Sleep–wake problems in patients with amyotrophic lateral sclerosis: implications for patient management

SUMMARY Sleep–wake problems are frequent, although unrecognized, complications of amyotrophic lateral sclerosis (ALS). Sleep disorders such as insomnia, sleep-disordered breathing and restless legs syndrome have all been reported in patients with ALS, despite the limited number of studies and the small populations investigated so far. Sleep disturbances gradually worsen with disease progression, suggesting a relationship between the severity of disease and the neurodegenerative process. However, poor sleep can also be a consequence of several disturbances such as anxiety, depression, pain, choking, sialorrhea, fasciculations, cramps, nocturia and the inability to get comfortable and move f…

Tumors preceding ALS onset and ALS: results from a case-control study.

Effects of a Vibro-Tactile P300 Based Brain-Computer Interface on the Coma Recovery Scale-Revised in Patients With Disorders of Consciousness

Persons diagnosed with disorders of consciousness (DOC) typically suffer from motor and cognitive disabilities. Recent research has shown that non-invasive brain-computer interface (BCI) technology could help assess these patients’ cognitive functions and command following abilities. 20 DOC patients participated in the study and performed 10 vibro-tactile P300 BCI sessions over 10 days with 8–12 runs each day. Vibrotactile tactors were placed on the each patient’s left and right wrists and one foot. Patients were instructed, via earbuds, to concentrate and silently count vibrotactile pulses on either their left or right wrist that presented a target stimulus and to ignore …

A Human-Humanoid Interaction Through the Use of BCI for Locked-In ALS Patients Using Neuro-Biological Feedback Fusion.

This paper illustrates a new architecture for a human–humanoid interaction based on EEG-brain computer interface (EEG-BCI) for patients affected by locked-in syndrome caused by Amyotrophic Lateral Sclerosis (ALS). The proposed architecture is able to recognise users’ mental state accordingly to the biofeedback factor $\text {B}_{\text f}$ , based on users’ attention, intention, and focus, that is used to elicit a robot to perform customised behaviours. Experiments have been conducted with a population of eight subjects: four ALS patients in a near locked-in status with normal ocular movement and four healthy control subjects enrolled for age, education, and computer expertise. The results s…

A Deletion of the Nuclear Localization Signal Domain in the Fus Protein Induces Stable Post-stress Cytoplasmic Inclusions in SH-SY5Y Cells

Mutations in Fused-in-Sarcoma (FUS) gene involving the nuclear localization signal (NLS) domain lead to juvenile-onset Amyotrophic Lateral Sclerosis (ALS). The mutant protein mislocalizes to the cytoplasm, incorporating it into Stress Granules (SG). Whether SGs are the first step to the formation of stable FUS-containing aggregates is still unclear. In this work, we used acute and chronic stress paradigms to study the SG dynamics in a human SH-SY5Y neuroblastoma cell line carrying a deletion of the NLS domain of the FUS protein (homozygous: ΔNLS–/–; heterozygous: ΔNLS+/–). Wild-type (WT) cells served as controls. We evaluated the subcellular localization of the mutant protein through immuno…

Great Auricular Neuralgia:

Intraspinal stem cell transplantation for amyotrophic lateral sclerosis: Ready for efficacy clinical trials?

Intraspinal stem cell (SC) transplantation represents a new therapeutic approach for amyotrophic lateral sclerosis (ALS) clinical trials. There are considerable difficulties in designing future efficacy trials, some related to the field of ALS and some that are specific to SCs or the mode of delivery. In October 2015, the most controversial points on SC transplantation were addressed during an international workshop intended to bring together international SC and ALS researchers in a public discussion on a topic for which expertise is limited. During the meeting, a discussion was started on the basic structure of the ideal clinical trial testing the efficacy and safety of SC transplantation…

Complete locked-in and locked-in patients: Command following assessment and communication with vibro-tactile P300 and motor imagery brain-computer interface tools

Many patients with locked-in syndrome (LIS) or complete locked-in syndrome (CLIS) also need brain-computer interface (BCI) platforms that do not rely on visual stimuli and are easy to use. We investigate command following and communication functions of mindBEAGLE with 9 LIS, 3 CLIS patients and three healthy controls. This tests were done with vibro-tactile stimulation with 2 or 3 stimulators (VT2 and VT3 mode) and with motor imagery (MI) paradigms. In VT2 the stimulators are fixed on the left and right wrist and the participant has the task to count the stimuli on the target hand in order to elicit a P300 response. In VT3 mode an additional stimulator is placed as a distractor on the shoul…

LEVITIRACETAM IN THE TREATMENT OF CREUTZFIELDT-JACOB DISEASE

Crossed aphasia in a dextral without impairment of visuo-spatial abilities: a case report

THORACIC SYRINGOMYELIA IN A PATIENT WITH AMYOTROPHIC LATERAL SCLEROSIS

We report a patient with bulba r - onset, clinically defined, sporadic amyotrophic lateral sclerosis bearing an isolated syringomyelia of the lower thoracic portion of the spinal cord. This is a very unusual association between two rare and progressive disorders, both affecting the spinal motoneurons. Syringomyelia might have acted as a phenotypic modifier in this ALS patient.

Reversible radiculomyelitis after ChAdOx1 nCoV-19 vaccination

Adverse events occurring after SARS-CoV-2 vaccination have been reported and are the subject of ongoing research. We present the case of a young woman with fully reversible radiculomyelitis, which happened after the first dose of the ChAdOx1 nCOVID-19 vaccine. A previously healthy woman in her 20s presented with a subacute onset of legs’ weakness and sensory disturbances, urinary dysfunction and cramping pain after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. A diagnostic workup led to the diagnosis of inflammatory radiculomyelitis. Her clinical status improved, with complete recovery after a few months. The case described a reversible radiculomyelitis associated with the ChAdOx…

Performance Differences Using a Vibro-Tactile P300 BCI in LIS-Patients Diagnosed With Stroke and ALS

High frequency of motoneuron dysfunction in FTD: a clinical and electrophysiological study

The serum level of free testosterone is reduced in amyotrophic lateral sclerosis

Sporadic amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motoneurons. There is an approximately 2:1 higher incidence of ALS in men compared to women, and this has raised the hypothesis of an involvement of sex hormones in the etiopathogenesis of the disorder. In this work, the serum levels of dehydroepiandrosterone sulphate (DHEAS), 17-betaestradiol, free and total testosterone were measured in 35 patients with defined or probable ALS, according to the El-Escorial/WFN revisited criteria, and compared to those obtained from 57 disease controls, matched for age and gender to the ALS group. We found no differences between ALS cases and …

Back to the life: a case of tretable dementia

METODI DI VALUTAZIONE DELLA PROGRESSIONE DI MALATTIA NELLA SCLEROSI LATERALE AMIOTROFICA

A PHASE I-II MULTICENTRE STUDY ON G-CSF IN AMYOTROPHIC LATERAL SCLEROSIS (STEMALS)

EXPRESSION OT THE CYSTINE/GLUTAMATE EXCHANGER IN THE RAT BRAIN

Differential subcellular expression of P525LFUS as a putative biomarker for ALS phenoconversion

P525LFused-in-Sarcoma ( FUS ) mutation is associated with a specific amyotrophic lateral sclerosis (ALS) phenotype characterized by a juvenile-onset and a severe course.1 This harmful point mutation is located in the nuclear localization signal (NLS) domain at the protein C-terminal.2 Although wild-type FUS protein is expressed almost exclusively in the nucleus, the P525L FUS mutation leads to a protein mislocalization into the cytoplasm3,4 because of its loss of capacity to bind its transporter karyopherin-2 and to be transferred back to the nucleus.3

FATIGUE, SLEEP, AND NOCTURNAL COMPLAINTS IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS.

