Publications by authors named "Maria A Rocca"

274 Publications

Effects of Fingolimod and Natalizumab on Brain T1-/T2-Weighted and Magnetization Transfer Ratios: a 2-Year Study.

Neurotherapeutics 2021 Jan 22. Epub 2021 Jan 22.

Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Fingolimod and natalizumab significantly reduce disease activity in relapsing-remitting multiple sclerosis (RRMS) and could promote tissue repair and neuroprotection. The ratio between conventional T1- and T2-weighted sequences (T1w/T2w-ratio) and magnetization transfer ratio (MTR) allow to quantify brain microstructural tissue abnormalities. Here, we compared fingolimod and natalizumab effects on brain T1w/T2w-ratio and MTR in RRMS over 2 years of treatment. RRMS patients starting fingolimod (n = 25) or natalizumab (n = 30) underwent 3T brain MRI scans at baseline (T0), month 6 (M6), month 12 (M12), and month 24 (M24). White matter (WM) lesions, normal-appearing (NA) WM, and gray matter (GM) T1w/T2w-ratio and MTR were estimated and compared between groups using linear mixed models. No baseline demographic, clinical, and MRI difference was found between groups. In natalizumab patients, lesion T1w/T2w-ratio and MTR significantly increased at M6 vs. T0 (p ≤ 0.035) and decreased at subsequent timepoints (p ≤ 0.037). In fingolimod patients, lesion T1w/T2w-ratio increased at M12 vs. T0 (p = 0.010), while MTR gradually increased at subsequent timepoints vs. T0 (p ≤ 0.027). Natalizumab stabilized NAWM and GM T1w/T2w-ratio and MTR. In fingolimod patients, NAWM T1w/T2w-ratio and MTR significantly increased at M24 vs. M12 (p ≤ 0.001). A significant GM T1w/T2w-ratio decrease at M6 vs. T0 (p = 0.014) and increase at M24 vs. M6 (p = 0.008) occurred, whereas GM MTR was significantly higher at M24 vs. previous timepoints (p ≤ 0.017) with significant between-group differences (p ≤ 0.034). Natalizumab may promote an early recovery of lesional damage and prevent microstructural damage accumulation in NAWM and GM during the first 2 years of treatment. Fingolimod enhances tissue damage recovery being visible after 6 months in lesions and after 2 years in NAWM and GM.
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http://dx.doi.org/10.1007/s13311-020-00997-1DOI Listing
January 2021

Association of Gray Matter Atrophy Patterns with Clinical Phenotype and Progression in Multiple Sclerosis.

Neurology 2021 01 13. Epub 2021 Jan 13.

Massimo Filippi, MD, Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, and Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy and Vita-Salute San Raffaele University, Milan, Italy.

Objectives: Grey matter (GM) involvement is clinically relevant in multiple sclerosis (MS). Using source-based morphometry (SBM), we characterized GM atrophy and its 1-year evolution across different MS phenotypes.

Methods: Clinical and MRI data were obtained at 8 European sites from 170 healthy controls (HCs) and 398 MS patients (34 clinically isolated syndromes [CIS], 226 relapsing-remitting [RR], 95 secondary progressive [SP] and 43 primary progressive [PP] MS). Fifty-seven HC and 144 MS underwent 1-year follow-up. Baseline GM loss, atrophy progression and correlations with disability and 1-year clinical worsening were assessed.

Results: SBM identified 26 cerebellar, subcortical, sensory, motor and cognitive GM components. GM atrophy was found in MS HC in almost all components (p=range<0.001-0.04). Compared to HCs, CIS patients showed circumscribed subcortical, cerebellar, temporal and salience GM atrophy, while RRMS patients exhibited widespread GM atrophy. Cerebellar, subcortical, sensorimotor, salience and fronto-parietal GM atrophy was found in PPMS patients HCs, and SPMS RRMS. At 1-year, 21 (15%) patients had clinically worsened. GM atrophy progressed in MS in subcortical, cerebellar, sensorimotor, and fronto-temporo-parietal components. Baseline higher disability was associated (R=0.65) with baseline lower normalized brain volume (beta=-0.13, p=0.001), greater sensorimotor GM atrophy (beta=-0.12, p=0.002) and longer disease duration (beta=0.09, p=0.04). Baseline normalized GM volume (odds ratio=0.98, p=0.008) and cerebellar GM atrophy (odds ratio=0.40, p=0.01) independently predicted clinical worsening (area-under-the-curve=0.83).

Conclusion: GM atrophy differed across disease phenotypes and progressed at 1-year in MS. In addition to global atrophy measures, sensorimotor and cerebellar GM atrophy explained baseline disability and clinical worsening.
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http://dx.doi.org/10.1212/WNL.0000000000011494DOI Listing
January 2021

Mind the gap: from neurons to networks to outcomes in multiple sclerosis.

Nat Rev Neurol 2021 Mar 12;17(3):173-184. Epub 2021 Jan 12.

National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, London, UK.

MRI studies have provided valuable insights into the structure and function of neural networks, particularly in health and in classical neurodegenerative conditions such as Alzheimer disease. However, such work is also highly relevant in other diseases of the CNS, including multiple sclerosis (MS). In this Review, we consider the effects of MS pathology on brain networks, as assessed using MRI, and how these changes to brain networks translate into clinical impairments. We also discuss how this knowledge can inform the targeting of MS treatments and the potential future directions for research in this area. Studying MS is challenging as its pathology involves neurodegenerative and focal inflammatory elements, both of which could disrupt neural networks. The disruption of white matter tracts in MS is reflected in changes in network efficiency, an increasingly random grey matter network topology, relative cortical disconnection, and both increases and decreases in connectivity centred around hubs such as the thalamus and the default mode network. The results of initial longitudinal studies suggest that these changes evolve rather than simply increase over time and are linked with clinical features. Studies have also identified a potential role for treatments that functionally modify neural networks as opposed to altering their structure.
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http://dx.doi.org/10.1038/s41582-020-00439-8DOI Listing
March 2021

Neurite density explains cortical T1-weighted/T2-weighted ratio in multiple sclerosis.

