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Sample records for advanced amyotrophic lateral

  1. Amyotrophic Lateral Sclerosis

    MedlinePlus

    Amyotrophic lateral sclerosis Overview By Mayo Clinic Staff Amyotrophic lateral sclerosis (a-my-o-TROE-fik LAT-ur-ul skluh-ROE-sis), or ALS, is a progressive nervous system (neurological) disease that ...

  2. Research advances in amyotrophic lateral sclerosis, 2009 to 2010.

    PubMed

    Traub, Rebecca; Mitsumoto, Hiroshi; Rowland, Lewis P

    2011-02-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of upper and lower motor neurons that causes progressive weakness and death. The breadth of research in ALS continues to grow with exciting new discoveries in disease pathogenesis and potential future therapeutics. There is a growing list of identified mutations in familial ALS, including those in genes encoding TDP-43 and FUS/TLS, which are expanding our understanding of the role of RNA modulation in ALS pathogenesis. There is a greater appreciation for the role of glial cells in motor neuron disease. Mitochondrial dysfunction is also being shown to be critical for motor neuron degeneration. In addition to pharmacotherapy, there are promising early developments with therapeutic implications in the areas of RNA interference, stem cell therapies, viral vector-mediated gene therapy, and immunotherapy. With greater understanding of ALS pathogenesis and exciting new therapeutic technologies, there is hope for future progress in treating this disease.

  3. Against All Odds: Positive Life Experiences of People with Advanced Amyotrophic Lateral Sclerosis.

    ERIC Educational Resources Information Center

    Young, Jenny M.; McNicoll, Paule

    1998-01-01

    Describes the nature of positive life experiences of 13 people coping exceptionally well while living with advanced amyotrophic lateral sclerosis (ALS), or Lou Gehrig's, disease and the resulting significant physical disabilities. Emerging themes were the use of cognitive reappraisal, reframing, and intellectual stimulation as coping mechanisms;…

  4. Amyotrophic Lateral Sclerosis

    MedlinePlus

    Amyotrophic lateral sclerosis (ALS) is a nervous system disease that attacks nerve cells called neurons in your brain and spinal cord. These neurons ... breathing machine can help, but most people with ALS die from respiratory failure. The disease usually strikes ...

  5. [Amyotrophic lateral sclerosis].

    PubMed

    Veldink, J H; Weikamp, J; Schelhaas, H J; van den Berg, L H

    2010-01-01

    Amyotrophic lateral sclerosis is one of the most severe and disabling diseases of the nervous system. Amyotrophic lateral sclerosis leads to the progressive weakening of the muscles in the arms, legs, face, mouth and trunk. The onset of the disease is insidious, starting with weakness in the hands or feet or with slurred speech. The weakness worsens and patients pass away as a result of weakness of the respiratory muscles on average within 3 years of the onset of the disease. In the Netherlands, approximately 400 patients are diagnosed with amyotrophic lateral sclerosis every year. There is no diagnostic test for this neuro-muscular disease; the diagnosis is established by excluding other disorders that resemble amyotrophic lateral sclerosis. Only one drug is able to inhibit the progression of the disease to any extent: riluzole. Treatment, therefore, is mainly focused on supportive measures and those which enhance the quality of life optimally.

  6. Amyotrophic lateral sclerosis.

    PubMed

    Malik, Rabia; Lui, Andrew; Lomen-Hoerth, Catherine

    2014-11-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting 20,000 to 30,000 people in the United States. The mainstay of care of patients affected by this disease is supportive and given the multifaceted nature of their needs is provided most efficiently through multidisciplinary clinics that have shown to prolong survival and improve quality of life. The authors discuss in detail evidence-based management of individuals affected by this condition.

  7. Conjugal amyotrophic lateral sclerosis

    PubMed Central

    Dewitt, John D.; Kwon, Julia; Burton, Rebecca

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a disease characterized by progressive degeneration of motor neurons in the motor cortex, brainstem, and spinal cord. The incidence of sporadic ALS is 1.5 to 2.7 in 100,000, and the prevalence is 5.2 to 6.0 in 100,000. Conjugal ALS is even rarer than sporadic ALS. We report a case of conjugal ALS encountered in our outpatient neurology clinic. PMID:22275781

  8. Amyotrophic Lateral Sclerosis Research Program

    DTIC Science & Technology

    2010-08-01

    U.S. Army Medical Research and Materiel Command Amyotrophic Lateral Sclerosis Research Program Report Documentation Page Form ApprovedOMB No. 0704...to 00-00-2010 4. TITLE AND SUBTITLE Amyotrophic Lateral Sclerosis Research Program 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT...research programs such as the Amyotrophic Lateral Sclerosis Research Program (ALSRP) is allo- cated via specific guidance from Congress. Proposal