Background and purpose: Fatigue is a common symptom in amyotrophic lateral sclerosis (ALS). Although sleep disturbances are a candidate factor that may interfere with fatigue in patients with ALS, the role of sleep-related abnormalities in determining fatigue in ALS is unknown. Objective: To evaluate the frequency and determinants of fatigue in a group of 91 consecutive patients with ALS, with special attention to the relationship between fatigue and sleep problems. Methods: Measures included the Fatigue Severity Scale (FSS), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), ALS Functional Rating Scale- Revised (ALSFRS-R), and Beck Depression Inventory (BDI). Results: T…

THE PALMOMENTAL REFLEX IN AMYOTROPHIC LATERA SCLEROSIS

A novel compound heterozygous mutation in GALC associated with adult-onset Krabbe disease: case report and literature review

Krabbe disease (KD) is a rare autosomal recessive lipid storage leukodystrophy. It is caused by deficient enzyme activity resulting from mutations of the β-galactocerebrosidase (GALC) gene. KD is distinguished into subtypes based on the age of onset; these are early infantile, late infantile, juvenile, and adult-onset. We report a case of a 47-year-old Caucasian man with a 2-year history of muscle atrophy and weakness in both hands associated with pyramidal signs and mild spasticity in the lower limbs. An extensive work-up led this motor neuron disease-like disorder to be diagnosed as adult-onset KD. The patient was found to be compound heterozygous for two GALC mutations (p.G286D and p.Y49…

Differential effect of beta-N-oxalylamino-L-alanine, the Lathyrus sativus neurotoxin, and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate on the excitatory amino acid and taurine levels in the brain of freely moving rats.

We studied the effect of beta-oxalylamino-L-alanine, a glutamate analog present in Lathyrus sativus seeds and implicated in the etiopathogenesis of neurolathyrism, and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate on the extracellular levels of aspartate, glutamate and taurine in the primary motor cortex of freely moving rats. We found that while both neurotoxins increase the level of aspartate and glutamate, only (+/-)-alpha(-amino-3-hydroxy-5-methylisoxazole-4-propionate is able to modulate the level of taurine. GYKI-52466, a non-competitive non-NMDA antagonist, inhibited beta-oxalylamino-L-alanine-induced increase of aspartate, but not that of glutamate. Conversely, this ant…

Performance Differences Using a Vibro-Tactile P300 BCI in LIS-Patients Diagnosed With Stroke and ALS

Patients with locked-in syndrome (LIS) are typically unable to move or communicate and can be misdiagnosed as patients with disorders of consciousness (DOC). Behavioral assessment scales are limited in their ability to detect signs of consciousness in this population. Recent research has shown that brain-computer interface (BCI) technology could supplement behavioral scales and allows to establish communication with these severely disabled patients. In this study, we compared the vibro-tactile P300 based BCI performance in two groups of patients with LIS of different etiologies: stroke (n = 6) and amyotrophic lateral sclerosis (ALS) (n = 9). Two vibro-tactile paradigms were administered to …

SISTEMA NEUROVEGETATIVO; PATOLOGIA E NOTE DI TERAPIA

Repeated courses of granulocyte colony-stimulating factor in amyotrophic lateral sclerosis: Clinical and biological results from a prospective multicenter study

Granulocyte colony-stimulating factor (G-CSF) induces a transient mobilization of hematopoietic progenitor cells from bone marrow to peripheral blood. Our aim was to evaluate safety of repeated courses of G-CSF in patients with amyotrophic lateral sclerosis (ALS), assessing disease progression and changes in chemokine and cytokine levels in serum and cerebrospinal fluid (CSF). Twenty-four ALS patients entered an open-label, multicenter trial in which four courses of G-CSF and mannitol were administered at 3-month intervals. Levels of G-CSF were increased after treatment in the serum and CSF. Few and transitory adverse events were observed. No significant reduction of the mean monthly decrea…

ALS-Related Mutant FUS Protein Is Mislocalized to Cytoplasm and Is Recruited into Stress Granules of Fibroblasts from Asymptomatic <b><i>FUS </i></b>P525L Mutation Carriers

<b><i>Background:</i></b> Amyotrophic lateral sclerosis (ALS) shows a strong genetic basis, with <i>SOD1</i>, <i>FUS</i>, <i>TARDBP</i>, and <i>C9ORF72 </i>being the genes most frequently involved<i>. </i>This has allowed identification of asymptomatic mutation carriers, which may be of help in understanding the molecular changes preceding disease onset. <b><i>Objectives:</i></b> We studied the cellular expression of FUS protein and the effect of heat-shock- and dithiothreitol-induced stress in fibroblasts from <i>FUS</i> P525L mutation carriers, healthy controls, and pati…

EFFECT OF A MULTIDISCIPLINARY ALS CLINIC ON NIV TOLERANCE AND SURVIVAL IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS AND BULBAR IMPAIRMENT: A PROSPECTIVE STUDY

...

Reaching and Grasping a Glass of Water by Locked-In ALS Patients through a BCI-Controlled Humanoid Robot

Locked-in Amyotrophic Lateral Sclerosis (ALS) patients are fully dependent on caregivers for any daily need. At this stage, basic communication and environmental control may not be possible even with commonly used augmentative and alternative communication devices. Brain Computer Interface (BCI) technology allows users to modulate brain activity for communication and control of machines and devices, without requiring a motor control. In the last several years, numerous articles have described how persons with ALS could effectively use BCIs for different goals, usually spelling. In the present study, locked-in ALS patients used a BCI system to directly control the humanoid robot NAO (Aldebar…

Production of CSSi013-A (9360) iPSC line from an asymptomatic subject carrying an heterozygous mutation in TDP-43 protein

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease affecting both upper and lower motoneurons. The transactive response DNA binding protein (TARDBP) gene, encoding for TDP-43, is one of the most commonly mutated gene associated with familial cases of ALS (10%). We generated a human induced pluripotent stem cell (hiPSC) line from the fibroblasts of an asymptomatic subject carrying the TARDBP p.G376D mutation. This mutation is very rare and was described in a large Apulian family, in which all ALS affected members are carriers of the mutation. The subject here described is the first identified asymptomatic carrier of the mutation.

DIABETIC THORACIC POLYRADICULOPATHY: A CASE WITH CLINICAL IMPROVEMENT FROM INTRAVENOUS IMMUNOGLOBULIN.

...

Interaction Between Uridine and GABA-Mediated Inhibitory Transmission: Studies In Vivo and In Vitro

Na+-independent [3H]gamma-aminobutyric acid (GABA) binding to membrane preparations from frontal cortex, hippocampus, and thalamus is competitively inhibited by the in vitro addition of a naturally occurring pyrimidinic compound, uridine. Moreover, the intraperitoneal injection of uridine produces a dose-related decrease in the cerebellar content of cyclic GMP and antagonizes its increase elicited by bicuculline. The pyrimidinic compound also shows an antagonism toward bicuculline-induced seizures. The relationship between the anti-convulsant actions of uridine and GABA-mediated inhibitory neurotransmission is discussed in terms of an activation of GABA receptor function by the naturally oc…

Neuroscienze

Prolonged and intensive monitoring after starting non-invasive ventilation improves tolerance in patients with amyotrophic lateral sclerosis.

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

© 2018 Elsevier Inc.

