This article has been accepted for publication and undergone full peer review but has not been th... more This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as
BackgroundFrontotemporal Spectrum Disorder (FTSD) and Amyotrophic Lateral Sclerosis (ALS) are neu... more BackgroundFrontotemporal Spectrum Disorder (FTSD) and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases often considered as a continuum from clinical, epidemiologic and genetic perspectives. We used localized brain volume alterations to evaluate common and specific features of FTSD, FTSD-ALS and ALS patients to further understand this clinical continuum.MethodsWe used voxel-based morphometry on structural MRI images to localize volume alterations in group comparisons: patients (20 FTSD, seven FTSD-ALS, 18 ALS) versus healthy controls (39 CTR), and patient groups between themselves. We used mean whole-brain cortical thickness to assess whether its correlations with local brain volume could propose mechanistic explanations of the heterogeneous clinical presentations. We also assessed whether volume reduction can explain cognitive impairment, measured with frontal assessment battery, verbal fluency and semantic fluency.ResultsCommon (mainly frontal) and specific areas ...
Preface Familial Amyuotrophic Lateral Sclerosis The Lesson We Can Learn from Familial ALS Patient... more Preface Familial Amyuotrophic Lateral Sclerosis The Lesson We Can Learn from Familial ALS Patients Carrying a SOD1 Mutation Interactions Between Excitotoxicity and Oxidative Stress in ALS: Clues for Pharmacotherapy Mitochondrial Alterations in a Murine Model of Amyotrophic Lateral Sclerosis Blood Oxidative Stress in Amyotrophic Lateral Sclerosis Excitability and Potentials of Human Fibres in Amyotrophic Lateral Sclerosis: Model Investigations Neuroinflammatory Insights into Amyotrophic Lateral Sclerosis Amyotrophic Lateral Sclerosis: On the Origin of the Degenerated Fibers in the White Matter of the Spinal Cord Involvement of Neurotrophins and their Common Receptor p75NTR in the Pathology of ALS The Use of Acoustic Speech Analysis and Dysarthria Profile Tests in Detecting Early Speech Disturbances in Patients with Amyotrophic Lateral Sclerosis Evaluation of Oesophageal Peristalsis in Amyotrophic Lateral Sclerosis Patients with Dysphagia (Early Report) Assessment of Deficient Motor Function of the Hand in Amyotrophic Lateral Sclerosis Satellite Potentials in Amyotrophic Lateral Sclerosis (ALS) -- a Simulation Study Magnetic Resonance Spectroscopic Investigation in Amyotrophic Lateral Sclerosis (ALS) Molecular Genetic and Biochemical Studies of Russian Patients with Sporadic Motor Neuron Disease Index.
The effect of doxorubicin and Congo Red on prion protein (PrP) infectivity in experimental scrapi... more The effect of doxorubicin and Congo Red on prion protein (PrP) infectivity in experimental scrapie was studied to better understand the effect of these compounds in prion diseases and to establish whether a dose-response correlation exists for Congo Red. This was performed in order to test the effectiveness of compounds that may easily be used in human prion diseases. Brain homogenate containing membrane bound PrPSc monomers was used as inoculum and was previously incubated with doxorubicin 10(-3) M and with increasing concentrations of Congo Red ranging from 10(-7) to 10(-2) M. This study shows for the first time that doxorubicin, and confirms that Congo Red, may interact with pathological PrP monomers modifying their infectious properties. Pre-incubation of infected brain homogenate with Congo Red resulted in prolonged incubation time and survival, independently of Congo Red concentration (p<0.05). Doxorubicin and Congo Red effects do not depend upon interaction with PrP amyloi...