J Neurol Neurosurg Psychiatry 2021 Jan 12. Epub 2021 Jan 12.

Department of Anatomy & Neurosciences, Amsterdam UMC, Location VU University Medical Center, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1136/jnnp-2020-324391DOI Listing
January 2021

Identifying the Distinct Cognitive Phenotypes in Multiple Sclerosis.

JAMA Neurol 2021 Jan 4. Epub 2021 Jan 4.

Section Neurosciences, Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, University of Florence, Florence, Italy.

Importance: Cognitive impairment is a common and disabling feature of multiple sclerosis (MS), but a precise characterization of cognitive phenotypes in patients with MS is lacking.

Objectives: To identify cognitive phenotypes in a clinical cohort of patients with MS and to characterize their clinical and magnetic resonance imaging (MRI) features.

Design, Setting, And Participants: This multicenter cross-sectional study consecutively screened clinically stable patients with MS and healthy control individuals at 8 MS centers in Italy from January 1, 2010, to October 31, 2019. Patients with MS and healthy control individuals who were not using psychoactive drugs and had no history of other neurological or medical disorders, learning disability, severe head trauma, and alcohol or drug abuse were enrolled.

Main Outcomes And Measures: Participants underwent a neurological examination and a cognitive evaluation with the Rao Brief Repeatable Battery and Stroop Color and Word Test. A subgroup of participants also underwent a brain MRI examination. Latent profile analysis was used on cognitive test z scores to identify cognitive phenotypes. Linear regression and mixed-effects models were used to define clinical and MRI features of each phenotype.

Results: A total of 1212 patients with MS (mean [SD] age, 41.1 [11.1] years; 784 women [64.7%]) and 196 healthy control individuals (mean [SD] age, 40.4 [8.6] years; 130 women [66.3%]) were analyzed in this study. Five cognitive phenotypes were identified: preserved cognition (n = 235 patients [19.4%]), mild-verbal memory/semantic fluency (n = 362 patients [29.9%]), mild-multidomain (n = 236 patients [19.5%]), severe-executive/attention (n = 167 patients [13.8%]), and severe-multidomain (n = 212 patients [17.5%]) involvement. Patients with preserved cognition and mild-verbal memory/semantic fluency were younger (mean [SD] age, 36.5 [9.8] years and 38.2 [11.1] years) and had shorter disease duration (mean [SD] 8.0 [7.3] years and 8.3 [7.6] years) compared with patients with mild-multidomain (mean [SD] age, 42.6 [11.2] years; mean [SD] disease duration, 12.8 [9.6] years; P < .001), severe-executive/attention (mean [SD] age, 42.9 [11.7] years; mean [SD] disease duration, 12.2 [9.5] years; P < .001), and severe-multidomain (mean [SD] age, 44.0 [11.0] years; mean [SD] disease duration, 13.3 [10.2] years; P < .001) phenotypes. Severe cognitive phenotypes prevailed in patients with progressive MS. At MRI evaluation, compared with those with preserved cognition, patients with mild-verbal memory/semantic fluency exhibited decreased mean (SE) hippocampal volume (5.42 [0.68] mL vs 5.13 [0.68] mL; P = .04), patients with the mild-multidomain phenotype had decreased mean (SE) cortical gray matter volume (687.69 [35.40] mL vs 662.59 [35.48] mL; P = .02), patients with severe-executive/attention had higher mean (SE) T2-hyperintense lesion volume (51.33 [31.15] mL vs 99.69 [34.07] mL; P = .04), and patients with the severe-multidomain phenotype had extensive brain damage, with decreased volume in all the brain structures explored, except for nucleus pallidus, amygdala and caudate nucleus.

Conclusions And Relevance: This study found that by defining homogeneous and clinically meaningful phenotypes, the limitations of the traditional dichotomous classification in MS can be overcome. These phenotypes can represent a more meaningful measure of the cognitive status of patients with MS and can help define clinical disability, support clinicians in treatment choices, and tailor cognitive rehabilitation strategies.
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http://dx.doi.org/10.1001/jamaneurol.2020.4920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783596PMC
January 2021

Effect of cognitive reserve on structural and functional MRI measures in healthy subjects: a multiparametric assessment.

J Neurol 2021 Jan 2. Epub 2021 Jan 2.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: Cognitive reserve (CR) contributes to inter-individual variability of cognitive performance and to preserve cognitive functioning facing aging and brain damage. However, brain anatomical and functional substrates of CR still need to be fully explored in young healthy subjects (HS). By evaluating a relatively large cohort of young HS, we investigated the associations between CR and structural and functional magnetic resonance imaging (MRI) measures in early adulthood.

Methods: A global Cognitive Reserve Index (CRI), combining intelligence quotient, leisure activities and education, was measured from 77 HS and its brain anatomical and functional substrates were evaluated through a multiparametric MRI approach. Substrates of the three subdomains (cognitive/social/physical) of leisure activities were also explored.

Results: Higher global and subdomain CRIs were associated with higher gray matter volume of brain regions involved in motor and cognitive functions, such as the right (R) supplementary motor area, left (L) middle frontal gyrus and L cerebellum. No correlation with measures of white matter (WM) integrity was found. Higher global and subdomains CRIs were associated with lower resting-state functional connectivity (RS FC) of L postcentral gyrus and R insula in sensorimotor network, L postcentral gyrus in salience network and R cerebellum in the executive-control network. Moreover, several CRIs were also associated with higher RS FC of R cuneus in default-mode network.

