Publications by authors named "Massimo Filippi"

773 Publications

Clinical correlates of hypothalamic functional changes in migraine patients.

Cephalalgia 2021 Oct 13:3331024211046618. Epub 2021 Oct 13.

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

Objective: To elucidate the hypothalamic involvement in episodic migraine and investigate the association between hypothalamic resting state functional connectivity changes and migraine patients' clinical characteristics and disease progression over the years.

Methods: Ninety-one patients with episodic migraine and 73 controls underwent interictal resting state functional magnetic resonance imaging. Twenty-three patients and controls were re-examined after a median of 4.5 years. Hypothalamic resting state functional connectivity changes were investigated using a seed-based correlation approach.

Results: At baseline, a decreased functional interaction between the hypothalamus and the parahippocampus, cerebellum, temporal, lingual and orbitofrontal gyrus was found in migraine patients versus controls. Increased resting state functional connectivity between the hypothalamus and bilateral orbitofrontal gyrus was demonstrated in migraine patients at follow-up versus baseline. Migraine patients also experienced decreased right hypothalamic resting state functional connectivity with ipsilateral lingual gyrus. A higher migraine attack frequency was associated with decreased hypothalamic-lingual gyrus resting state functional connectivity at baseline, while greater headache impact at follow-up correlated with decreased hypothalamic-orbitofrontal gyrus resting state functional connectivity at baseline. At follow-up, a lower frequency of migraine attacks was associated with higher hypothalamic-orbitofrontal gyrus resting state functional connectivity.

Conclusions: During the interictal phase, the hypothalamus modulates the activity of pain and visual processing areas in episodic migraine patients. The hypothalamic-cortical interplay changes dynamically over time according to patients' clinical features.
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http://dx.doi.org/10.1177/03331024211046618DOI Listing
October 2021

A multiparametric MRI study of structural brain damage in dementia with lewy bodies: A comparison with Alzheimer's disease.

Parkinsonism Relat Disord 2021 Sep 30;91:154-161. Epub 2021 Sep 30.

Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address:

Introduction: Differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) is crucial for an adequate patients' management but might be challenging. We investigated with advanced MRI techniques gray (GM) and white matter (WM) damage in DLB patients compared to those with AD.

Methods: 24 DLB patients, 26 age- and disease severity-matched AD patients, and 20 age and sex-matched controls performed clinical and neuropsychological assessment, and brain structural and diffusion-tensor MRI. We measured GM atrophy using voxel-based morphometry, WM hyperintensities (WMH) using a local thresholding segmentation technique, and normal-appearing WM (NAWM) damage using tract-based spatial statistic.

Results: DLB and AD patients exhibited mild-to-moderate-stage dementia. Compared to controls, GM damage was diffuse in AD, while limited to bilateral thalamus and temporal regions in DLB. Compared to DLB, AD patients exhibited GM atrophy in bilateral fronto-temporal and occipital regions. DLB and AD patients showed higher WMH load than controls, with no differences among each other. WMH in DLB were diffuse with relative prevalence in posterior parietal-occipital regions. Compared to controls, both DLB and AD patients showed reduced microstructural integrity of the main supratentorial and infratentorial NAWM tracts. AD patients exhibited greater posterior NAWM damage than DLB.

Conclusions: DLB showed prominent WM degeneration compared to the limited GM atrophy, while in AD both tissue compartments were severely involved. In DLB, NAWM microstructural degeneration was independent of WMH, thus revealing two possible underlying processes. Different pathophysiological mechanisms are likely to drive GM and WM damage distribution in DLB and AD.
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http://dx.doi.org/10.1016/j.parkreldis.2021.09.025DOI Listing
September 2021

Early and unrestricted access to high-efficacy disease-modifying therapies: a consensus to optimize benefits for people living with multiple sclerosis.

J Neurol 2021 Oct 9. Epub 2021 Oct 9.

University of Bari, Bari, Italy.

Early intervention with high-efficacy disease-modifying therapy (HE DMT) may be the best strategy to delay irreversible neurological damage and progression of multiple sclerosis (MS). In European healthcare systems, however, patient access to HE DMTs in MS is often restricted to later stages of the disease due to restrictions in reimbursement despite broader regulatory labels. Although not every patient should be treated with HE DMTs at the initial stages of the disease, early and unrestricted access to HE DMTs with a positive benefit-risk profile and a reasonable value proposition will provide the freedom of choice for an appropriate treatment based on a shared decision between expert physicians and patients. This will further optimize outcomes and facilitate efficient resource allocation and sustainability in healthcare systems and society.
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http://dx.doi.org/10.1007/s00415-021-10836-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501364PMC
October 2021

PCA-LBD in Gaucher disease type 1: a case description.

Neurol Sci 2021 Oct 7. Epub 2021 Oct 7.

Neurology Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy.

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http://dx.doi.org/10.1007/s10072-021-05648-7DOI Listing
October 2021

Effects on cognition of DMTs in multiple sclerosis: moving beyond the prevention of inflammatory activity.

J Neurol 2021 Oct 7. Epub 2021 Oct 7.

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

In this review, we critically summarize recent findings derived from randomized controlled trials (RCTs), observational studies and meta-analyses that have been published in the last 3 years and that included the effects of DMTs on cognitive performances among their outcomes.
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http://dx.doi.org/10.1007/s00415-021-10832-yDOI Listing
October 2021

Association of Age at Onset With Gray Matter Volume and White Matter Microstructural Abnormalities in People With Multiple Sclerosis.

Neurology 2021 Oct 4. Epub 2021 Oct 4.

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

Objective: To investigate whether age at onset influences brain gray matter volume (GMV) and white matter (WM) microstructural abnormalities in adult multiple sclerosis (MS) patients, given its influence on clinical phenotype and disease course.

Method: In this hypothesis-driven cross-sectional study, we enrolled 67 pediatric-onset MS (POMS) patients and 143 sex- and disease duration (DD)-matched randomly-selected adult-onset MS (AOMS) patients, together with 208 healthy controls. All subjects underwent neurological evaluation and 3T MRI acquisition. MRI variables were standardized based on healthy controls, to remove effects of age and sex. Associations with DD in POMS and AOMS patients were studied with linear models. Time to reach clinical and MRI milestones was assessed with product-limit approach.

