Publications by authors named "Nilo Riva"

82 Publications

ALS Mimics due to Affection of the Cervical Spine: From Common Compressive Myelopathy to Rare CSF Epidural Collection.

Case Rep Neurol 2021 Jan-Apr;13(1):145-156. Epub 2021 Mar 4.

Neurology Unit, San Gerardo Hospital, and School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.

Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disease, with chameleon presentations and several mimics. Considering the poor prognosis of ALS, their precise and timely identification is pivotal. Affection of the cervical spine represents one potential source of ALS mimics that should never be missed, since it is potentially treatable. We hereby present 5 cases initially diagnosed as ALS but eventually found to have different kinds of cervical spine affection, from a common compressive myelopathy to a rare space-occupying cystic fluid collection.
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http://dx.doi.org/10.1159/000512810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989791PMC
March 2021

Current application of neurofilaments in amyotrophic lateral sclerosis and future perspectives.

Neural Regen Res 2021 Oct;16(10):1985-1991

Neuropathology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute; Neurology and Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Motor neuron disease includes a heterogeneous group of relentless progressive neurological disorders defined and characterized by the degeneration of motor neurons. Amyotrophic lateral sclerosis is the most common and aggressive form of motor neuron disease with no effective treatment so far. Unfortunately, diagnostic and prognostic biomarkers are lacking in clinical practice. Neurofilaments are fundamental structural components of the axons and neurofilament light chain and phosphorylated neurofilament heavy chain can be measured in both cerebrospinal fluid and serum. Neurofilament light chain and phosphorylated neurofilament heavy chain levels are elevated in amyotrophic lateral sclerosis, reflecting the extensive damage of motor neurons and axons. Hence, neurofilaments are now increasingly recognized as the most promising candidate biomarker in amyotrophic lateral sclerosis. The potential usefulness of neurofilaments regards various aspects, including diagnosis, prognosis, patient stratification in clinical trials and evaluation of treatment response. In this review paper, we review the body of literature about neurofilaments measurement in amyotrophic lateral sclerosis. We also discuss the open issues concerning the use of neurofilaments clinical practice, as no overall guideline exists to date; finally, we address the most recent evidence and future perspectives.
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http://dx.doi.org/10.4103/1673-5374.308072DOI Listing
October 2021

X-ray phase contrast tomography for the investigation of amyotrophic lateral sclerosis.

J Synchrotron Radiat 2020 Jul 9;27(Pt 4):1042-1048. Epub 2020 Jun 9.

Physics Department `Sapienza' University, CNR-Institute of Nanotechnology, Piazzale Aldo Moro 5, 00185 Rome, Italy.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. Pre-clinical studies drive the development of animal models that well mimic ALS disorder and enable both the dissection of disease processes and an early assessment of therapy efficacy. A comprehensive knowledge of neuronal and vascular lesions in the brain and spinal cord is an essential factor to understand the development of the disease. Spatial resolution and bidimensional imaging are important drawbacks limiting current neuroimaging tools, while neuropathology relies on protocols that may alter tissue chemistry and structure. In contrast, recent ex vivo studies in mice demonstrated that X-ray phase-contrast tomography enables study of the 3D distribution of both vasculature and neuronal networks, without sample sectioning or use of staining. Here we present our findings on ex vivo SOD1 ALS mice spinal cord at a micrometric scale. An unprecedented direct quantification of neuro-vascular alterations at different stages of the disease is shown.
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http://dx.doi.org/10.1107/S1600577520006785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336179PMC
July 2020

Serum naturally occurring anti-TDP-43 auto-antibodies are increased in amyotrophic lateral sclerosis.

Sci Rep 2021 Jan 21;11(1):1978. Epub 2021 Jan 21.

Lab of Neurobiology, School of Medicine and Surgery and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.

Amyotrophic Lateral Sclerosis (ALS) patients express significant clinical heterogeneity that often hinders a correct diagnostic definition. Intracellular deposition of TDP-43, a protein involved in RNA metabolism characterizes the pathology. Interestingly, this protein can be detected in serum, wherein cognate naturally-occurring auto-antibodies (anti-TDP-43 NAb) might be also present, albeit they have never been documented before. In this exploratory study, we quantified the levels of both anti-TDP-43 NAb and TDP-43 protein as putative accessible markers for improving the ALS diagnostic process by using ELISA in N = 70 ALS patients (N = 4 carrying TARDBP mutations), N = 40 age-comparable healthy controls (CTRL), N = 20 motor neuron disease mimics (MN-m), N = 20 Alzheimer's disease (AD) and N = 15 frontotemporal lobar degeneration (FTLD) patients. Anti-TDP-43 NAb were found to be significantly increased in ALS patients compared to all the other groups (p < 0.001). On the other hand, the distribution of serum levels of TDP-43 protein was highly variable among the various groups. Levels were increased in ALS patients, albeit the highest values were detected in MN-m patients. NAb and protein serum levels failed to correlate. For the first time, we report that serum anti-TDP-43 NAb are detectable in human serum of both healthy controls and patients affected by a variety of neurodegenerative disorders; furthermore, their levels are increased in ALS patients, representing a potentially interesting trait core marker of this disease. Further studies are needed to clarify the exact role of the NAb. This information might be extremely useful for paving the way toward targeting TDP-43 by immunotherapy in ALS.
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http://dx.doi.org/10.1038/s41598-021-81599-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820419PMC
January 2021

Progression of cognitive and behavioral disturbances in motor neuron diseases assessed using standard and computer-based batteries.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Jan 19:1-14. Epub 2021 Jan 19.

Neuroimaging Research Unit, Division of Neuroscience, Milan, Italy.

