Spatial correspondence among regional gene expressions and gray matter volume loss in multiple sclerosis.

In multiple sclerosis (MS), a non-random and clinically relevant pattern of gray matter (GM) volume loss has been described. Whether differences in regional gene expression might underlay distinctive pathological processes contributing to this regional variability has not been explored yet. Two hundred eighty-six MS patients and 172 healthy controls (HC) underwent a brain 3T MRI, a complete neurological evaluation and a neuropsychological assessment. Using Allen Human Brain Atlas, voxel-based morphometry and MENGA platform, we integrated brain transcriptome and neuroimaging data to explore the spatial cross-correlations between regional GM volume loss and expressions of 2710 genes involved in MS (p < 0.05, family-wise error-corrected). Enrichment analyses were performed to evaluate overrepresented molecular functions, biological processes and cellular components involving genes significantly associated with voxel-based morphometry-derived GM maps (p < 0.05, Bonferroni-corrected). A diffuse GM volume loss was found in MS patients compared to HC and it was spatially correlated with 74 genes involved in GABA neurotransmission and mitochondrial oxidoreductase activity mainly expressed in neurons and astrocytes. A more severe GM volume loss was spatially associated, in more disabled MS patients, with 44 genes involved in mitochondrial integrity of all resident cells of the central nervous system (CNS) and, in cognitively impaired MS patients, with 64 genes involved in mitochondrial protein heterodimerization and oxidoreductase activities expressed also in microglia and endothelial cells. Specific differences in the expressions of genes involved in synaptic GABA receptor activities and mitochondrial functions in resident CNS cells may influence regional susceptibility to MS-related excitatory/inhibitory imbalance and oxidative stress, and subsequently, to GM volume loss.

Brain and cervical spinal cord MRI correlates of sensorimotor impairment in patients with multiple sclerosis.

BACKGROUND: Cervical spinal cord (cSC) lesions and atrophy contribute to disability in multiple sclerosis (MS), but associations with specific sensorimotor dysfunction require further exploration. OBJECTIVE: To investigate the associations of brain and cSC magnetic resonance imaging (MRI) measures with sensorimotor impairment in MS. METHODS: One hundred fifty-one MS patients and 69 healthy controls underwent 3T MRI and clinical assessments including Expanded Disability Status Scale (EDSS), 9-hole peg test (9-HPT), finger tapping test (FTT), timed 25-foot walk test (T25FWT), and vibration detection threshold (VDT). Random forest ranked brain (T2-hyperintense lesion volume (T2-LV) and normalized deep gray matter (GM), cortical and white matter (WM) volumes) and cSC (T2-LV and total, GM, and WM cross-sectional areas (CSAs) at C2/C3 level) MRI measures relevance in explaining EDSS milestones (EDSS ⩾3.0, ⩾4.0, and ⩾6.0), VDT, pyramidal and sensory functional systems (P-FS and S-FS ⩾2), and motor tests impairment. RESULTS: Various combinations of brain and cSC MRI measures explained EDSS milestones (area under the curve (AUC) =0.879-0.900), VDT (R2 = 0.194), and impaired P-FS (AUC = 0.820), S-FS (AUC = 0.795), 9-HPT (AUC = 0.793), FTT (AUC = 0.740), and T25FWT (AUC = 0.825). cSC GM CSA was the most informative feature for all outcomes, except 9-HPT. CONCLUSION: cSC MRI measures, especially GM CSA, explain EDSS and sensorimotor dysfunction better than brain measures in MS.

Ocrelizumab extended-interval dosing in multiple sclerosis during SARS-CoV-2 pandemic: a real-world experience.