Results: At DD=1 year, GMV and WM fractional anisotropy (FA) were abnormal in AOMS but not in POMS patients. Significant interaction of age at onset (POMS AOMS) into the association with DD was found for GMV and WM FA. The crossing point of regression lines in POMS and AOMS patients was at 20 years of DD for GMV and 14 for WM FA. For POMS and AOMS patients, median DD was 29 and 19 years to reach Expanded Disability Status Scale=3 (p<0.001), 31 and 26 years to reach abnormal Paced Auditory Serial Addition Task-3 (p=0.01), 24 and 18 years to reach abnormal GMV (p=0.04), and 19 and 17 years to reach abnormal WM FA (p=0.36).

Conclusions: Younger patients are initially resilient to MS-related damage. Then, compensatory mechanisms start failing with loss of WM integrity, followed by GM atrophy and finally disability.
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http://dx.doi.org/10.1212/WNL.0000000000012869DOI Listing
October 2021

Characterizing 1-year development of cervical cord atrophy across different MS phenotypes: A voxel-wise, multicentre analysis.

Mult Scler 2021 Oct 4:13524585211045545. Epub 2021 Oct 4.

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

Background: Spatio-temporal evolution of cord atrophy in multiple sclerosis (MS) has not been investigated yet.

Objective: To evaluate voxel-wise distribution and 1-year changes of cervical cord atrophy in a multicentre MS cohort.

Methods: Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluations of 54 healthy controls (HC) and 113 MS patients (14 clinically isolated syndromes (CIS), 77 relapsing-remitting (RR), 22 progressive (P)) were used to investigate voxel-wise cord volume loss in patients versus HC, 1-year volume changes and clinical correlations (SPM12).

Results: MS patients exhibited baseline cord atrophy versus HC at anterior and posterior/lateral C1/C2 and C4-C6 ( < 0.05, corrected). While CIS patients showed baseline volume increase at C4 versus HC ( < 0.001, uncorrected), RRMS exhibited posterior/lateral C1/C2 atrophy versus CIS, and PMS showed widespread cord atrophy versus RRMS ( < 0.05, corrected). At 1 year, 13 patients had clinically worsened. Cord atrophy progressed in MS, driven by RRMS, at posterior/lateral C2 and C3-C6 ( < 0.05, corrected). CIS patients showed no volume changes, while PMS showed circumscribed atrophy progression. Baseline cord atrophy at posterior/lateral C1/C2 and C3-C6 correlated with concomitant and 1-year disability ( = -0.40/-0.62, < 0.05, corrected).

Conclusions: Voxel-wise analysis characterized spinal cord neurodegeneration over 1 year across MS phenotypes and helped to explain baseline and 1-year disability.
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http://dx.doi.org/10.1177/13524585211045545DOI Listing
October 2021

Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group.

Transl Psychiatry 2021 10 1;11(1):502. Epub 2021 Oct 1.

Center Of Excellence On Mood Disorders, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.
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http://dx.doi.org/10.1038/s41398-021-01622-1DOI Listing
October 2021

Cardiorespiratory fitness and free-living physical activity are not associated with cognition in persons with progressive multiple sclerosis: Baseline analyses from the CogEx study.

Mult Scler 2021 Oct 1:13524585211048397. Epub 2021 Oct 1.

Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

Background: Aerobic exercise training (physical activity for improving cardiorespiratory fitness) represents a promising approach for managing cognitive impairment in multiple sclerosis (MS). However, there is limited evidence that levels of physical activity and fitness are associated with cognition in progressive MS.

Objective: We examined associations among cardiorespiratory fitness, moderate-to-vigorous physical activity (MVPA), and cognitive performance in a large, international progressive MS sample.

Methods: Two hundred forty European and North American persons with progressive MS underwent cardiorespiratory fitness measurement on a recumbent stepper, wore an ActiGraph GT3X + accelerometer for 7 days for measuring MVPA, and underwent the Brief International Cognitive Assessment in MS.

Results: Cardiorespiratory fitness was not significantly correlated with Symbol Digit Modalities Test (SDMT;  = -0.01;  = -0.04), California Verbal Learning Test-II (CVLT-II;  = 0.05;  = 0.05), or Brief Visuospatial Memory Test-Revised (BVMT-R;  = -0.14;  = -0.14) -scores controlling for age, sex, and education. MVPA and SDMT ( = 0.05), CVLT-II ( = -0.07), and BVMT-R ( = 0.01) -scores were not significantly correlated.

Conclusion: Cardiorespiratory fitness and MVPA were not associated with cognition in this large progressive MS sample, yet these outcomes represent critical manipulation checks for documenting the success of the CogEx trial. This highlights the importance of examining other exercise-related mechanisms-of-action for improving cognition in progressive MS.
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http://dx.doi.org/10.1177/13524585211048397DOI Listing
October 2021

Improved Assessment of Longitudinal Spinal Cord Atrophy in Multiple Sclerosis Using a Registration-Based Approach: Relevance for Clinical Studies.

J Magn Reson Imaging 2021 Sep 28. Epub 2021 Sep 28.

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

Background: Reliable measurements of cervical cord atrophy progression may be useful for monitoring neurodegeneration in multiple sclerosis (MS).

Purpose: To compare a new, registration-based (Reg) method with two existing methods (active surface [AS] and propagation segmentation [PropSeg]) to measure cord atrophy changes over time in MS.

Study Type: Retrospective.

Subjects: Cohort I: Eight healthy controls (HC) and 28 MS patients enrolled at a single institution, and cohort II: 25 HC and 63 MS patients enrolled at three European sites.

Field Strength/sequence: 3D T1-weighted gradient echo sequence, acquired at 1.5 T (cohort I) and 3.0 T (cohort II).

Assessment: Percentage cord area changes (PCACs) between baseline and follow-up (cohort I: 2.34 years [interquartile range = 2.00-2.55 years], cohort II: 1.05 years [interquartile range = 1.01-1.18 years]) were evaluated for all subjects using Reg, AS, and PropSeg. Reg included an accurate registration of baseline and follow-up straightened cord images, followed by AS-based optimized cord segmentation. A subset of studies was analyzed twice by two observers.