Pulmonary function deterioration and chronic hypoventilation in Amyotrophic Lateral Sclerosis

URIC ACID LEVELS IN SERUM AND CSF OF ALS PATIENTS

Objective: Urate (UA) is a potent antioxidant that effectively scavenges reactive nitrogen and oxygen radicals, and persons with a high plasma UA level may be at lower risk of some neurodegenerative disorders, as Parkinson’s disease (PD). Low plasma UA level has been observed in Alzheimer’s disease (AD) and vascular dementia, but there is no data on correlations to neuropsychological test results in these patient groups. Amyotrophic Lateral Sclerosis (ALS) is a devastating motor neuron disease, with a highly variable rate of progression and whose diagnosis is chiefly based on clinical and neurophysiological parameters. The etiopathogenesis is unknown, but the oxidative stress seems to play …

Chronic inflammatory demyelinating polyneuropathy presenting as isolated unilateral ptosis and adduction deficit

ATXN2 trinucleotide repeat length correlates with risk of ALS

We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carry…

Cerebral Venous Sinus Espansion in Post Puncture Headache

THE COGNITIVE AND BEHAVIOURAL IMPAIRMENT IN AMYOTROPHIC LATERAL SCLEROSIS

Early and rapidly progressing respiratory failure in a patient with amyotrophic lateral sclerosis: when FVC% is misleading

Introduction Respiratory failure is the leading cause of death in amyotrophic lateral sclerosis (ALS) [1]. The involvement of respiratory function is a negative predictor of survival, which can be in part overcome by a prompt initiation of non-invasive mechanical ventilation (NIV). Seated forced vital capacity (FVC%) is a widely used measure to monitor respiratory function, and it is often taken as a surrogate outcome measure in clinical trials. However, it may be within a normal range in ALS patients with respiratory dysfunction [2]. Here we report on a case of an ALS patient with a rapidly evolving respiratory insufficiency, despite a rather normal FVC%. Case presentation The patient, a 6…

Preserved somatosensory discrimination predicts consciousness recovery in unresponsive wakefulness syndrome

Objective: To assess somatosensory discrimination and command following using a vibrotactile P300-based Brain-Computer Interface (BCI) in Unresponsive Wakefulness Syndrome (UWS), and investigate the predictive role of this cognitive process on the clinical outcomes.Methods: Thirteen UWS patients and six healthy controls each participated in two experimental runs in which they were instructed to count vibrotactile stimuli delivered to the left or right wrist. A BCI determined each subject's task performance based on EEG measures. All of the patients were followed up six months after the BCI assessment, and correlations analysis between accuracy rates and clinical outcome were investigated.Re…

Prognostic Role of CSF β-amyloid 1–42/1–40 Ratio in Patients Affected by Amyotrophic Lateral Sclerosis

The involvement of β-amyloid (Aβ) in the pathogenesis of amyotrophic lateral sclerosis (ALS) has been widely discussed and its role in the disease is still a matter of debate. Aβ accumulates in the cortex and the anterior horn neurons of ALS patients and seems to affect their survival. To clarify the role of cerebrospinal fluid (CSF) Aβ 1–42 and Aβ 42/40 ratios as a potential prognostic biomarker for ALS, we performed a retrospective observational study on a cohort of ALS patients who underwent a lumbar puncture at the time of the diagnosis. CSF Aβ 1–40 and Aβ 1–42 ratios were detected by chemiluminescence immunoassay and their values were correlated with clinical features. We found a signi…

PROLONGED AND INTENSIVE MONITORING AFTER STARTING NON-INVASIVE VENTILTION IMPROVES TOLERANCE IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS.

Restless legs syndrome in patients with amyotrophic lateral sclerosis

We aimed to evaluate the frequency and determinants of restless legs syndrome (RLS) in a group of 76 patients with amyotrophic lateral sclerosis (ALS) and 100 control subjects. A diagnosis of RLS was made according to the criteria of the International RLS Study Group, and severity was assessed by the RLS severity scale. RLS was significantly more frequent in patients with ALS (ALS/RLS(+)) than in control subjects (25% vs. 8%; P = 0.002). Compared with control subjects, patients with ALS/RLS(+) showed shorter history of RLS complaints and higher frequency of symptoms occurrence. Moreover, compared with those without RLS, patients with ALS/RLS(+) showed increased functional impairment and mor…

Effect of beta-N-oxalylamino-L-alanine on cerebellar cGMP level in vivo.

Beta-N-oxalylamino-L-alanine (BOAA), a non-protein amino acid present in the seeds of Lathyrus Sativus (LS), is one of several neuroactive glutamate analogs reported to stimulate excitatory receptors and, in high concentrations, cause neuronal degeneration. In the present study, the in vivo acute effects of synthetic BOAA and LS seed extract were investigated on rat cerebellar cyclic GMP following intraperitoneal (10-100 mg/kg) or oral (100 mg/kg) administration of subconvulsive doses of toxin. Furthermore, the BOAA content in LS seeds and in the cerebellum of injected rats was determined by high performance liquid chromatograph analysis. A dose- and time-dependent increase of cerebellar cy…

Percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: effect on survival.

Abstract Background Percutaneous endoscopic gastrostomy (PEG) is offered to amyotrophic lateral sclerosis (ALS) patients with severe dysphagia. Immediate benefits of PEG are adequate food intake and weight stabilization. However, the impact of PEG on survival is still uncertain. In this work we retrospectively evaluated the effect of PEG on survival in a cohort of ALS patients followed in a tertiary referral centre. Methods Between 2000 and 2007, 150 dysphagic ALS patients were followed until death or tracheostomy. PEG was placed in 76 patients who accepted the procedure and survival was analysed using the Kaplan–Meier life-table method. Results In ALS patients submitted to PEG, no major co…

NON-INVASIVE VENTILATION IN AMYOTROPHIC LATERAL SCLEROSIS: A RETROSPECTIVE STUDY

EVALUATION OF PROGRESSION IN AMYOTROPHIC LATERAL SCLEROSIS: A NEUROPHYSIOLOGICAL APPROACH

G-CSF (filgrastim) treatment for amyotrophic lateral sclerosis: protocol for a phase II randomised, double-blind, placebo-controlled, parallel group, multicentre clinical study (STEMALS-II trial)

IntroductionAmyotrophic lateral sclerosis (ALS) is a fatal progressive neurological disorder characterised by a selective degeneration of motor neurons (MNs). Stem cell transplantation is considered as a promising strategy in neurological disorders therapy and the possibility of inducing bone marrow cells (BMCs) to circulate in the peripheral blood is suggested to investigate stem cells migration in degenerated ALS nerve tissues where potentially repair MN damage. Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates haematopoietic progenitor cells, mobilises BMCs into injured brain and it is itself a neurotrophic factor for MN. G-CSF safety in humans has been de…

Expression and developmental regulation of the cystine/glutamate exchanger (xc-) in the rat.

The cystine/glutamate exchanger (antiporter x c − ) is a membrane transporter involved in the uptake of cystine, the rate-limiting amino acid in the synthesis of glutathione. Recent studies suggest that the antiporter plays a role in the slow oxidative excitotoxity and in the pathological effects of β-N-oxalylamino-l-alanine, the molecule responsible for neurolathyrism, a neurotoxic upper motor neuron disease. The mouse cystine/glutamate exchanger has been cloned and showed to be composed of two distinct proteins, one of which being a novel protein, named xCT, of 502 amino acids and 12 putative trans-membrane domains. We have generated and purified a polyclonal antibody to mouse xCT and stu…

Acute reversible parkinsonism in a diabetic-uremic patient.

Acute movement disorders with basal ganglia lesions have been recently described in diabetic-uremic patients of Asian descent. The process is often reversible, with a favourable clinical outcome. Metabolic (i.e. uremic toxins) and microangiopathic changes have been suggested to be involved in its pathophysiology, even though racial and/or genetic factors might play a role too. In this report, we present a Caucasian diabetic patient with a long-lasting mild uremia in which acute parkinsonism occurred after a steep and unexpected increase of the serum creatinine. The follow-up demonstrated a significant improvement of the neurological signs and symptoms, the creatinine level lowered close to …

Predictors of non-invasive ventilation tolerance in amyotrophic lateral sclerosis

Abstract Background The most frequent cause of death in patients with Amyotrophic Lateral Sclerosis (ALS) is respiratory failure. Recently, it has been shown that non-invasive ventilation improves survival and quality of life in ALS patients with respiratory failure, but little is known about predictors of non-invasive ventilation adaptation and tolerance. In this study we evaluated the effect of a comprehensive information about non-invasive ventilation use and a prolonged and intensive monitoring on tolerance to this palliative care. Methods We prospectively monitored all consecutive ALS patients with chronic respiratory failure and indication to non-invasive ventilation between January 2…

EXPRESSION OF THE CYSTINE/GLUTAMATE EXCHANGER IN THE RAT BRAIN

Sensory System Abnormalities In Amyotrophic Lateral Sclerosis: An Electrophysiological Approach.

