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1. Inflammatory signature in amyotrophic lateral sclerosis predicting disease progression

Author

Cinzia Femiano, Antonio Bruno, Luana Gilio, Fabio Buttari, Ettore Dolcetti, Giovanni Galifi, Federica Azzolini, Angela Borrelli, Roberto Furlan, Annamaria Finardi, Alessandra Musella, Georgia Mandolesi, Marianna Storto, Diego Centonze, and Mario Stampanoni Bassi

Subjects
Amyotrophic lateral sclerosis (ALS), Neuroinflammation, Disease progression, Cerebrospinal fluid (CSF), Cytokines, Neutrophil-to-lymphocytes ratio (NLR), Medicine, Science
Abstract

Abstract Experimental studies identified a role of neuroinflammation in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the role of inflammatory molecules as diagnostic and prognostic biomarkers in patients with ALS is unclear. In this cross-sectional study, the cerebrospinal fluid (CSF) levels of a set of inflammatory cytokines and chemokines were analyzed in 56 newly diagnosed ALS patients and in 47 age- and sex-matched control patients without inflammatory or degenerative neurological disorders. The molecules analyzed included: interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-17, granulocyte colony stimulating factor (GCSF), macrophage inflammatory protein (MIP)-1a, MIP-1b, tumor necrosis factors (TNF), eotaxin. Principal component analysis (PCA) was used to explore possible associations between CSF molecules and ALS diagnosis. In addition, we analyzed the association between CSF cytokine profiles and clinical characteristics, including the disease progression rate score, and peripheral inflammation assessed using the Neutrophil-to-lymphocyte ratio (NLR). PCA identified six principal components (PCs) explaining 70.67% of the total variance in the CSF cytokine set. The principal component (PC1) explained 26.8% of variance and showed a positive load with CSF levels of IL-9, IL-4, GCSF, IL-7, IL-17, IL-13, IL-6, IL-1β, TNF, and IL-2. Logistic regression showed a significant association between PC1 and ALS diagnosis. In addition, in ALS patients, the same component was significantly associated with higher disease progression rate score and positively correlated with NLR. CSF inflammatory activation in present in ALS at the time of diagnosis and may characterize patients at higher risk for disease progression.

Published
2024
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2. Visual vertical neglect in acquired brain injury: a systematic review

Author

Pasquale Moretta, Nicola Davide Cavallo, Eleonora Fonzo, Antonio Maiorino, Cesario Ferrante, Pasquale Ambrosino, Cinzia Femiano, Gabriella Santangelo, and Laura Marcuccio

Subjects
visual vertical neglect, visuospatial disorders, acquired brain injury, rehabilitation, clinical neuropsychology, Psychology, BF1-990
Abstract

Vertical neglect represents a visuospatial deficit occurring as a possible consequence of acquired brain injury (ABI). Differently from unilateral spatial neglect on horizontal space, vertical neglect is poorly studied in the literature and rarely assessed in clinical practice. In the available studies, the terms “radial,” “vertical,” and “altitudinal” neglect are often used interchangeably, although they do not describe the same spatial dimension. “Altitudinal” and “vertical” refer to the sagittal plane, whereas “radial” refers to the transverse plane. The term “vertical” is sometimes used interchangeably with respect to both axes. The aim of this systematic review was to identify the main characteristics of vertical neglect after ABI, the diagnostic tools used, and the treatment options. We also proposed a clarification of the manifestations and characteristics of vertical and radial neglect. The 23 articles reviewed, showed that the vertical neglect occurred more frequently on the lower space than on the upper space, that its presence was associated with horizontal neglect, and that it could also occur with compromise of the radial space, with the near radial being more common. The most frequent etiology associated with vertical neglect is vascular, particularly ischaemic. The lesions side are very heterogeneous and include both cortical and subcortical areas and all lobes, although the temporal lobe is most affected. With regard to the assessment tools, paper and pencil tasks are the most commonly used diagnostic tools to identify vertical neglect, although in recent years the use of computer-based tasks increased. Taken together, our results suggest that vertical neglect may be underestimated in patients with right hemisphere lesions and should always be assessed, especially in cases where the patient shows signs of horizontal neglect. The clinical assessment of vertical neglect is very important since it can lead to important functional limitations in everyday life, such as poor wheelchair handling, stumbling over unnoticed obstacles located below (or above), walking down stairs, taking off shoes.

Published
2024
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3. A Novel Homozygous Variant in the Fork-Head-Associated Domain of Polynucleotide Kinase Phosphatase in a Patient Affected by Late-Onset Ataxia With Oculomotor Apraxia Type 4

Author

Rosa Campopiano, Rosangela Ferese, Fabio Buttari, Cinzia Femiano, Diego Centonze, Francesco Fornai, Francesca Biagioni, Maria Antonietta Chiaravalloti, Mauro Magnani, Emiliano Giardina, Anna Ruzzo, and Stefano Gambardella

Subjects
ataxia with oculomotor apraxia, PNKP gene, clinical exome, late onset, neurogenetics, Neurology. Diseases of the nervous system, RC346-429
Abstract

Ataxia with oculomotor apraxia (AOA) is a clinical syndrome featuring a group of genetic diseases including at least four separate autosomal-recessive cerebellar ataxias. All these disorders are due to altered genes involved in DNA repair. AOA type 4 (AOA4) is caused by mutations in DNA repair factor polynucleotide kinase phosphatase (PNKP), which encodes for a DNA processing enzyme also involved in other syndromes featured by microcephaly or neurodegeneration. To date, only a few AOA4 patients have been reported worldwide. All these patients are homozygous or compound heterozygous carriers for mutations in the kinase domain of PNKP. In this report, we describe a 56 years old patient affected by AOA4 characterized by ataxia, polyneuropathy, oculomotor apraxia, and cognitive impairment with the absence of dystonia. The disease is characterized by a very late onset (50 years) when compared with other AOA4 patients described so far (median age of onset at 4 years). In this proband, Clinical Exome Analysis through Next Generation Sequencing (NGS) consisting of 4,800 genes, identified the PNKP homozygous mutation p.Gln50Glu. This variant, classified as a likely pathogenic variant according to American College of Medical Genetics (ACMG) guidelines, does not involve the kinase domain but falls in the fork-head-associated (FHA) domain. So far, mutations in such a domain were reported to associate only with a pure seizure syndrome without the classic AOA4 features. Therefore, this is the first report of patients carrying a mutation of the FHA domain within the PNKP gene which expresses the clinical phenotype known as the AOA4 syndrome and the lack of any seizure activity. Further studies are required to investigate specifically the significance of various mutations within the FHA domain, and it would be worth to correlate these variants with the age of onset of the AOA4 syndrome.

Published
2020
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4. Brain functional networks become more connected as amyotrophic lateral sclerosis progresses: a source level magnetoencephalographic study

Author

Pierpaolo Sorrentino, Rosaria Rucco, Francesca Jacini, Francesca Trojsi, Anna Lardone, Fabio Baselice, Cinzia Femiano, Gabriella Santangelo, Carmine Granata, Antonio Vettoliere, Maria Rosaria Monsurrò, Gioacchino Tedeschi, and Giuseppe Sorrentino

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

This study hypothesizes that the brain shows hyper connectedness as amyotrophic lateral sclerosis (ALS) progresses. 54 patients (classified as “early stage” or “advanced stage”) and 25 controls underwent magnetoencephalography and MRI recordings. The activity of the brain areas was reconstructed, and the synchronization between them was estimated in the classical frequency bands using the phase lag index. Brain topological metrics such as the leaf fraction (number of nodes with degree of 1), the degree divergence (a measure of the scale-freeness) and the degree correlation (a measure of disassortativity) were estimated. Betweenness centrality was used to estimate the centrality of the brain areas.In all frequency bands, it was evident that, the more advanced the disease, the more connected, scale-free and disassortative the brain networks. No differences were evident in specific brain areas. Such modified brain topology is sub-optimal as compared to controls. Within this framework, our study shows that brain networks become more connected according to disease staging in ALS patients. Keywords: Motor neuron disease, Connectivity, Magnetic source imaging, Neuroimaging biomarker

Published
2018
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5. Comparative Analysis of C9orf72 and Sporadic Disease in a Large Multicenter ALS Population: The Effect of Male Sex on Survival of C9orf72 Positive Patients

