Browsing by Author "Rocca, Maria A (34973365100)"

Objectives To evaluate white matter and grey matter T1-weighted (w)/T2w ratio (T1w/T2w ratio) in healthy controls and patients with multiple sclerosis, and its association with clinical disability. Methods In this cross-sectional study, 270 healthy controls and 434 patients with multiple sclerosis were retrospectively selected from 7 European sites. T1w/T2w ratio was obtained from brain T2w and T1w scans after intensity calibration using eyes and temporal muscle. Results In healthy controls, T1w/T2w ratio increased until 50-60 years both in white and grey matter. Compared with healthy controls, T1w/T2w ratio was significantly lower in white matter lesions of all multiple sclerosis phenotypes, and in normal-appearing white matter and cortex of patients with relapsing-remitting and secondary progressive multiple sclerosis (p≤0.026), but it was significantly higher in the striatum and pallidum of patients with relapsing-remitting, secondary progressive and primary progressive multiple sclerosis (p≤0.042). In relapse-onset multiple sclerosis, T1w/T2w ratio was significantly lower in white matter lesions and normal-appearing white matter already at Expanded Disability Status Scale (EDSS) <3.0 and in the cortex only for EDSS ≥3.0 (p≤0.023). Conversely, T1w/T2w ratio was significantly higher in the striatum and pallidum for EDSS ≥4.0 (p≤0.005). In primary progressive multiple sclerosis, striatum and pallidum showed significantly higher T1w/T2w ratio beyond EDSS=6.0 (p≤0.001). In multiple sclerosis, longer disease duration, higher EDSS, higher brain lesional volume and lower normalised brain volume were associated with lower lesional and cortical T1w/T2w ratio and a higher T1w/T2w ratio in the striatum and pallidum (β from-1.168 to 0.286, p≤0.040). Conclusions T1w/T2w ratio may represent a clinically relevant marker sensitive to demyelination, neurodegeneration and iron accumulation occurring at the different multiple sclerosis phases. ©

Background: Functional magnetic resonance imaging (fMRI) correlates of cognitive deficits have not been thoroughly studied in patients with neuromyelitis optica spectrum disorders (NMOSDs). Objective: To investigate resting state (RS) functional connectivity (FC) abnormalities within the main cognitive networks in NMOSD patients and their correlation with cognitive performance. Methods: We acquired RS fMRI from 25 NMOSD patients and 30 healthy controls (HC). Patients underwent an extensive neuropsychological evaluation. Between-group RS FC comparisons and correlations with cognitive performance were assessed on the main cognitive RS networks identified by independent component analysis. Results: NMOSD patients showed higher RS FC versus HC in the precuneus of the default mode network (DMN) and right working memory network (WMN), as well as in several frontoparietal regions of the salience network (SN) and bilateral WMNs. Reduced frontal RS FC in NMOSD versus HC was detected in the left WMN. Increased RS FC in the DMN and right WMN was correlated with better cognitive performance, while decreased RS FC in the left WMN was associated with worse cognitive performance. Conclusion: Cognitive-network reorganization occurs in NMOSD. Clinico-imaging correlations suggest an adaptive role of increased RS FC. Conversely, reduced RS FC seems to be a maladaptive mechanism associated with a worse cognitive performance. © The Author(s), 2019.

Background: Functional magnetic resonance imaging (fMRI) correlates of cognitive deficits have not been thoroughly studied in patients with neuromyelitis optica spectrum disorders (NMOSDs). Objective: To investigate resting state (RS) functional connectivity (FC) abnormalities within the main cognitive networks in NMOSD patients and their correlation with cognitive performance. Methods: We acquired RS fMRI from 25 NMOSD patients and 30 healthy controls (HC). Patients underwent an extensive neuropsychological evaluation. Between-group RS FC comparisons and correlations with cognitive performance were assessed on the main cognitive RS networks identified by independent component analysis. Results: NMOSD patients showed higher RS FC versus HC in the precuneus of the default mode network (DMN) and right working memory network (WMN), as well as in several frontoparietal regions of the salience network (SN) and bilateral WMNs. Reduced frontal RS FC in NMOSD versus HC was detected in the left WMN. Increased RS FC in the DMN and right WMN was correlated with better cognitive performance, while decreased RS FC in the left WMN was associated with worse cognitive performance. Conclusion: Cognitive-network reorganization occurs in NMOSD. Clinico-imaging correlations suggest an adaptive role of increased RS FC. Conversely, reduced RS FC seems to be a maladaptive mechanism associated with a worse cognitive performance. © The Author(s), 2019.