SCA17 AS CAUSE OF EARLY-ONSET DEMENTIA IN SOUTHERN ITALY: REPORT OF A NEW FAMILY

NON - INVASIVE VENTILATION IN AMYOTROPHIC LATERAL SCLEROSIS: A RETROSPECTIVE STUDY

Sleep-wake disturbances in patients with amyotrophic lateral sclerosis

Objective To evaluate the frequency, severity and determinants of sleep disturbances in patients with amyotrophic lateral sclerosis (ALS). Methods Information about night-time complaints was collected using a standardised questionnaire, the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS) in a group of 100 patients with ALS and in 100 control subjects matched for age and sex. Functional disability was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R). Sleep was studied by overnight polysomnography in 12 patients. Results Fifty-nine patients with ALS and 36 controls reported sleep disturbances. The mean global PSQI score of patients with ALS was s…

Unilateral laryngeal and hypoglossal paralysis (Tapia's syndrome) in a patient with an inflammatory pseudotumor of the neck

Tapia’s syndrome (TS) is a rare condition thought tobe causedby njury to the extracranial course of both recurrent laryngeal branch f the vagal nerve and hypoglossal nerve. First described in 1904, t occurs with unilateral paralysis of the vocal cord and tongue, ith normal function of the soft palate. Commonly reported causes re direct trauma, neurofibromatosis of X and XII nerves, carotid rtery dissection involving the ascending pharyngeal artery, and isplacement of endotracheal tube during general anesthesia [1].

PERCUTANEOUS ENDOSCOPIC GASTROSTOMY (PEG) IMPROVES SURVIVAL IN AMYOTROPHIC LATERAL SCLEROSIS

The amyotrophic lateral sclerosis functional rating scale predicts survival time in amyotrophic lateral sclerosis patients on invasive mechanical ventilation.

Objective: To determine whether the amyotrophic lateral sclerosis functional rating scale (ALSFRS), which is a validated instrument that assesses the functional status and the disease progression in patients with amyotrophic lateral sclerosis (ALS), predicts hospital length of stay and survival time in ALS patients treated with tracheostomy-intermittent positive-pressure ventilation (TIPPV). Methods: Thirty-three consecutive ALS patients with acute respiratory failure who received therapy with TIPPV were prospectively followed up from their admission to the hospital until death. The association of ALSFRS score at hospital admission with length of hospital stay and survival after TIPPV were …

La valutazione della qualità della vita nei caregiver dei pazienti con patologia neurologica degenerativa

Genetic investigation of amyotrophic lateral sclerosis patients in south Italy: a two-decade analysis

Amyotrophic lateral sclerosis (ALS) is a multifactorial disease characterized by the interplay of genetic and environmental factors. In the majority of cases, ALS is sporadic, whereas familial forms occur in less than 10% of patients. Herein, we present the results of molecular analyses performed in a large cohort of Italian ALS patients, focusing on novel and already described variations in ALS-linked genes. Our analysis revealed that more than 10% of tested patients carried a mutation in one of the major ALS genes, with C9orf72 hexanucleotide expansion being the most common mutation. In addition, our study confirmed a significant association between ALS patients carrying the ATNX-1 interm…

Additional file 1: of Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion

Figure S1. a Schematic of the endogenous zebrafish atp13a2 ortholog. The exons are shown are rectangles and the introns as horizontal lines. The splice junctions targeted with antisense morpholino oligonucleotides (atp13a2_3x4_SB and atp13a2_3x6_SB) are shown with red asterisks. b Gel images showing the efficiency of the atp13a2_3x4_SB and atp13a2_3x6_SB morpholinos. The first lane in each gel photograph shows amplicons from the respective loci flanking the targeted sequences, with no aberrations observed. In the embryos injected with morpholino oligonucleotides, aberrant bands were evident, showing that the morpholinos were efficient in knocking down the expression of endogenous atp13a2. F…

RESTLESS LEGS SYNDROME IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS: A CASE-CONTROL STUDY.

THE VALUE OF PHYSICAL AND OCCUPATIONAL THERAPY FOR PATIENTS WITH ADVANCED MOTOR NEURON DISEASE (MND) AND SEVERE MOTOR AND FUNCTIONAL IMPAIRMENT

Ethical issues: invasive ventilation in amyotrophic lateral sclerosis.

The first man was a school headmaster. By his eye-gaze system he is able to order coins to enlarge his 10-year collection. His grandchildren extort presents from him in exchange for help. The second was a prefect and even now insists that the flowers in the garden represent the national flag. In spite of his gastrostomy, he still likes to sip his espresso from porcelain cups. The ventilation circuit 24/7 has not changed his custom to read the newspapers and listen to classical music in the living room. That girl is a young mum. She is fed by a tube, but she always makes her little child laugh with the dialectal phrases that she writes on the screen. The surgeon, every day in his electric wh…

Additional file 1 of ALS monocyte-derived microglia-like cells reveal cytoplasmic TDP-43 accumulation, DNA damage, and cell-specific impairment of phagocytosis associated with disease progression

Additional file 1. Additional tables and figures.

The Primitive Palmomental Reflex in Amyotrophic Lateral Sclerosis

<b><i>Background and Purpose:</i></b> The palmomental reflex (PMR) is a primitive reflex that might be released due to inhibition in adulthood. It has been associated with several neurodegenerative conditions. The aim of the present study was to evaluate the frequency of PMR in amyotrophic lateral sclerosis (ALS). <b><i>Patients and Methods:</i></b> Non-demented ALS patients (<i>n</i> = 179) were recruited. Two groups of disease controls were enrolled: (a) non-demented patients with other neurological disorders (NC;<i> n</i> = 86, mean age 60 ± 14 years); (b) healthy subjects, healthy controls (HC; <i>n</i> …

Incidence and prevalence of amyotrophic lateral sclerosis in Sicily: a population based study

Genomic portrait of a sporadic amyotrophic lateral sclerosis case in a large spinocerebellar ataxia type 1 family

Background: Repeat expansions in the spinocerebellar ataxia type 1 (SCA1) gene ATXN1 increases the risk for amyotrophic lateral sclerosis (ALS), supporting a relationship between these disorders. We recently reported the co-existence, in a large SCA1 family, of a clinically definite ALS individual bearing an intermediate ATXN1 expansion and SCA1 patients with a full expansion, some of which manifested signs of lower motor neuron involvement. Methods: In this study, we employed a systems biology approach that integrated multiple genomic analyses of the ALS patient and some SCA1 family members. Results: Our analysis identified common and distinctive candidate genes/variants and related biolog…

LA DISFUNZIONE RESPIRATORIA NELLA SCLEROSI LATERALE AMIOTROFICA

HFE p.H63D polymorphism does not influence ALS phenotype and survival.