Statistical Tests: Linear regression models were used to estimate annualized PCAC, and effect sizes expressed as the ratio between the estimated differences and HC error term (P < 0.05). Reproducibility was assessed by linear mixed-effect models. Annualized PCACs were used for sample size calculations (significance: α = 0.05, power: 1 - β = 0.80).

Results: Annualized PCACs and related standard errors (SEs) were lower with Reg than with other methods: PCAC in MS patients at 1.5 T was -1.12% (SE = 0.22) with Reg, -1.32% (SE = 0.30) with AS, and -1.40% (SE = 0.33) with PropSeg, while at 3.0 T PCAC was -0.83% (SE = 0.25) with Reg, -0.92% (SE = 0.32) with AS, and -1.18 (SE = 0.53) with PropSeg. This was reflected in larger effect sizes and lower sample sizes. Intra- and inter-observer agreement range was 0.72-0.91 with AS, and it was >0.96 with Reg.

Data Conclusion: The results support the use of the registration method to measure cervical cord atrophy progression in future MS clinical studies.

Level Of Evidence: 3 TECHNICAL EFFICACY STAGE: 2.
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http://dx.doi.org/10.1002/jmri.27937DOI Listing
September 2021

Is There a Gender Difference in the Response to onabotulinumtoxinA in Chronic Migraine? Insights from a Real-Life European Multicenter Study on 2879 Patients.

Pain Ther 2021 Sep 26. Epub 2021 Sep 26.

Neuroscience Section, Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, Via Vetoio 1 Coppito, 67100, L'Aquila, Italy.

Introduction: Migraine is mostly a female disorder because of its lower prevalence in men. Less than 20% of patients included in the available studies on migraine treatments are men; hence, the evidence on migraine treatments might not apply to men. The aims of the present study were to provide reliable information on the effectiveness of onabotulinumtoxinA (BT-A) for chronic migraine in men and to compare clinical benefits between men and women.

Methods: We performed a pooled patient-level gender-specific analysis of real-life data on BT-A for chronic migraine of patients followed-up to 9 months. We reported the 50% responder rates during each BT-A cycle, defined as percentage of reduction in monthly headache days (MHDs) compared to baseline, along with 75% and 30% responder rates. We also reported the mean decrease in MHDs and in days of acute medication use (DAMs) during each BT-A cycle as compared to baseline. We also evaluated the reasons for stopping the treatment within the third cycle.

Results: We included an overall cohort of 2879 patients, 522 of whom (18.1%) were men. In men, 50% responder rates were 27.7% during the first BT-A cycle, 29.2% during the second, and 35.6% during the third cycle; in women, the corresponding rates were 26.6%, 33.5%, and 41.0%. In the overall cohort, responder rates did not differ between men and women during the first two cycles; during the third cycle, the distribution was different (P < 0.001) mostly because of higher rates of treatment stopping and non-responders in men. In the propensity score matched cohort, the trend was maintained but lost its statistical significance. Both men and women had a significant decrease in MHDs and in DAMs with BT-A treatment (P < 0.001). There were no gender differences in those changes with the only exception of MHD decrease which, during the third cycle, was lower in men than in women (7.4 vs 8.2 days, P = 0.016 in the overall cohort and 9.1 vs 12.5 days, P = 0.009 in the propensity score matched cohort). At the end of follow-up, 152 men and 485 women stopped BT-A treatment (29.1% vs 20.6%; P < 0.001). The relative proportion of patients stopping treatment because of inadequate response (less than 30% decrease in MHDs from baseline) was higher in men than in women (42.8% vs 39.6%), while the proportion of patients stopping because of adverse events was higher in women than in men (5.6% vs 0%; P = 0.031).

Conclusions: Our pooled analysis suggests that the response to BT-A is significant in both men and women with a small gender difference in favor of women. Men tended to stop the treatment more frequently than women. We emphasize the need for more gender-specific data on migraine treatments from randomized controlled trials and observational studies.
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http://dx.doi.org/10.1007/s40122-021-00328-yDOI Listing
September 2021

Dual-task clinical and functional MRI correlates in Parkinson's disease with postural instability and gait disorders.

Parkinsonism Relat Disord 2021 Sep 15;91:88-95. Epub 2021 Sep 15.

Neuroimaging Research Unit, 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. Electronic address:

Background: Dual-task is a challenge for Parkinson's disease patients with postural instability and gait disorders (PD-PIGD).

Objective: This study investigated clinical, cognitive and functional brain correlates of dual-task deficits in PD-PIGD patients using quantitative gait analysis, neuropsychological evaluations and functional MRI (fMRI).

Methods: Twenty-three PD-PIGD patients performed a clinical assessment of gait/balance abilities. Single and dual-task Timed-Up-and-Go tests were monitored using an optoelectronic system to study turning velocity. Patients underwent executive-attentive function evaluation and two fMRI tasks: motor-task (foot anti-phase movements), and dual-task (foot anti-phase movements while counting backwards by threes starting from 100). Twenty-three healthy subjects underwent neuropsychological and fMRI assessments.

Results: Dual-task in PD-PIGD patients resulted in worse gait performance, particularly during turning. Performing the dual-task relative to the motor-fMRI task, healthy subjects showed widespread increased recruitment of sensorimotor, cognitive and cerebellar areas and reduced activity of inferior frontal and supramarginal gyri, while PD-PIGD patients showed increased recruitment of inferior frontal gyrus and supplementary motor area and reduced activity of primary motor, supramarginal and caudate areas. Dual-task gait alterations in patients correlated with balance and executive deficits and with altered dual-task fMRI brain activity of frontal areas.

Conclusions: This study suggested the correlation between dual-task gait difficulties, postural instability and executive dysfunction in PD-PIGD patients. FMRI results suggest that an optimized recruitment of motor and cognitive networks is associated with a better dual-task performance in PD-PIGD. Future studies should evaluate the effect of specific gait/balance and dual-task trainings to improve gait parameters and optimize brain functional activity during dual-tasks.
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http://dx.doi.org/10.1016/j.parkreldis.2021.09.003DOI Listing
September 2021

Structural MRI Signatures in Genetic Presentations of the Frontotemporal Dementia-Motor Neuron Disease Spectrum.

Neurology 2021 Sep 20. Epub 2021 Sep 20.

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

Objective: To assess cortical, subcortical and cerebellar grey matter (GM) atrophy using magnetic resonance imaging (MRI) in patients with disorders of the frontotemporal lobar degeneration (FTLD) spectrum with known genetic mutations.