Conclusions: CR modulates structure and function of several brain motor and cognitive networks responsible for complex cognitive functioning already in young HS. CR could promote optimization of the recruitment of brain networks.
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http://dx.doi.org/10.1007/s00415-020-10331-6DOI Listing
January 2021

Quantitative MRI adds to neuropsychiatric lupus diagnostics.

Rheumatology (Oxford) 2020 Dec 26. Epub 2020 Dec 26.

Università Vita-Salute San Raffaele.

Objective: Attributing neuropsychiatric manifestations to SLE is often challenging. Brain white matter lesions are frequent in SLE at MRI, but their diagnostic role is unclear. Here, we assessed whether white matter lesions count, volume and distribution measurement can help in the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE).

Methods: Brain dual-echo and 3D T1-weighted sequences were acquired from 32 patients with SLE and 32 healthy controls with a 3 T-scanner and employed to derive T2-hyperintense lesion volume (T2LV), number (T2LN) and probability maps (LPM) using a semi-automatic local thresholding segmentation technique. NPSLE was classified as per the ACR nomenclature, the Italian Society for Rheumatology algorithm and by clinical impression. Clinical descriptors including the SLE International Collaborating Clinics/ACR damage index (SDI) were also recorded.

Results: Higher T2LV were observed in SLE vs healthy controls (P < 0.001) and in NPSLE vs other SLE (P =0.006). Patients with NPSLE also had higher T2LN (P =0.003) compared with other SLE. In SLE, T2LPM revealed a high prevalence of lesions in the splenium of the corpus callosum, right superior longitudinal fasciculus and right corona radiata. T2LV and T2LN correlated with SLE duration (rho = 0.606; P <0.001 and rho = 0.483; P =0.005, respectively) and age (rho = 0.478; P =0.006 and rho = 0.362; P = 0.042, respectively). T2LV also correlated with SDI (rho = 0.352; P =0.048). SLE patients with fatigue had lower T2LN (P =0.038) compared with patients without fatigue. Thresholds of T2LV ≥ 0.423 cm3 or of T2LN ≥ 12 were associated with definite NPSLE and improved the classification of patients with possible NPSLE per clinical impression.

Conclusion: Brain white matter lesions (WML) quantitation adds to NPSLE diagnostics.
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http://dx.doi.org/10.1093/rheumatology/keaa779DOI Listing
December 2020

Diagnosis of Progressive Multiple Sclerosis From the Imaging Perspective: A Review.

JAMA Neurol 2020 Dec 14. Epub 2020 Dec 14.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Istituto di Ricovero e di Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.

Importance: Although magnetic resonance imaging (MRI) is useful for monitoring disease dissemination in space and over time and excluding multiple sclerosis (MS) mimics, there has been less application of MRI to progressive MS, including diagnosing primary progressive (PP) MS and identifying patients with relapsing-remitting (RR) MS who are at risk of developing secondary progressive (SP) MS. This review addresses clinical application of MRI for both diagnosis and prognosis of progressive MS.

Observations: Although nonspecific, some spinal cord imaging features (diffuse abnormalities and lesions involving gray matter [GM] and ≥2 white matter columns) are typical of PPMS. In patients with PPMS and those with relapse-onset MS, location of lesions in critical central nervous system regions (spinal cord, infratentorial regions, and GM) and MRI-detected high inflammatory activity in the first years after diagnosis are risk factors for long-term disability and future progressive disease course. These measures are evaluable in clinical practice. In patients with established MS, GM involvement and neurodegeneration are associated with accelerated clinical worsening. Subpial demyelination and slowly expanding lesions are novel indicators of progressive MS.

Conclusions And Relevance: Diagnosis of PPMS is more challenging than diagnosis of RRMS. No qualitative clinical, immunological, histopathological, or neuroimaging features differentiate PPMS and SPMS; both are characterized by imaging findings reflecting neurodegeneration and are also impacted by aging and comorbidities. Unmet diagnostic needs include identification of MRI markers capable of distinguishing PPMS from RRMS and predicting the evolution of RRMS to SPMS. Integration of multiple parameters will likely be essential to achieve these aims.
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http://dx.doi.org/10.1001/jamaneurol.2020.4689DOI Listing
December 2020

In vivo gradients of thalamic damage in paediatric multiple sclerosis: a window into pathology.

Brain 2021 Feb;144(1):186-197

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

The thalamus represents one of the first structures affected by neurodegenerative processes in multiple sclerosis. A greater thalamic volume reduction over time, on its CSF side, has been described in paediatric multiple sclerosis patients. However, its determinants and the underlying pathological changes, likely occurring before this phenomenon becomes measurable, have never been explored. Using a multiparametric magnetic resonance approach, we quantified, in vivo, the different processes that can involve the thalamus in terms of focal lesions, microstructural damage and atrophy in paediatric multiple sclerosis patients and their distribution according to the distance from CSF/thalamus interface and thalamus/white matter interface. In 70 paediatric multiple sclerosis patients and 26 age- and sex-matched healthy controls, we tested for differences in thalamic volume and quantitative MRI metrics-including fractional anisotropy, mean diffusivity and T1/T2-weighted ratio-in the whole thalamus and in thalamic white matter, globally and within concentric bands originating from CSF/thalamus interface. In paediatric multiple sclerosis patients, the relationship of thalamic abnormalities with cortical thickness and white matter lesions was also investigated. Compared to healthy controls, patients had significantly increased fractional anisotropy in whole thalamus (f2 = 0.145; P = 0.03), reduced fractional anisotropy (f2 = 0.219; P = 0.006) and increased mean diffusivity (f2 = 0.178; P = 0.009) in thalamic white matter and a trend towards a reduced thalamic volume (f2 = 0.027; P = 0.058). By segmenting the whole thalamus and thalamic white matter into concentric bands, in paediatric multiple sclerosis we detected significant fractional anisotropy abnormalities in bands nearest to CSF (f2 = 0.208; P = 0.002) and in those closest to white matter (f2 range = 0.183-0.369; P range = 0.010-0.046), while we found significant mean diffusivity (f2 range = 0.101-0.369; P range = 0.018-0.042) and T1/T2-weighted ratio (f2 = 0.773; P = 0.001) abnormalities in thalamic bands closest to CSF. The increase in fractional anisotropy and decrease in mean diffusivity detected at the CSF/thalamus interface correlated with cortical thickness reduction (r range = -0.27-0.34; P range = 0.004-0.028), whereas the increase in fractional anisotropy detected at the thalamus/white matter interface correlated with white matter lesion volumes (r range = 0.24-0.27; P range = 0.006-0.050). Globally, our results support the hypothesis of heterogeneous pathological processes, including retrograde degeneration from white matter lesions and CSF-mediated damage, leading to thalamic microstructural abnormalities, likely preceding macroscopic tissue loss. Assessing thalamic microstructural changes using a multiparametric magnetic resonance approach may represent a target to monitor the efficacy of neuroprotective strategies early in the disease course.
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http://dx.doi.org/10.1093/brain/awaa379DOI Listing
February 2021