Detecting and monitoring cognitive and behavioral deficits in motor neuron diseases (MND) is critical due to their considerable clinical impact. In this scenario, computer-based batteries may play an important role. In this study, we investigated the progression of cognitive and behavioral deficits in MND patients using both standard and computer-based neuropsychological batteries. : This is a retrospective study on 74 MND patients (52 amyotrophic lateral sclerosis [ALS], 12 primary lateral sclerosis [PLS], and 10 progressive muscular atrophy [PMA]) who were followed up for 12 months and underwent up to three cognitive/behavioral assessments, 6 months apart, including standard and/or computerized based (the Test of Attentional Performance [TAP]) batteries. Behavioral/cognitive changes were investigated over time using generalized linear model for longitudinal data accounting for time and revised-ALS Functional Rating Scale. : Over 12 months, ALS patients showed a global cognitive decline (Mini Mental State Examination) at the standard battery and reduced performance in the alertness, sustained and divided attention, go/nogo, cross-modal and incompatibility TAP tasks. Most of these findings remained significant when ALSFRS-R changes over time were included as covariate in the analyses. ALS patients did not show significant behavioral abnormalities over time. No cognitive and behavioral changes were found in PLS and PMA cases. : Computer-based neuropsychological evaluations are able to identify subtle cognitive changes in ALS, unique to this condition. This study highlights the need of specific, accurate and well-tolerated tools for the monitoring of cognitive deficits in MND.
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http://dx.doi.org/10.1080/21678421.2020.1867179DOI Listing
January 2021

Progression of brain functional connectivity and frontal cognitive dysfunction in ALS.

Neuroimage Clin 2020 19;28:102509. Epub 2020 Nov 19.

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

Objective: To investigate the progression of resting-state functional connectivity (rs-FC) changes in patients with amyotrophic lateral sclerosis (ALS) and their relationship with frontal cognitive alterations.

Methods: This is a multicentre, observational and longitudinal study. At baseline and after six months, 25 ALS patients underwent 3D T1-weighted MRI, resting-state functional MRI (rs-fMRI), and the computerized Test of Attentional Performance (TAP). Using independent component analysis, rs-FC changes of brain networks involving connections to frontal lobes and their relationship with baseline cognitive scores and cognitive changes over time were assessed. With a seed-based approach, rs-FC longitudinal changes of the middle frontal gyrus (MFG) were also explored.

Results: After six months, ALS patients showed an increased rs-FC of the left anterior cingulate, left middle frontal gyrus (MFG) and left superior frontal gyrus within the frontostriatal network, and of the left MFG, left supramarginal gyrus and right angular gyrus within the left frontoparietal network. Within the frontostriatal network, a worse baseline performance at TAP divided attention task was associated with an increased rs-FC over time in the left MFG and a worse baseline performance at the category fluency index was related with increased rs-FC over time in the left frontal superior gyrus. After six months, the seed-based rs-FC analysis of the MFG with the whole brain showed decreased rs-FC of the right MFG with frontoparietal regions in patients compared to controls.

Conclusions: Rs-FC changes in ALS patients progressed over time within the frontostriatal and the frontoparietal networks and are related to frontal-executive dysfunction. The MFG seems a potential core region in the framework of a frontoparietal functional breakdown, which is typical of frontotemporal lobar degeneration. These findings offer new potential markers for monitoring extra-motor progression in ALS.
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http://dx.doi.org/10.1016/j.nicl.2020.102509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708866PMC
November 2020

Diet, Microbiota and Brain Health: Unraveling the Network Intersecting Metabolism and Neurodegeneration.

Int J Mol Sci 2020 Oct 10;21(20). Epub 2020 Oct 10.

Experimental Neuropathology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy.

Increasing evidence gives support for the idea that extra-neuronal factors may affect brain physiology and its predisposition to neurodegenerative diseases. Epidemiological and experimental studies show that nutrition and metabolic disorders such as obesity and type 2 diabetes increase the risk of Alzheimer's and Parkinson's diseases after midlife, while the relationship with amyotrophic lateral sclerosis is uncertain, but suggests a protective effect of features of metabolic syndrome. The microbiota has recently emerged as a novel factor engaging strong interactions with neurons and glia, deeply affecting their function and behavior in these diseases. In particular, recent evidence suggested that gut microbes are involved in the seeding of prion-like proteins and their spreading to the central nervous system. Here, we present a comprehensive review of the impact of metabolism, diet and microbiota in neurodegeneration, by affecting simultaneously several aspects of health regarding energy metabolism, immune system and neuronal function. Advancing technologies may allow researchers in the future to improve investigations in these fields, allowing the buildup of population-based preventive interventions and development of targeted therapeutics to halt progressive neurologic disability.
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http://dx.doi.org/10.3390/ijms21207471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590163PMC
October 2020

Structural and functional brain connectome in motor neuron diseases: A multicenter MRI study.

Neurology 2020 11 10;95(18):e2552-e2564. Epub 2020 Sep 10.

From the Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, (S.B., F.A., C.C., E.G.S., V.C., E.C., M.F.), Neurorehabilitation Unit (N.R.), Neurology Unit (Y.F., M.F.), Neurophysiology Unit (M.F.), and Department of Neuroradiology and CERMAC (A.F.), IRCCS San Raffaele Scientific Institute; Vita-Salute San Raffaele University (F.A., C.C., E.G.S., V.C., Y.F., A.F., M.F.), Milan; Department of Advanced Medical and Surgical Sciences (F.T., C.F., M.R.M., G.T.), University of Campania "Luigi Vanvitelli," Naples; and ALS Center (C.M., A.C.), "Rita Levi Montalcini" Department of Neuroscience, University of Torino, Italy.

Objective: To investigate structural and functional neural organization in amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), and progressive muscular atrophy (PMA).

Methods: A total of 173 patients with sporadic ALS, 38 patients with PLS, 28 patients with PMA, and 79 healthy controls were recruited from 3 Italian centers. Participants underwent clinical, neuropsychological, and brain MRI evaluations. Using graph analysis and connectomics, global and lobar topologic network properties and regional structural and functional brain connectivity were assessed. The association between structural and functional network organization and clinical and cognitive data was investigated.

Results: Compared with healthy controls, patients with ALS and patients with PLS showed altered structural global network properties, as well as local topologic alterations and decreased structural connectivity in sensorimotor, basal ganglia, frontal, and parietal areas. Patients with PMA showed preserved global structure. Patient groups did not show significant alterations of functional network topologic properties relative to controls. Increased local functional connectivity was observed in patients with ALS in the precentral, middle, and superior frontal areas, and in patients with PLS in the sensorimotor, basal ganglia, and temporal networks. In patients with ALS and patients with PLS, structural connectivity alterations correlated with motor impairment, whereas functional connectivity disruption was closely related to executive dysfunction and behavioral disturbances.