BACKGROUND AND PURPOSE: During the COVID-19 pandemic, ocrelizumab administration was frequently postponed because of a lack of safety information and to favour vaccination. The clinical implications of ocrelizumab administration delay in multiple sclerosis (MS) patients were assessed. METHODS: Relapsing (RMS) and primary progressive (PPMS) MS patients receiving ocrelizumab for at least 6 months at our centre were retrospectively classified, according to the possible occurrence of a delay (≥4 weeks) in treatment administration. Patients were categorized in the extended-interval dosing (EID) group in the presence of at least one delayed infusion; otherwise they were considered as part of the standard interval dosing (SID) cohort. MS history, magnetic resonance imaging examinations and B-cell counts were also retrospectively collected and analysed. RESULTS: A total of 213 RMS and 61 PPMS patients were enrolled; 115 RMS and 29 PPMS patients had been treated according to the SID regimen, whilst 98 RMS and 32 PPMS patients were included in the EID cohort. Average follow-up after delay was 1.28 ± 0.7 years in the EID cohort. In RMS, comparing SID and EID patients, no differences were found considering the occurrence of clinical relapses (9.6% vs. 16.3%, p = 0.338), magnetic resonance imaging activity (9.8% vs. 14.1%, p = 0.374) or disability progression (11.3% vs. 18.4%, p = 0.103). Similar findings were observed in PPMS patients. In the pooled EID group, treatment delay correlated with CD19-positive relative (r = 0.530, p < 0.001) and absolute (r = 0.491, p < 0.001) cell counts, without implications on disease activity. CONCLUSIONS: Sporadic ocrelizumab administration delay granted sustained treatment efficacy in our cohort. Prospective data should be obtained to confirm these observations and set up systematic extended-interval regimens.

CSF-based liquid biopsy pointing to a diagnosis of diffuse glioma in a patient with supposed neurodegenerative disorder.

INTRODUCTION: The differential diagnosis of brain diseases becomes challenging in cases where imaging is not sufficiently informative, and surgical biopsy is impossible or unacceptable to the patient. METHODS: An elderly patient with progressive short-term memory loss and cognitive impairment presented with a normal brain CT scan, a brain FDG-PET that indicated symmetrical deterioration of the white matter in the frontal lobes, and inconclusive results of a molecular marker analysis of suspected dementia in cerebrospinal fluid (CSF). Brain MRI suggested the diagnosis of lower grade glioma. The patient refused surgical biopsy. In order to investigate whether somatic mutations associated with gliomas existed, we performed a "liquid biopsy" by the targeted sequencing of cell-free DNA (cfDNA) from his CSF. RESULTS: Deep sequencing of the cfDNA from CSF revealed somatic mutations characteristically found in gliomas, including mutations of the TP53 (Arg282Trp), BRAF (Val600Glu), and IDH1 (Arg132His) genes. The patient is currently treated with temozolomide, and his clinical and MRI findings suggest the stabilization of his disease. CONCLUSION: Neurological patients may benefit from liquid biopsy diagnostic work-up as it can reveal therapeutically targetable mutations.

Unraveling the heterogeneous pathological substrates of relapse-onset multiple sclerosis: a multiparametric voxel-wise 3 T MRI study.

BACKGROUND: In multiple sclerosis (MS), pathological processes affecting brain gray (GM) and white matter (WM) are heterogeneous. OBJECTIVE: To apply a multimodal MRI approach to investigate the regional distribution of the different pathological processes occurring in the brain WM and GM of relapse-onset MS patients. METHODS: Fifty-seven MS patients (forty-two relapsing remitting [RR], fifteen secondary progressive [SP]) and forty-seven age- and sex-matched healthy controls (HC) underwent a multimodal 3 T MRI acquisition. Between-group voxel-wise differences of brain WM and GM volumes, magnetization transfer ratio (MTR), T1-weighted(w)/T2w ratio, intracellular volume fraction (ICV_f), and quantitative susceptibility mapping (QSM) maps were investigated. RESULTS: Compared to HC, RRMS showed significant WM, deep GM and cortical atrophy, significantly lower MTR and T1w/T2w ratio of periventricular and infratentorial WM, deep GM and several cortical areas, lower ICV_f in supratentorial and cerebellar WM and in some cortical areas, and lower QSM values in bilateral periventricular WM (p < 0.001). Compared to RRMS, SPMS patients showed significant deep GM and widespread cortical atrophy, significantly lower MTR of periventricular WM, deep GM and cerebellum, lower T1w/T2w ratio of fronto-temporal WM regions, lower ICV_f of some fronto-tempo-occipital WM and cortical areas. They also had increased QSM and T1w/T2w ratio in the pallidum, bilaterally (p < 0.001). CONCLUSION: A periventricular pattern of demyelination and widespread GM and WM neuro-axonal loss are detectable in RRMS and are more severe in SPMS. Higher T1w/T2w ratio and QSM in the pallidum, possibly reflecting iron accumulation and neurodegeneration, may represent a relevant MRI marker to differentiate SPMS from RRMS.