It has been recently reported that the p.His63Asp polymorphism of the HFE gene accelerates disease progression both in the SOD1 transgenic mouse and in amyotrophic lateral sclerosis (ALS) patients. We have evaluated the effect of HFE p.His63Asp polymorphism on the phenotype in 1351 Italian ALS patients (232 of Sardinian ancestry). Patients were genotyped for the HFE p.His63Asp polymorphism (CC, GC, and GG). All patients were also assessed for C9ORF72, TARDBP, SOD1, and FUS mutations. Of the 1351 ALS patients, 363 (29.2%) were heterozygous (GC) for the p.His63Asp polymorphism and 30 (2.2%) were homozygous for the minor allele (GG). Patients with CC, GC, and GG polymorphisms did not significa…

ESPRESSIONE DELL’ANTIPORTER CISTINA/GLUTAMMATO XC- NEL SISTEMA NERVOSO DI RATTO

MALATTIE DEL TRONCO DELL’ENCEFALO

Post-translational modifications in the survival motor neuron protein

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by a progressive loss of the spinal motoneurons. The SMA-determining gene has been termed survival motor neuron (SMN) and is deleted or mutated in over 98% of patients. The encoded gene product is a protein expressed as different isoforms. In particular, we showed that the rat SMN cDNA produces two isoforms with Mr of 32 and 35 kDa, both localized in nuclear coiled bodies, but the 32 kDa form is also cytoplasmic, whereas the 35 kDa form is also microsomal. To determine the molecular relationship between these two isoforms and potential post-translational modifications, we performed transfection experiments with a …

MTHFR C677T allelic variant is not associated to plasma and cerebrospinal fluid homocysteine in amyotrophic lateral sclerosis

ALS monocyte-derived microglia reveal cytoplasmic TDP-43 accumulation, DNA damage, and cell-specific impairment of phagocytosis associated with disease progression

AbstractAimsAmyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterised by the loss of upper and lower motor neurons. Neuroinflammation mediated by microglial activation is evident in post-mortem brain tissues, and in brain imaging of patients with ALS. However, the exact role of microglia in ALS remains to be elucidated partly due to the lack of an accurate microglial model system that is able to recapitulate the clinical pathology of ALS. Moreover, direct sampling of microglia from patients with ALS is not feasible, further limiting the study of microglial function in ALS. To address this shortcoming, we describe an approach that generates monocyte-deri…

Assessing Command-Following and Communication With Vibro-Tactile P300 Brain-Computer Interface Tools in Patients With Unresponsive Wakefulness Syndrome

Persons diagnosed with disorders of consciousness (DOC) typically suffer from motor disablities, and thus assessing their spared cognitive abilities can be difficult. Recent research from several groups has shown that non-invasive brain-computer interface (BCI) technology can provide assessments of these patients' cognitive function that can supplement information provided through conventional behavioral assessment methods. In rare cases, BCIs may provide a binary communication mechanism. Here, we present results from a vibrotactile BCI assessment aiming at detecting command-following and communication in 12 unresponsive wakefulness syndrome (UWS) patients. Two different paradigms were admi…

Further evidence that D90A-SOD1 mutation is recessively inherited in ALS patients in Italy.

Mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene have been reported to cause adult-onset autosomal dominant amyotrophic lateral sclerosis (FALS). In sporadic cases (SALS), de novo mutations in the SOD1 gene have occasionally been observed. All the SOD1 mutations are autosomal dominantly inherited with the exception of D90A. To date, in Italy, only two sporadic ALS cases carrying the D90A mutation have been reported in a homozygous state. We investigated for the presence of this mutation in 169 unrelated ALS patients from southern Italy. The genetic analysis revealed three ALS patients (1.8%) with mild phenotype carrying the homozygous D90A mutation.

A rapidly progressive motor neuron disease associated to a natural killer cells leukaemia

une system play a complex role, either protective or toxic, in ALS pathogenesis [1–3]. In particular, compelling evidence indicate that increased blood level of natural killer (NK) and NK-T cells may contribute to the disease development and progression [2,3]. Here, we report on a patient with an aggressive Motor Neuron Disease (MND) associated with NK/NK-T cells leukaemia. 1. Case report A 79-year-old man presented with several months-history of a progressive atrophy and weakness of the upper limbs, which quickly spread to the lower limbs. Onset was subtle and apparently occurred in the month of July (the specific date is not shown for privacy), when the patient noticed a mild weakness in …

Biomarkers Related to Synaptic Dysfunction to Discriminate Alzheimer’s Disease from Other Neurological Disorders

Recently, the synaptic proteins neurogranin (Ng) and α-synuclein (α-Syn) have attracted scientific interest as potential biomarkers for synaptic dysfunction in neurodegenerative diseases. In this study, we measured the CSF Ng and α-Syn concentrations in patients affected by AD (n = 69), non-AD neurodegenerative disorders (n-AD = 50) and non-degenerative disorders (n-ND, n = 98). The concentrations of CSF Ng and α-Syn were significantly higher in AD than in n-AD and n-ND. Moreover, the Aβ42/Ng and Aβ42/α-Syn ratios showed statistically significant differences between groups and discriminated AD patients from n-AD patients, better than Ng or α-Syn…

Memoria

Could mitochondrial haplogroups play a role in sporadic amyotrophic lateral sclerosis?

Mitochondrial impairment has been implicated in the pathogenesis of the amyotrophic lateral sclerosis (ALS). Furthermore, mitochondrial-specific polymorphisms were previously related to other neurodegenerative diseases, such as Parkinson, Friedreich and Alzheimer disease. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of sporadic ALS (sALS), we have genotyped predefined European mtDNA haplogroups in 222 Italian patients with sALS and 151 matched controls. Individuals classified as haplogroup I demonstrated a significant decrease in risk of ALS versus individuals carrying t…

Bilateral Iatrogenic Femoral Neuropathy

Dear Editor, Postoperative femoral neuropathy is an uncommon complication associated with pelvic/abdominal surgery. The main mechanism underlying this neuropathy is stretching and/or prolonged compression of the nerve.1,2 The nerve compression can be caused by the self-retaining retractors that are sometimes used during surgery directly constricting the nerve against the pelvic sidewall and inducing ischemia.1 Symptoms of femoral neuropathy are weakness of ipsilateral hip flexion and knee extension, and sensory deficit on the anteromedial thigh. The prognosis is generally good, with partial or complete recovery being common. Postoperative femoral neuropathy is generally unilateral2,3,4; bil…

PROLONGED AND INTENSIVE MONITORING AFTER STARTIN NON-INVASIVE VENTILATION IMPROVES TOLERANCE IN PATIENT WITH AMYOTROPHIC LATERAL SCLEROSIS

Tracheostomy mechanical ventilation in patients with amyotrophic lateral sclerosis: Clinical features and survival analysis

article i nfo Background: Tracheostomy mechanical ventilation (TMV) is performed in amyotrophic lateral sclerosis (ALS) patients with a respiratory failure or when the non-invasive ventilation (NIV) is no longer effective. We evaluated the clinical characteristics and survival of a cohort of tracheostomized ALS patients, followed in a single ALS Clinical Center. Methods: Between 2001 and 2010, 87 out of 279 ALS patients were submitted to TMV. Onset was spinal in 62 and bulbar in 25. After tracheostomy, most patients were followed up through telephone interviews to caregivers. A complete survival analysis could be performed in fifty-two TMV patients. Results: 31.3% ALS patients underwent tra…

OROPHARINGEAL CARCINOMA MIMIKING BULBAR ONSET AMYOTROPHIC LATERAL SCLEROSIS

Levetiracetam in the Treatment of Creutzfeldt-Jacob Disease.