Methods: Sixty-six patients carrying FTLD-related mutations were enrolled, including 44 with pure motor neuron disease (MND) and 22 with frontotemporal dementia (FTD). Sixty-one patients with sporadic FTLD (sFTLD) matched for age, sex and disease severity with genetic FTLD (gFTLD) were also included, as well as 52 healthy controls. A whole-brain voxel-based morphometry (VBM) analysis was performed. GM volumes of subcortical and cerebellar structures were obtained.

Results: Compared with controls, GM atrophy on VBM was greater and more diffuse in genetic FTD, followed by sporadic FTD and genetic MND cases, whereas sporadic MND (sMND) patients showed focal motor cortical atrophy. Patients carrying and mutations showed the most widespread cortical volume loss, in contrast with GM sparing in and . Globally, gFTLD patients showed greater atrophy of parietal cortices and thalami compared with sFTLD. In volumetric analysis, gFTLD patients showed volume loss compared with sFTLD in the caudate nuclei and thalami, in particular comparing C9-MND with sMND cases. In the cerebellum, gFTLD patients showed greater atrophy of the right lobule VIIb than sFTLD. Thalamic volumes of gFTLD patients with a mutation showed an inverse correlation with Frontal Behavioral Inventory scores.

Conclusions: Measures of deep GM and cerebellar structural involvement may be useful markers of gFTLD, particularly -related disorders, regardless the clinical presentation within the FTLD spectrum.
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http://dx.doi.org/10.1212/WNL.0000000000012702DOI Listing
September 2021

Unexpected (I)FP-CIT SPECT findings: SWIDD, SWEDD and all DAT.

J Neurol 2021 Sep 18. Epub 2021 Sep 18.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", Neuroscience Section, University of Salerno, Baronissi, SA, Italy.

Although the diagnosis of Parkinson's disease (PD) is essentially clinical, the implementation of imaging techniques can improve diagnostic accuracy. While some techniques (e.g. magnetic resonance imaging-MRI, computerized tomography-CT) are used to exclude secondary syndromes, presynaptic dopaminergic imaging including imaging of dopamine transporter (DAT)-can help the Neurologist in the differential diagnosis between neurodegenerative parkinsonian syndromes and parkinsonism without dopamine deficiency. DAT imaging can be useful in cases in which the clinical picture is not univocal, as in case of overlapping clinical features in patients with early disease, atypical syndromes or unsatisfying response to therapy. Currently, (I)FP-CIT ([123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane) (trade name DaTSCAN) is the only agent approved by international regulatory agencies for this purpose. With the increasing use of this technique, some unexpected findings have been reported, including patients clinically diagnosed with PD with a normal SPECT scan [e.g. Scans Without Evidence of Dopaminergic Deficit (SWEDD)]; PD patients with a greater dopaminergic deficit in the striatum ipsilateral to the clinically more affected side [e.g. Scans With Ipsilateral Dopaminergic Deficit (SWIDD)]; as well as some artifacts. Moreover, the neurologist must remember that structural lesions and administration of some drugs might alter the result of DAT imaging. Unexpected findings, artifacts, and misinterpretation of imaging findings can lead to an erroneous diagnosis and inappropriate therapy, neglect of other medical conditions that might explain the clinical picture, and undermine the selection phase in clinical trials. The aim of the present review is to bring clarity on these controversial (and sometimes erroneous) results, in order to inform of these possibilities the clinicians requesting a DaTSCAN in clinical practice.
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http://dx.doi.org/10.1007/s00415-021-10809-xDOI Listing
September 2021

Impaired recognition of disgust in amyotrophic lateral sclerosis is related to basal ganglia involvement.

Neuroimage Clin 2021 Sep 2;32:102803. Epub 2021 Sep 2.

Neuroimaging Research Unit, 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. Electronic address:

In the present study we investigated emotion recognition in pure motor amyotrophic lateral sclerosis (ALS) patients and its relationship with the integrity of basal ganglia, hippocampus and amygdala. Twenty ALS patients without either cognitive or behavioural impairment, and 52 matched healthy controls performed a neuropsychological assessment including the Comprehensive Affect Testing System (CATS) investigating emotion recognition. All participants underwent also a 3T brain MRI. Volumes of basal ganglia, hippocampus and amygdala bilaterally were measured using FIRST in FSL. Sociodemographic, cognitive and MRI data were compared between groups. In ALS patients, correlations between CATS significant findings, brain volumes, cognition, mood and behaviour were explored. ALS patients showed altered performances at the CATS total score and, among the investigated emotions, patients were significantly less able to recognize disgust compared with controls. No brain volumetric differences were observed between groups. In ALS patients, a lower performance in disgust recognition was related with a reduced volume of the left pallidum and a lower performance on the Edinburgh Cognitive and Behavioural ALS Screen. Cognitively/behaviourally unimpaired ALS patients showed impaired disgust recognition, which was associated with pallidum volume. The association with cognitive alterations may suggest impaired disgust recognition as an early marker of cognitive decline.
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http://dx.doi.org/10.1016/j.nicl.2021.102803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478135PMC
September 2021

Alterations of brain structural MRI are associated with outcome of surgical treatment in trigeminal neuralgia.

Eur J Neurol 2021 Sep 14. Epub 2021 Sep 14.

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

Background And Purpose: To assess magnetic resonance imaging (MRI) alterations occurring in patients with trigeminal neuralgia (TN) and to explore the predictive ability of MRI for initial surgical outcome and long-term pain relief/recurrence after Gamma Knife radiosurgery (GKS).

Methods: Thirty patients with idiopathic or classic TN, who underwent GKS and were followed for at least 24 months, were retrospectively included. Pre-treatment structural MRI and pre- and serial, postoperative clinical features were investigated. Fifteen age- and sex-matched healthy controls were also enrolled. Cortical thickness and gray matter (GM) volumes were assessed in TN patients relative to controls, as well as between patient subgroups according to treatment outcomes (initial responders/non-responders, patients with pain recurrence/long-lasting pain relief at the last follow-up). Clinical and MRI predictors of treatment outcomes were explored.