In vivo quantification of brain soma and neurite density abnormalities in multiple sclerosis.

BACKGROUND: Soma and neurite density imaging (SANDI) is a new biophysical model that incorporates soma in addition to neurite density, thus possibly providing more specific information about the complex pathological processes of multiple sclerosis (MS). PURPOSE: To discriminate the pathological abnormalities of MS white matter (WM) lesions, normal-appearing (NA) WM and cortex and to evaluate the associations among SANDI-derived measures, clinical disability, and conventional MRI variables. METHODS: Twenty healthy controls (HC) and 23 MS underwent a 3 T brain MRI. Using SANDI on diffusion-weighted sequence, the fractions of neurite (fneurite) and soma (fsoma) were assessed in WM lesions, NAWM, and cortex. RESULTS: Compared to HC WM, MS NAWM showed lower fneurite (false discovery rate [FDR]-p = 0.011). In MS patients, WM lesions showed lower fneurite and fsoma compared to both HC and MS NAWM (FDR-p < 0.001 for all). In the cortex, MS patients had lower fneurite and fsoma compared to HC (FDR-p ≤ 0.009). Compared to both HC and RRMS, PMS patients had lower fneurite in NAWM (vs HC: FDR-p < 0.001; vs RRMS: FDR-p = 0.003) and cortex (vs HC: FDR-p < 0.001; vs RRMS: p = 0.031, not surviving FDR correction), and lower cortical fsoma (vs HC: FDR-p < 0.001; vs RRMS: FDR-p = 0.009). Compared to HC, PMS also showed a higher fsoma in NAWM (FDR-p = 0.015). Fneurite and fsoma in the different brain compartments were correlated with age, phenotype, disease duration, disability, WM lesion volumes, normalized brain, cortical, and WM volumes (r from - 0.761 to 0.821, FDR-p ≤ 0.4). CONCLUSIONS: SANDI may represent a clinically relevant model to discriminate different neurodegenerative phenomena that gradually accumulate through MS disease course.

Functional and structural brain MRI changes associated with cognitive worsening in multiple sclerosis: a 3-year longitudinal study.

BACKGROUND: Heterogeneous processes may contribute to cognitive impairment in multiple sclerosis (MS). OBJECTIVE: To apply a longitudinal multiparametric MRI approach to identify mechanisms associated with cognitive worsening in MS patients. METHODS: 3 T brain functional and structural MRI scans were acquired at baseline and after a median follow-up of 3.4 years in 35 MS patients and 22 healthy controls (HC). Associations between cognitive worsening (reliable change index score < - 1.25 at the Rao's battery) and longitudinal changes in regional T2-hyperintense white matter (WM) lesions, diffusion tensor microstructural WM damage, gray matter (GM) atrophy and resting state (RS) functional connectivity (FC) were explored. RESULTS: At follow-up, HC showed no clusters of significant microstructural WM damage progression, GM atrophy or changes in RS FC. At follow-up, 10 MS patients (29%) showed cognitive worsening. Compared to cognitively stable, cognitively worsened MS patients showed more severe GM atrophy of the right anterior cingulate cortex and bilateral supplementary motor area (p < 0.001). Cognitively worsened vs cognitively stable MS patients showed also decreased RS FC in the right hippocampus of the right working memory network and in the right insula of the default mode network. Increased RS FC in the left insula of the executive control network was found in the opposite comparison (p < 0.001). No significant regional accumulation of focal WM lesions nor microstructural WM abnormalities occurred in both patients' groups. CONCLUSIONS: GM atrophy progression in cognitively relevant brain regions combined with functional impoverishment in networks involved in cognitive functions may represent the substrates underlying cognitive worsening in MS.