Author

Francesca Trojsi, Mattia Siciliano, Cinzia Femiano, Gabriella Santangelo, Christian Lunetta, Andrea Calvo, Cristina Moglia, Kalliopi Marinou, Nicola Ticozzi, Christian Ferro, Carlo Scialò, Gianni Sorarù, Amelia Conte, Yuri M. Falzone, Rosanna Tortelli, Massimo Russo, Valeria Ada Sansone, Adriano Chiò, Gabriele Mora, Vincenzo Silani, Paolo Volanti, Claudia Caponnetto, Giorgia Querin, Mario Sabatelli, Nilo Riva, Giancarlo Logroscino, Sonia Messina, Antonio Fasano, Maria Rosaria Monsurrò, Gioacchino Tedeschi, and Jessica Mandrioli

Subjects
amyotrophic lateral sclerosis, C9orf72 expansion, gender, comorbidity, survival, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

We investigated whether the C9orf72 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 C9orf72 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 (n = 84) were younger at disease onset, at the first clinical observation and at diagnosis (p < 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 (p < 0.05). Cox proportional hazards regression multivariate analysis suggested that carrying the C9orf72 repeat expansion was an independent factor negatively impacting on survival time in men (HR 1.58, 95% CI 1.07–2.33, p = 0.021), but not in women (p > 0.05) as well as in the whole sample (p > 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 C9orf72-related disease.

Published
2019
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6. Apathy Is Correlated with Widespread Diffusion Tensor Imaging (DTI) Impairment in Amyotrophic Lateral Sclerosis

Author

Cinzia Femiano, Francesca Trojsi, Giuseppina Caiazzo, Mattia Siciliano, Carla Passaniti, Antonio Russo, Alvino Bisecco, Mario Cirillo, Maria Rosaria Monsurrò, Fabrizio Esposito, Gioacchino Tedeschi, and Gabriella Santangelo

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Apathy is recognized as the most common behavioral change in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disorder. Particularly, apathy has been reported to be associated with poor ALS prognosis. However, the brain microstructural correlates of this behavioral symptom, reported as the most common in ALS, have not been completely elucidated. Using diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS), here we aimed to quantify the correlation between brain microstructural damage and apathy scores in the early stages of ALS. Twenty-one consecutive ALS patients, in King’s clinical stage 1 or 2, and 19 age- and sex-matched healthy controls (HCs) underwent magnetic resonance imaging and neuropsychological examination. Between-group comparisons did not show any significant difference on cognitive and behavioral variables. When compared to HCs, ALS patients exhibited a decreased fractional anisotropy (FA) [p

Published
2018
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7. Theory of Mind and its neuropsychological and Quality of Life correlates in the early stages of amyotrophic lateral sclerosis

Author

Francesca Trojsi, Mattia Siciliano, Antonio Russo, Carla Passaniti, Cinzia Femiano, Teresa Ferrantino, Stefania De Liguoro, Luigi Lavorgna, Maria Rosaria Monsurrò, Gioacchino Tedeschi, and Gabriella Santangelo

Subjects
Amyotrophic Lateral Sclerosis, Quality of Life, Theory of Mind, social cognition, Emotion attribution, Psychology, BF1-990
Abstract

This study aims to explore the potential impairment of Theory of Mind (ToM) (i.e., the ability to represent cognitive and affective mental states to both self and others) and the clinical, neuropsychological and Quality of Life (QoL) correlates of these cognitive abnormalities in the early stages of amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disease recently recognized as a part of the same clinical and pathological spectrum of frontotemporal lobar degeneration.Twenty-two consecutive, cognitively intact ALS patients, and 15 healthy controls, underwent assessment of executive, verbal comprehension, visuospatial, behavioural and QoL measures, as well as of the ToM abilities by Emotion Attribution Task (EAT), Advanced Test of ToM (ATT) and Eyes Task (ET).ALS patients obtained significantly lower scores than controls on EAT and ET. No significant difference was found between the two groups on ATT. As regard to type of ALS onset, patients with bulbar onset performed worse than those with spinal onset on ET. Correlation analysis revealed that EAT and ET were positively correlated with education, memory prose, visuo-spatial performances and Mental Health scores among QoL items.Our results suggest that not only cognitive but also affective subcomponents of ToM may be impaired in the early stages of ALS, with significant linkage to disease onset and dysfunctions of less executively demanding conditions, causing potential impact on patients' Mental Health.

Published
2016
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8. Microstructural changes across different clinical milestones of disease in amyotrophic lateral sclerosis.

Author

Francesca Trojsi, Giuseppina Caiazzo, Daniele Corbo, Giovanni Piccirillo, Viviana Cristillo, Cinzia Femiano, Teresa Ferrantino, Mario Cirillo, Maria Rosaria Monsurrò, Fabrizio Esposito, and Gioacchino Tedeschi

Subjects
Medicine, Science
Abstract

Neurodegenerative process in amyotrophic lateral sclerosis (ALS) has been proven to involve several cortical and subcortical brain regions within and beyond motor areas. However, how ALS pathology spreads progressively during disease evolution is still unknown. In this cross-sectional study we investigated 54 ALS patients, divided into 3 subsets according to the clinical stage, and 18 age and sex-matched healthy controls, by using tract-based spatial statistics (TBSS) diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) analyses. We aimed to identify white (WM) and gray matter (GM) patterns of disease distinctive of each clinical stage, corresponding to specific clinical milestones. ALS cases in stage 2A (i.e., at diagnosis) were characterized by GM and WM impairment of left motor and premotor cortices and brainstem at ponto-mesenchephalic junction. ALS patients in clinical stage 2B (with impairment of two functional regions) exhibited decreased fractional anisotropy (FA) (p

Published
2015
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9. Amyotrophic Lateral Sclerosis and Multiple Sclerosis Overlap: A Case Report

Author

Francesca Trojsi, Anna Sagnelli, Giovanni Cirillo, Giovanni Piccirillo, Cinzia Femiano, Francesco Izzo, Maria Rosaria Monsurrò, and Gioacchino Tedeschi

Subjects
Medicine
Abstract

The concurrence of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) is extremely rare. We reported the case of a 33-year-old woman with a past history of paresthesias at the right hand, who developed progressive quadriparesis with muscular atrophy of limbs and, finally, bulbar signs and dyspnea. Clinical and neurophysiologic investigations revealed upper and lower motor neuron signs in the bulbar region and extremities, suggesting the diagnosis of ALS. Moreover, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis demonstrated 3 periventricular and juxtacortical lesions, hyperintense in T2 and FLAIR sequences, and 3 liquoral immunoglobulin G (IgG) oligoclonal bands, consistent with diagnosis of primary progressive MS (PPMS). This unusual overlap of ALS and MS leads to the discussion of a hypothetical common pathological process of immunological dysfunction in these two disorders, although the role of immune response in ALS remains ambivalent and unclear.

Published
2012
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10. Continuous subcutaneous apomorphine infusion in Parkinson’s disease: causes of discontinuation and subsequent treatment strategies

Author

Marco Santilli, Sara Varanese, Alfonso Fasano, Francesco Lena, Enrica Olivola, Nicola Modugno, Cinzia Femiano, and Diego Centonze

Subjects
Male, Pediatrics, Neurology, Parkinson's disease, Apomorphine, Deep Brain Stimulation, DBS, Dyskinesia, Parkinson’s disease, Infusions, Subcutaneous, Levodopa, 0302 clinical medicine, 80 and over, Electronic Health Records, Medicine, 030212 general & internal medicine, Neuroradiology, Aged, 80 and over, Drug Substitution, Subcutaneous, Carbidopa, Parkinson Disease, General Medicine, Middle Aged, Drug Combinations, Psychiatry and Mental health, Dopamine Agonists, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, Neurosurgery, medicine.symptom, medicine.drug, Adult, Infusions, medicine.medical_specialty, Mistake, Dermatology, Settore MED/26, GeneralLiterature_MISCELLANEOUS, Medication Adherence, 03 medical and health sciences, Aged, Cognitive Dysfunction, Humans, Retrospective Studies, ComputingMethodologies_COMPUTERGRAPHICS, business.industry, medicine.disease, Discontinuation, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Continuous subcutaneous apomorphine infusion (CSAI) is a well-recognized therapeutic option for the management of motor fluctuations in Parkinson's disease (PD), although clinical experience suggests that most patients discontinue CSAI after a variable amount of time due to several causes and circumstances. The objective of the present study was to evaluate the reasons of CSAI discontinuation and to investigate which treatment was adopted afterwards. Two independent raters retrospectively reviewed the electronic medical record of 114 patients treated with CSAI for at least 6 months. The records were reviewed regarding efficacy, safety, and evolution of CSAI treatment. Most of PD patients on CSAI had a significant improvement in their clinical condition. Lack of improvement of dyskinesia was the most frequent causes of treatment discontinuation. The second reason for CSAI discontinuation was cognitive deterioration. At CSAI discontinuation, younger patients were more likely to undergo deep brain stimulation (DBS), while older patients and patients with cognitive impairment were more likely switched to oral therapy alone (OTA). CSAI is an effective treatment that unfortunately must be discontinued in a great number of patients with advanced PD. As older age is the main limiting factor for accessing second-level therapies at CSAI discontinuation, CSAI treatment should not be postponed to older age. CSAI might be considered a good first-line and fast strategy in patients undergoing rapid deterioration of their quality of life while waiting for DBS or levodopa/carbidopa intestinal gel therapy.