Results: Cortical thinning of temporal, prefrontal, cingulate, somatosensory and occipital areas bilaterally was found in TN patients relative to controls. No cortical thickness and GM volume differences were observed when TN initial responders and non-responders were compared. Patients who experienced TN recurrence after initial pain relief were characterized by thicker parahippocampal and temporal cortices bilaterally and greater volume of right amygdala and hippocampus compared to patients with long-lasting pain relief. In TN patients, disease duration and baseline cortical thinning of right parahippocampal, left fusiform and middle temporal cortices were associated with poor outcome after GKS at the last follow-up (R =0.57, p<0.001).

Conclusion: The study provides novel insights into structural brain alterations of TN patients, which might contribute to disease development and pain maintenance.
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http://dx.doi.org/10.1111/ene.15105DOI Listing
September 2021

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

JAMA Neurol 2021 Oct;78(10):1236-1248

Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

Objective: To identify the genetic variants associated with juvenile ALS.

Design, Setting, And Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.

Main Outcomes And Measures: De novo variants present only in the index case and not in unaffected family members.

Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.

Conclusions And Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
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http://dx.doi.org/10.1001/jamaneurol.2021.2598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406220PMC
October 2021

Editorial for "Utility of Advanced DWI in the Detection of Spinal Cord Microstructural Alterations and Assessment of Neurologic Function in Cervical Spondylotic Myelopathy Patients".

J Magn Reson Imaging 2021 Aug 28. Epub 2021 Aug 28.

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

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http://dx.doi.org/10.1002/jmri.27902DOI Listing
August 2021

Quantification of Cervical Cord Cross-Sectional Area: Which Acquisition, Vertebra Level, and Analysis Software? A Multicenter Repeatability Study on a Traveling Healthy Volunteer.

Front Neurol 2021 4;12:693333. Epub 2021 Aug 4.

Department of Radiology and Nuclear Medicine, Multiple Sclerosis Center Amsterdam, Amsterdam Neuroscience Amsterdam University Medical Centers (UMC), Vrije Universiteit Medical Center (VUmc), Amsterdam, Netherlands.

Considerable spinal cord (SC) atrophy occurs in multiple sclerosis (MS). While MRI-based techniques for SC cross-sectional area (CSA) quantification have improved over time, there is no common agreement on whether to measure at single vertebral levels or across larger regions and whether upper SC CSA can be reliably measured from brain images. To compare in a multicenter setting three CSA measurement methods in terms of repeatability at different anatomical levels. To analyze the agreement between measurements performed on the cervical cord and on brain MRI. One healthy volunteer was scanned three times on the same day in six sites (three scanner vendors) using a 3T MRI protocol including sagittal 3D T1-weighted imaging of the brain (covering the upper cervical cord) and of the SC. Images were analyzed using two semiautomated methods [NeuroQLab (NQL) and the Active Surface Model (ASM)] and the fully automated Spinal Cord Toolbox (SCT) on different vertebral levels (C1-C2; C2/3) on SC and brain images and the entire cervical cord (C1-C7) on SC images only. CSA estimates were significantly smaller using SCT compared to NQL and ASM ( < 0.001), regardless of the cord level. Inter-scanner repeatability was best in C1-C7: coefficients of variation for NQL, ASM, and SCT: 0.4, 0.6, and 1.0%, respectively. CSAs estimated in brain MRI were slightly lower than in SC MRI (all ≤ 0.006 at the C1-C2 level). Despite protocol harmonization between the centers with regard to image resolution and use of high-contrast 3D T1-weighted sequences, the variability of CSA was partly scanner dependent probably due to differences in scanner geometry, coil design, and details of the MRI parameter settings. For CSA quantification, dedicated isotropic SC MRI should be acquired, which yielded best repeatability in the entire cervical cord. In the upper part of the cervical cord, use of brain MRI scans entailed only a minor loss of CSA repeatability compared to SC MRI. Due to systematic differences between scanners and the CSA quantification software, both should be kept constant within a study. The MRI dataset of this study is available publicly to test new analysis approaches.
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http://dx.doi.org/10.3389/fneur.2021.693333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371197PMC
August 2021

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

Eur J Neurol 2021 Aug 20. Epub 2021 Aug 20.

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

Background: Aquaporin-4 (AQP4) water channel is involved in hippocampal plasticity and is the target of neuromyelitis optica spectrum disorders (NMOSD) autoimmunity. We measured volumes of hippocampal subfields and their association with cognitive performance in AQP4-seropositive NMOSD patients.

Methods: Global and regional hippocampal volumes were derived from 28 AQP4-seropositive NMOSD patients and 101 healthy controls (HC) from 3D-T1-weighted images. Normalized brain volumes were also calculated. A neuropsychological evaluation, including the Brief Repeatable Battery of Neuropsychological Tests, was performed in patients. Based on HC data, we estimated mean z-scores of volumes in the whole NMOSD group and compared them according to the status of global and domain-selective cognitive impairment.

Results: Global cognitive impairment was detected in 46.4% of NMOSD patients, with attentive (60.7%) and executive (21.4%) domains being the most affected. NMOSD patients had left hippocampal atrophy at global (p = 0.012) and regional level (fimbria, Cornu Ammonis [CA] 3, molecular layer, dentate gyrus [DG], and subicular complex, p values ranging between 0.033 and <0.001). On the right side the fimbria and hippocampal tail were atrophic (p = 0.024 for both). Cognitively impaired patients showed atrophy in the left CA3 and CA4 (p = 0.025-0.028), while patients presenting verbal and visual memory impairment had significant CA3 and DG atrophy. Those patients with attentive or executive impairment had preserved brain and hippocampal volumes.

Conclusions: NMOSD patients showed hippocampal atrophy associated with verbal and visual memory impairment. Such damage did not explain attention and executive function alterations, which were the most common cognitive deficits in this population.
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http://dx.doi.org/10.1111/ene.15073DOI Listing
August 2021

A preliminary comparison between ECAS and ALS-CBS in classifying cognitive-behavioural phenotypes in a cohort of non-demented amyotrophic lateral sclerosis patients.

J Neurol 2021 Aug 19. Epub 2021 Aug 19.

Neuromuscular Omnicentre (NEMO), Fondazione Serena Onlus, Piazza Ospedale Maggiore, 3, 20162, Milan, Italy.