A Deep Learning Approach to Predicting Disease Progression in Multiple Sclerosis Using Magnetic Resonance Imaging.

OBJECTIVES: Magnetic resonance imaging (MRI) is an important tool for diagnosis and monitoring of disease course in multiple sclerosis (MS). However, its prognostic value for predicting disease worsening is still being debated. The aim of this study was to propose a deep learning algorithm to predict disease worsening at 2 years of follow-up on a multicenter cohort of MS patients collected from the Italian Neuroimaging Network Initiative using baseline MRI, and compare it with 2 expert physicians. MATERIALS AND METHODS: For 373 MS patients, baseline T2-weighted and T1-weighted brain MRI scans, as well as baseline and 2-year clinical and cognitive assessments, were collected from the Italian Neuroimaging Network Initiative repository. A deep learning architecture based on convolutional neural networks was implemented to predict: (1) clinical worsening (Expanded Disability Status Scale [EDSS]-based model), (2) cognitive deterioration (Symbol Digit Modalities Test [SDMT]-based model), or (3) both (EDSS + SDMT-based model). The method was tested on an independent data set and compared with the performance of 2 expert physicians. RESULTS: For the test set, the convolutional neural network model showed high predictive accuracy for clinical (83.3%) and cognitive (67.7%) worsening, although the highest accuracy was reached when training the algorithm using both EDSS and SDMT information (85.7%). Artificial intelligence classification performance exceeded that of 2 expert physicians (70% of accuracy for the human raters). CONCLUSIONS: We developed a robust and accurate model for predicting clinical and cognitive worsening of MS patients after 2 years, based on conventional T2-weighted and T1-weighted brain MRI scans obtained at baseline. This algorithm may be valuable for supporting physicians in their clinical practice for the earlier identification of MS patients at risk of disease worsening.

Distinct patterns of MRI lesions in MOG antibody disease and AQP4 NMOSD: a systematic review and meta-analysis.

BACKGROUND: the distinct MRI features of MOG-antibody disease (MOG-AD) and AQP4-NMOSD are still poorly defined. We performed a systematic review and meta-analysis to identify specific patterns of MRI abnormalities able to discriminate between MOG-AD and AQP4-NMOSD. METHODS: fourteen case-series (1028 patients) were included. Outcomes were MRI lesion patterns in optic nerve (ON), brain and spinal cord (SC) that were selected after a systematic literature review and analysed separately as the event rate for individual MRI lesions in MOG-AD (experimental group) and AQP4-NMOSD (control group) by using a random effect model. RESULTS: MOG-AD showed a higher number of MRI lesions than AQP4-NMOSD patients in the retrobulbar ON (OR=5.67; 95%CI=2.11-15.24; p=0.0006) with ON head swelling (OR=8.20; 95%CI=4.13-16.28; p<0.00001), corpus callosum (OR=2.30; 95%CI=1.11-4.76; p=0.02), pons (OR=2.87; 95%CI=1.45-5.67; p=0.002), and lumbar/conus SC (OR=3.47; 95%CI=1.66-7.24; p=0.0009). Conversely, lesions in the canalicular (OR=0.42; 95%CI=0.18-0.98; p=0.05) and intracranial ON (OR=0.30; 95%CI=0.11=0.84; p=0.02), area postrema (OR=0.12; 95%CI=0.02-0.61; p=0.01), medulla (OR=0.40; 95%CI=0.20-0.78; p=0.007), and cervical SC (OR=0.29; 95%CI=0.09-0.92; p=0.04) were prominent in patients with AQP4-NMOSD. Participants' age was found to be a source of heterogeneity across studies. CONCLUSION: our study provides further evidence that MOG-AD and AQP4-NMOSD have distinct MRI features that may help clinicians for an early differential diagnosis.