In this randomized phase III study, the effectiveness as well as the side-effects of intraarteria... more In this randomized phase III study, the effectiveness as well as the side-effects of intraarterial [i.a.] (17 patients) versus intravenous [i.v.] (16 patients) ACNU [Nimustine] administration in newly diagnosed glioblastoma, were compared. All patients undenwent extensive surgical resection, and both groups were homogeneous for the other known risk factors. Thirty-three patients with glioblastoma were treated with ACNU at the dose of 80-100 mg/m2. Treatment was repeated every 5-8 weeks for a minimum of 2 and maximum of 14 cycles. Total survival time (TST) and to time to progression were chosen as outcome variables. No significant differences in systemic and hematological toxicity between the i.a. and iv. ACNU administration routes were detected. In both groups, tolerance of the procedure was excellent. Analysis of the main outcome measured showed no significant differences between i.a. and i.v. ACNU administration: time to progression was 6 months for i.a. ACNU and 4 months for i.v....
A case of parietal atrophy: etiopathogenetic evaluation
Acta neurologica, 1993
We report on the case of a patient presenting a muscle atrophy of the right hand and a left parie... more We report on the case of a patient presenting a muscle atrophy of the right hand and a left parietal neoplastic lesion rapidly progressing. EMG findings showed no signs of denervation nor sensory-motor conduction impairments. Parietal lesions might interrupt sensory control mechanisms of motor activity.
Clustering of ALS patients in central Italy due to the occurrence of the L84F SOD1 gene mutation
Neurology, 1999
To study three new apparently unrelated Italian families with ALS and several sporadic ALS patien... more To study three new apparently unrelated Italian families with ALS and several sporadic ALS patients living in the same rural area. One Italian family with ALS carrying a superoxide dismutase 1 (SOD1) gene mutation (G41S) and no regional ALS clustering has been reported in Italy. Genetic analysis was performed by automated and manual sequencing of the SOD1 gene in 13 family members and in 6 of 10 unrelated patients with sporadic cases of ALS living in the same area. The authors also determined SOD1 activity in erythrocytes and lymphocytes. The three families included a total of 28 affected members distributed over six generations. Despite a wide variability in age at onset and disease duration, the clinical pattern is uniform, with onset in the lower limbs, ascending progression, and predominant lower motor neuron involvement in all subjects. Generational anticipation is evident in the last two generations. All familial ALS patients and one of the six sporadic patients carry the same L84F missense point mutation in exon 4 of the SOD1 gene. SOD1 enzyme activity and SOD1 protein levels were not decreased significantly in the L84F patients. The ALS patients carrying the L84F mutation derive from a common ancestor. This mutation is responsible for ALS clustering in the area. The L84F mutation does not modify SOD1-specific activity.
Mutations in the profilin 1 (PFN1) gene, encoding a protein regulating filamentous actin growth t... more Mutations in the profilin 1 (PFN1) gene, encoding a protein regulating filamentous actin growth through its binding to monomeric G-actin, have been recently identified in familial amyotrophic lateral sclerosis (ALS). Functional studies performed on ALS-associated PFN1 mutants demonstrated aggregation propensity, alterations in growth cone and cytoskeletal dynamics. Previous screening of PFN1 gene in sporadic ALS (SALS) cases led to the identification of the p.E117G mutation, which is likely to represent a less pathogenic variant according to both frequency data in controls/cases and functional experiments. To determine the effective contribution of PFN1 mutations in SALS, we analyzed a large cohort of 1168 Italian SALS patients and also included 203 FTD (Frontotemporal Dementia) cases given the great overlap between these two neurodegenerative diseases. We detected the p.E117G variant in 1 SALS and the novel synonymous change p.G15G in another patient, but none in a panel of 1512 controls. Our results suggest that PFN1 mutations in sporadic ALS and in FTD are rare, at least in the Italian population.
Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided... more Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from
We want to stress the irreducibility of subjectivity to a pure physical process and, related to t... more We want to stress the irreducibility of subjectivity to a pure physical process and, related to this the existence of an actual free will. A discussion on the existence of free will goes back at least to the Middle Ages. Today however the problem has been considered again in the framework of Neurophysiology and in connection with specific experiments. The problem is related to reductionism, i.e. the claim that subjectivity could be considered an epiphenomenon of the cerebral processes, the argument being that all our sensorial perceptions, the control of movement, our states of wakefulness or of unconsciousness can be related to the activation or to the block of specific areas of our cerebral cortex. In the frame of this conception free will is denied essentially on the basis of physical determinism. In contrast to such attitude, we argue that experiences like consciousness of ourselves, of a personal identity or even simply of qualia completely escape from concepts of physical nature. As a consequence of the specific epistemological choice, they cannot even be expressed in the language of Physics. The point of view of Physics and introspection appear both essential but complementary and irreducible one to the other; any attempt to do so brings to unresolvable aporias. Specifically on free will, we note that our nervous system is a complex mesoscopic system, for an understanding of its occurrences, reference to Quantum Theory is essential. As consequence, its reaction to any external input is not uniquely determined but is open to a plurality of responses for which only a distribution of probability is given. Physics does not provide any cause for one response rather than another, while we experience our response to be intentional. Quantum Mechanics seems to offer the logical space to reconcile Physics with introspection. Some basic notions on the structure and working of neurons and of the central nervous systems are also recalled, Liebet's experiments on retarded awareness and the role of free will in the knowledge process are discussed.
Anti-aquaporin-4 antibody-positive recurrent isolated optic neuritis and primary Sjögren's syndrome
Journal of …, 2012
... 3]. G. Mallucci (&amp;) 4 D. Franciotta 4 A. Romani 4 M. Ceroni 4 R. Bergamaschi IRCCS, N... more ... 3]. G. Mallucci (&amp;) 4 D. Franciotta 4 A. Romani 4 M. Ceroni 4 R. Bergamaschi IRCCS, Neurological Institute C. Mondino, University of Pavia, via Ferrata 2, 27100 Pavia, Italy e-mail: [email protected] M. Ceroni ...
This article has been accepted for publication and undergone full peer review but has not been th... more This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as
BackgroundFrontotemporal Spectrum Disorder (FTSD) and Amyotrophic Lateral Sclerosis (ALS) are neu... more BackgroundFrontotemporal Spectrum Disorder (FTSD) and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases often considered as a continuum from clinical, epidemiologic and genetic perspectives. We used localized brain volume alterations to evaluate common and specific features of FTSD, FTSD-ALS and ALS patients to further understand this clinical continuum.MethodsWe used voxel-based morphometry on structural MRI images to localize volume alterations in group comparisons: patients (20 FTSD, seven FTSD-ALS, 18 ALS) versus healthy controls (39 CTR), and patient groups between themselves. We used mean whole-brain cortical thickness to assess whether its correlations with local brain volume could propose mechanistic explanations of the heterogeneous clinical presentations. We also assessed whether volume reduction can explain cognitive impairment, measured with frontal assessment battery, verbal fluency and semantic fluency.ResultsCommon (mainly frontal) and specific areas ...
Preface Familial Amyuotrophic Lateral Sclerosis The Lesson We Can Learn from Familial ALS Patient... more Preface Familial Amyuotrophic Lateral Sclerosis The Lesson We Can Learn from Familial ALS Patients Carrying a SOD1 Mutation Interactions Between Excitotoxicity and Oxidative Stress in ALS: Clues for Pharmacotherapy Mitochondrial Alterations in a Murine Model of Amyotrophic Lateral Sclerosis Blood Oxidative Stress in Amyotrophic Lateral Sclerosis Excitability and Potentials of Human Fibres in Amyotrophic Lateral Sclerosis: Model Investigations Neuroinflammatory Insights into Amyotrophic Lateral Sclerosis Amyotrophic Lateral Sclerosis: On the Origin of the Degenerated Fibers in the White Matter of the Spinal Cord Involvement of Neurotrophins and their Common Receptor p75NTR in the Pathology of ALS The Use of Acoustic Speech Analysis and Dysarthria Profile Tests in Detecting Early Speech Disturbances in Patients with Amyotrophic Lateral Sclerosis Evaluation of Oesophageal Peristalsis in Amyotrophic Lateral Sclerosis Patients with Dysphagia (Early Report) Assessment of Deficient Motor Function of the Hand in Amyotrophic Lateral Sclerosis Satellite Potentials in Amyotrophic Lateral Sclerosis (ALS) -- a Simulation Study Magnetic Resonance Spectroscopic Investigation in Amyotrophic Lateral Sclerosis (ALS) Molecular Genetic and Biochemical Studies of Russian Patients with Sporadic Motor Neuron Disease Index.