Objective Since astrocytes at the blood-brain barrier are targeted by neuromyelitis optica spectrum disorder (NMOSD), this study aims to assess whether patients with NMOSD have a subclinical accumulation of brain water and if it differs according to disease activity. Methods Seventy-seven aquaporin-4-positive patients with NMOSD and 105 healthy controls were enrolled at two European centres. Brain dual-echo turbo spin-echo MR images were evaluated and maps of T2 relaxation time (T2rt) in the normal-appearing white matter (NAWM), grey matter and basal ganglia were obtained. Patients with a clinical relapse within 1 month before or after MRI acquisition were defined 'active'. Differences between patients and controls were assessed using z-scores of T2rt obtained with age-adjusted and sex-adjusted linear models from each site. A stepwise binary logistic regression was run on clinical and MRI variables to identify independent predictors of disease activity. Results Patients had increased T2rt in both white and grey matter structures (p range: 0.014 to <0.0001). Twenty patients with NMOSD were defined active. Despite similar clinical and MRI features, active patients had a significantly increased T2rt in the NAWM and grey matter compared with those clinically stable (p range: 0.010-0.002). The stepwise binary logistic regression selected the NAWM as independently associated with disease activity (beta=2.06, SE=0.58, Nagelkerke R 2 =0.46, p<0.001). Conclusions In line with the research hypothesis, patients with NMOSD have increased brain T2rt. The magnitude of this alteration might be useful for identifying those patients with active disease. © 2022 BMJ Publishing Group. All rights reserved.

Background: In 2016, the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) network proposed modifications to the MRI criteria to define dissemination in space (DIS) and time (DIT) for the diagnosis of multiple sclerosis in patients with clinically isolated syndrome (CIS). Changes to the DIS definition included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested. We compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for multiple sclerosis diagnosis in a large multicentre cohort of patients with CIS to provide evidence to guide revisions of multiple sclerosis diagnostic criteria. Methods: Brain and spinal cord MRI and optic nerve assessments from patients with typical CIS suggestive of multiple sclerosis done less than 3 months from clinical onset in eight European multiple sclerosis centres were included in this retrospective study. Eligible patients were 16–60 years, and had a first CIS suggestive of CNS demyelination and typical of relapsing-remitting multiple sclerosis, a complete neurological examination, a baseline brain and spinal cord MRI scan obtained less than 3 months from clinical onset, and a follow-up brain scan obtained less than 12 months from CIS onset. We recorded occurrence of a second clinical attack (clinically definite multiple sclerosis) at months 36 and 60. We evaluated MRI criteria performance for DIS, DIT, and DIS plus DIT with a time-dependent receiver operating characteristic curve analysis. Findings: Between June 16, 1995, and Jan 27, 2017, 571 patients with CIS were screened, of whom 368 met all study inclusion criteria. At the last evaluation (median 50·0 months [IQR 27·0–78·4]), 189 (51%) of 368 patients developed clinically definite multiple sclerosis. At 36 months, the two DIS criteria showed high sensitivity (2010 McDonald 0·91 [95% CI 0·85–0·94] and 2016 MAGNIMS 0·93 [0·88–0·96]), similar specificity (0·33 [0·25–0·42] and 0·32 [0·24–0·41]), and similar area under the curve values (AUC; 0·62 [0·57–0·67] and 0·63 [0·58–0·67]). Performance was not affected by inclusion of symptomatic lesions (sensitivity 0·92 [0·87–0·96], specificity 0·31 [0·23–0·40], AUC 0·62 [0·57–0·66]) or cortical lesions (sensitivity 0·92 [0·87–0·95], specificity 0·32 [0·24–0·41], AUC 0·62 [0·57–0·67]). Requirement of three periventricular lesions resulted in slightly lower sensitivity (0·85 [0·78–0·90], slightly higher specificity (0·40 [0·32–0·50], and similar AUC (0·63 [0·57–0·68]). Inclusion of optic nerve evaluation resulted in similar sensitivity (0·92 [0·87–0·96]), and slightly lower specificity (0·26 [0·18–0·34]) and AUC (0·59 [0·55–0·64]). AUC values were also similar for DIT (2010 McDonald 0·61 [0·55–0·67] and 2016 MAGNIMS 0·61 [0·55–0·66]) and DIS plus DIT (0·62 [0·56–0·67] and 0·64 [0·58–0·69]). Interpretation: The 2016 MAGNIMS criteria showed similar accuracy to the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis. Inclusion of symptomatic lesions is expected to simplify the clinical use of MRI criteria without reducing accuracy, and our findings suggest that needing three lesions to define periventricular involvement might slightly increase specificity, suggesting that these two factors could be considered during further revisions of multiple sclerosis diagnostic criteria. Funding: UK MS Society, National Institute for Health Research University College London Hospitals Biomedical Research Centre, Dutch MS Research Foundation. © 2018 Elsevier Ltd