Conclusions: This multicenter study showed widespread motor and extramotor network degeneration in ALS and PLS, suggesting that graph analysis and connectomics might represent a powerful approach to detect upper motor neuron degeneration, extramotor brain changes, and network reorganization associated with the disease. Network-based advanced MRI provides an objective in vivo assessment of motor neuron diseases, delivering potential prognostic markers.
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http://dx.doi.org/10.1212/WNL.0000000000010731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682834PMC
November 2020

Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis.

Nat Commun 2020 07 31;11(1):3848. Epub 2020 Jul 31.

INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milano, Italy.

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker. We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29. Indeed, while increasing retromer stability in ALS mice, compound 2a attenuates locomotion impairment and increases MNs survival. Moreover, compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability. Our results clearly suggest the retromer as a valuable druggable target in ALS.
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http://dx.doi.org/10.1038/s41467-020-17524-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395176PMC
July 2020

Urinary neopterin, a new marker of the neuroinflammatory status in amyotrophic lateral sclerosis.

J Neurol 2020 Dec 8;267(12):3609-3616. Epub 2020 Jul 8.

CNR Institute of Clinical Physiology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

Objective: To comprehensively assess whether neopterin in urine could be a candidate biomarker for determining the neuroinflammatory status in ALS.

Methods: We performed an observational, cross-sectional study in 81 pALS, 68 age- and sex-comparable healthy controls (HC), 14 patients affected by MS and 24 OND patients. ALS patients underwent a neurological evaluation to assess the global functional status evaluated by Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) and the disease progression rate. Urinary neopterin concentrations were determined by high-performance liquid chromatography method and were recorded at the time of first examination to assess their effect on disease severity and survival.

Results: Urinary neopterin was significantly higher in pALS (263.90 [198.71-474.90]) compared to MS (155.28 [131.74-190.38], p =  < .001), OND patients (205.60 [158.96-299.41], p = 0.04) and HC (169.55 [134.91-226.10], p < .001). Moreover, a significant negative correlation was found between neopterin level and the severity of symptoms evaluated by ALSFRS-R total score (r = - 0.46, p < .001) and its subscores (bulbar r = - 0.34, p = 0.002; motor r = - 0.33, p = 0.003; respiratory r = - 0.53, p < .001), also adjusting for the effect of sex, site of onset, age at evaluation and time from onset to evaluation.

Conclusions: Our finding indicates that urine neopterin is elevated in ALS, emphasizing the role of the cell-mediated inflammation in the disease. Moreover, whether confirmed in further studies, our results will underline the neopterin's potential use as non-invasive clinical biomarker of ALS, to discriminate patients possibly candidates to clinical interventions aimed to interfere the neuroinflammatory processes.
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http://dx.doi.org/10.1007/s00415-020-10047-7DOI Listing
December 2020

Structural MRI outcomes and predictors of disease progression in amyotrophic lateral sclerosis.

Neuroimage Clin 2020 17;27:102315. Epub 2020 Jun 17.

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

Background And Aims: Considering the great heterogeneity of amyotrophic lateral sclerosis (ALS), the identification of accurate prognostic predictors is fundamental for both the clinical practice and the design of treatment trials. This study aimed to explore the progression of clinical and structural brain changes in patients with ALS, and to assess magnetic resonance imaging (MRI) measures of brain damage as predictors of subsequent functional decline.

Methods: 50 ALS patients underwent clinical evaluations and 3 T MRI scans at regular intervals for a maximum of 2 years (total MRI scans = 164). MRI measures of cortical thickness, as well as diffusion tensor (DT) metrics of microstructural damage along white matter (WM) tracts were obtained. Voxel-wise regression models and longitudinal mixed-effects models were used to test the relationship between clinical decline and baseline and longitudinal MRI features.

Results: The rate of decline of the ALS Functional Rating Scale revised (ALSFRS-r) was significantly associated with the rate of fractional anisotropy (FA) decrease in the body of the corpus callosum (CC). Corticospinal tract (CST) and CC-body alterations had a faster progression in patients with higher baseline ALSFRS-r scores and greater CC-body disruption at baseline. Lower FA of the cerebral peduncle was associated with faster subsequent clinical progression.

Conclusions: In this longitudinal study, we identified a significant association between measures of WM damage of the motor tracts and functional decline in ALS patients. Our data suggest that a multiparametric approach including DT MRI measures of brain damage would provide an optimal method for an accurate stratification of ALS patients into prognostic classes.
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http://dx.doi.org/10.1016/j.nicl.2020.102315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327879PMC
June 2020

Focus on the heterogeneity of amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11 25;21(7-8):485-495. Epub 2020 Jun 25.

Mario Negri-ALS Study Group, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.

The clinical manifestations of amyotrophic lateral sclerosis (ALS) are variable in terms of age at disease onset, site of onset, progression of symptoms, motor neuron involvement, and the occurrence of cognitive and behavioral changes. Genetic background is a key determinant of the ALS phenotype. The mortality of the disease also varies with the ancestral origin of the affected population and environmental factors are likely to be associated with ALS at least within some cohorts. Disease heterogeneity is likely underpinned by the presence of different pathogenic mechanisms. A variety of ALS animal models can be informative about the heterogeneity of the neuropathological or genetic aspects of the disease and can support the development of new therapeutic intervention. Evolving biomarkers can contribute to the identification of differing genotypes and phenotypes, and can be used to explore whether genotypic and phenotypic differences in animal models might help to provide a better definition of the heterogeneity of ALS in humans. These include neurofilaments, peripheral blood mononuclear cells, extracellular vesicles, microRNA and imaging findings. These biomarkers might predict not only the development of the disease, but also the variability in progression, although robust validation is required. A promising area of progress in modeling the heterogeneity of human ALS is represented by the use of human induced pluripotent stem cell (iPSCs)-derived motor neurons. Although the translational value of iPSCs remains unclear, this model is attractive in the perspective of replicating the heterogeneity of sporadic ALS as a first step toward a personalized medicine strategy.
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http://dx.doi.org/10.1080/21678421.2020.1779298DOI Listing
November 2020

Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort.