COVID-19 in cladribine-treated relapsing-remitting multiple sclerosis patients: a monocentric experience.

J Neurol 2020 Nov 20. Epub 2020 Nov 20.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

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http://dx.doi.org/10.1007/s00415-020-10309-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677903PMC
November 2020

Occurrence and microstructural features of slowly expanding lesions on fingolimod or natalizumab treatment in multiple sclerosis.

Mult Scler 2020 Nov 13:1352458520969105. Epub 2020 Nov 13.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy/Vita-Salute San Raffaele University, Milan, Italy.

Background: In multiple sclerosis (MS), up to 57% of white matter lesions are chronically active. These slowly expanding lesions (SELs) contribute to disability progression.

Objective: The aim of this study is to compare fingolimod and natalizumab effects on progressive linearly enlarging lesions (i.e. SELs), a putative biomarker of smouldering inflammation.

Methods: Relapsing-remitting MS patients starting fingolimod ( = 24) or natalizumab ( = 28) underwent 3T brain magnetic resonance imaging (MRI) at baseline, months 6, 12 and 24. SELs were identified among baseline-visible lesions showing ⩾ 12.5% of annual increase, calculated by linearly fitting the Jacobian of the nonlinear deformation field between timepoints obtained combining - and -weighted scans. SEL burden, magnetization transfer ratio (MTR) and signal intensity were compared using linear models.

Results: The prevalences of fingolimod (75%) and natalizumab patients (46%) with ⩾ 1 SEL were not significantly different (adjusted- = 0.08). Fingolimod group had higher SEL number and volume (adjusted- ⩽ 0.047, not false discovery rate (FDR) survived). In both groups, SELs versus non-SELs showed lower MTR and signal intensity (adjusted- ⩽ 0.01, FDR-survived). Longitudinally, non-SEL MTR increased in both treatment groups (adjusted- ⩽ 0.005, FDR-survived). signal intensity decreased in SELs with both treatments (adjusted- ⩽ 0.049, FDR-survived in fingolimod group) and increased in natalizumab non-SELs (adjusted- = 0.03, FDR-survived).

Conclusion: The effects of natalizumab and fingolimod on SEL occurrence seem modest, with natalizumab being slightly more effective. Both treatments may promote reparative mechanisms in stable or chronic inactive lesions.
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http://dx.doi.org/10.1177/1352458520969105DOI Listing
November 2020

Deep Learning on Conventional Magnetic Resonance Imaging Improves the Diagnosis of Multiple Sclerosis Mimics.

Invest Radiol 2021 Apr;56(4):252-260

From the Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience.

Objectives: The aims of this study were to present a deep learning approach for the automated classification of multiple sclerosis and its mimics and compare model performance with that of 2 expert neuroradiologists.

Materials And Methods: A total of 268 T2-weighted and T1-weighted brain magnetic resonance imagin scans were retrospectively collected from patients with migraine (n = 56), multiple sclerosis (n = 70), neuromyelitis optica spectrum disorders (n = 91), and central nervous system vasculitis (n = 51). The neural network architecture, trained on 178 scans, was based on a cascade of 4 three-dimensional convolutional layers, followed by a fully dense layer after feature extraction. The ability of the final algorithm to correctly classify the diseases in an independent test set of 90 scans was compared with that of the neuroradiologists.

Results: The interrater agreement was 84.9% (Cohen κ = 0.78, P < 0.001). In the test set, deep learning and expert raters reached the highest diagnostic accuracy in multiple sclerosis (98.8% vs 72.8%, P < 0.001, for rater 1; and 81.8%, P < 0.001, for rater 2) and the lowest in neuromyelitis optica spectrum disorders (88.6% vs 4.4%, P < 0.001, for both raters), whereas they achieved intermediate values for migraine (92.2% vs 53%, P = 0.03, for rater 1; and 64.8%, P = 0.01, for rater 2) and vasculitis (92.1% vs 54.6%, P = 0.3, for rater 1; and 45.5%, P = 0.2, for rater 2). The overall performance of the automated method exceeded that of expert raters, with the worst misdiagnosis when discriminating between neuromyelitis optica spectrum disorders and vasculitis or migraine.

Conclusions: A neural network performed better than expert raters in terms of accuracy in classifying white matter disorders from magnetic resonance imaging and may help in their diagnostic work-up.
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http://dx.doi.org/10.1097/RLI.0000000000000735DOI Listing
April 2021

Resting state network functional connectivity abnormalities in systemic lupus erythematosus: correlations with neuropsychiatric impairment.