To define the presence and type of frontotemporal dysfunction in amyotrophic lateral sclerosis (ALS), different screening tools have been created. Currently, the most used screening tests are the Edinburgh cognitive and behavioural ALS screen (ECAS) and the ALS cognitive behavioural screen (ALS-CBS). The objective of this study was to compare the ability of ECAS and ALS-CBS in classifying non-demented ALS patients according to Strong criteria. One-hundred and fifty-four in- and out-patients with an age > 18 and a definite or probable ALS diagnosis were recruited between September 2019 and February 2020 at NeMO Clinical Centre and at Istituto Auxologico Italiano in Milan and underwent the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and the ALS Cognitive Behavioural Screen (ALS-CBS). Exclusion criteria involved patients with a diagnosis of FTD, with a severe cognitive deterioration and/or an important behavioural impairment, with a significant psychiatric disorder or with the co-presence of another significant illness. The distribution of patients according to Strong criteria was different for ECAS and ALS-CBS and the degree of agreement between the two tests in terms of Cohen's Kappa coefficient resulted equal to 0.2047 with a 95% confidence limits interval between 0.1122 and 0.2973. This study for the first time compares the ability of ECAS and ALS-CBS in stratifying ALS patients. Further studies will be conducted to better understand the reasons underlying the differences between these two tests in classifying the different subtypes of fronto-temporal dysfunction in ALS.
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http://dx.doi.org/10.1007/s00415-021-10753-wDOI Listing
August 2021

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

Mult Scler 2021 Aug 13:13524585211033184. Epub 2021 Aug 13.

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

Background: Executive dysfunctions, including difficulties in attention, working memory, planning, and inhibition affect 15%-28% of multiple sclerosis (MS) patients.

Objectives: To investigate structural and functional magnetic resonance imaging (MRI) abnormalities underlying executive function (EF) in MS patients.

Methods: A total 116 MS patients and 65 controls underwent resting-state (RS) and diffusion-weighted sequences and neuropsychological examination, including Wisconsin Card Sorting Test (WCST) to test EF. Brain RS cognitive networks and fractional anisotropy (FA) from a priori selected white matter tracts were derived. Associations of WCST scores with RS functional connectivity (FC) and FA abnormalities were investigated.

Results: In MS patients, predictors of working memory/updating were: lower corpus callosum (CC) FA, lower left working-memory network (WMN), right WMN RS FC for worse performance; lower executive control network (ECN), higher default-mode network (DMN), and salience network (SN) RS FC for better performance ( = 0.35). Predictors of attention were lower CC genu FA, lower left WMN, and DMN RS FC for worse performance; higher left WMN and ECN RS FC for better performance ( = 0.24). Predictors of worse shifting/inhibition were lower CC genu and superior cerebellar peduncle (SCP) FA, lower left WMN RS FC for worse performance; and higher ECN RS FC for better performance ( = 0.24).

Conclusions: CC and SCP microstructural damage and RS FC abnormalities in cognitive networks underlie EF frailty in MS.
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http://dx.doi.org/10.1177/13524585211033184DOI Listing
August 2021

Anti-CD20 therapies for multiple sclerosis: current status and future perspectives.

J Neurol 2021 Aug 11. Epub 2021 Aug 11.

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

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease affecting the central nervous system (CNS), often characterized by the accumulation of irreversible clinical disability over time. During last years, there has been a dramatic evolution in several key concepts of immune pathophysiology of MS and in the treatment of this disease. The demonstration of the strong efficacy and good safety profile of selective B-cell-depleting therapies (such as anti-CD20 monoclonal antibodies) has significantly expanded the therapeutic scenario for both relapsing and progressive MS patients with the identification of a new therapeutic target. The key role of B cells in triggering MS disease has been also pointed out, determining a shift from the traditional view of MS activity as largely being 'T-cell mediated' to the notion that MS-related pathological processes involve bi-directional interactions between several immune cell types, including B cells, both in the periphery and in the CNS. This review provides an updated overview of the involvement of B cells in the immune pathophysiology and pathology of MS. We summarize the rationale regarding the use of anti-CD20 therapies and the results of the main randomized controlled trials and observational studies investigating the efficacy and safety profile of rituximab, ocrelizumab, ofatumumab and ublituximab. Suggestions regarding vaccinations and management of MS patients during COVID-19 pandemic with anti-CD20 therapies are also discussed. Finally, therapies under investigation and future perspectives of anti-CD20 therapies are taken into consideration.
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http://dx.doi.org/10.1007/s00415-021-10744-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356891PMC
August 2021

CONCERTO: A randomized, placebo-controlled trial of oral laquinimod in relapsing-remitting multiple sclerosis.

Mult Scler 2021 Aug 11:13524585211032803. Epub 2021 Aug 11.

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

Background: Interventions targeting the adaptive immune response are needed in multiple sclerosis (MS).

Objective: Evaluate laquinimod's efficacy, safety, and tolerability in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: CONCERTO was a randomized, double-blind, placebo-controlled, phase-3 study. RRMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 or 1.2 mg or placebo for ⩽24 months ( = 727,  = 732, and  = 740, respectively). Primary endpoint was time to 3-month confirmed disability progression (CDP). The laquinimod 1.2-mg dose arm was discontinued (1 January 2016) due to cardiovascular events at high doses. Safety was monitored throughout the study.

Results: CONCERTO did not meet the primary endpoint of significant effect with laquinimod 0.6-mg versus placebo on 3-month CDP (hazard ratio: 0.94; 95% confidence interval: 0.67-1.31;  = 0.706). Secondary endpoint values were nominal and non-inferential. Laquinimod 0.6 mg demonstrated 40% reduction in percent brain volume change from baseline to Month 15 versus placebo ( < 0.0001). The other secondary endpoint, time to first relapse, and annualized relapse rate (an exploratory endpoint) were numerically lower (both,  = 0.0001). No unexpected safety findings were reported with laquinimod 0.6 mg.

Conclusion: Laquinimod 0.6 mg demonstrated only nominally significant effects on clinical relapses and magnetic resonance imaging (MRI) outcomes and was generally well tolerated.

Clinical Trial Registration Number: ClinicalTrials.gov (NCT01707992).
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http://dx.doi.org/10.1177/13524585211032803DOI Listing
August 2021

The hypometabolic state: a good predictor of a better prognosis in amyotrophic lateral sclerosis.