Int J Mol Sci 2020 May 8;21(9). Epub 2020 May 8.

Experimental Neuropathology Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy.

Although the genetic architecture of amyotrophic lateral sclerosis (ALS) is incompletely understood, recent findings suggest a complex model of inheritance in ALS, which is consistent with a multistep pathogenetic process. Therefore, the aim of our work is to further explore the architecture of ALS using targeted next generation sequencing (NGS) analysis, enriched in motor neuron diseases (MND)-associated genes which are also implicated in axonal hereditary motor neuropathy (HMN), in order to investigate if disease expression, including the progression rate, could be influenced by the combination of multiple rare gene variants. We analyzed 29 genes in an Italian cohort of 83 patients with both familial and sporadic ALS. Overall, we detected 43 rare variants in 17 different genes and found that 43.4% of the ALS patients harbored a variant in at least one of the investigated genes. Of note, 27.9% of the variants were identified in other MND- and HMN-associated genes. Moreover, multiple gene variants were identified in 17% of the patients. The burden of rare variants is associated with reduced survival and with the time to reach King stage 4, i.e., the time to reach the need for percutaneous endoscopic gastrostomy (PEG) positioning or non-invasive mechanical ventilation (NIMV) initiation, independently of known negative prognostic factors. Our data contribute to a better understanding of the molecular basis of ALS supporting the hypothesis that rare variant burden could play a role in the multistep model of disease and could exert a negative prognostic effect. Moreover, we further extend the genetic landscape of ALS to other MND-associated genes traditionally implicated in degenerative diseases of peripheral axons, such as HMN and CMT2.
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http://dx.doi.org/10.3390/ijms21093346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246633PMC
May 2020

Serum phosphorylated neurofilament heavy-chain levels reflect phenotypic heterogeneity and are an independent predictor of survival in motor neuron disease.

J Neurol 2020 Aug 18;267(8):2272-2280. Epub 2020 Apr 18.

Division of Neuroscience, Neuropathology Unit, San Raffaele Scientific Institute, via Olgettina 48, 20132, Milan, Italy.

To investigate the prognostic role and the major determinants of serum phosphorylated neurofilament heavy -chain (pNfH) concentration across a large cohort of motor neuron disease (MND) phenotypes. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum pNfH concentration in 219 MND patients consecutively enrolled in our tertiary MND clinic. A multifactorial analysis was carried out to investigate the major clinical determinants of serum pNfH. Kaplan-Meier survival curves and Cox regression analysis were performed to explore the prognostic value of serum pNfH. Serum pNfH levels were not homogenous among MND phenotypes; higher concentrations in pyramidal, bulbar, and classic phenotypes were observed. C9orf72-MND exhibited higher pNfH concentrations compared to non-C9orf72 MND. Multiple linear regression analysis revealed mean MEP/cMAP and disease progression rate as the two major predictors of serum pNfH levels (R = 0.188; p ≤ 0.001). Kaplan-Meier curves showed a significant difference of survival among MND subgroups when divided into quartiles based on pNfH concentrations, log-rank X = 53.0, p ≤ 0.0001. Our study evidenced that higher serum pNfH concentration is a negative independent prognostic factor for survival. In Cox multivariate model, pNfH concentration showed the highest hazard ratio compared to the other factors influencing survival included in the analysis. pNfH differs among the MND phenotypes and is an independent prognostic factor for survival. This study provides supporting evidence of the role of pNfH as useful prognostic biomarker for MND patients. Neurofilament measurements should be considered in the future prognostic models and in clinical trials for biomarker-based stratification, and to evaluate treatment response.
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http://dx.doi.org/10.1007/s00415-020-09838-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166001PMC
August 2020

Temporal variant of frontotemporal dementia in C9orf72 repeat expansion carriers: two case studies.

Brain Imaging Behav 2020 Apr;14(2):336-345

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS Ospedale San Raffaele, Via Olgettina, 60, 20132, Milan, Italy.

The temporal variant of frontotemporal dementia (tv-FTD) is a progressive neurodegenerative disease with a complex clinical picture mainly characterized by behavioral and language disorders. In this work, we describe clinical, genetic, neuroanatomical and neuropathological (only in one case) features of two patients with tv-FTD carrying C9orf72 repeat expansion. The first patient (AB) presented with a 1-year disease duration showing focal right anterior temporal lobe (ATL) atrophy on magnetic resonance imaging (MRI). The second patient (BC) came to medical attention 13 years after disease onset and showed a prominent bilateral ATL involvement. Both patients showed naming deficits, impairment in identifying known faces and proper names, and personality changes with new onset behavioral rigidity, and progressing language difficulties to single-word and sentence comprehension difficulties. They were classified as tv-FTD. Clinical, cognitive and MRI follow-up were performed. As cognitive impairment progressed, MRI atrophy worsened in ATL and frontotemporal areas in both patients. Both cases had clear family histories of neurological and/or psychiatric disease. Genetic testing revealed a C9orf72 hexanucleotide repeat expansion in both cases. BC passed away after 15 years of disease and autopsy showed the expected TDP-type B pathology. These genetic cases of tv-FTD highlight the susceptibility of ATL to C9orf72-related pathology and emphasize the importance of genetical testing in FTD-spectrum disorders, regardless of the clinical phenotype.
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http://dx.doi.org/10.1007/s11682-019-00253-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467111PMC
April 2020

ALS Cognitive Behavioral Screen (ALS-CBS): normative values for the Italian population and clinical usability.

Neurol Sci 2020 Apr 5;41(4):835-841. Epub 2019 Dec 5.

School of Medicine and Surgery and Milan Center for Neuroscience (NeuroMI), University of Milano-Bicocca, U8 Via Cadore 48 -, 20900, Monza, MB, Italy.