  9. Advances in the Development of Disease-Modifying Treatments for Amyotrophic Lateral Sclerosis.

    PubMed

    Moujalled, Diane; White, Anthony R

    2016-03-01

    Amyotrophic lateral sclerosis (ALS) is a progressive adult-onset, neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. Over recent years, numerous genes ha ve been identified that promote disease pathology, including SOD1, TARDBP, and the expanded hexanucleotide repeat (GGGGCC) within C9ORF72. However, despite these major advances in identifying genes contributing to ALS pathogenesis, there remains only one currently approved therapeutic: the glutamate antagonist, riluzole. Seminal breakthroughs in the pathomechanisms and genetic factors associated with ALS have heavily relied on the use of rodent models that recapitulate the ALS phenotype; however, while many therapeutics have proved to be significant in animal models by prolonging life and rescuing motor deficits, they have failed in human clinical trials. This may be due to fundamental differences between rodent models and human disease, the fact that animal models are based on overexpression of mutated genes, and confounding issues such as difficulties mimicking the dosing schedules and regimens implemented in mouse models to humans. Here, we review the major pathways associated with the pathology of ALS, the rodent models engineered to test efficacy of candidate drugs, the advancements being made in stem cell therapy for ALS, and what strategies may be important to circumvent the lack of successful translational studies in the clinic.

  10. What causes amyotrophic lateral sclerosis?

    PubMed Central

    Martin, Sarah; Al Khleifat, Ahmad; Al-Chalabi, Ammar

    2017-01-01

    Amyotrophic lateral sclerosis is a neurodegenerative disease predominantly affecting upper and lower motor neurons, resulting in progressive paralysis and death from respiratory failure within 2 to 3 years. The peak age of onset is 55 to 70 years, with a male predominance. The causes of amyotrophic lateral sclerosis are only partly known, but they include some environmental risk factors as well as several genes that have been identified as harbouring disease-associated variation. Here we review the nature, epidemiology, genetic associations, and environmental exposures associated with amyotrophic lateral sclerosis.

  11. Amyotrophic lateral sclerosis

    PubMed Central

    Wijesekera, Lokesh C; Leigh, P Nigel

    2009-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence (average 1.89 per 100,000/year) and prevalence (average 5.2 per100,000) are relatively uniform in Western countries, although foci of higher frequency occur in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male prevalence (M:F ratio~1.5:1). Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, where the symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solid or liquids, and limbs symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1–2 years. Paralysis is progressive and leads to death due to respiratory failure within 2–3 years for bulbar onset cases and 3–5 years for limb onset ALS cases. Most ALS cases are sporadic but 5–10% of cases are familial, and of these 20% have a mutation of the SOD1 gene and about 2–5% have mutations of the TARDBP (TDP-43) gene. Two percent of apparently sporadic patients have SOD1 mutations, and TARDBP mutations also occur in sporadic cases. The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. cervical spondylotic myelopathies, multifocal motor neuropathy, Kennedy's disease) by appropriate investigations. The pathological hallmarks comprise loss of motor neurones with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurones and TDP-43 immunoreactive inclusions in

  12. Optineurin and amyotrophic lateral sclerosis.

    PubMed

    Maruyama, Hirofumi; Kawakami, Hideshi

    2013-07-01

    Amyotrophic lateral sclerosis is a devastating disease, and thus it is important to identify the causative gene and resolve the mechanism of the disease. We identified optineurin as a causative gene for amyotrophic lateral sclerosis. We found three types of mutations: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Optineurin negatively regulates the tumor necrosis factor-α-induced activation of nuclear factor kappa B. Nonsense and missense mutations abolished this function. Mutations related to amyotrophic lateral sclerosis also negated the inhibition of interferon regulatory factor-3. The missense mutation showed a cyotoplasmic distribution different from that of the wild type. There are no specific clinical symptoms related to optineurin. However, severe brain atrophy was detected in patients with homozygous deletion. Neuropathologically, an E478G patient showed transactive response DNA-binding protein of 43 kDa-positive neuronal intracytoplasmic inclusions in the spinal and medullary motor neurons. Furthermore, Golgi fragmentation was identified in 73% of this patient's anterior horn cells. In addition, optineurin is colocalized with fused in sarcoma in the basophilic inclusions of amyotrophic lateral sclerosis with fused in sarcoma mutations, and in basophilic inclusion body disease. These findings strongly suggest that optineurin is involved in the pathogenesis of amyotrophic lateral sclerosis.