Causes and place of death in Italian patients with amyotrophic lateral sclerosis

Objectives - To determine the causes and place of death in a cohort of Italian patients with amyotrophic lateral sclerosis (ALS). A better understanding of the likely causes of death in ALS might improve the palliative care at the end-of-life, whereas knowing the place of death will help to verify the need for highly specialized care services, e.g. hospice and nursing home. Patients and methods - Between 2000 and 2008, 182 ALS patients (onset: spinal, 127; bulbar, 55; M/F: 1.6) were followed in a single ALS Tertiary Centre in Palermo, Sicily, Italy until death. Medical data for each individual patient were recorded in a large database throughout the disease course. Information concerning ca…

Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion

Background Amyotrophic lateral sclerosis [1] is a genetically heterogeneous neurodegenerative disorder, characterized by late-onset degeneration of motor neurons leading to progressive limb and bulbar weakness, as well as of the respiratory muscles, which is the primary cause of disease fatality. To date, over 25 genes have been implicated as causative in ALS with C9orf72, SOD1, FUS, and TARDBP accounting for the majority of genetically positive cases. Results We identified two patients of Italian and French ancestry with a clinical diagnosis of juvenile-onset ALS who were mutation-negative in any of the known ALS causative genes. Starting with the index case, a consanguineous family of Ita…

Allele-specific silencing as therapy for familial amyotrophic lateral sclerosis caused by the p.G376D TARDBP mutation

Abstract Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons. There is no treatment for this disease that affects the ability to move, eat, speak and finally breathe, causing death. In an Italian family, a heterozygous pathogenic missense variant has been previously discovered in Exon 6 of the gene TARDBP encoding the TAR DNA-binding protein 43 protein. Here, we developed a potential therapeutic tool based on allele-specific small interfering RNAs for familial amyotrophic lateral sclerosis with the heterozygous missense mutation c.1127G>A. We designed a small interfering RNA that was able to diminish specifically the express…

The capacity to consent to treatment in amyotrophic lateral sclerosis: a preliminary report

Background: Facing the relentless worsening of their condition, ALS patients are required to make decisions on treatments and end-of-life care. A cognitive impairment showed to be a negative prognostic factor in ALS patients, perhaps affecting the ability to make informed decisions. Notwithstanding its crucial role, the capacity to consent to treatment (CCT) has never been evaluated in these patients. Objectives: To assess the CCT in an ALS cohort in comparison to a control group, and to study the effects of demographic and clinical variables on this high-level cognitive function. Methods: 102 ALS patients and 106 healthy controls (HC) were enrolled. CCT was assessed using the MacArthur Com…

Tracheostomy mechanical ventilation in amyotrophic lateral sclerosis.

Protein misfolding, amyotrophic lateral sclerosis and guanabenz: Protocol for a phase II RCT with futility design (ProMISe trial)

IntroductionRecent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumula…

INDIVIDUAL AND HEALTH-RELATED QUALITY OF LIFE ASSESSMENT IN AMYOTROPHIC LATERAL SCLEROSIS PATIENTS AND THEIR CAREGIVERS

Abstract: We performed a cross-sectional study aimed to address the quality of life (QoL) and putative associated variables in amyotrophic lateral sclerosis (ALS) patients and their respective caregivers, using both health-related (WHOQOL-BREF) and individual (SEIQoL-DW) QoL instruments. Further, we sought to investigate concordance within patient-caregiver pairs for ratings of respective QoL. Thirty-seven patient-caregiver pairs were included in the study. QoL was rated low by both patients and caregivers, and there was no significant difference between them on scores of overall QoL, even if caregivers showed higher scores on the physical and psychological WHOQOL-BREF domains compared to p…

A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis

The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 …

A novel S379A TARDBP mutation associated to late-onset sporadic ALS

Since 2008, several groups have reported a lot of dominant mutations in TARDBP gene as a primary cause of Amyotrophic lateral sclerosis (ALS). Mutations in TARDBP gene are responsible for 4–5% of familial ALS (fALS) and nearly 1% of sporadic ALS (sALS). To date, over 50 dominant mutations were found in TDP-43 in both familial and sporadic ALS patients, most of which were missense mutations in the C-terminal glycine-rich region. Herein, we describe the clinical and genetic analysis of an Italian non-familial ALS patient with a late onset and a rapid disease progression, which led to the discovery of a novel TARDBP mutation. After neurological evaluation, molecular investigation highlighted t…

NEUROPHYSIOLOGIC AND CLINICAL SIGNS OF MOTONEURONAL DEGENERATION IN FRONTOTEMPORAL DEMENTIA

Percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis

Background: Percutaneous endoscopic gastrostomy (PEG) is offered to amyotrophic lateral sclerosis (ALS) patients with severe dysphagia. Immediate benefits of PEG are adequate food intake and weight stabilization. However, the impact of PEG on survival is still uncertain. In this work we retrospectively evaluated the effect of PEG on survival in a cohort of ALS patients followed in a tertiary referral centre. Methods: Between 2000 and 2007, 150 dysphagic ALS patients were followed until death or tracheostomy. PEG was placed in 76 patients who accepted the procedure and survival was analysed using the Kaplan-Meier life-table method. Results: In ALS patients submitted to PEG, no major complica…

NONINTENSIVE POSITIVE-PRESSURE VENTILATION IN ALS.

Plasma cortisol level in amyotrophic lateral sclerosis

Background. Amyotrophic Lateral sclerosis (ALS) is associated with a significant distress, being linked to changes in hypothalamic-pituitary-adrenal axis activity. A loss of cortisol circadian rhythmicity in ALS patients was suggested, while more recently an increased plasma cortisol level in the disease has been reported. Objective. To assay the circadian plasma cortisol level in ALS and to study its relationship with the clinical phenotype and the rate of disease progression. Patients and methods. 135 ALS patients (Bulbar, 33; Spinal, 102; M/F = 1.73) and 110 controls (not affected by neurological or psychiatric disorders, free of drugs; M/F = 1.75) were recruited. Disease progression was…

A phase I-II multicentre study on G-CSF in Amyotrophic Lateral Sclerosis

ACUTE REVERSIBLE PARKINSONISM IN A DIABETIC UREMIC PATIENT

Neurogranin as a Reliable Biomarker for Synaptic Dysfunction in Alzheimer’s Disease

(1) Background: Neurogranin is a post-synaptic protein expressed in the neurons of the hippocampus and cerebral cortex. It has been recently proposed as a promising biomarker of synaptic dysfunction, especially in Alzheimer’s disease (AD). However, more efforts are needed before introducing it in clinical practice, including the definition of its reference interval (RI). The aim of the study was to establish the RI of cerebrospinal fluid (CSF) neurogranin levels in controls and individuals with non-neurodegenerative neurological diseases; (2) We included a total of 136 individuals that were sub-grouped as follows: AD patients (n = 33), patients with non-neurodegenerative neurological …

Development of chronic hypoventilation in amyotrophic lateral sclerosis patients

SummaryEarly prediction of respiratory muscle involvement and chronic hypoventilation (CH) in amyotrophic lateral sclerosis (ALS) patients can help to plan mechanical ventilatory aids and palliative care interventions well before respiratory failure occurs. To describe the natural history of the progressive pulmonary dysfunction leading to CH, and to identify potential parameters associated with its development in ALS, we prospectively followed 38 ALS patients up to 26 months, starting from their first presentation at our Clinic. At study entry, median FVC was 87% (interquartile range: 72–104%) and declined by 10% after 6 months (range: 2–49%), showing a very high inter-patient variability.…

TOXICITY OF B-N-OXALYLAMINO-L-ALANINE ANDB-N-METHYLAMINO-L-ALANINE IN NIH3T3 CELLS IS MEDIATED BY INHIBITIONOF THE XC¯ ANTIPORTER

Beta-N-oxalylamino-L-alanine (BOAA) and beta-N-methylamino-L-alanine (BMAA) are two non-protein amino acids reported to induce neuronal degeneration. They have been involved in the pathogenesis of rare motor neuron diseases, as neurolathyrism or the ALS-Parkinson-Dementia complex of Guam. The mechanisms by which BOAA and BMAA toxicity is explicated is still unknown, but there is evidence that it might involve the inhibition of Xc¯ antiporter, that is the rate-limiting transporter of the synthesis of intracellular glutathione. In the present study, we investigated the mechanisms of BOAA and BMAA toxicity in the non-neuronal NIH3T3 cells. First, we treated NIH3T3 cells with BOAA or BMAA at di…

Variant Creutzfeldt-Jakob disease in an Italian woman.