Amyotrophic lateral sclerosis (ALS) patients often express cognitive and behavioral dysfunctions within the so-called "frontotemporal spectrum disorders." Guidelines recommend screening of such dysfunctions, albeit only ALS dedicated tools are eventually suitable, due to the profound motor limitations induced by the disease. ALS Cognitive Behavioral Screen (ALS-CBS) is such a screening tool but normative data are not available, limiting its widespread implementation. Our aim consisted in producing normative data for the Italian version of the ALS-CBS. The scale was administered to n = 458 healthy controls with different age and education. Following translation and back translation of the original version of the test, normative data and correction scores for the ALS-CBS cognitive subtest (ALS-CBSci) were generated. Furthermore, n = 100 ALS consecutive outpatients with a wide range of cognitive and motor severity underwent to the ALS-CBS, besides FAB and Weigl sorting test (WST), in order to check its usability. Completion rate was 100% for ALS-CBS and WST, and 68% for the FAB. Corrected ALS-CBS scores showed 12% detection rate of significant cognitive dysfunction with a moderate kappa with FAB and WST. For the ALS-CBS behavioral subtest (ALS-CBSbi), a caregiver was available for n = 81 ALS patients and asked to complete the subset. The detection rate for behavioral dysfunction was 55.5%, and a mild correlation between with the Caregiver Burden Inventory was present (r = - 0.26, p = 0.04). In conclusion, we offer here normative data for the ALS-CBS, a handy tool for screening frontotemporal spectrum dysfunctions in ALS patients, and confirm its usability and validity in an outpatient setting.
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http://dx.doi.org/10.1007/s10072-019-04154-1DOI Listing
April 2020

HSC70 expression is reduced in lymphomonocytes of sporadic ALS patients and contributes to TDP-43 accumulation.

Amyotroph Lateral Scler Frontotemporal Degener 2020 02 30;21(1-2):51-62. Epub 2019 Oct 30.

School of Medicine and Surgery and Milan Center for Neuroscience (NeuroMI), University of Milano-Bicocca, Monza, Italy.

: The demonstration that chaperone-mediated autophagy (CMA) contributes to the degradation of TDP-43, the main constituent of cytoplasmic inclusions typically found in motor neurons of patients with sporadic amyotrophic lateral sclerosis (sALS), has pointed out a possible involvement of CMA in aggregate formation. To explore this possibility, in this study, we verified the presence of a possible systemic CMA alteration in sALS patients and its effect on TDP-43 expression. : Gene and protein expression of the cytosolic chaperone HSC70 and the lysosome receptor LAMP2A, the two pivotal mediators of CMA, was assessed in peripheral blood mononuclear cells (PBMCs) derived from 30 sALS patients and 30 healthy controls. The expression of TDP-43 and co-chaperones BAG1 and BAG3 was also analyzed. : We found reduced HSC70 expression in patient cells, with no change in LAMP2A, and increased insoluble TDP-43 protein levels, with an aberrant intracellular localization. We also observed an unbalanced expression of co-chaperones BAG1 and BAG3. HSC70 down-regulation was confirmed in immortalized lymphoblastoid cell lines derived from sporadic and TARDBP mutant ALS patients. Lastly, we demonstrated that HSC70 silencing directly increases TDP-43 protein levels in human neuroblastoma cells. : Our results do not support the existence of a systemic CMA alteration in sALS patients but indicate a direct involvement of HSC70 alterations in ALS pathogenesis.
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http://dx.doi.org/10.1080/21678421.2019.1672749DOI Listing
February 2020

Limitations in daily activities and general perception of quality of life: Long term follow-up in patients with anti-myelin-glycoprotein antibody polyneuropathy.

J Peripher Nerv Syst 2019 09 26;24(3):276-282. Epub 2019 Aug 26.

Department of Neurosciences, University of Padova, Padova, Italy.

In this study, we assessed the modifications over time of daily activities and quality of life (QoL) in 32 subjects with anti-myelin-glycoprotein (MAG) antibody neuropathy. A widespread panel including clinical scores and patient-reported questionnaires, in compliance of the terms by the International Classification of Functioning, Disability, and Health (ICF) of the World Health Organization (WHO), was employed at enrollment (T0) and at follow-up evaluation (T1) after a mean interval of 15.4 ± 5.7 months. The Sensory Modality Sum score (SMS) at four limbs showed a significant worsening over time (mean score 27.2 ± 3.9 at T0 vs 25.7 ± 3 at T1 at upper limbs, P = .03; 20.5 ± 4.8 at T0 vs 18.6 ± 5.9 at T1 at lower limbs, P = .04). The Visual Analogue Scale (VAS) for pain significantly worsened at upper limbs at T1 (mean values 0.84 ± 1.95 at T0 vs 1.78 ± 2.6 at T1, P = .03). All the other tests did not show significant differences between T0 and T1. In the subgroup who underwent rituximab (15/32 treated before T0, 3/32 patients treated between T0 and T1 with median interval of 1 year), no significant differences were observed between T0 and T1. Despite the quite long follow-up, statistical significance was not achieved either for the limited number of patients or for the lack of sensitive outcome measures. In our cohort, the significant worsening of the SMS and VAS after a median of 14 months can be considered as a reliable expression of the natural history of the disease, and suggest that these scales might represent possible outcome measures in anti-MAG antibody neuropathy.
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http://dx.doi.org/10.1111/jns.12342DOI Listing
September 2019

Riluzole Selective Antioxidant Effects in Cell Models Expressing Amyotrophic Lateral Sclerosis Endophenotypes.

Clin Psychopharmacol Neurosci 2019 Aug;17(3):438-442

Labaratory of Neurobiology, School of Medicine and Surgery and Milan Center for Neuroscience (NeuroMI), University of Milano-Bicocca, Milano, Italy.

Objective: Until recently, riluzole was the only drug licensed for amyotrophic lateral sclerosis (ALS). In spite of its efficacy, the mechanism of action remains elusive, and both blocking of glutamate release and antioxidant properties have been postulated. Here we characterized human SH-SY5Y neuroblastoma cell lines, taking advantage of their insensitivity to excitotoxic insults, in order to selectively assess the presence of a direct antioxidant effect of riluzole.

Methods: SH-SY5Y cells, either parental or overexpressing the G93A SOD1 mutation, were exposed for 24 hours to the selected stimuli.