J Neurol Neurosurg Psychiatry 2021 Aug 5. Epub 2021 Aug 5.

NeuroMuscular Omnicentre (NeMO)-Fondazione Serena Onlus, Milano, Italy

Background: Malnutrition and weight loss are negative prognostic factors for survival in patients with amyotrophic lateral sclerosis (ALS). However, energy expenditure at rest (REE) is still not included in clinical practice, and no data are available concerning hypometabolic state in ALS.

Objective: To evaluate in a referral cohort of patients with ALS the prevalence of hypometabolic state as compared with normometabolic and hypermetabolic states, and to correlate it with clinical phenotype, rate of progression and survival.

Design: We conducted a retrospective study examining REE measured by indirect calorimetry in patients with ALS referred to Milan, Limoges and Tours referral centres between January 2011 and December 2017. Hypometabolism and hypermetabolism states were defined when REE difference between measured and predictive values was ≤-10% and ≥10%, respectively. We evaluated the relationship between these metabolic alterations and measures of body composition, clinical characteristics and survival.

Results: Eight hundred forty-seven patients with ALS were recruited. The median age at onset was 63.79 years (IQR 55.00-71.17). The male/female ratio was 1.26 (M/F: 472/375). Ten per cent of patients with ALS were hypometabolic whereas 40% were hypermetabolic. Hypometabolism was significantly associated with later need for gastrostomy, non-invasive ventilation and tracheostomy placement. Furthermore, hypometabolic patients with ALS significantly outlived normometabolic (HR=1.901 (95% CI 1.080 to 3.345), p=0.0259) and hypermetabolic (HR=2.138 (95% CI 1.154 to 3.958), p=0.0157) patients.

Conclusion: Hypometabolism in ALS is not uncommon and is associated with slower disease progression and better survival than normometabolic and hypermetabolic subjects. Indirect calorimetry should be performed at least at time of diagnosis because alterations in metabolism are correlated with prognosis.
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http://dx.doi.org/10.1136/jnnp-2021-326184DOI Listing
August 2021

Genomic and functional evaluation of TNFSF14 in multiple sclerosis susceptibility.

J Genet Genomics 2021 06 25;48(6):497-507. Epub 2021 May 25.

Department of Health Sciences, Center on Autoimmune and Allergic Diseases (CAAD), UPO, University of Eastern Piedmont, A. Avogadro, Novara 28100, Italy. Electronic address:

Among multiple sclerosis (MS) susceptibility genes, the strongest non-human leukocyte antigen (HLA) signal in the Italian population maps to the TNFSF14 gene encoding LIGHT, a glycoprotein involved in dendritic cell (DC) maturation. Through fine-mapping in a large Italian dataset (4,198 patients with MS and 3,903 controls), we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the region. Expression quantitative trait locus (eQTL) analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells, which is consistent with the allelic imbalance in RNA-Seq reads (P < 0.0001). The MS risk allele is associated with reduced levels of TNFSF14 gene expression (P < 0.01) in blood cells from 84 Italian patients with MS and 80 healthy controls (HCs). Interestingly, patients with MS are lower expressors of TNFSF14 compared to HC (P < 0.007). Individuals homozygous for the MS risk allele display an increased percentage of LIGHT-positive peripheral blood myeloid DCs (CD11c, P = 0.035) in 37 HCs, as well as in in vitro monocyte-derived DCs from 22 HCs (P = 0.04). Our findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells, which may play a role in MS pathogenesis.
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http://dx.doi.org/10.1016/j.jgg.2021.03.017DOI Listing
June 2021

Application of deep-learning to the seronegative side of the NMO spectrum.

J Neurol 2021 Jul 30. Epub 2021 Jul 30.

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

Objectives: To apply a deep-learning algorithm to brain MRIs of seronegative patients with neuromyelitis optica spectrum disorders (NMOSD) and NMOSD-like manifestations and assess whether their structural features are similar to aquaporin-4-seropositive NMOSD or multiple sclerosis (MS) patients.

Patients And Methods: We analyzed 228 T2- and T1-weighted brain MRIs acquired from aquaporin-4-seropositive NMOSD (n = 85), MS (n = 95), aquaporin-4-seronegative NMOSD [n = 11, three with anti-myelin oligodendrocyte glycoprotein antibodies (MOG)], and aquaporin-4-seronegative patients with NMOSD-like manifestations (idiopathic recurrent optic neuritis and myelitis, n = 37), who were recruited from February 2010 to December 2019. Seventy-three percent of aquaporin-4-seronegative patients with NMOSD-like manifestations also had a clinical follow-up (median duration of 4 years). The deep-learning neural network architecture was based on four 3D convolutional layers. It was trained and validated on MRI scans of aquaporin-4-seropositive NMOSD and MS patients and was then applied to aquaporin-4-seronegative NMOSD and NMOSD-like manifestations. Assignment of unclassified aquaporin-4-seronegative patients was compared with their clinical follow-up.

Results: The final algorithm differentiated aquaporin-4-seropositive NMOSD and MS patients with an accuracy of 0.95. All aquaporin-4-seronegative NMOSD and 36/37 aquaporin-4-seronegative patients with NMOSD-like manifestations were classified as NMOSD. Anti-MOG patients had a similar probability of being NMOSD or MS. At clinical follow-up, one unclassified aquaporin-4-seronegative patient evolved to MS, three developed NMOSD, and the others did not change phenotype.

Conclusions: Our findings support the inclusion of aquaporin4-seronegative patients into NMOSD and suggest a possible expansion to aquaporin-4-seronegative unclassified patients with NMOSD-like manifestations. Anti-MOG patients are likely to have intermediate brain features between NMOSD and MS.
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http://dx.doi.org/10.1007/s00415-021-10727-yDOI Listing
July 2021

Direct oral anticoagulants in patients with nonvalvular atrial fibrillation and extreme body weight.

Eur J Clin Invest 2021 Jul 26:e13658. Epub 2021 Jul 26.

Cardiology Unit, IRCCS San Raffaele Hospital, Milan, Italy.

Background: Limited clinical data exist describing the use of direct oral anticoagulants (DOACs) in patient with extreme body weight. Thus, the International Society of Thrombosis and Haemostasis (ISTH) recommends avoiding DOACs in patients with weight >120 Kg, and on the contrary, no restrictions exist for underweight patients.