Background: The features of functional network connectivity reorganization at the earliest stages of MS have not been investigated yet. Objective: To combine static and dynamic analysis of resting state (RS) functional connectivity (FC) to identify mechanisms of clinical dysfunction and recovery occurring in clinically isolated syndrome (CIS) patients. Methods: RS functional magnetic resonance imaging (fMRI) and clinical data were prospectively acquired from 50 CIS patients and 13 healthy controls (HC) at baseline, month 12 and month 24. Between-group differences and longitudinal evolution of network FC were analysed across 41 functionally relevant networks. Results: At follow-up, 47 patients developed MS. Disability remained stable (and relatively low). CIS and HC exhibited two recurring RS FC states (states 1 and 2, showing low and high internetwork connectivity, respectively). At baseline, patients showed reduced state 2 connectivity strength in the default-mode and cerebellar networks, and no differences in global dynamism versus HC. A selective FC reduction in networks affected by the clinical attack was also detected. At follow-up, increased state 2 connectivity strength and global connectivity dynamism was observed in patients versus HC. Conclusion: Longitudinal FC modifications occurring relatively early in the course of multiple sclerosis may represent a protective mechanism contributing to preserve clinical function over time. © The Author(s), 2019.

Background: The features of functional network connectivity reorganization at the earliest stages of MS have not been investigated yet. Objective: To combine static and dynamic analysis of resting state (RS) functional connectivity (FC) to identify mechanisms of clinical dysfunction and recovery occurring in clinically isolated syndrome (CIS) patients. Methods: RS functional magnetic resonance imaging (fMRI) and clinical data were prospectively acquired from 50 CIS patients and 13 healthy controls (HC) at baseline, month 12 and month 24. Between-group differences and longitudinal evolution of network FC were analysed across 41 functionally relevant networks. Results: At follow-up, 47 patients developed MS. Disability remained stable (and relatively low). CIS and HC exhibited two recurring RS FC states (states 1 and 2, showing low and high internetwork connectivity, respectively). At baseline, patients showed reduced state 2 connectivity strength in the default-mode and cerebellar networks, and no differences in global dynamism versus HC. A selective FC reduction in networks affected by the clinical attack was also detected. At follow-up, increased state 2 connectivity strength and global connectivity dynamism was observed in patients versus HC. Conclusion: Longitudinal FC modifications occurring relatively early in the course of multiple sclerosis may represent a protective mechanism contributing to preserve clinical function over time. © The Author(s), 2019.

Background: The understanding of disease pathophysiology is pivotal for tailored treatments. The spatial distribution of brain damage relies on the regional antigen expression and the local balance of susceptibility and protective elements. Objective: As proof-of-concept, we investigated the spatial association between brain damage and gene expression in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD). Methods: In this multicenter cross-sectional study, 90 AQP4 + NMOSD patients and 94 age-matched healthy controls underwent a brain magnetic resonance imaging (MRI). We used T2-hyperintense lesion probability maps and white/gray matter atrophy as proxies of inflammation and neurodegeneration. The association with the expression of 266 candidate genes was obtained with the Multimodal Environment for Neuroimaging and Genomic Analysis platform. A functional-enrichment analysis investigated overrepresented biological processes. Results: In AQP4 + NMOSD, T2-hyperintense lesions were mainly periventricular; atrophy mostly involved the visual pathway. The expression of AQP4 and complement (C4a and C5) was associated with both inflammation and neurodegeneration. Complement activation and regulation/uptake of the insulin-like growth factor were the most relevant enriched pathways. Nonspecific pathways related to DNA synthesis and repair were associated with brain atrophy. Conclusions: Quantitative MRI and gene expression atlas identified the key elements of AQP4 + NMOSD pathophysiology. This analysis could help in understanding the pathophysiology of antibody-mediated autoimmune disorders. © The Author(s), 2024.

Background: The understanding of disease pathophysiology is pivotal for tailored treatments. The spatial distribution of brain damage relies on the regional antigen expression and the local balance of susceptibility and protective elements. Objective: As proof-of-concept, we investigated the spatial association between brain damage and gene expression in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD). Methods: In this multicenter cross-sectional study, 90 AQP4 + NMOSD patients and 94 age-matched healthy controls underwent a brain magnetic resonance imaging (MRI). We used T2-hyperintense lesion probability maps and white/gray matter atrophy as proxies of inflammation and neurodegeneration. The association with the expression of 266 candidate genes was obtained with the Multimodal Environment for Neuroimaging and Genomic Analysis platform. A functional-enrichment analysis investigated overrepresented biological processes. Results: In AQP4 + NMOSD, T2-hyperintense lesions were mainly periventricular; atrophy mostly involved the visual pathway. The expression of AQP4 and complement (C4a and C5) was associated with both inflammation and neurodegeneration. Complement activation and regulation/uptake of the insulin-like growth factor were the most relevant enriched pathways. Nonspecific pathways related to DNA synthesis and repair were associated with brain atrophy. Conclusions: Quantitative MRI and gene expression atlas identified the key elements of AQP4 + NMOSD pathophysiology. This analysis could help in understanding the pathophysiology of antibody-mediated autoimmune disorders. © The Author(s), 2024.