Results: Riluzole (1‒10 µM) was able to counteract the effects of HO exposure (200 µM/24 hr), limiting both cell death and whole-cell reactive oxygen species (ROS) increase. The same experiments were repeated using SH-SY5Y cells carrying the familial ALS-related G93A-SOD1 mutation and constitutively expressing two-fold increased whole-cell ROS levels with respect to wild-type cells: riluzole was ineffective in this paradigm. Analogously, riluzole was ineffective in preventing cell death induced by exposing SH-SY5Y cells to 3-morpholino-sydnonimine (SIN-1, 1.5 mM/24 hr), a reactive nitrogen species (RNS) donor.

Conclusion: Our data support a direct antioxidant action of riluzole. Furthermore, the lack of efficacy of riluzole observed in the SOD1 cell model mirrors the lack of efficacy already demonstrated in cognate mouse models of ALS, plausibly reflecting differences in the underlying pathogenic mechanisms. Finally, riluzole inefficacy against nitrosative stress might support the idea that a combined therapeutic intervention may result more effective in ALS patients, as in the case of co-administration of edaravone, a drug known to reduce RNS.
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http://dx.doi.org/10.9758/cpn.2019.17.3.438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705104PMC
August 2019

The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research.

Front Neurosci 2019 25;13:601. Epub 2019 Jun 25.

Experimental Neuropathology Unit, Division of Neuroscience, Institute of Experimental Neurology - San Raffaele Scientific Institute, Milan, Italy.

Although amyotrophic lateral sclerosis (ALS) has been considered as a disorder of the motor neuron (MN) cell body, recent evidences show the non-cell-autonomous pathogenic nature of the disease. Axonal degeneration, loss of peripheral axons and destruction of nerve terminals are early events in the disease pathogenic cascade, anticipating MN degeneration, and the onset of clinical symptoms. Therefore, although ALS and peripheral axonal neuropathies should be differentiated in clinical practice, they also share damage to common molecular pathways, including axonal transport, RNA metabolism and proteostasis. Thus, an extensive evaluation of the molecular events occurring in the peripheral nervous system (PNS) could be fundamental to understand the pathogenic mechanisms of ALS, favoring the discovery of potential disease biomarkers, and new therapeutic targets.
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http://dx.doi.org/10.3389/fnins.2019.00601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603245PMC
June 2019

Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial.

Amyotroph Lateral Scler Frontotemporal Degener 2020 02 7;21(1-2):5-14. Epub 2019 Jul 7.

AB Science, Paris, France.

To assess masitinib in the treatment of ALS. Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d. Following a blinded transition from phase 2 to phase 2/3, a prospectively defined two-tiered design was implemented based on ALSFRS-R progression rate from disease-onset to baseline (ΔFS). This approach selects a more homogeneous primary efficacy population ("Normal Progressors", ΔFS < 1.1 points/month) while concurrently permitting secondary assessment of the broader population. Primary endpoint was decline in ALSFRS-R at week-48 (ΔALSFRS-R), with the high-dose "Normal Progressor" cohort being the prospectively declared primary efficacy population. Missing data were imputed last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. For the primary efficacy population, masitinib ( = 99) showed significant benefit over placebo ( = 102) with a ΔALSFRS-R between-group difference (ΔLSM) of 3.4 (95% CI 0.65-6.13; p = 0.016), corresponding to a 27% slowing in rate of functional decline (LOCF methodology). Sensitivity analyses were all convergent, including the conservative multiple imputation technique of FCS-REGPMM with a ΔLSM of 3.4 (95% CI 0.53-6.33; p = 0.020). Secondary endpoints (ALSAQ-40, FVC, and time-to-event analysis) were also significant. Conversely, no significant treatment-effect according to ΔALSFRS-R was seen for the broader "Normal and Fast Progressor" masitinib 4.5 mg/kg/d cohort, or either of the low-dose (masitinib 3.0 mg/kg/d) cohorts. Rates of treatment-emergent adverse events (AEs) (regardless of causality or post-onset ΔFS) were 88% with masitinib 4.5 mg/kg/d, 85% with 3.0 mg/kg/d, and 79% with placebo. Likewise, rates of serious AE were 31, 23, and 18%, respectively. No distinct event contributed to the higher rate observed for masitinib and no deaths were related to masitinib. Results show that masitinib at 4.5 mg/kg/d can benefit patients with ALS. A confirmatory phase 3 study will be initiated to substantiate these data.
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http://dx.doi.org/10.1080/21678421.2019.1632346DOI Listing
February 2020

Expanding the spectrum of genes responsible for hereditary motor neuropathies.

J Neurol Neurosurg Psychiatry 2019 10 5;90(10):1171-1179. Epub 2019 Jun 5.

Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS Ospedale San Raffaele, Milano, Italy

Background: Inherited peripheral neuropathies (IPNs) represent a broad group of genetically and clinically heterogeneous disorders, including axonal Charcot-Marie-Tooth type 2 (CMT2) and hereditary motor neuropathy (HMN). Approximately 60%-70% of cases with HMN/CMT2 still remain without a genetic diagnosis. Interestingly, mutations in HMN/CMT2 genes may also be responsible for motor neuron disorders or other neuromuscular diseases, suggesting a broad phenotypic spectrum of clinically and genetically related conditions. Thus, it is of paramount importance to identify novel causative variants in HMN/CMT2 patients to better predict clinical outcome and progression.

Methods: We designed a collaborative study for the identification of variants responsible for HMN/CMT2. We collected 15 HMN/CMT2 families with evidence for autosomal recessive inheritance, who had tested negative for mutations in 94 known IPN genes, who underwent whole-exome sequencing (WES) analyses. Candidate genes identified by WES were sequenced in an additional cohort of 167 familial or sporadic HMN/CMT2 patients using next-generation sequencing (NGS) panel analysis.

Results: Bioinformatic analyses led to the identification of novel or very rare variants in genes, which have not been previously associated with HMN/CMT2 (, , and ); in genes previously associated with HMN/CMT2 but in combination with different clinical phenotypes ( and ), and in the gene, which has been linked to HMN/CMT2 in only a few cases. These findings were further validated by Sanger sequencing, segregation analyses and functional studies.