Mol Psychiatry 2020 Oct 13. Epub 2020 Oct 13.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Neuropsychiatric manifestations are highly prevalent in systemic lupus erythematosus (SLE)-patients. We aimed to unravel the substrates of these manifestations by investigating abnormalities of resting state (RS) functional connectivity (FC) and their correlations with neuropsychiatric variables in SLE-patients. Thirty-two SLE-patients and 32 age- and sex-matched healthy controls (HC) underwent brain 3T RS fMRI. Neuropsychological assessment was performed for all SLE-patients. The main large-scale cognitive and psychiatric functional networks were derived and between-group comparisons and correlations with neuropsychological measures were performed. Compared to HC, SLE-patients exhibited increased RS FC in the right middle cingulate cortex and decreased RS FC in the left precuneus within default-mode network (DMN). They also showed increased RS FC in the left cerebellar crus I and left posterior cingulate cortex, and decreased RS FC in the left angular gyrus within working-memory networks (WMN). Compared to HC, SLE-patients exhibited increased RS FC in the left insular cortex and decreased RS FC in the right anterior cingulate cortex within salience network (SN), as well as decreased RS FC in the right middle frontal gyrus within executive-control network (ECN). Correlation analysis indicated a maladaptive role for left angular gyrus and cerebellar RS FC abnormalities in WMN, affecting memory and executive functions; and for precuneus and insular abnormalities in DMN and SN for psychiatric symptoms. Cingulate cortex modifications within DMN and SN correlated with better memory and global cognitive performance. Significant RS FC alterations in relevant cognitive and psychiatric networks occur in SLE-patients and participate in the pathophysiology of neuropsychiatric symptoms.
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http://dx.doi.org/10.1038/s41380-020-00907-zDOI Listing
October 2020

MRI correlates of clinical disability and hand-motor performance in multiple sclerosis phenotypes.

Mult Scler 2020 Sep 14:1352458520958356. Epub 2020 Sep 14.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: Hand-motor impairment affects a large proportion of multiple sclerosis (MS) patients; however, its substrates are still poorly understood.

Objectives: To investigate the association between global disability, hand-motor impairment, and alterations in motor-relevant structural and functional magnetic resonance imaging (MRI) networks in MS patients with different clinical phenotypes.

Methods: One hundred thirty-four healthy controls (HC) and 364 MS patients (250 relapsing-remitting MS (RRMS) and 114 progressive MS (PMS)) underwent Expanded Disability Status Scale (EDSS) rating, nine-hole peg test (9HPT), and electronic finger tapping rate (EFTR). Structural and resting state (RS) functional MRI scans were used to perform a source-based morphometry on gray matter (GM) components, to analyze white matter (WM) tract diffusivity indices and to perform a RS seed-based approach from the primary motor cortex involved in hand movement (hand-motor cortex). Random forest analyses identified the predictors of clinical impairment.

Result: In RRMS, global measures of atrophy and lesions together with measures of structural damage of motor-related regions predicted EDSS (out-of-bag (OOB)- = 0.19, -range = <0.001-0.04), z9HPT (right: OOB- = 0.14; left: OOB- = 0.24, -range = <0.001-0.03). No RS functional connectivity (FC) abnormalities were identified in RRMS models. In PMS, cerebellar and sensorimotor regions atrophy, cerebellar peduncles integrity and increased RS FC between left hand-motor cortex and right inferior frontal gyrus predicted EDSS (OBB- = 0.16, -range = 0.02-0.04).

Conclusion: In RRMS, only measures of structural damage contribute to explain motor impairment, whereas both structural and functional MRI measures predict clinical disability in PMS. A multiparametric MRI approach could be relevant to investigate hand-motor impairment in different MS phenotypes.
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http://dx.doi.org/10.1177/1352458520958356DOI Listing
September 2020

Extent and characteristics of carotid plaques and brain parenchymal loss in asymptomatic patients with no indication for revascularization.

Int J Cardiol Heart Vasc 2020 Oct 20;30:100619. Epub 2020 Aug 20.

Vita-Salute University and San Raffaele Hospital, Milan, Italy.

Background And Aims: Extent of subclinical atherosclerosis has been associated with brain parenchymal loss in community-dwelling aged subjects. Identification of patient-related and plaque-related markers could identify subjects at higher risk of brain atrophy, independent of cerebrovascular accidents. Aim of the study was to investigate the relation between extent and characteristics of carotid plaques and brain atrophy in asymptomatic patients with no indication for revascularization.

Methods And Results: Sixty-four patients (aged 69 ± 8 years, 45% females) with carotid stenosis <70% based on Doppler flow velocity were enrolled in the study. Potential causes of cerebral damage other than atherosclerosis, including history of atrial fibrillation, heart failure, previous cardiac or neurosurgery and neurological disorders were excluded. All subjects underwent carotid computed tomography angiography, contrast enhanced ultrasound for assessment of plaque neovascularization and brain magnetic resonance imaging for measuring brain volumes. On multivariate regression analysis, age and fibrocalcific plaques were independently associated with lower total brain volumes (β = -3.13 and β = -30.7, both p < 0.05). Fibrocalcific plaques were also independently associated with lower gray matter (GM) volumes (β = -28.6, p = 0.003). On the other hand, age and extent of carotid atherosclerosis were independent predictors of lower white matter (WM) volumes.

Conclusions: WM and GM have different susceptibility to processes involved in parenchymal loss. Contrary to common belief, our results show that presence of fibrocalcific plaques is associated with brain atrophy.
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http://dx.doi.org/10.1016/j.ijcha.2020.100619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452655PMC
October 2020

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

Radiology 2020 10 28;297(1):154-163. Epub 2020 Jul 28.

From the Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience (L.C., P.V., M.F., M.A.R.) and Neurology Unit (L.C., V.M., M.F., M.A.R.), IRCCS San Raffaele Scientific Institute, via Olgettina 60, Milan 20132, Italy; Vita-Salute San Raffaele University, Milan, Italy (L.C., M.F.); and Clinic of Neurology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia (S.M., J.D.).