Published
2019

11. A Large Family with p.Arg554His Mutation in

Author

Rosa, Campopiano, Cinzia, Femiano, Maria Antonietta, Chiaravalloti, Rosangela, Ferese, Diego, Centonze, Fabio, Buttari, Stefania, Zampatti, Mirco, Fanelli, Stefano, Amatori, Carmelo, D'Alessio, Emiliano, Giardina, Francesco, Fornai, Francesca, Biagioni, Marianna, Storto, and Stefano, Gambardella

Subjects
Adult, Male, next generation sequencing, diagnosis, Motor Disorders, ABCD1, Brain, Middle Aged, ATP Binding Cassette Transporter, Subfamily D, Member 1, Article, Mutation, Humans, Disabled Persons, Female, X-linked adrenoleukodystrophy, Adrenoleukodystrophy, neurogenetics, Genetic Association Studies, Aged, Demyelinating Diseases
Abstract

X-linked adrenoleukodystrophy (X-ALD, OMIM #300100) is the most common peroxisomal disorder clinically characterized by two main phenotypes: adrenomyeloneuropathy (AMN) and the cerebral demyelinating form of X-ALD (cerebral ALD). The disease is caused by defects in the gene for the adenosine triphosphate (ATP)-binding cassette protein, subfamily D (ABCD1) that encodes the peroxisomal transporter of very-long-chain fatty acids (VLCFAs). The defective function of ABCD1 protein prevents β-oxidation of VLCFAs, which thus accumulate in tissues and plasma, to represent the hallmark of the disease. As in many X-linked diseases, it has been routinely expected that female carriers are asymptomatic. Nonetheless, recent findings indicate that most ABCD1 female carriers become symptomatic, with a motor disability that typically appears between the fourth and fifth decade. In this paper, we report a large family in which affected males died during the first decade, while affected females develop, during the fourth decade, progressive lower limb weakness with spastic or ataxic-spastic gait, tetra-hyperreflexia with sensory alterations. Clinical and genetic evaluations were performed in nine subjects, eight females (five affected and three healthy) and one healthy male. All affected females were carriers of the c.1661G>A (p.Arg554His, rs201568579) mutation. This study strengthens the relevance of clinical symptoms in female carriers of ABCD1 mutations, which leads to a better understanding of the role of the genetic background and the genotype-phenotype correlation. This indicates the relevance to include ABCD1 genes in genetic panels for gait disturbance in women.

Published
2021

12. A large family with p.Arg554his mutation in abcd1: Clinical features and genotype/phenotype correlation in female carriers

Author

Rosangela Ferese, Stefania Zampatti, Carmelo D'Alessio, Francesca Biagioni, Mirco Fanelli, Stefano Gambardella, Stefano Amatori, Maria Antonietta Chiaravalloti, Emiliano Giardina, Cinzia Femiano, Diego Centonze, Fabio Buttari, Rosa Campopiano, Francesco Fornai, and Marianna Storto

Subjects
0301 basic medicine, diagnosis, Physiology, Neurogenetics, Disease, QH426-470, medicine.disease_cause, Asymptomatic, ABCD1, X-linked adrenoleukodystrophy, neurogenetics, next generation sequencing, 03 medical and health sciences, 0302 clinical medicine, Next generation sequencing, Peroxisomal disorder, Diagnosis, Genetics, Spastic, Medicine, Genetics (clinical), Mutation, business.industry, medicine.disease, Phenotype, 030104 developmental biology, Settore MED/03, Adrenoleukodystrophy, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

X-linked adrenoleukodystrophy (X-ALD, OMIM #300100) is the most common peroxisomal disorder clinically characterized by two main phenotypes: adrenomyeloneuropathy (AMN) and the cerebral demyelinating form of X-ALD (cerebral ALD). The disease is caused by defects in the gene for the adenosine triphosphate (ATP)-binding cassette protein, subfamily D (ABCD1) that encodes the peroxisomal transporter of very-long-chain fatty acids (VLCFAs). The defective function of ABCD1 protein prevents β-oxidation of VLCFAs, which thus accumulate in tissues and plasma, to represent the hallmark of the disease. As in many X-linked diseases, it has been routinely expected that female carriers are asymptomatic. Nonetheless, recent findings indicate that most ABCD1 female carriers become symptomatic, with a motor disability that typically appears between the fourth and fifth decade. In this paper, we report a large family in which affected males died during the first decade, while affected females develop, during the fourth decade, progressive lower limb weakness with spastic or ataxic-spastic gait, tetra-hyperreflexia with sensory alterations. Clinical and genetic evaluations were performed in nine subjects, eight females (five affected and three healthy) and one healthy male. All affected females were carriers of the c.1661G&gt, A (p.Arg554His, rs201568579) mutation. This study strengthens the relevance of clinical symptoms in female carriers of ABCD1 mutations, which leads to a better understanding of the role of the genetic background and the genotype-phenotype correlation. This indicates the relevance to include ABCD1 genes in genetic panels for gait disturbance in women.

Published
2021

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

Author

Yuri Matteo Falzone, Camilla Cividini, Silvia Basaia, Maria Rosaria Monsurrò, Francesca Trojsi, Andrea Falini, Gioacchino Tedeschi, Elisa Canu, Cristina Moglia, Nilo Riva, Edoardo G. Spinelli, Adriano Chiò, Veronica Castelnovo, Massimo Filippi, Cinzia Femiano, Federica Agosta, Basaia, Silvia, Agosta, Federica, Cividini, Camilla, Trojsi, Francesca, Riva, Nilo, Spinelli, Edoardo G, Moglia, Cristina, Femiano, Cinzia, Castelnovo, Veronica, Canu, Elisa, Falzone, Yuri, Monsurrò, Maria Rosaria, Falini, Andrea, Chiò, Adriano, Tedeschi, Gioacchino, Filippi, Massimo, Basaia, S., Agosta, F., Cividini, C., Trojsi, F., Riva, N., Spinelli, E. G., Moglia, C., Femiano, C., Castelnovo, V., Canu, E., Falzone, Y., Monsurro, M. R., Falini, A., Chio, A., Tedeschi, G., and Filippi, M.

Subjects
Adult, Male, Connectomics, Neuropsychological Tests, Article, 030218 nuclear medicine & medical imaging, Muscular Atrophy, Spinal, 03 medical and health sciences, 0302 clinical medicine, Basal ganglia, medicine, Connectome, Humans, Cognitive Dysfunction, Prospective Studies, Amyotrophic lateral sclerosis, Motor Neuron Disease, Primary Lateral Sclerosis, Aged, Aged, 80 and over, business.industry, Amyotrophic Lateral Sclerosis, Neuropsychology, Brain, Motor neuron, Progressive muscular atrophy, Middle Aged, medicine.disease, Magnetic Resonance Imaging, medicine.anatomical_structure, Case-Control Studies, Female, Neurology (clinical), business, Neuroscience, 030217 neurology & neurosurgery
Abstract

ObjectiveTo investigate structural and functional neural organization in amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), and progressive muscular atrophy (PMA).MethodsA 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.ResultsCompared 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.ConclusionsThis 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.