Summary As of May, 2002, 128 cases of variant Creutzfeldt-Jakob (vCJD) disease have been identified in the UK, France, and Ireland. We report the first case of vCJD in Italy. The patient was a young Italian woman who had never travelled to a country with bovine spongiform encephalopathy (BSE). She was diagnosed by cerebral MRI and western blot analysis of tonsil biopsy samples. The results of these analyses suggest that vCJD in continental Europe and the UK share genetic, clinical, and neuroimaging features, with similar western blot patterns. The identification of vCJD in Italy could have important implications for public-health policy decisions and clinical surveillance in Italy and other…

No effect of MTHFR C677T variant on homocysteine metabolism in Amiotrophic Lateral Sclerosis

ELECTROCARDIOGRAPHIC FINDINGS IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS.

THE “CROSS SIGN” FREQUENCY IN A LARGE SERIES OF NEUROLOGICAL PATIENTS

Sporadic Parkinson disease and amyotrophic lateral sclerosis complex (Brait-Fahn-Schwartz disease).

Clinical evidence for parkinsonism may accompany Amyotrophic Lateral Sclerosis with a frequency ranging from 5% to 17%. The concurrence of Amyotrophic Lateral Sclerosis and Parkinson's disease, outside the known Guam and Kii Peninsula foci, is instead rare, but this raises the possibility of a common pathogenesis. Clinically this complex presents with a levodopa-responsive parkinsonism and Amyotrophic Lateral Sclerosis and has been termed Brait-Fahn-Schwartz disease. Here we describe two patients with this uncommon neurodegenerative complex. Both presented with Parkinson disease and progressed to a full blown Amyotrophic Lateral Sclerosis. We further suggest that the association of Parkinso…

HOMOZIGOUS DJ-1 MUTATION IN A FAMILY FROM SOUTHERN ITALY WITH AMYOTROPHIC LATERAL SCLEROSIS-PARKINSONISM-DEMENTIA COMPLEX

FACTORS AFFECTING THE DIAGNOSTIC DELAY IN AMYOTROPHIC LATERAL SCLEROSIS

Abstract Background Although amyotrophic lateral sclerosis (ALS) is a relentlessly progressive disorder, early diagnosis allows a prompt start with the specific drug riluzole and an accurate palliative care planning. ALS at onset may however mimic several disorders, some of them treatable ( e.g. , multifocal motor neuropathy) or epidemiologically more frequent ( e.g. , cervical myelopathy). Objective To study the delay from onset to diagnosis in a cohort of ALS patients and to the variables that may affect it. Methods We performed a retrospective analysis of the diagnostic delays in a cohort of 260 patients affected by ALS (M/F = 1.32) followed at our tertiary referral ALS Center between 20…

CSF neurofilament proteins as diagnostic and prognostic biomarkers for amyotrophic lateral sclerosis

Elevated cerebrospinal fluid (CSF), Neurofilament Light (NF-L) and phosphorylated Heavy (pNF-H) chain levels have been found in Amyotrophic Lateral Sclerosis (ALS), with studies reporting a correlation of both neurofilaments (NFs) with the disease progression. Here, we measured NF-L and pNF-H concentrations in the CSF of ALS patients from a single tertiary Center and investigated their relationship with disease-related variables. A total of 190 ALS patients (Bulbar, 29.9%; Spinal, 70.1%; M/F = 1.53) and 130 controls with mixed neurological diseases were recruited. Demographic and clinical variables were recorded, and Delta FS was used to rate the disease progression. Controls were divided i…

Sleep–wake problems in patients with amyotrophic lateral sclerosis: implications for patient management. NEURODEGENERATIVE DISEASE MANAGEMENT

SUMMARY Sleep–wake problems are frequent, although unrecognized, complications of amyotrophic lateral sclerosis (ALS). Sleep disorders such as insomnia, sleep-disordered breathing and restless legs syndrome have all been reported in patients with ALS, despite the limited number of studies and the small populations investigated so far. Sleep disturbances gradually worsen with disease progression, suggesting a relationship between the severity of disease and the neurodegenerative process. However, poor sleep can also be a consequence of several disturbances such as anxiety, depression, pain, choking, sialorrhea, fasciculations, cramps, nocturia and the inability to get comfortable and move fr…

PREDICTORS OF SURVIVAL AFTER NON - INVASIVE POSITIVE - PRESSURE VENTILATION IN ALS PATIENTS

Repeated courses of granulocyte colony-stimulating factor in amyotrophic lateral sclerosis: clinical and biological results from a prospective multicenter study

Granulocyte colony-stimulating factor (G-CSF) induces a transient mobilization of hematopoietic progenitor cells from bone marrow to peripheral blood. Our aim was to evaluate safety of repeated courses of G-CSF in patients with amyotrophic lateral sclerosis (ALS), assessing disease progression and changes in chemokine and cytokine levels in serum and cerebrospinal fluid (CSF). Twenty-four ALS patients entered an open-label, multicenter trial in which four courses of G-CSF and mannitol were administered at 3-month intervals. Levels of G-CSF were increased after treatment in the serum and CSF. Few and transitory adverse events were observed. No significant reduction of the mean monthly decrea…

Diabetic thoracic radiculopathy: a case of a young woman with clinical improvement following immunotherapy.

Thoracic radiculopathy is a rare cause of thoracic-abdominal or abdominal pain in subjects with poorly controlled diabetes. We present a case of a young woman with type I diabetes and a severe abdominal pain in both lower quadrants. An extensive diagnostic gastroenterological and gynaecological workup did not disclose abnormalities. Electromyography revealed an initial polyneuropathy and significant neurogenic abnormalities in the T10-T12 paravertebral muscles. Following the hypothesis that the radiculopathy-related abdominal pain might have an immuno-mediated pathogenesis, the patient underwent a complex trial of immunotherapy, which was accompanied by a sustained improvement over months t…

FUS MUTATIONS IN SPORADIC AMYOTROPHIC LATERAL SCLEROSIS: CLINICAL AND GENETIC ANALYSIS

Fused in sarcoma (FUS) or translocation in liposarcoma (TLS), a DNA/RNA-binding protein, causes a dominant autosomal inherited form of amyotrophic lateral sclerosis (ALS), ALS 6. Its main role in neurodegeneration is highlighted by the presence of cytoplasmic accumulation of its mutant protein form in ALS patients. To further define the frequency and spectrum of FUS gene mutations, we have performed a molecular screening of a cohort of 327 Italian patients from Southern Italy with sporadic ALS (SALS). We identified 4 patients carrying 3 different missense mutations and several polymorphisms. Two different substitutions occurring in the same amino acidic position have been observed in 2 pati…

MALATTIE DEL MIDOLLO SPINALE

A cervical myelopathy with a Hirayama disease-like phenotype

A 21-year-old man with a muscular atrophy of the left distal upper extremity is presented. The disorder had been progressive over a few years, showing an exacerbation of the hand's weakness when the patient worked in a chilled environment (i.e., in a cold room). The patient's diagnostic work-up was extensive and the MRI documented the presence of a cervical myelopathy, associated to an inversion of the physiological lordosis at the C5-C6 level, with a phenotype highly resembling Hirayama disease. This case indirectly supports the debated hypothesis that juvenile amyotrophy of the upper limb (Hirayama disease) is actually a type of cervical myelopathy, with a likely ischaemic pathogenesis of…

Evaluation of Alpha-Synuclein Cerebrospinal Fluid Levels in Several Neurological Disorders