Objective: To evaluate the effects of extreme body weight on DOAC activity and to compare the clinical outcomes of patients with an extreme body weight versus patients with a normal weight (61-119 Kg) treated with DOACs.

Methods: Single tertiary care Italian centre multidisciplinary registry including nonvalvular atrial fibrillation (NVAF) patients treated with DOACs. Based on weight, three subcohorts were defined: (i) underweight patients (≤60 Kg); (ii) patients with a normal weight (61-119 Kg, as control group); and (iii) overweight patients (≥120 Kg). Primary efficacy endpoint was 2-year rate of thromboembolic events. Primary safety endpoint was 2-year rate of major bleeding. Event-free survival curves among groups were compared using Cox-Mantel test.

Results: 812 NVAF patients were included, 108 patients weighed ≤60 Kg (13%, underweight), 688 weighed between 61 and 119 Kg (85%, normal weight), and 16 weighed ≥120 Kg (2%, overweight). In particular, among underweight patients, dabigatran was prescribed in 26% patients, apixaban in 27%, rivaroxaban in 28% and edoxaban in 22% ones. Instead, among overweight patients, 44% were treated with dabigatran, 25% with apixaban, 25% with rivaroxaban and 4% with edoxaban. Underweight patients were older, more frequently women, with lower creatinine clearance and a history of previous strokes, resulting in higher CHA2DS2-VASc score than in both remaining groups. Up to 2 years, no statistically significant difference was observed between the three groups of weight for thromboembolic events (P = .765) and for overall bleeding (P = .125), but a trend towards decreased overall bleeding rates was noticed as weight increased (24.1% vs 16.7% vs 12.5%, respectively).

Conclusion: In this tertiary care centre registry, 15% of patients treated with DOACs presented an extreme weight. Compared to patients with a normal weight, no significant rates of thromboembolic events were observed for underweight or overweight patients. A trend towards decreased overall bleeding frequency as weight increased was highlighted up to 2 years. The present results should be considered as preliminary and hypothesis generating.
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http://dx.doi.org/10.1111/eci.13658DOI Listing
July 2021

Long-term (48 weeks) effectiveness, safety, and tolerability of erenumab in the prevention of high-frequency episodic and chronic migraine in a real world: Results of the EARLY 2 study.

Headache 2021 Jul 26. Epub 2021 Jul 26.

Headache and Neurosonology Unit, Policlinico Universitario Campus Bio-Medico, Rome, Italy.

Objective: To evaluate the long-term effectiveness, safety, and tolerability of erenumab in a real-world migraine population, looking for putative predictors of responsiveness.

Background: Erenumab proved to be effective, safe, and well tolerated in the prevention of episodic migraine (EM) and chronic migraine (CM) in long-term extension studies of double-blind, placebo-controlled trials in patients with no more than two (EM) or three (CM) prior preventive treatment failures.

Methods: A 48-week, multicenter, longitudinal cohort real-life study was conducted at 15 headache centers across eight Italian regions between December 20, 2018 and July 31, 2020. We considered all consecutive patients with high-frequency episodic migraine (HFEM) or CM aged 18-65 years. Each patient was treated with erenumab 70 mg, administered monthly. The dose was switched to 140 mg in nonresponders and in responders who had become nonresponders for at least 4 weeks. Change in monthly migraine days (MMDs) or monthly headache days (MHDs) at Weeks 45-48 compared with baseline was the primary efficacy endpoint. Secondary endpoints encompassed variation in monthly analgesic intake, achievement of a ≥50%, ≥75%, or 100% reduction in migraine or headache days, and any change in the Visual Analogue Scale (VAS) and Headache Impact Test-6 scores (HIT-6) during the same time interval.

Results: A total of 242 patients with migraine received at least one dose of erenumab 70 mg and were considered for safety analysis, whereas 221 received a monthly erenumab dose for ≥48 weeks and were included in the effectiveness and safety analysis set. All patients had previously been treated unsuccessfully with ≥3 migraine-preventive medication classes. From baseline to Weeks 45-48, erenumab treatment reduced MMD by 4.3 ± 5.3 (mean ± SD) in patients with HFEM, and MHD by 12.8 ± 8.9 (mean ± SD) in subjects with CM. VAS and HIT-6 scores were decreased by 1.8 ± 1.9 (mean ± SD) and 12.3 ± 11 (mean ± SD) in HFEM, and by 3.0 ± 2.2 (mean ± SD) and 13.1 ± 11.2 (mean ± SD) in CM. Median monthly analgesic intake passed from 11.0 (interquartile range [IQR] 10.0-13.0) to 5 (IQR 2.0-8.0) in HFEM and from 20.0 (IQR 15.0-30.0) to 6.0 (IQR 3.8-10.0) in CM. The ≥50% responders were 56.1% (32/57) in HFEM and 75.6% (124/164) in CM; ≥75% responders were 31.6% (18/57) and 44.5% (73/164); and 100% responders were 8.8% (5/57) and 1.2% (2/164), respectively. At Week 48, 83.6% (137/164) of patients with CM had reverted to EM. Erenumab was safe and well tolerated. Responsiveness to erenumab was positively associated with cutaneous allodynia (OR: 5.44, 95% CI: 1.52-19.41; p = 0.009) in HFEM. In patients with CM, ≥50% responsiveness was positively associated with male sex (OR: 2.99, 95% CI: 1.03-8.7; p = 0.044) and baseline migraine frequency (OR: 1.12, 95% CI: 1.05-1.20; p = 0.001) and negatively associated with psychiatric comorbidities (OR: 0.37, 95% CI: 0.15-0.87; p = 0.023) and prior treatment failures (OR: 0.77, 95% CI: 0.64-0.92; p = 0.004).

Conclusions: Long-term (48-week) erenumab treatment provides sustained effectiveness, safety, and tolerability in real-life patients with HFEM or CM with ≥3 prior preventive treatment failures. The dose of 140 mg was required in most patients along the study and should be taken into consideration as the starting dose. Allodynia (in HFEM), male sex, and baseline migraine frequency (in CM) might represent positive responsiveness predictors. Conversely, psychiatric comorbidities and multiple prior preventive treatment failures could be negative predictors in patients with CM.
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http://dx.doi.org/10.1111/head.14194DOI Listing
July 2021
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