Published
2020

14. Brain functional networks become more connected as amyotrophic lateral sclerosis progresses: a source level magnetoencephalographic study

Author

Francesca Trojsi, Pierpaolo Sorrentino, Gioacchino Tedeschi, Carmine Granata, Fabio Baselice, Maria Rosaria Monsurrò, Cinzia Femiano, Gabriella Santangelo, Giuseppe Sorrentino, Francesca Jacini, Antonio Vettoliere, Anna Lardone, Rosaria Rucco, Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Sorrentino, Pierpaolo, Rucco, Rosaria, Jacini, Francesca, Trojsi, Francesca, Lardone, Anna, Baselice, Fabio, Femiano, Cinzia, Santangelo, Gabriella, Granata, Carmine, Vettoliere, Antonio, Monsurrò, Maria Rosaria, Tedeschi, Gioacchino, and Sorrentino, Giuseppe

Subjects
0301 basic medicine, Male, Social connectedness, Cognitive Neuroscience, Magnetic source imaging, Source level, Biology, lcsh:Computer applications to medicine. Medical informatics, lcsh:RC346-429, Functional networks, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Betweenness centrality, Nuclear Medicine and Imaging, medicine, Humans, Radiology, Nuclear Medicine and imaging, Motor neuron disease, Amyotrophic lateral sclerosis, ComputingMilieux_MISCELLANEOUS, lcsh:Neurology. Diseases of the nervous system, Aged, Connectivity, Neuroimaging biomarker, Radiology, Nuclear Medicine and Imaging, Neurology, Neurology (clinical), medicine.diagnostic_test, [SCCO.NEUR]Cognitive science/Neuroscience, Amyotrophic Lateral Sclerosis, Brain, Magnetoencephalography, Regular Article, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Phase lag, 030104 developmental biology, Disease Progression, lcsh:R858-859.7, Female, Nerve Net, Centrality, Radiology, Neuroscience, 030217 neurology & neurosurgery
Abstract

This study hypothesizes that the brain shows hyper connectedness as amyotrophic lateral sclerosis (ALS) progresses. 54 patients (classified as “early stage” or “advanced stage”) and 25 controls underwent magnetoencephalography and MRI recordings. The activity of the brain areas was reconstructed, and the synchronization between them was estimated in the classical frequency bands using the phase lag index. Brain topological metrics such as the leaf fraction (number of nodes with degree of 1), the degree divergence (a measure of the scale-freeness) and the degree correlation (a measure of disassortativity) were estimated. Betweenness centrality was used to estimate the centrality of the brain areas. In all frequency bands, it was evident that, the more advanced the disease, the more connected, scale-free and disassortative the brain networks. No differences were evident in specific brain areas. Such modified brain topology is sub-optimal as compared to controls. Within this framework, our study shows that brain networks become more connected according to disease staging in ALS patients., Highlights • Brain networks grow more connected as amyotrophic lateral sclerosis progresses. • Such changes affect the brain globally, they are not focal. • The topology of brain networks reaches a suboptimal configuration as amyotrophic lateral sclerosis progresses. • Brain networks modifications involve multiple frequency bands. • Brain networks become more scale-free and more disassortative as disease progresses.

Published
2018

15. Comparative Analysis of

Author

Francesca, Trojsi, Mattia, Siciliano, Cinzia, Femiano, Gabriella, Santangelo, Christian, Lunetta, Andrea, Calvo, Cristina, Moglia, Kalliopi, Marinou, Nicola, Ticozzi, Christian, Ferro, Carlo, Scialò, Gianni, Sorarù, Amelia, Conte, Yuri M, Falzone, Rosanna, Tortelli, Massimo, Russo, Valeria Ada, Sansone, Adriano, Chiò, Gabriele, Mora, Vincenzo, Silani, Paolo, Volanti, Claudia, Caponnetto, Giorgia, Querin, Mario, Sabatelli, Nilo, Riva, Giancarlo, Logroscino, Sonia, Messina, Antonio, Fasano, Maria Rosaria, Monsurrò, Gioacchino, Tedeschi, and Jessica, Mandrioli

Subjects
C9orf72 expansion, amyotrophic lateral sclerosis, comorbidity, gender, survival, Neuroscience, Original Research
Abstract

We investigated whether the C9orf72 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 C9orf72 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 (n = 84) were younger at disease onset, at the first clinical observation and at diagnosis (p < 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 (p < 0.05). Cox proportional hazards regression multivariate analysis suggested that carrying the C9orf72 repeat expansion was an independent factor negatively impacting on survival time in men (HR 1.58, 95% CI 1.07–2.33, p = 0.021), but not in women (p > 0.05) as well as in the whole sample (p > 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 C9orf72-related disease.

Published
2019

16. Apathy Is Correlated with Widespread Diffusion Tensor Imaging (DTI) Impairment in Amyotrophic Lateral Sclerosis

Author

Fabrizio Esposito, Maria Rosaria Monsurrò, Francesca Trojsi, Gabriella Santangelo, Giuseppina Caiazzo, Mario Cirillo, Antonio Russo, Mattia Siciliano, Gioacchino Tedeschi, Cinzia Femiano, Alvino Bisecco, Carla Passaniti, Femiano, Cinzia, Trojsi, Francesca, Caiazzo, Giuseppina, Siciliano, Mattia, Passaniti, Carla, Russo, Antonio, Bisecco, Alvino, Cirillo, Mario, Monsurrò, Maria Rosaria, Esposito, Fabrizio, Tedeschi, Gioacchino, and Santangelo, Gabriella

Subjects
Male, medicine.medical_specialty, Article Subject, Apathy, Neurosciences. Biological psychiatry. Neuropsychiatry, Audiology, Corpus callosum, Gyrus Cinguli, Severity of Illness Index, 050105 experimental psychology, Corpus Callosum, White matter, 03 medical and health sciences, 0302 clinical medicine, Fractional anisotropy, medicine, Humans, 0501 psychology and cognitive sciences, Amyotrophic lateral sclerosis, Aged, medicine.diagnostic_test, business.industry, 05 social sciences, Amyotrophic Lateral Sclerosis, Neuropsychology, Magnetic resonance imaging, General Medicine, Middle Aged, medicine.disease, White Matter, Neuropsychology and Physiological Psychology, medicine.anatomical_structure, Diffusion Tensor Imaging, Neurology, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, RC321-571, Diffusion MRI, Research Article
Abstract

Apathy is recognized as the most common behavioral change in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disorder. Particularly, apathy has been reported to be associated with poor ALS prognosis. However, the brain microstructural correlates of this behavioral symptom, reported as the most common in ALS, have not been completely elucidated. Using diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS), here we aimed to quantify the correlation between brain microstructural damage and apathy scores in the early stages of ALS. Twenty-one consecutive ALS patients, in King’s clinical stage 1 or 2, and 19 age- and sex-matched healthy controls (HCs) underwent magnetic resonance imaging and neuropsychological examination. Between-group comparisons did not show any significant difference on cognitive and behavioral variables. When compared to HCs, ALS patients exhibited a decreased fractional anisotropy (FA) [p<.05, threshold-free cluster enhancement (TFCE) corrected] in the corpus callosum and in bilateral anterior cingulate cortices. Self-rated Apathy Evaluation Scale (AES) scores and self-rated apathy T-scores of the Frontal Systems Behavior (FrSBe) scale were found inversely correlated to FA measures (p<.05, TFCE corrected) in widespread white matter (WM) areas, including several associative fiber tracts in the frontal, temporal, and parietal lobes. These results point towards an early microstructural degeneration of brain areas biologically involved in cognition and behavior regulation in ALS. Moreover, the significant correlations between apathy and DTI measures in several brain areas may suggest that subtle WM changes may be associated with mild behavioral symptoms in ALS even in the absence of overt cognitive and behavioral impairment.