Conclusions: These results demonstrate the broad spectrum of clinical phenotypes that can be associated with a specific disease gene, as well as the complexity of the pathogenesis of neuromuscular disorders.
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http://dx.doi.org/10.1136/jnnp-2019-320717DOI Listing
October 2019

Comparative Analysis of and Sporadic Disease in a Large Multicenter ALS Population: The Effect of Male Sex on Survival of Positive Patients.

Front Neurosci 2019 17;13:485. Epub 2019 May 17.

Department of Neuroscience, S. Agostino-Estense Hospital and University of Modena and Reggio Emilia, Modena, Italy.

We investigated whether the repeat expansion is associated with specific clinical features, comorbidities, and prognosis in patients with amyotrophic lateral sclerosis (ALS). A cohort of 1417 ALS patients, diagnosed between January 1, 2009 and December 31, 2013 by 13 Italian ALS Referral Centers, was screened for the repeat expansion, and the analyses were performed comparing patients carrying this expansion (ALS-C9Pos) to those negative for this and other explored ALS-related mutations (ALS without genetic mutations, ALSwoGM). Compared to the ALSwoGM group, ALS-C9Pos patients ( = 84) were younger at disease onset, at the first clinical observation and at diagnosis ( < 0.001). After correcting for these differences, we found that ALS-C9Pos patients had higher odds of bulbar onset, diagnosis of frontotemporal dementia (FTD) and family history of ALS, FTD, and Alzheimer's disease and had lower odds of spinal onset, non-invasive ventilation, hypertension and psychiatric diseases than ALSwoGM patients. Among these variables, those related to shorter survival time were: bulbar onset, presence of FTD, hypertension, psychiatric disease, and family history of ALS ( < 0.05). Cox proportional hazards regression multivariate analysis suggested that carrying the repeat expansion was an independent factor negatively impacting on survival time in men (HR 1.58, 95% CI 1.07-2.33, = 0.021), but not in women ( > 0.05) as well as in the whole sample ( > 0.05). When compared to ALSwoGM, ALS-C9Pos showed an earlier disease onset, no significant diagnostic delay and a higher odds of bulbar onset, FTD and family history of ALS and dementia. Moreover, male sex drove the negative effect of expanded variant on survival, confirming the hypothesis that sex is likely to be a crucial factor in the biology of -related disease.
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http://dx.doi.org/10.3389/fnins.2019.00485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534038PMC
May 2019

Proteostasis and ALS: protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS).

BMJ Open 2019 05 30;9(5):e028486. Epub 2019 May 30.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.

Introduction: Disruptions of proteasome and autophagy systems are central events in amyotrophic lateral sclerosis (ALS) and support the urgent need to find therapeutic compounds targeting these processes. The heat shock protein B8 (HSPB8) recognises and promotes the autophagy-mediated removal of misfolded mutant SOD1 and TDP-43 fragments from ALS motor neurons (MNs), as well as aggregating species of dipeptides produced in C9ORF72-related diseases. In ALS-SOD1 mice and in human ALS autopsy specimens, HSPB8 is highly expressed in spinal cord MNs that survive at the end stage of disease. Moreover, the HSPB8-BAG3-HSP70 complex maintains granulostasis, which avoids conversion of dynamic stress granules (SGs) into aggregation-prone assemblies. We will perform a randomised clinical trial (RCT) with colchicine, which enhances the expression of HSPB8 and of several autophagy players, blocking TDP-43 accumulation and exerting crucial activities for MNs function.

Methods And Analysis: Colchicine in amyotrophic lateral sclerosis (Co-ALS) is a double-blind, placebo-controlled, multicentre, phase II RCT. ALS patients will be enrolled in three groups (placebo, colchicine 0.01 mg/day and colchicine 0.005 mg/day) of 18 subjects treated with riluzole; treatment will last 30 weeks, and follow-up will last 24 weeks. The primary aim is to assess whether colchicine decreases disease progression as measured by ALS Functional Rating Scale - Revised (ALSFRS-R) at baseline and at treatment end. Secondary aims include assessment of (1) safety and tolerability of Colchicine in patiets with ALS; (2) changes in cellular activity (autophagy, protein aggregation, and SG and exosome secretion) and in biomarkers of disease progression (neurofilaments); (3) survival and respiratory function and (4) quality of life. Preclinical studies with a full assessment of autophagy and neuroinflammation biomarkers in fibroblasts, peripheral blood mononuclear cells and lymphoblasts will be conducted in parallel with clinic assessment to optimise time and resources.

Ethics And Dissemination: The study protocol was approved by the Ethics Committee of Area Vasta Emilia Nord and by Agenzia Italiana del Farmaco (EUDRACT N.2017-004459-21) based on the Declaration of Helsinki. This research protocol was written without patient involvement. Patients' association will be involved in disseminating the study design and results. Results will be presented during scientific symposia or published in scientific journals.

Trial Registration Number: EUDRACT 2017-004459-21 NCT03693781; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-028486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549675PMC
May 2019

Concurrence of NMOSD and ALS in a patient with hexanucleotide repeat expansions of C9orf72.

Amyotroph Lateral Scler Frontotemporal Degener 2019 08 22;20(5-6):449-452. Epub 2019 Apr 22.

a Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, IRCCS San Raffaele Scientific Institute , Vita-Salute San Raffaele University , Milan , Italy.

We describe a patient, previously known for NMOSD, who presented a rapidly progressive worsening of muscle strength, respiratory, and bulbar functions. ALS associated with cognitive impairment was diagnosed, while genetic analysis revealed a hexanucleotide repeat expansion in the C9orf72 gene. To the best of our knowledge, this is the first reported C9orf72-ALS patient with concurrent NMOSD. In consideration of the low prevalence of these two diseases, a by-chance co-occurrence is unlikely. Although the discovery of a disease-specific serum AQP4-IgG antibody has led to a broadening of the NMOSD, a progressive neurological deterioration, as shown by our patient, should be considered as a "red flag", leading to alternative diagnostic hypotheses. Our report supports the hypothesis that in C9orf72-ALS neuroinflammation may contribute to disease penetrance or to determine an aggressive clinical phenotype. Further investigations are needed in order to establish possible shared neuroinflammatory patterns between ALS, NMOSD, and other neuroinflammatory disorders.
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http://dx.doi.org/10.1080/21678421.2019.1604761DOI Listing
August 2019

Coexistence of variants in TBK1 and in other ALS-related genes elucidates an oligogenic model of pathogenesis in sporadic ALS.