The effect of doxorubicin and Congo Red on prion protein (PrP) infectivity in experimental scrapi... more The effect of doxorubicin and Congo Red on prion protein (PrP) infectivity in experimental scrapie was studied to better understand the effect of these compounds in prion diseases and to establish whether a dose-response correlation exists for Congo Red. This was performed in order to test the effectiveness of compounds that may easily be used in human prion diseases. Brain homogenate containing membrane bound PrPSc monomers was used as inoculum and was previously incubated with doxorubicin 10(-3) M and with increasing concentrations of Congo Red ranging from 10(-7) to 10(-2) M. This study shows for the first time that doxorubicin, and confirms that Congo Red, may interact with pathological PrP monomers modifying their infectious properties. Pre-incubation of infected brain homogenate with Congo Red resulted in prolonged incubation time and survival, independently of Congo Red concentration (p<0.05). Doxorubicin and Congo Red effects do not depend upon interaction with PrP amyloi...
In this randomized phase III study, the effectiveness as well as the side-effects of intraarteria... more In this randomized phase III study, the effectiveness as well as the side-effects of intraarterial [i.a.] (17 patients) versus intravenous [i.v.] (16 patients) ACNU [Nimustine] administration in newly diagnosed glioblastoma, were compared. All patients undenwent extensive surgical resection, and both groups were homogeneous for the other known risk factors. Thirty-three patients with glioblastoma were treated with ACNU at the dose of 80-100 mg/m2. Treatment was repeated every 5-8 weeks for a minimum of 2 and maximum of 14 cycles. Total survival time (TST) and to time to progression were chosen as outcome variables. No significant differences in systemic and hematological toxicity between the i.a. and iv. ACNU administration routes were detected. In both groups, tolerance of the procedure was excellent. Analysis of the main outcome measured showed no significant differences between i.a. and i.v. ACNU administration: time to progression was 6 months for i.a. ACNU and 4 months for i.v....
A case of parietal atrophy: etiopathogenetic evaluation
Acta neurologica, 1993
We report on the case of a patient presenting a muscle atrophy of the right hand and a left parie... more We report on the case of a patient presenting a muscle atrophy of the right hand and a left parietal neoplastic lesion rapidly progressing. EMG findings showed no signs of denervation nor sensory-motor conduction impairments. Parietal lesions might interrupt sensory control mechanisms of motor activity.
Clustering of ALS patients in central Italy due to the occurrence of the L84F SOD1 gene mutation
Neurology, 1999
To study three new apparently unrelated Italian families with ALS and several sporadic ALS patien... more To study three new apparently unrelated Italian families with ALS and several sporadic ALS patients living in the same rural area. One Italian family with ALS carrying a superoxide dismutase 1 (SOD1) gene mutation (G41S) and no regional ALS clustering has been reported in Italy. Genetic analysis was performed by automated and manual sequencing of the SOD1 gene in 13 family members and in 6 of 10 unrelated patients with sporadic cases of ALS living in the same area. The authors also determined SOD1 activity in erythrocytes and lymphocytes. The three families included a total of 28 affected members distributed over six generations. Despite a wide variability in age at onset and disease duration, the clinical pattern is uniform, with onset in the lower limbs, ascending progression, and predominant lower motor neuron involvement in all subjects. Generational anticipation is evident in the last two generations. All familial ALS patients and one of the six sporadic patients carry the same L84F missense point mutation in exon 4 of the SOD1 gene. SOD1 enzyme activity and SOD1 protein levels were not decreased significantly in the L84F patients. The ALS patients carrying the L84F mutation derive from a common ancestor. This mutation is responsible for ALS clustering in the area. The L84F mutation does not modify SOD1-specific activity.