Published
2018

17. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, null Shankaracharya, Bradley N. Smith, Giuseppe Marangi, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, Luigi Ferrucci, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, Aaron D. Gitler, Tim Harris, Richard M. Myers, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael C. Zody, Julia Kaye, Steven Finkbeiner, Stacia K. Wyman, Alex LeNail, Leandro Lima, Ernest Fraenkel, Clive N. Svendsen, Leslie M. Thompson, Jennifer E. Van Eyk, James D. Berry, Timothy M. Miller, Stephen J. Kolb, Merit Cudkowicz, Emily Baxi, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hisham Hamdalla, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H. Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik P. Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S. Mora, Vivian E. Drory, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Orla Hardiman, Kelly L. Williams, Jennifer A. Fifita, Garth A. Nicholson, Ian P. Blair, Guy A. Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Ekaterina Rogaeva, Lorne Zinman, Lyle W. Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, William Camu, John Q. Trojanowski, Vivianna M. Van Deerlin, Robert H. Brown, Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone, Pentti Tienari, Vincenzo Silani, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor, John E. Landers, Isabella Simone, Giancarlo Logroscino, Ilaria Bartolomei, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Stefania Tranquilli, Stefania Cuccu, Daniela Corongiu, Maurizio Melis, Antonio Milia, Francesco Marrosu, Maria Giovanna Marrosu, Gianluca Floris, Antonino Cannas, Gianluigi Mancardi, Paola Origone, Paola Mandich, Sebastiano Cavallaro, Kalliopi Marinou, Riccardo Sideri, Silvana Penco, Lorena Mosca, Giuseppe Lauria Pinter, Massimo Corbo, Paola Carrera, Nicola Fini, Antonio Fasano, Lucio Tremolizzo, Alessandro Arosio, Carlo Ferrarese, Gioacchino Tedeschi, Maria Rosaria Monsurrò, Giovanni Piccirillo, Cinzia Femiano, Anna Ticca, Enzo Ortu, Rossella Spataro, Tiziana Colletti, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Marialuisa Santarelli, Antonio Petrucci, Maura Pugliatti, Angelo Pirisi, Leslie D. Parish, Patrizia Occhineri, Fabio Giannini, Claudia Ricci, Michele Benigni, Tea B. Cau, Daniela Loi, Cristina Moglia, Maura Brunetti, Marco Barberis, Gabriella Restagno, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Canosa, Antonio Ilardi, Umberto Manera, Maurizio Grassano, Raffaella Tanel, Fabrizio Pisano, Neil A. Shneider, Stephen Goutman, Siddharthan Chandran, Suvankar Pal, George Manousakis, Stanley H. Appel, Ericka Simpson, Leo Wang, Summer Gibson, Richard Bedlack, David Lacomis, Dhruv Sareen, Alexander Sherman, Lucie Bruijn, Michelle Penny, Andrew S. Allen, Stanley Appel, Richard S. Bedlack, Braden E. Boone, Robert Brown, John P. Carulli, Alessandra Chesi, Wendy K. Chung, Elizabeth T. Cirulli, Gregory M. Cooper, Julien Couthouis, Aaron G. Day-Williams, Patrick A. Dion, Yujun Han, Sebastian D. Hayes, Angela L. Jones, Jonathan Keebler, Brian J. Krueger, Brittany N. Lasseigne, Shawn E. Levy, Yi-Fan Lu, Tom Maniatis, Slavé Petrovski, Alya R. Raphael, Zhong Ren, Katherine B. Sims, John F. Staropoli, Lindsay L. Waite, Quanli Wang, Jack R. Wimbish, Winnie W. Xin, Justin Kwan, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Noah Zaitlen, Gregory A. Cox, Steve Finkbeiner, Efthimios Dardiotis, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos A. Patsopoulos, Joshua Dubnau, Avindra Nath, Stacia Wyman, Alexander LeNail, Jenny Van Eyk, Stephan Züchner, Rebecca Schule, Jacob McCauley, Sumaira Hussain, Anne Cooley, Marielle Wallace, Christine Clayman, Richard Barohn, Jeffrey Statland, John Ravits, Andrea Swenson, Carlayne Jackson, Jaya Trivedi, Shaida Khan, Jonathan Katz, Liberty Jenkins, Ted Burns, Kelly Gwathmey, James Caress, Corey McMillan, Lauren Elman, Erik Pioro, Jeannine Heckmann, Yuen So, David Walk, Samuel Maiser, Jinghui Zhang, Fabiola De Marchi, Stefania Corti, Mauro Ceroni, Gabriele Siciliano, Massimiliano Filosto, Maurizio Inghilleri, Silvia Peverelli, Claudia Colombrita, Barbara Poletti, Luca Maderna, Roberto Del Bo, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Viviana Pensato, Barbara Castellotti, Vincent Meininger, Gérard Besson, Emmeline Lagrange, Pierre Clavelou, Nathalie Guy, Philippe Couratier, Patrick Vourch, Véronique Danel, Emilien Bernard, Gwendal Lemasson, Ahmad Al Kheifat, Peter Andersen, Adriano Chio, Jonathan Cooper-Knock, Annelot Dekker, Vivian Drory, Alberto Garcia Redondo, Marc Gotkine, Winston Hide, Alfredo Iacoangeli, Jonathan Glass, Kevin Kenna, Matthew Kiernan, John Landers, Russell McLaughlin, Jonathan Mill, Miguel Mitne Neto, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Susana Pinto, Sara Pulit, Pamela Shaw, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristel van Eijk, Michael van Es, Joke van Vugt, Jan Veldink, Mayana Zatz, Denis C. Bauer, Natalie A. Twine, Department of Neurosciences, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Clinicum, Research Programme for Molecular Neurology, University of Helsinki, Medicum, Department of Pathology, HUS Neurocenter, Nicolas A., Kenna K.P., Renton A.E., Ticozzi N., Faghri F., Chia R., Dominov J.A., Kenna B.J., Nalls M.A., Keagle P., Rivera A.M., van Rheenen W., Murphy N.A., van Vugt J.J.F.A., Geiger J.T., Van der Spek R.A., Pliner H.A., Shankaracharya, Smith B.N., Marangi G., Topp S.D., Abramzon Y., Gkazi A.S., Eicher J.D., Kenna A., Logullo F.O., Simone I.L., Logroscino G., Salvi F., Bartolomei I., Borghero G., Murru M.R., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M.G., Floris G., Cannas A., Capasso M., Caponnetto C., Mancardi G., Origone P., Mandich P., Conforti F.L., Cavallaro S., Mora G., Marinou K., Sideri R., Penco S., Mosca L., Lunetta C., Pinter G.L., Corbo M., Riva N., Carrera P., Volanti P., Mandrioli J., Fini N., Fasano A., Tremolizzo L., Arosio A., Ferrarese C., Trojsi F., Tedeschi G., Monsurro M.R., Piccirillo G., Femiano C., Ticca A., Ortu E., La Bella V., Spataro R., Colletti T., Sabatelli M., Zollino M., Conte A., Luigetti M., Lattante S., Santarelli M., Petrucci A., Pugliatti M., Pirisi A., Parish L.D., Occhineri P., Giannini F., Battistini S., Ricci C., Benigni M., Cau T.B., Loi D., Calvo A., Moglia C., Brunetti M., Barberis M., Restagno G., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Canosa A., Ilardi A., Manera U., Grassano M., Tanel R., Pisano F., Mazzini L., Messina S., D'Alfonso S., Corrado L., Ferrucci L., Harms M.B., Goldstein D.B., Shneider N.A., Goutman S.A., Simmons Z., Miller T.M., Chandran S., Pal S., Manousakis G., Appel S.H., Simpson E., Wang L., Baloh R.H., Gibson S.B., Bedlack R., Lacomis D., Sareen D., Sherman A., Bruijn L., Penny M., Moreno C.D.A.M., Kamalakaran S., Allen A.S., Boone B.E., Brown R.H., Carulli J.P., Chesi A., Chung W.K., Cirulli E.T., Cooper G.M., Couthouis J., Day-Williams A.G., Dion P.A., Gitler A.D., Glass J.D., Han Y., Harris T., Hayes S.D., Jones A.L., Keebler J., Krueger B.J., Lasseigne B.N., Levy S.E., Lu Y.