(1) Background: Alpha-synuclein (α-syn) is a presynaptic neuronal protein that regulates several neuronal functions. In recent decades, the role of α-syn as a biomarker of neurodegenerative diseases has been explored, especially in synucleinopathies. However, only a few studies have assessed its role as biomarker in other neurological disorders. The aim of the study was to evaluate cerebrospinal fluid (CSF) α-syn levels in several neurological disorders; (2) Methods: We measured CSF α-syn levels by a commercial ELISA kit in 158 patients classified in the following group: controls, Alzheimer’s Disease (AD), cerebrovascular diseases, inflammatory central nervous …

Tau protein as a diagnostic and prognostic biomarker in amyotrophic lateral sclerosis

BACKGROUND AND PURPOSE To test the hypothesis that total tau (tTau), tau phosphorylated at threonine 181 (pTau) and pTau/tTau ratio in the cerebrospinal fluid (CSF) are diagnostic and prognostic biomarkers of amyotrophic lateral sclerosis (ALS), we performed a retrospective observational study in a large cohort of ALS patients and controls. METHODS We enrolled 196 ALS patients and 91 controls, who included patients with ALS-mimicking diseases and those with non-neurodegenerative diseases. All patients underwent lumbar puncture for CSF analysis at the time of the diagnostic evaluation or to first referral. We measured tTau and pTau levels in the CSF by chemiluminescence enzyme immunoassay. R…

Is the focal signal hyperintensity within the capsula interna on MRI a marker of CST degeneration?

Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS

Summary Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein ( VCP ) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in families with Inclusion Body Myopathy, Paget disease, and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on…

The role of ethical attitudes in the mortality of patients with disorders of consciousness.

Long-Lasting Cranial Nerve III Palsy as a Presenting Feature of Chronic Inflammatory Demyelinating Polyneuropathy

We describe a patient with chronic inflammatory demyelinating polyneuropathy (CIDP) in which an adduction deficit and ptosis in the left eye presented several years before the polyneuropathy. A 52-year-old man presented with a 14-year history of unremitting diplopia, adduction deficit, and ptosis in the left eye. At the age of 45 a mild bilateral foot drop and impaired sensation in the four limbs appeared, with these symptoms showing a progressive course. The diagnostic workup included EMG/ENG which demonstrated reduced conduction velocity with bilateral and symmetrical sensory and motor involvement. Cerebrospinal fluid studies revealed a cytoalbuminologic dissociation. A prolonged treatmen…

ALS monocyte-derived microglia-like cells reveal cytoplasmic TDP-43 accumulation, DNA damage, and cell-specific impairment of phagocytosis associated with disease progression

Abstract Background Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterised by the loss of upper and lower motor neurons. Increasing evidence indicates that neuroinflammation mediated by microglia contributes to ALS pathogenesis. This microglial activation is evident in post-mortem brain tissues and neuroimaging data from patients with ALS. However, the role of microglia in the pathogenesis and progression of amyotrophic lateral sclerosis remains unclear, partly due to the lack of a model system that is able to faithfully recapitulate the clinical pathology of ALS. To address this shortcoming, we describe an approach that generates monocyte-derived mi…

MindBEAGLE — A new system for the assessment and communication with patients with disorders of consciousness and complete locked-in syndrom

Patients with disorders of consciousness (DOC) cannot reply to questions or clinical assessments using voluntary motor control, and therefore it is very difficult to assess their cognitive capabilities and conscious awareness. Patients who are locked-in (LIS) are instead fully conscious, and they can communicate with their preserved eye movements. However, when the residual oculomotor activity is also lost (e.g., patients with amyotrophic lateral sclerosis disease of very long duration), the locked-in status becomes complete (CLIS). In CLIS patients, detection of conscious awareness may become very challenging, similarly to the subjects with DOC. mindBEAGLE has a physiological testing batte…

MTHFR C677T allelic variant is not associated to plasma and cerebrospinal fluid homocysteine in amyotrophic lateral sclerosis

Amiotrophic lateral sclerosis (ALS) is a neurological disorder with a multifactorial etiopathogenesis including excitotoxicity, intracellular calcium increase and mitochondrial damage together with oxidative stress and apoptosis. Overall, the relationship between homocysteine (Hcy), motoneuron death and ALS appears to be complex and still under investigation. It has been already shown that Hcy is elevated in plasma and cerebrospinal fluid (CSF) of ALS patients, although mechanisms of hyperhomocysteinemia have not been elucidated yet. MTHFR C677T variant is the most common genetic determinant of increased homocysteinemia, but no studies regarding the effect of this polymorphism in ALS patien…

CSF HOMOCYSTEINE LEVELS IN AMYOTROPHC LATERAL SCLEROSIS

CSF homocysteine levels in Amyotrophic Lateral Sclerosis

Neurogranin as a Novel Biomarker in Alzheimer's Disease

Abstract Background In this study, we investigated the possible role of 2 novel biomarkers of synaptic damage, namely, neurogranin and α-synuclein, in Alzheimer disease (AD). Methods The study was performed in a cohort consisting of patients with AD and those without AD, including individuals with other neurological diseases. Cerebrospinal fluid (CSF) neurogranin and α-synuclein levels were measured by sensitive enzyme-linked immunosorbent assays (ELISAs). Results We found significantly increased levels of CSF neurogranin and α-synuclein in patients with AD than those without AD. Neurogranin was correlated with total tau (tTau) and phosphorylated tau (pTau), as well as with cognitive declin…

How brain-computer interface technology may improve the diagnosis of the disorders of consciousness: A comparative study

ObjectiveClinical assessment of consciousness relies on behavioural assessments, which have several limitations. Hence, disorder of consciousness (DOC) patients are often misdiagnosed. In this work, we aimed to compare the repetitive assessment of consciousness performed with a clinical behavioural and a Brain-Computer Interface (BCI) approach.Materials and methodsFor 7 weeks, sixteen DOC patients participated in weekly evaluations using both the Coma Recovery Scale-Revised (CRS-R) and a vibrotactile P300 BCI paradigm. To use the BCI, patients had to perform an active mental task that required detecting specific stimuli while ignoring other stimuli. We analysed the reliability and the effic…

SERUM CREATINE KINASE LEVEL IN AMYOTROPHIC LATERAL SCLEROSIS: A USEFUL DIAGNOSTIC AID?

...

FOCAL SIGNAL-INTENSITY VARIATIONS IN THE POSTERIOR ARM OF THE INTERNAL CAPSULE IN CONVENTIONAL MRI

DJ-1 mutations and parkinsonism-dementia-amyotrophic lateral sclerosis complex.

Mutations in DJ-1 gene have been recently shown to cause autosomal recessive early-onset Parkinson’s disease (EOPD) in a large Dutch family and in a small consanguineous Italian family.1 Subsequent to this initial finding, several additional DJ-1 mutations were identified in subjects with EOPD.2–6 We describe a family from southern Italy with three brothers affected by a complex disorder characterized by early-onset parkinsonism-dementia-amyotrophic lateral sclerosis (EOPD-D-ALS). The analysis of the DJ-1 gene showed a novel homozygous mutation (E163K) in exon 7 and a novel homozygous mutation (g.168_185dup) in the promoter region of this gene in living affected subjects

Architecture of cell differentiation, stress-mediated protein expression and transport in iPSC-derived Motor Neurons bearing a pG376D TDP-43 mutation

BACKGROUND AND RATIONALE. ALS is a fatal neurodegenerative disease caused by loss of motoneurons (MNs). Growingevidence suggests that the disease has a strong genetic basis. Up to now, more than 50 ALS-related genes have beenfound. Among these, TARDBP plays a critical role in ALS. Pathogenic mutations in TARDBP gene are found in 1–3% offamilial ALS cases. A few years ago, a novel G376D TARDBP mutation associated to ALS was reported (Conforti et al, 2011). Recently, a verylarge genealogic tree from this G376D family was made (2HE Association, personal communication) leading to a largecollection of DNA, plasma and fibroblasts (FBs) from several family members, both affected and not clinically…