Neurobiol Aging 2019 12 27;84:239.e9-239.e14. Epub 2019 Mar 27.

Centro Clinico NEMO, Roma, Italy; Dipartimento Scienze dell'invecchiamento, Neurologiche, Ortopediche e della testa-collo, Fondazione Policlinico Universitario A. Gemelli IRCCS, UOC Neurologia, Roma, Italy; Università Cattolica del Sacro Cuore, Istituto di Neurologia, Roma, Italy. Electronic address:

Variants in tank-binding kinase 1 (TBK1) are responsible for a significant proportion of amyotrophic lateral sclerosis (ALS) cases. In the present study, we analyzed variants in TBK1 extracted by targeted sequencing of 32 genes in a group of 406 Italian patients with ALS. We identified 7 different TBK1 variants in 7 sporadic cases, resulting in a frequency of 1.7%. Three patients had missense variants (p.R357Q, p.R358H, and p.R724C), one patient had a small deletion (p.E618del), and 3 had truncating variants (p.Y482*, p.R229*, and p.N681*). Notably, we found that 4 patients had an additional variant in ALS-related genes: 2 in OPTN and 2 in the 3'UTR region of FUS. By studying an independent group of 7 TBK1-mutated patients previously reported, we found another variant in the 3'UTR region of FUS in one patient. The presence of a second variant in TBK1 variant carriers is an interesting finding that needs to be investigated in larger cohorts of patients. These findings suggest that TBK1 belongs to the category of genes conferring a significantly increased risk but not sufficient to cause disease.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.03.010DOI Listing
December 2019

Brain MRI shows white matter sparing in Kennedy's disease and slow-progressing lower motor neuron disease.

Hum Brain Mapp 2019 07 28;40(10):3102-3112. Epub 2019 Mar 28.

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

The extent of central nervous system involvement in Kennedy's disease (KD) relative to other motor neuron disease (MND) phenotypes still needs to be clarified. In this study, we investigated cortical and white matter (WM) MRI alterations in 25 patients with KD, compared with 24 healthy subjects, 25 patients with sporadic amyotrophic lateral sclerosis (ALS), and 35 cases with lower motor neuron-predominant disease (LMND). LMND patients were clinically differentiated into 24 fast and 11 slow progressors. Whole-brain cortical thickness, WM tract-based spatial statistics and corticospinal tract (CST) tractography analyses were performed. No significant difference in terms of cortical thickness was found between groups. ALS patients showed widespread decreased fractional anisotropy and increased mean (MD) and radial diffusivity (radD) in the CST, corpus callosum and fronto-temporal extra-motor tracts, compared with healthy controls and other patient groups. CST tractography showed significant alterations of DT MRI metrics in ALS and LMND-fast patients whereas KD and LMND-slow patients were comparable with healthy controls. Our study demonstrated the absence of WM abnormalities in patients with KD and LMND-slow, in contrast with diffuse WM damage in ALS and focal CST degeneration in LMND-fast, supporting the use of DT MRI measures as powerful tools to differentiate fast- and slow-progressing MND syndromes, including KD.
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http://dx.doi.org/10.1002/hbm.24583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865482PMC
July 2019

Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial.

Lancet Neurol 2019 02 13;18(2):155-164. Epub 2018 Dec 13.

Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy. Electronic address:

Background: Spasticity is a major determinant of disability and decline in quality of life in patients with motor neuron disease. Cannabinoids have been approved for symptomatic treatment of spasticity in multiple sclerosis. We investigated whether cannabinoids might also reduce spasticity in patients with motor neuron disease.

Methods: We did an investigator-initiated, randomised, double-blind, placebo-controlled, phase 2 clinical trial at four tertiary motor neuron disease centres in Italy. Eligible patients were aged 18-80 years; had possible, laboratory-supported probable, probable, or definite amyotrophic lateral sclerosis as defined by revised El Escorial criteria, or primary lateral sclerosis according to Pringle's criteria; had spasticity symptoms due to motor neuron disease for at least 3 months; had spasticity scores of 1 or greater in at least two muscle groups on the Modified Ashworth Scale; and were taking an antispasticity regimen that was maintained at a stable dose for 30 days before enrolment. Participants were assigned (1:1) by an independent statistician via a computer-generated randomisation sequence to a standardised oromucosal spray (nabiximols) containing a defined combination of delta-9-tetrahydrocannabinol and cannabidiol (each 100 μL actuation contained 2·7 mg delta-9-tetrahydrocannabinol and 2·5 mg cannabidiol) or to placebo for 6 weeks. Participants self-titrated during the first 14 treatment days according to a predefined escalation scheme (maximum 12 actuations per 24 h), then maintained that dose for 4 weeks. The primary endpoint was the change in the score on the Modified Ashworth Scale, which was assessed at baseline and after 6 weeks. Safety and tolerability were also monitored. Participants, investigators, site personnel, and the study statistician were masked to treatment allocation. All randomised participants who received at least one dose of study drug were included in the analysis. This trial is registered with ClinicalTrials.gov, number NCT01776970. The trial is closed to new participants with follow-up completed.

Findings: Between Jan 19, 2013, and Dec 15, 2014, 60 participants were randomly assigned, and 59 participants were included in the final analysis (29 in the nabiximols group and 30 in the placebo group). Modified Ashworth Scale scores improved by a mean of 0·11 (SD 0·48) in the nabiximols group and deteriorated by a mean of 0·16 (0·47) in the placebo group (adjusted effect estimate -0·32 [95% CI -0·57 to -0·069]; p=0·013). Nabiximols was well tolerated, and no participants withdrew from the double-blind phase of the study. No serious adverse effects occurred.

Interpretation: In this proof-of-concept trial, nabiximols had a positive effect on spasticity symptoms in patients with motor neuron disease and had an acceptable safety and tolerability profile. These findings should be investigated further in larger clinical trials.

Funding: Italian Research Foundation for Amyotrophic Lateral Sclerosis.
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http://dx.doi.org/10.1016/S1474-4422(18)30406-XDOI Listing
February 2019