-F., Maniatis T., McKenna-Yasek D., Myers R.M., Petrovski S., Pulst S.M., Raphael A.R., Ravits J.M., Ren Z., Rouleau G.A., Sapp P.C., Sims K.B., Staropoli J.F., Waite L.L., Wang Q., Wimbish J.R., Xin W.W., Phatnani H., Kwan J., Broach J., Arcila-Londono X., Lee E.B., Van Deerlin V.M., Fraenkel E., Ostrow L.W., Baas F., Zaitlen N., Berry J.D., Malaspina A., Fratta P., Cox G.A., Thompson L.M., Finkbeiner S., Dardiotis E., Hornstein E., MacGowan D.J.L., Heiman-Patterson T., Hammell M.G., Patsopoulos N.A., Dubnau J., Nath A., Musunuri R.L., Evani U.S., Abhyankar A., Zody M.C., Kaye J., Wyman S.K., LeNail A., Lima L., Rothstein J.D., Svendsen C.N., Van Eyk J.E., Maragakis N.J., Kolb S.J., Cudkowicz M., Baxi E., Benatar M., Taylor J.P., Wu G., Rampersaud E., Wuu J., Rademakers R., Zuchner S., Schule R., McCauley J., Hussain S., Cooley A., Wallace M., Clayman C., Barohn R., Statland J., Swenson A., Jackson C., Trivedi J., Khan S., Katz J., Jenkins L., Burns T., Gwathmey K., Caress J., McMillan C., Elman L., Pioro E.P., Heckmann J., So Y., Walk D., Maiser S., Zhang J., Silani V., Gellera C., Ratti A., Taroni F., Lauria G., Verde F., Fogh I., Tiloca C., Comi G.P., Soraru G., Cereda C., De Marchi F., Corti S., Ceroni M., Siciliano G., Filosto M., Inghilleri M., Peverelli S., Colombrita C., Poletti B., Maderna L., Del Bo R., Gagliardi S., Querin G., Bertolin C., Pensato V., Castellotti B., Camu W., Mouzat K., Lumbroso S., Corcia P., Meininger V., Besson G., Lagrange E., Clavelou P., Guy N., Couratier P., Vourch P., Danel V., Bernard E., Lemasson G., Laaksovirta H., Myllykangas L., Jansson L., Valori M., Ealing J., Hamdalla H., Rollinson S., Pickering-Brown S., Orrell R.W., Sidle K.C., Hardy J., Singleton A.B., Johnson J.O., Arepalli S., Polak M., Asress S., Al-Sarraj S., King A., Troakes C., Vance C., de Belleroche J., ten Asbroek A.L.M.A., Munoz-Blanco J.L., Hernandez D.G., Ding J., Gibbs J.R., Scholz S.W., Floeter M.K., Campbell R.H., Landi F., Bowser R., Kirby J., Pamphlett R., Gerhard G., Dunckley T.L., Brady C.B., Kowall N.W., Troncoso J.C., Le Ber I., Heiman-Patterson T.D., Kamel F., Van Den Bosch L., Strom T.M., Meitinger T., Shatunov A., Van Eijk K.R., de Carvalho M., Kooyman M., Middelkoop B., Moisse M., McLaughlin R.L., Van Es M.A., Weber M., Boylan K.B., Van Blitterswijk M., Morrison K.E., Basak A.N., Mora J.S., Drory V.E., Shaw P.J., Turner M.R., Talbot K., Hardiman O., Williams K.L., Fifita J.A., Nicholson G.A., Blair I.P., Esteban-Perez J., Garcia-Redondo A., Al-Chalabi A., Al Kheifat A., Andersen P.M., Chio A., Cooper-Knock J., Dekker A., Redondo A.G., Gotkine M., Hide W., Iacoangeli A., Kiernan M., Landers J.E., Mill J., Neto M.M., Pardina J.M., Newhouse S., Pinto S., Pulit S., Robberecht W., Shaw C., Sproviero W., Tazelaar G., Van Damme P., van den Berg L.H., van Vugt J., Veldink J.H., Zatz M., Bauer D.C., Twine N.A., Rogaeva E., Zinman L., Brice A., Feldman E.L., Ludolph A.C., Weishaupt J.H., Trojanowski J.Q., Stone D.J., Tienari P., Shaw C.E., Traynor B.J., ITALSGEN Consortium, Genomic Translation ALS Care GTAC, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Fdn, Clinical Res ALS Related Disorders, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consor, Medical Research Council (MRC), ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Università cattolica del Sacro Cuore [Roma] (Unicatt), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Lunar and Planetary Laboratory [Tucson] (LPL), University of Arizona, Università degli studi di Torino (UNITO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), New York Genome Center [New York], New York Genome Center, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), St Jude Children's Research Hospital, Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University College of London [London] (UCL), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), King‘s College London, University of New Haven [Connecticut], Princeton University, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), University Medical Center [Utrecht], Deutsches Forschungszentrum für Künstliche Intelligenz GmbH = German Research Center for Artificial Intelligence (DFKI), Mayo Clinic [Jacksonville], Trinity College Dublin, Maurice Wohl Clinical Neuroscience Institut, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Repositório da Universidade de Lisboa, Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke J F A, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Null, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Logullo, Fo, Murru, Mr, Marrosu, Mg, Conforti, Fl, Pinter, Gl, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Parish, Ld, Cau, Tb, Moreno, Cristiane de Araujo Martin, Kamalakaran, Sitharthan, Goldstein, David B, Gitler, Aaron D, Harris, Tim, Myers, Richard M, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, Lenail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W, Sidle, Katie C, Malaspina, Andrea, Hardy, John, Singleton, Andrew B, Johnson, Janel O, Arepalli, Sampath, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, Ten Asbroek, Anneloor L M A, Muñoz-Blanco, José Lui, Hernandez, Dena G, Ding, Jinhui, Gibbs, J Raphael, Scholz, Sonja W, Floeter, Mary Kay, Campbell, Roy H, Landi, Francesco, Bowser, Robert, Pulst, Stefan M, Ravits, John M, Macgowan, Daniel J L, Kirby, Janine, Pioro, Erik P, Pamphlett, Roger, Broach, Jame, Gerhard, Glenn, Dunckley, Travis L, Brady, Christopher B, Kowall, Neil W, Troncoso, Juan C, Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D, Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H, Strom, Tim M, Meitinger, Thoma, Shatunov, Aleksey, Van Eijk, Kristel R, de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Ba, Moisse, Matthieu, Mclaughlin, Russell L, Van Es, Michael A, Weber, Marku, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E, Basak, A Nazli, Mora, Jesús S, Drory, Vivian E, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Hardiman, Orla, Williams, Kelly L, Fifita, Jennifer A, Nicholson, Garth A, Blair, Ian P, Rouleau, Guy A, Esteban-Pérez, Jesú, García-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W, Maragakis, Nicholas J, Rothstein, Jeffrey D, Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexi, Goutman, Stephen A, Feldman, Eva L, Gibson, Summer B, Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Camu, William, Trojanowski, John Q, Van Deerlin, Vivianna M, Brown, Robert H, van den Berg, Leonard H, Veldink, Jan H, Harms, Matthew B, Glass, Jonathan D, Stone, David J, Tienari, Pentti, Silani, Vincenzo, Chiò, Adriano, Shaw, Christopher E, Traynor, Bryan J, Landers, John E, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Male, Als gene, Genome-wide association study, FAMILIAL ALS, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, 0302 clinical medicine, 80 and over, Psychology, Aetiology, Aged, 80 and over, 0303 health sciences, French ALS Consortium, Kinesin, KINESIN HEAVY-CHAIN, Cognitive Sciences, Human, Hereditary spastic paraplegia, Neuroscience(all), Single-nucleotide polymorphism, TARGETED DISRUPTION, Article, 03 medical and health sciences, Genetics, Humans, Amino Acid Sequence, Loss function, Aged, HEXANUCLEOTIDE REPEAT, Neuroscience (all), MUTATIONS, Amyotrophic Lateral Sclerosis, 3112 Neurosciences, 1702 Cognitive Science, medicine.disease, ITALSGEN Consortium, Answer ALS Foundation, 030104 developmental biology, ALS Sequencing Consortium, Human medicine, 1109 Neurosciences, 030217 neurology & neurosurgery, 0301 basic medicine, [SDV]Life Sciences [q-bio], Kinesins, Neurodegenerative, Genetic analysis, Genome, AMYOTROPHIC-LATERAL-SCLEROSIS, 3124 Neurology and psychiatry, Cohort Studies, Pathogenesis, Loss of Function Mutation, Missense mutation, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, NYGC ALS Consortium, General Neuroscience, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, Middle Aged, Phenotype, Settore MED/26 - NEUROLOGIA, Neurological, Project MinE ALS Sequencing Consortium, Female, Adult, Biology, GENOTYPE IMPUTATION, Genome-Wide Association Study, Young Adult, NO, Rare Diseases, medicine, SLAGEN Consortium, Gene, 030304 developmental biology, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Neurology & Neurosurgery, Human Genome, Neurosciences, AXONAL-TRANSPORT, Brain Disorders, Family member, DNA-DAMAGE, MOTOR-NEURONS, 3111 Biomedicine, Cohort Studie, Genomic Translation for ALS Care (GTAC) Consortium, Amyotrophic Lateral Sclerosi
Abstract

© 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Published
2018

18. Correction to: Continuous subcutaneous apomorphine infusion in Parkinson’s disease: causes of discontinuation and subsequent treatment strategies

Author

Enrica Olivola, Alfonso Fasano, Sara Varanese, Francesco Lena, Marco Santilli, Cinzia Femiano, Diego Centonze, and Nicola Modugno

Subjects
Psychiatry and Mental health, Neurology (clinical), Dermatology, General Medicine
Abstract

The published version of this article unfortunately contained a mistake in Table 2. CGI-S and CGI-I values has been interchanged. The Table is corrected here.