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 ( value range, .007-.04), with a higher percentage lesion extent in the gray matter ( < .001). Atrophy colocalized with focal cord lesions and correlated with pyramidal subscore ( ranging from -0.53 to -0.40; < .001) and sensitive subscore ( ranging from -0.48 to -0.46; = .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
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http://dx.doi.org/10.1148/radiol.2020192664DOI Listing
October 2020

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

Mult Scler 2020 Jul 16:1352458520941493. Epub 2020 Jul 16.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurophysiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy/Vita-Salute San Raffaele University, Milan, Italy.

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 ( = 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 ( = 0.009-0.013) and reduced T1/T2-weighted ratio ( = 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 ( = 0.001-0.043) in periventricular bands, increased mean ( < 0.001), radial ( < 0.001-0.004), and axial diffusivity ( = 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.
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http://dx.doi.org/10.1177/1352458520941493DOI Listing
July 2020

Longitudinal cortical thinning progression differs across multiple sclerosis phenotypes and is clinically relevant: A multicentre study.

Mult Scler 2020 Jul 14:1352458520940548. Epub 2020 Jul 14.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: Longitudinal evolution of cortical thickness (CTh) in different MS phenotypes has been rarely studied.

Aim: To investigate the regional pattern and 1-year progression of cortical thinning in relapsing-remitting (RR) and progressive (P) MS.

Methods: 3T high-resolution T1-weighted magnetic resonance imaging (MRI) was obtained from 86 patients (75 RRMS, 11 PMS) and 34 healthy controls (HC) at three European sites at baseline and 1-year follow-up. Using FreeSurfer, baseline CTh between-group differences, longitudinal CTh changes and their correlations with clinical and MRI variables were assessed.

Results: Baseline frontal, parietal and sensorimotor atrophy was found in MS versus HC. Such pattern was driven by RRMS, while PMS showed additional parietal, insular and sensorimotor cortical atrophy versus RRMS. At 1-year versus baseline, additional frontal and temporal cortical thinning was detected in RRMS patients, while a widespread CTh reduction was found in PMS patients (significant at time-by-group interaction vs RRMS). In MS, baseline fronto-parietal atrophy correlated with more severe disability and higher lesion volume. Baseline inferior parietal CTh decrease and 1-year temporal cortical thinning correlated with more severe disability.

Conclusion: Parieto-temporal baseline CTh abnormalities and thinning pattern over time characterized the main MS clinical phenotypes and were associated with 1-year disability worsening.
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http://dx.doi.org/10.1177/1352458520940548DOI Listing
July 2020

Measurement of white matter fiber-bundle cross-section in multiple sclerosis using diffusion-weighted imaging.

Mult Scler 2020 Jul 14:1352458520938999. Epub 2020 Jul 14.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: When investigating white matter (WM) microstructure, the axonal fiber orientation should be considered. Constrained spherical deconvolution (CSD) is a diffusion-weighted imaging (DWI) method that estimates distribution of fibers within each imaging voxel.

Objective: To study fiber-bundle cross-section (FC) as measured by CSD in multiple sclerosis (MS) patients versus healthy controls (HCs).

Methods: DWI and three-dimensional (3D) T-weighted magnetic resonance imaging (MRI) were obtained from 45 MS patients and 45 HCs. We applied fixel-based morphometry analysis to assess differences of FC in MS against HCs and voxel-based analysis of fractional anisotropy (FA).

Results: We found a significant widespread reduction of WM FC in MS compared to HCs. The decrease in FA was less extensive, mainly located in regions with high lesion occurrence such as the periventricular WM and the corpus callosum. Progressive MS patients showed a significant FC reduction in the right anterior cingulum, bilateral cerebellum, and in several mesencephalic and diencephalic regions compared to relapsing-remitting MS patients.

Conclusion: The CSD method can be applied in MS for a fiber-specific study of WM microstructure and quantification of FC. Fixel-based findings offered greater anatomical specificity and biological interpretability by identifying tract-specific differences and allowed substantial abnormalities to be detected.
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http://dx.doi.org/10.1177/1352458520938999DOI Listing
July 2020

Cognitive impairment in benign multiple sclerosis: a multiparametric structural and functional MRI study.

J Neurol 2020 Dec 2;267(12):3508-3517. Epub 2020 Jul 2.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Introduction: The substrates of cognitive impairment in benign MS (BMS) still need to be identified. We investigated whether cognitive impairment in BMS patients is associated with specific patterns of brain structural and functional abnormalities.

Methods: Thirty-seven BMS patients (EDSS score ≤ 3.0 and disease duration ≥ 15 years) and 50 healthy controls (HC) were studied. In BMS patients, a cognitive impairment index (CII) was derived. Gray matter (GM) volumes, white matter (WM) fractional anisotropy (FA) and resting-state (RS) functional connectivity (FC) were investigated for whole-brain relevant regions (cortex, lobes, subcortical nuclei, fiber tracts) and functional networks. Univariate and multivariate analyses identified independent predictors of cognitive impairment.

Results: In BMS, median CII was 9 (IQR: 4-16). Compared to HC, BMS patients showed reduced WM FA, GM atrophy and increased RS FC in fronto-temporo-parietal regions. At multivariate analysis, percentage of T2-lesions of the corpus callosum, reduced posterior corona radiata (PCR) FA and caudate nucleus atrophy were independent predictors of worse CII. A multivariate model identified reduced PCR FA (R = 0.39; p = 0.001) as the only predictor of CII.

Conclusions: Cognitive impairment in BMS is associated with structural damage of relevant brain areas. WM damage of parietal regions was the predominant predictor of worse cognitive performance in these patients.
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http://dx.doi.org/10.1007/s00415-020-10025-zDOI Listing
December 2020

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

Radiology 2020 09 23;296(3):605-615. Epub 2020 Jun 23.

