI, and 46 HC subjects had 24-month follow-up MRI scans. Bilateral MTA was evaluated using a medial temporal lobe atrophy scale (MTAS). Common changes in the aging brain were summarized using a brain atrophy and lesion index (BALI). The performance of the MTAS, BALI, and a score combining both, using a logistic regression model, were assessed. Results: The MTAS and BALI scores were closely correlated (r2 > 0.56); each differed between the diagnostic groups. Having an unfavorable MTAS score was associated with an increased risk of MCI-AD conversion (OR = 3.71, p = 0.039), adjusted for age, sex, and education; having an unfavorable BALI score marginally contributed to such risks (OR = 4.08, p = 0.080). Combining MTAS and BALI components resulted in a greater OR (8.99, p = 0.007) and an improved predictive accuracy (75.9%, p = 0.002). Conclusion: Multiple structural changes have an additive effect on AD. The data support potential future roles of combining multiple coexisting structural changes to benefit AD diagnosis, progression monitoring, and/or treatment effect evaluation. Copyright © 2012 S. Karger AG, Basel.

approximately 90% of the total variation are used as features. Hippocampal volume corrected for total intracranial volume is added as independent feature. The shape components are evaluated in the AD classification using bagged SVM with 25 resamplings. Results: Using hippocampal volume gave on average 83.47% accuracy (average of 20 repetitions). sing the features produced by SSMs alone provided the best performance (87.36%) when computed on the landmarks selected at p