  13. Amyotrophic lateral sclerosis mimic syndromes

    PubMed Central

    Ghasemi, Majid

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) misdiagnosis has many broad implications for the patient and the neurologist. Potentially curative treatments exist for certain ALS mimic syndromes, but delay in starting these therapies may have an unfavorable effect on outcome. Hence, it is important to exclude similar conditions. In this review, we discuss some of the important mimics of ALS. PMID:27326363

  14. Practical respiratory management in amyotrophic lateral sclerosis: evidence, controversies and recent advances.

    PubMed

    Bourke, Stephen C; Steer, John

    2016-04-01

    In amyotrophic lateral sclerosis, the onset of respiratory muscle weakness is silent, but survival following symptom recognition may only be a few weeks. Consequently, respiratory function and symptoms should be assessed every 2-3 months. Noninvasive ventilation improves symptoms, quality of life and survival, without increasing carer burden. Lung volume recruitment helps to reverse and prevent atelectasis, improving gas exchange, while techniques to enhance sputum clearance reduce the risk of mucus plugging and lower respiratory tract infections. When noninvasive support fails, often due to severe bulbar impairment, tracheostomy ventilation prolongs life. Most patients receiving tracheostomy ventilation at home report satisfactory quality of life, but at the expense of high carer burden. Diaphragmatic pacing is associated with an increased risk of death.

  15. Acoustic reflex patterns in amyotrophic lateral sclerosis.

    PubMed

    Canale, Andrea; Albera, Roberto; Lacilla, Michelangelo; Canosa, Antonio; Albera, Andrea; Sacco, Francesca; Chiò, Adriano; Calvo, Andrea

    2017-02-01

    The aim of the study is to investigate acoustic reflex testing in amyotrophic lateral sclerosis patients. Amplitude, latency, and rise time of stapedial reflex were recorded for 500 and 1000 Hz contralateral stimulus. Statistical analysis was performed by the Wilcoxon test and the level of significance was set at 5 %. Fifty-one amyotrophic lateral sclerosis patients and ten sex- and age-matched control subjects were studied. Patients were further divided in two groups: amyotrophic lateral sclerosis-bulbar (38 cases, with bulbar signs at evaluation) and amyotrophic lateral sclerosis-spinal (13 cases, without bulbar signs at evaluation). Stapedial reflex was present in all patients. There was a statistically significant difference in the mean amplitude, latency, and rise time between the amyotrophic lateral sclerosis patients as compared with the controls. Amplitude was lower in both the amyotrophic lateral sclerosis-bulbar and the amyotrophic lateral sclerosis-spinal patients than in the controls (p < 0.05) and rise time was longer in both patient groups compared with the controls (p < 0.05). These results confirm the presence of abnormal acoustic reflex patterns in amyotrophic lateral sclerosis cases with bulbar signs and, moreover, suggesting a possible subclinical involvement of the stapedial motor neuron even in amyotrophic lateral sclerosis-spinal patients. Amplitude and rise time seem to be good sensitive parameters for investigating subclinical bulbar involvement.

  16. Diagnosis of amyotrophic lateral sclerosis.

    PubMed

    Rowland, L P

    1998-10-01

    This review of the differential diagnosis of amyotrophic lateral sclerosis focuses on two themes. The first is practical, how to establish the diagnosis based primarily on clinical findings buttressed by electrodiagnosis. The main considerations are multifocal motor neuropathy and cervical spondylotic myelopathy. The second theme is the relationship of motor neuron disease to other conditions, including benign fasciculation (Denny-Brown, Foley syndrome), paraneoplastic syndromes, lymphoproliferative disease, radiation damage, monomelic amyotrophy (Hirayama syndrome), as well as an association with parkinsonism, dementia and multisystem disorders of the central nervous system.

  17. Quantifying disease progression in amyotrophic lateral sclerosis.

    PubMed

    Simon, Neil G; Turner, Martin R; Vucic, Steve; Al-Chalabi, Ammar; Shefner, Jeremy; Lomen-Hoerth, Catherine; Kiernan, Matthew C

    2014-11-01

    Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic.

  18. Amyotrophic Lateral Sclerosis Regional Variants (Brachial Amyotrophic Diplegia, Leg Amyotrophic Diplegia, and Isolated Bulbar Amyotrophic Lateral Sclerosis).

    PubMed

    Jawdat, Omar; Statland, Jeffrey M; Barohn, Richard J; Katz, Jonathan S; Dimachkie, Mazen M

    2015-11-01

    Amyotrophic lateral sclerosis (ALS), a rapidly progressive, invariably fatal disease, involves mixed upper and lower motor neurons in different spinal cord regions. Patients with bulbar onset progress more rapidly than patients with limb onset or with a lower motor neuron presentation. Recent descriptions of regional variants suggest some patients have ALS isolated to a single spinal region for many years, including brachial amyotrophic diplegia, leg amyotrophic diplegia, and isolated bulbar palsy. Clearer definitions of regional variants will have implications for prognosis, understanding the pathophysiology of ALS, identifying genetic factors related to slower disease progression, and future planning of clinical trials.