From the Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience (R.B., E.P., A.M., L.C., P.P., E.D.M., M.F., M.A.R.), Neurology Unit (R.B., L.C., P.P., E.D.M., M.F., M.A.R.), and Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, Milan 20132, Italy; and Vita-Salute San Raffaele University, Milan, Italy (R.B., L.C., E.D.M., M.F.).

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 ( = 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 ( = 0.51). The independent predictors of EDSS score in PMS were cervical spinal cord GM CSA and brain GM volume ( = 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 mm 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 See also the editorial by Zivadinov and Bergsland in this issue.
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http://dx.doi.org/10.1148/radiol.2020200430DOI Listing
September 2020

Multiple sclerosis lesions in motor tracts from brain to cervical cord: spatial distribution and correlation with disability.

Brain 2020 07;143(7):2089-2105

NeuroPoly Lab, Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, Canada.

Despite important efforts to solve the clinico-radiological paradox, correlation between lesion load and physical disability in patients with multiple sclerosis remains modest. One hypothesis could be that lesion location in corticospinal tracts plays a key role in explaining motor impairment. In this study, we describe the distribution of lesions along the corticospinal tracts from the cortex to the cervical spinal cord in patients with various disease phenotypes and disability status. We also assess the link between lesion load and location within corticospinal tracts, and disability at baseline and 2-year follow-up. We retrospectively included 290 patients (22 clinically isolated syndrome, 198 relapsing remitting, 39 secondary progressive, 31 primary progressive multiple sclerosis) from eight sites. Lesions were segmented on both brain (T2-FLAIR or T2-weighted) and cervical (axial T2- or T2*-weighted) MRI scans. Data were processed using an automated and publicly available pipeline. Brain, brainstem and spinal cord portions of the corticospinal tracts were identified using probabilistic atlases to measure the lesion volume fraction. Lesion frequency maps were produced for each phenotype and disability scores assessed with Expanded Disability Status Scale score and pyramidal functional system score. Results show that lesions were not homogeneously distributed along the corticospinal tracts, with the highest lesion frequency in the corona radiata and between C2 and C4 vertebral levels. The lesion volume fraction in the corticospinal tracts was higher in secondary and primary progressive patients (mean = 3.6 ± 2.7% and 2.9 ± 2.4%), compared to relapsing-remitting patients (1.6 ± 2.1%, both P < 0.0001). Voxel-wise analyses confirmed that lesion frequency was higher in progressive compared to relapsing-remitting patients, with significant bilateral clusters in the spinal cord corticospinal tracts (P < 0.01). The baseline Expanded Disability Status Scale score was associated with lesion volume fraction within the brain (r = 0.31, P < 0.0001), brainstem (r = 0.45, P < 0.0001) and spinal cord (r = 0.57, P < 0.0001) corticospinal tracts. The spinal cord corticospinal tracts lesion volume fraction remained the strongest factor in the multiple linear regression model, independently from cord atrophy. Baseline spinal cord corticospinal tracts lesion volume fraction was also associated with disability progression at 2-year follow-up (P = 0.003). Our results suggest a cumulative effect of lesions within the corticospinal tracts along the brain, brainstem and spinal cord portions to explain physical disability in multiple sclerosis patients, with a predominant impact of intramedullary lesions.
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http://dx.doi.org/10.1093/brain/awaa162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364770PMC
July 2020

COVID-19 will change MS care forever - No.

Mult Scler 2020 09 22;26(10):1149-1151. Epub 2020 Jun 22.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurophysiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy/Vita-Salute San Raffaele University, Milan, Italy.

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http://dx.doi.org/10.1177/1352458520929971DOI Listing
September 2020

Identifying Progression in Multiple Sclerosis: New Perspectives.

Ann Neurol 2020 09 6;88(3):438-452. Epub 2020 Jul 6.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

The identification of progression in multiple sclerosis is typically retrospective. Given the profound burden of progressive multiple sclerosis, and the recent development of effective treatments for these patients, there is a need to establish measures capable of identifying progressive multiple sclerosis early in the disease course. Starting from recent pathological findings, this review assesses the state of the art of potential measures able to predict progressive multiple sclerosis. Future promising biomarkers that might shed light on mechanisms of progression are also discussed. Finally, expansion of the concept of progressive multiple sclerosis, by including an assessment of cognition, patient-reported outcomes, and comorbidities, is considered. ANN NEUROL 2020;88:438-452.
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http://dx.doi.org/10.1002/ana.25808DOI Listing
September 2020

Cortical axonal loss is associated with both gray matter demyelination and white matter tract pathology in progressive multiple sclerosis: Evidence from a combined MRI-histopathology study.

Mult Scler 2021 Mar 11;27(3):380-390. Epub 2020 May 11.

Department of Anatomy & Neurosciences, Amsterdam UMC, locatie VU University Medical Center, Amsterdam, The Netherlands/Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam, The Netherlands.

Background: Neuroaxonal degeneration is one of the hallmarks of clinical deterioration in progressive multiple sclerosis (PMS).

Objective: To elucidate the association between neuroaxonal degeneration and both local cortical and connected white matter (WM) tract pathology in PMS.

Methods: 3T magnetic resonance imaging (MRI) and cortical tissue blocks were collected from 16 PMS donors and 10 controls. Cortical neuroaxonal, myelin, and microglia densities were quantified histopathologically. From diffusion tensor MRI, fractional anisotropy, axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were quantified in normal-appearing white matter (NAWM) and white matter lesions (WML) of WM tracts connected to dissected cortical regions. Between-group differences and within-group associations were investigated through linear mixed models.