Published
2019

19. Comorbidity of dementia with amyotrophic lateral sclerosis (ALS): insights from a large multicenter Italian cohort

Author

Giorgia Querin, Sonia Messina, Claudia Caponnetto, Amelia Conte, Gioacchino Tedeschi, Yuri Matteo Falzone, Gabriella Santangelo, Carlo Scialò, Christian Lunetta, Nicola Ticozzi, Adriano Chiò, Cristina Moglia, Andrea Calvo, Giancarlo Logroscino, Massimo Russo, Gabriele Mora, Paolo Volanti, Francesca Trojsi, Kalliopi Marinou, Gianni Sorarù, Nilo Riva, Valeria A. Sansone, Mario Sabatelli, Maria Rosaria Monsurrò, Jessica Mandrioli, Rosanna Tortelli, Gianluca Drago Ferrante, Mattia Siciliano, Barbara Poletti, Cinzia Femiano, Antonio Fasano, Trojsi, Francesca, Siciliano, Mattia, Femiano, Cinzia, Santangelo, Gabriella, Lunetta, Christian, Calvo, Andrea, Moglia, Cristina, Marinou, Kalliopi, Ticozzi, Nicola, Drago Ferrante, Gianluca, Scialã², Carlo, Sorarã¹, Gianni, Conte, Amelia, Falzone, Yuri M., Tortelli, Rosanna, Russo, Massimo, Sansone, Valeria Ada, Chiã², Adriano, Mora, Gabriele, Poletti, Barbara, Volanti, Paolo, Caponnetto, Claudia, Querin, Giorgia, Sabatelli, Mario, Riva, Nilo, Logroscino, Giancarlo, Messina, Sonia, Fasano, Antonio, Monsurrã², Maria Rosaria, Tedeschi, Gioacchino, and Mandrioli, Jessica

Subjects
Male, medicine.medical_specialty, Neurology, Survival, Amyotrophic lateral sclerosis, Clinical phenotype, Dementia, Comorbidity, Kaplan-Meier Estimate, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Female, Humans, Italy, Neurology (clinical), 030212 general & internal medicine, Family history, Amyotrophic lateral sclerosi, Survival analysis, business.industry, medicine.disease, Settore MED/26 - NEUROLOGIA, Cohort, Physical therapy, business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

To assess the association, at diagnosis, between amyotrophic lateral sclerosis (ALS) and dementia in a large cohort of well-characterized Italian patients. We investigated the phenotypic profile of 1638 incident patients with definite, probable or laboratory-supported probable ALS, diagnosed from January 2009 to December 2013 in 13 Italian Referral Centers, located in 10 Italian Regions, and classified in two independent subsamples accounting for presence or not of dementia. The collected ALS features, including survival and other follow-up data, were compared between the two subgroups using a one-way analysis of variance and Chi-square test, as appropriate, logistic regression models and Kaplan–Meier survival analysis. Between-subgroup comparisons showed an older age at clinical observation (p = .006), at onset and at diagnosis (p = .002) in demented versus non demented ALS patients. After adjustment for these variables, diagnosis of dementia was significantly associated with higher odds of family history of ALS (p = .001) and frontotemporal dementia (p = .003) and of bulbar onset (p = .004), and lower odds of flail leg phenotype (p = .019) and spinal onset (p = .008). The median survival time was shorter in demented versus non-demented patients, especially in case of classical, bulbar and flail limb phenotypes and both bulbar and spinal onset. Our multicenter study emphasized the importance of an early diagnosis of comorbid dementia in ALS patients, which may have clinical impact and prognostic relevance. Moreover, our results may give further inputs to validation of ALS-specific tools for the screening of cognitive impairment in clinical practice.

Published
2017

20. Neuropsychological assessment in different King's clinical stages of amyotrophic lateral sclerosis

Author

Cinzia Femiano, Giovanni Piccirillo, Gabriella Santangelo, Giuseppina Caiazzo, Francesca Trojsi, Maria Rosaria Monsurrò, Gioacchino Tedeschi, Teresa Ferrantino, Mattia Siciliano, Viviana Cristillo, Fabrizio Esposito, Trojsi, Francesca, Santangelo, Gabriella, Caiazzo, Giuseppina, Siciliano, Mattia, Ferrantino, Teresa, Piccirillo, Giovanni, Femiano, Cinzia, Cristillo, Viviana, Monsurro', Maria Rosaria, Esposito, Fabrizio, and Tedeschi, Gioacchino

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Physical disability, Neurology, Trail Making Test, Neuropsychological Tests, Statistics, Nonparametric, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, clinical staging, medicine, Humans, Neuropsychological assessment, Amyotrophic lateral sclerosis, Amyotrophic lateral sclerosi, Aged, cognitive impairment, medicine.diagnostic_test, Neuropsychology, Cognition, Middle Aged, neuropsychological assessment, Neurology (clinical), medicine.disease, Cross-Sectional Studies, 030104 developmental biology, Frontal lobe, Physical therapy, Female, Cognition Disorders, Psychology, 030217 neurology & neurosurgery
Abstract

Emerging evidence shows that cognitive deficits associated with frontal lobe dysfunction occur from early stages of amyotrophic lateral sclerosis (ALS). We aimed to assess neuropsychological functioning at different stages of ALS to further delineate the occurrence of cognitive impairment alongside the trajectory of ALS as defined by standard assessment procedures. We investigated several cognitive domains in 74 ALS patients classified into four different clinical stages of disease, according to a recently validated staging system for ALS (known as ‘King's’ system), and evaluated and compared the corresponding cognitive profiles. We found that data derived from global cognitive assessment and several executive (i.e. Frontal Assessment Battery and Trail Making Test B-A) and long-term memory (i.e. memory prose) tests were significantly different among the subsets of ALS patients, showing poorer performances with increasing clinical disability. In conclusion, our preliminary results support the notion that mainly frontotemporal abilities may be impaired during the ALS course and suggest that neuropsychological information could supplement the current clinical staging of patients. However, ALS-specific multi-domain screening instruments, which allow to correct neuropsychological scores for physical disability, should be validated in larger populations worldwide and routinely introduced in clinical practice.