Mutations in the profilin 1 (PFN1) gene, encoding a protein regulating filamentous actin growth t... more Mutations in the profilin 1 (PFN1) gene, encoding a protein regulating filamentous actin growth through its binding to monomeric G-actin, have been recently identified in familial amyotrophic lateral sclerosis (ALS). Functional studies performed on ALS-associated PFN1 mutants demonstrated aggregation propensity, alterations in growth cone and cytoskeletal dynamics. Previous screening of PFN1 gene in sporadic ALS (SALS) cases led to the identification of the p.E117G mutation, which is likely to represent a less pathogenic variant according to both frequency data in controls/cases and functional experiments. To determine the effective contribution of PFN1 mutations in SALS, we analyzed a large cohort of 1168 Italian SALS patients and also included 203 FTD (Frontotemporal Dementia) cases given the great overlap between these two neurodegenerative diseases. We detected the p.E117G variant in 1 SALS and the novel synonymous change p.G15G in another patient, but none in a panel of 1512 controls. Our results suggest that PFN1 mutations in sporadic ALS and in FTD are rare, at least in the Italian population.
Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided... more Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from
We want to stress the irreducibility of subjectivity to a pure physical process and, related to t... more We want to stress the irreducibility of subjectivity to a pure physical process and, related to this the existence of an actual free will. A discussion on the existence of free will goes back at least to the Middle Ages. Today however the problem has been considered again in the framework of Neurophysiology and in connection with specific experiments. The problem is related to reductionism, i.e. the claim that subjectivity could be considered an epiphenomenon of the cerebral processes, the argument being that all our sensorial perceptions, the control of movement, our states of wakefulness or of unconsciousness can be related to the activation or to the block of specific areas of our cerebral cortex. In the frame of this conception free will is denied essentially on the basis of physical determinism. In contrast to such attitude, we argue that experiences like consciousness of ourselves, of a personal identity or even simply of qualia completely escape from concepts of physical nature. As a consequence of the specific epistemological choice, they cannot even be expressed in the language of Physics. The point of view of Physics and introspection appear both essential but complementary and irreducible one to the other; any attempt to do so brings to unresolvable aporias. Specifically on free will, we note that our nervous system is a complex mesoscopic system, for an understanding of its occurrences, reference to Quantum Theory is essential. As consequence, its reaction to any external input is not uniquely determined but is open to a plurality of responses for which only a distribution of probability is given. Physics does not provide any cause for one response rather than another, while we experience our response to be intentional. Quantum Mechanics seems to offer the logical space to reconcile Physics with introspection. Some basic notions on the structure and working of neurons and of the central nervous systems are also recalled, Liebet's experiments on retarded awareness and the role of free will in the knowledge process are discussed.
Anti-aquaporin-4 antibody-positive recurrent isolated optic neuritis and primary Sjögren's syndrome
Journal of …, 2012
... 3]. G. Mallucci (&amp;) 4 D. Franciotta 4 A. Romani 4 M. Ceroni 4 R. Bergamaschi IRCCS, N... more ... 3]. G. Mallucci (&amp;) 4 D. Franciotta 4 A. Romani 4 M. Ceroni 4 R. Bergamaschi IRCCS, Neurological Institute C. Mondino, University of Pavia, via Ferrata 2, 27100 Pavia, Italy e-mail: [email protected] M. Ceroni ...
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