Results: The PMS donors displayed significant axonal loss in both demyelinated and normal-appearing (NA) cortices ( < 0.001 and  = 0.02) compared with controls. In PMS, cortical axonal density was associated with WML MD and AD ( = 0.003;  = 0.02, respectively), and NAWM MD and AD ( = 0.04;  = 0.049, respectively). NAWM AD and WML AD explained 12.6% and 22.6%, respectively, of axonal density variance in NA cortex. Additional axonal loss in demyelinated cortex was associated with cortical demyelination severity ( = 0.002), explaining 34.4% of axonal loss variance.

Conclusion: Reduced integrity of connected WM tracts and cortical demyelination both contribute to cortical axonal loss in PMS.
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http://dx.doi.org/10.1177/1352458520918978DOI Listing
March 2021

Moving beyond anti-aquaporin-4 antibodies: emerging biomarkers in the spectrum of neuromyelitis optica.

Expert Rev Neurother 2020 06 29;20(6):601-618. Epub 2020 May 29.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute , Milan, Italy.

Introduction: With the advent of targeted drugs, a correct identification of patients with neuromyelitis optica spectrum disorders (NMOSD) is fundamental. Moreover, to assess treatment efficacy, sensitive biomarkers for monitoring disease activity are needed.

Areas Covered: In this review, the authors provide an up-to-date guide to NMOSD biomarkers, starting from the pathogenetic mechanisms and moving to clinical findings, focusing on their diagnostic meaning, their possible application for disease monitoring and their correlation with clinical features.

Expert Opinion: Beside anti-AQP4-IgG, other emerging biomarkers for NMOSD have been proposed. Elements supporting antibody production, such as T Helper 17 and T Follicular Helper cells, plasmablasts, and their related cytokines, can be supportive criteria for NMOSD diagnosis since their levels are related to disease activity. Similarly, indices of granulocyte and complement activation, associated with markers of astrocyte damage, reflect disease status and correlate with clinical features. Among all cytokines, IL6 and IL17a represent the bridge between innate and acquired immunity and between cellular and humoral arms of the immune system, therefore being useful for both diagnosis and disease monitoring. Paraclinical tools, such as magnetic resonance imaging and optical coherence tomography, can provide useful diagnostic information, especially in double-seronegative patients.
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http://dx.doi.org/10.1080/14737175.2020.1764352DOI Listing
June 2020

Current state-of-art of the application of serum neurofilaments in multiple sclerosis diagnosis and monitoring.

Expert Rev Neurother 2020 08 12;20(8):747-769. Epub 2020 May 12.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute , Milan, Italy.

Introduction: Neurodegenerative processes occur from the beginning of multiple sclerosis, contribute to irreversible clinical disability and are only partially addressed by current disease-modifying therapies. Reliable quantification of neuro-axonal damage may contribute to improve the assessment of disease activity and progression, the definition of patients' prognosis and treatment monitoring. Neurofilaments are neuron-specific cytoskeletal components that are released after neuro-axonal damage. Among them, neurofilament light chains represent a promising biomarker of neuro-axonal damage in multiple sclerosis.

Areas Covered: This review summarizes the current state-of-art of neurofilament light chain quantification in multiple sclerosis, starting from their quantification in the cerebrospinal fluid to the most recent and sensitive techniques for their assessment in the blood. Their associations with clinical activity, disability, and MRI measures and their prognostic role during the different phases of the diseases are also discussed. Finally, their promise as biomarker of treatment effect and response is also examined.

Expert Opinion: Serum neurofilaments light chain quantification is technically feasible and is likely to provide relevant pieces of information to understand MS pathophysiology, and identify patients at higher risk to develop multiple sclerosis and more severe disability. A future role in monitoring treatment effects and response and drug-related side-effects is envisaged.
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http://dx.doi.org/10.1080/14737175.2020.1760846DOI Listing
August 2020

Clinical predictivity of thalamic sub-regional connectivity in clinically isolated syndrome: a 7-year study.

Mol Psychiatry 2020 Apr 22. Epub 2020 Apr 22.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Here, we explored trajectories of sub-regional thalamic resting state (RS) functional connectivity (FC) modifications occurring in clinically isolated syndrome (CIS) patients early after their first clinical episode, and assessed their relationship with disability over 7 years. RS fMRI and clinical data were prospectively acquired from 59 CIS patients and 13 healthy controls (HC) over 2 years. A clinical re-assessment was performed in 53 (89%) patients after 7 years. Using a structural connectivity-based atlas, five thalamic sub-regions (frontal, motor, postcentral, occipital, and temporal) were used for seed-based RS FC. Thalamic RS FC abnormalities and their longitudinal changes were correlated with disability. Thirty-nine (66.1%) patients suffered a second clinical relapse, but the median EDSS remained stable over time. At baseline, CIS patients vs HC showed reduced RS FC (p < 0.001, uncorrected) with: (1) frontal cortices, for the whole thalamus, occipital, postcentral, and temporal thalamic sub-regions, (2) occipital cortices, for the occipital thalamic sub-region. In CIS, the longitudinal analysis revealed at year 2 vs baseline: (1) no significant whole-thalamic RS FC changes; (2) reduction of motor, postcentral, and temporal sub-regional RS FC with occipital cortices (p < 0.05, corrected); (3) an increase (p < 0.001, uncorrected) of postcentral and occipital sub-regional thalamic RS FC with frontal cortices, left putamen, and ipsi- and contralateral thalamus, this latter correlating with less severe clinical disability at year 7. Thalamo-cortical disconnections were present in CIS mainly in thalamic sub-regions closer to the third ventricle early after the demyelinating event, evolved in the subsequent 2 years, and were associated with long-term clinical disability.
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http://dx.doi.org/10.1038/s41380-020-0726-4DOI Listing
April 2020

Rethinking multiple sclerosis treatment strategies.

Lancet Neurol 2020 04 18;19(4):281-282. Epub 2020 Mar 18.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy; Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.

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http://dx.doi.org/10.1016/S1474-4422(20)30063-6DOI Listing
April 2020