Published
2016
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21. Impact on children of a parent with ALS: a case-control study

Author

Arianna Palmieri, Giorgia Querin, Enrico Benelli, Marco Sambin, Vincenzo Calvo, Maria Rosaria Monsurrò, Cinzia Femiano, Francesca Bianco, Gianni Sorarù, Calvo, Vincenzo, Bianco, Francesca, Benelli, Enrico, Sambin, Marco, Monsurro', Maria Rosaria, Femiano, Cinzia, Querin, Giorgia, Sorarù, Gianni, and Palmieri, Arianna

Subjects
amyotrophic lateral sclerosis, problem behavior, medicine.medical_specialty, Psychology (all), media_common.quotation_subject, lcsh:BF1-990, CBCL, Rorschach test, chronic medical condition, Rorschach, Exner’s Rorschach Comprehensive System (CS), Internalizing problem behavior, medicine, Psychology, Personality, Psychiatry, Child Behavior Checklist, General Psychology, Depression (differential diagnoses), Original Research, media_common, Case-control study, parents-children, Parental illness, lcsh:Psychology, Psychological pain, chronic medical condition (CMC), Anxiety, ALS, medicine.symptom, Clinical psychology
Abstract

Background: Numerous studies have explored how patients and their caregivers cope with amyotrophic lateral sclerosis (ALS), but the literature completely lacks research on the psychological impact of the disease on patients’ children. The aim of our study was to investigate the emotional and psychological impact of a parent with ALS on school-age children and adolescents in terms of problem behavior, adjustment, and personality characteristics. Methods: The study involved 23 children (mean age = 10.62 years, six females) with a parent suffering from ALS, and both their parents. Children were matched for age, gender, and birth-order with a control group of children with healthy parents. They were administered the Youth Self Report (YSR) questionnaire and the Rorschach Comprehensive System, and their healthy parent completed the Child Behavior Checklist (CBCL). Results: Findings clearly showed that, compared with controls, children with a parent who had ALS had several clinically significant adverse emotional and behavioral consequences, with emotional and behavioral problems, internalizing problems, anxiety and depressive symptoms. Children of a parent with ALS scored higher than controls for the Total Problems, Internalizing Problems, Anxious/Depressed and Withdrawn/Depressed scales in the YSR. A relevant percentage of children fell within the clinical range (42.9%) and borderline range (28.6%) for Internalizing Problems. The Rorschach CS confirmed the substantial impact of ALS in a parent on their offspring in terms of internalizing behavior and depression, with adjustment difficulties, psychological pain, and thought problems. Conclusion: Our findings indicate that school-aged children and adolescents with a parent who has ALS are vulnerable and carry a substantially higher risk of internalizing behavior, depressive symptoms, and reactive problems than children with healthy parents. Families affected may need support to cope with such an overwhelming disease.

Published
2015

22. Microstructural changes across different clinical milestones of disease in amyotrophic lateral sclerosis

Author

Mario Cirillo, Giuseppina Caiazzo, Gioacchino Tedeschi, Francesca Trojsi, Daniele Corbo, Viviana Cristillo, Giovanni Piccirillo, Fabrizio Esposito, Maria Rosaria Monsurrò, Teresa Ferrantino, Cinzia Femiano, Trojsi, Francesca, Caiazzo, G, Corbo, D, Piccirillo, G, Cristillo, V, Femiano, C, Ferrantino, T, Cirillo, Mario, Monsurro', Maria Rosaria, Esposito, F, and Tedeschi, Gioacchino

Subjects
Pathology, amyotrophic lateral sclerosis, lcsh:Medicine, Corpus callosum, Cuneus, inferior frontal gyrus, Medicine, Amyotrophic lateral sclerosis, lcsh:Science, Aged, 80 and over, Multidisciplinary, neuroimaging, primary motor cortex, adult, cingulate gyrus, disease course, Brain, gray matter, right handedness, Middle Aged, diffusion tensor imaging, Magnetic Resonance Imaging, medicine.anatomical_structure, female, motor neuron disease, quadriplegia, Primary motor cortex, cuneus, amygdaloid nucleus, motor dysfunction, white matter, fractional anisotropy, Research Article, medicine.medical_specialty, pyramidal tract, Article, White matter, Atrophy, male, voxel based morphometry, mesencephalon, premotor cortex, Fractional anisotropy, Humans, cross-sectional study, degenerative disease, controlled study, human, brain atrophy, brain stem, disease duration, gliosis, major clinical study, Aged, Pyramidal tracts, business.industry, lcsh:R, medicine.disease, Cross-Sectional Studies, Case-Control Studies, lcsh:Q, business
Abstract

Neurodegenerative process in amyotrophic lateral sclerosis (ALS) has been proven to involve several cortical and subcortical brain regions within and beyond motor areas. However, how ALS pathology spreads progressively during disease evolution is still unknown. In this cross-sectional study we investigated 54 ALS patients, divided into 3 subsets according to the clinical stage, and 18 age and sex-matched healthy controls, by using tract-based spatial statistics (TBSS) diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) analyses. We aimed to identify white (WM) and gray matter (GM) patterns of disease distinctive of each clinical stage, corresponding to specific clinical milestones. ALS cases in stage 2A (i.e., at diagnosis) were characterized by GM and WM impairment of left motor and premotor cortices and brainstem at ponto-mesenchephalic junction. ALS patients in clinical stage 2B (with impairment of two functional regions) exhibited decreased fractional anisotropy (FA) (p

Published
2015

23. Neuropsychological assessment in different King's clinical stages of amyotrophic lateral sclerosis

Author

Francesca Trojsi, Gabriella Santangelo, Giuseppina Caiazzo, Mattia Siciliano, Teresa Ferrantino, Giovanni Piccirillo, Cinzia Femiano, Viviana Cristillo, Maria Rosaria Monsurrò, Fabrizio Esposito, Gioacchino Tedeschi, Francesca Trojsi, Gabriella Santangelo, Giuseppina Caiazzo, Mattia Siciliano, Teresa Ferrantino, Giovanni Piccirillo, Cinzia Femiano, Viviana Cristillo, Maria Rosaria Monsurrò, Fabrizio Esposito, and Gioacchino Tedeschi

Published
2016
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24. An Italian kindred with FALS due to c.149TC mutation in the SOD1 gene: case report of an affected family member

Author

Francesca, Trojsi, Giovanni, Piccirillo, Cinzia, Femiano, Raffaele, Damiano, and Maria, Rosaria Monsurrò

Subjects
Case reportS, Genotype, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, DNA Mutational Analysis, DNA, Exons, Middle Aged, Pedigree, Superoxide Dismutase-1, superoxide dismutase 1 (SOD1), Mutation, Humans, Family, Female, Genetic Predisposition to Disease, Familial ALS (FALS)
Abstract

We report the first Italian kindred with Familial Amyotrophic Lateral Sclerosis (FALS) due to c.149T>C mutation in the exon 5 of superoxide dismutase-1 (SOD1) gene. The proband was a 49-year-old woman who came to our observation because of an history of progressive limbs weakness and gait impairment. She belonged to a family of 24 affected members. The prevalent phenotype of the affected members was characterized by slowly progressive spinal impairment with proximal distribution of weakness, and bulbar involvement in advanced stages. We briefly reviewed the few previous reports about the same SOD1 mutation and discussed the hypothesis that structural instability of the mutant codon 149 protein may underlie some toxic effects significantly involved in FALS pathogenesis.

Published
2013

25. Amyotrophic lateral sclerosis and multiple sclerosis overlap: A case report

Author

Gioacchino Tedeschi, Francesca Trojsi, Maria Rosaria Monsurrò, Cinzia Femiano, Francesco Izzo, Giovanni Cirillo, Giovanni Piccirillo, Anna Sagnelli, Trojsi, Francesca, Sagnelli, Anna, Cirillo, Giovanni, Piccirillo, Giovanni, Femiano, Cinzia, Izzo, Francesco, Monsurrò, Maria Rosaria, and Tedeschi, Gioacchino

Subjects
Pathology, medicine.medical_specialty, biology, medicine.diagnostic_test, business.industry, Multiple sclerosis, Medicine (all), lcsh:R, lcsh:Medicine, Case Report, Magnetic resonance imaging, General Medicine, Fluid-attenuated inversion recovery, medicine.disease, Immunoglobulin G, Cerebrospinal fluid, Atrophy, medicine, biology.protein, Amyotrophic lateral sclerosis, business, Pathological
Abstract

The concurrence of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) is extremely rare. We reported the case of a 33-year-old woman with a past history of paresthesias at the right hand, who developed progressive quadriparesis with muscular atrophy of limbs and, finally, bulbar signs and dyspnea. Clinical and neurophysiologic investigations revealed upper and lower motor neuron signs in the bulbar region and extremities, suggesting the diagnosis of ALS. Moreover, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis demonstrated 3 periventricular and juxtacortical lesions, hyperintense in T2 and FLAIR sequences, and 3 liquoral immunoglobulin G (IgG) oligoclonal bands, consistent with diagnosis of primary progressive MS (PPMS). This unusual overlap of ALS and MS leads to the discussion of a hypothetical common pathological process of immunological dysfunction in these two disorders, although the role of immune response in ALS remains ambivalent and unclear. © 2012 Francesca Trojsi et al.

Published
2012

Catalog

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