  19. Genetics Home Reference: amyotrophic lateral sclerosis

    MedlinePlus

    ... DW. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron. 2013 Aug 7;79( ... Miller CC, Shaw CE. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type ...

  20. Exercise and amyotrophic lateral sclerosis.

    PubMed

    de Almeida, J P Lopes; Silvestre, R; Pinto, A C; de Carvalho, M

    2012-02-01

    Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease in which much burden is geared towards end-of-life care. Particularly in the earlier stages of ALS, many people have found both physiological and psychological boosts from various types of physical exercise for disused muscles. Proper exercise is important for preventing atrophy of muscles from disuse-a key for remaining mobile for as long as possible-and as long as it is possible to exercise comfortably and safely, for preserving cardiovascular fitness. However, the typical neuromuscular patient features a great physical inactivity and disuse weakness, and for that reason many controversial authors have contested exercise in these patients during years, especially in ALS which is rapidly progressive. There is an urgent need for dissecting in detail the real risks or benefits of exercise in controlled clinical trials to demystify this ancient paradigm. Yet, recent research studies document significant benefits in terms of survival and quality of life in ALS, poor cooperation, small sample size, uncontrolled and short-duration trials, remain the main handicaps. Sedentary barriers such as early fatigue and inherent muscle misuse should be overcome, for instance with body-weight supporting systems or non-invasive ventilation, and exercise should be faced as a potential non-monotonous way for contributing to better health-related quality of life.

  1. Memory-related white matter tract integrity in amyotrophic lateral sclerosis: an advanced neuroimaging and neuropsychological study.

    PubMed

    Christidi, Foteini; Karavasilis, Efstratios; Zalonis, Ioannis; Ferentinos, Panagiotis; Giavri, Zoi; Wilde, Elisabeth A; Xirou, Sophia; Rentzos, Michalis; Zouvelou, Vasiliki; Velonakis, George; Toulas, Panagiotis; Efstathopoulos, Efstathios; Poulou, Loukia; Argyropoulos, Georgios; Athanasakos, Athanasios; Zambelis, Thomas; Levin, Harvey S; Karandreas, Nikolaos; Kelekis, Nikolaos; Evdokimidis, Ioannis

    2017-01-01

    We aimed to investigate structural changes in vivo in memory-related white matter tracts (i.e., perforant pathway zone [PPZ]; uncinate fasciculus [UF]; fornix) using diffusion tensor tractography and evaluate possible associations with memory performance in nondemented patients with amyotrophic lateral sclerosis (ALS). Forty-two ALS patients and 25 healthy controls (HCs) underwent a 30-directional diffusion-weighted imaging on a 3T MR scanner, followed by tractography of PPZ, UF, and fornix and analysis of fractional anisotropy (FA), axial diffusivity and radial diffusivity (Dr). Patients were administered neuropsychological measures of verbal (list learning via Rey Auditory Verbal Learning Test [RAVLT] and prose memory via Babcock Story Recall Test) and nonverbal (Rey's Complex Figure Test) episodic memory. After correcting for multiple comparisons, ALS patients showed increased Dr in the left PPZ compared to HC. We then fitted a multivariate general linear model within ALS patients with neuropsychological measures as dependent variables and age, age(2), gender, verbal IQ, and diffusion tensor tractography metrics with at least medium effect size differences between ALS and HC as independent variables. We found that (1) left PPZ FA, gender, and verbal IQ contributed to RAVLT-Total Learning; (2) left PPZ FA, left UF Dr, and gender contributed to RAVLT-Immediate Recall; and (3) left PPZ FA and left UF axial diffusivity contributed to Babcock Story Recall Test-Immediate and Delayed Recall. Advanced neuroimaging techniques verified in this study previously reported neuropathological findings regarding PPZ degeneration in ALS. We also detected a unique contribution of microstructural changes in hippocampal and frontotemporal white matter tracts on patients' memory profile.

  2. Amyotrophic Lateral Sclerosis: A Historical Perspective.

    PubMed

    Katz, Jonathan S; Dimachkie, Mazen M; Barohn, Richard J

    2015-11-01

    This article looks back in time to see where the foundational basis for the understanding of amyotrophic lateral sclerosis originated. This foundation was created primarily in France by Jean-Martin Charcot and his fellow countrymen and disciples, along with key contributions from early clinicians in England and Germany. The early work on amyotrophic lateral sclerosis provides a useful foundation for today's clinicians with respect to tying together genetic and biologic aspects of the disorder that have been discovered over the past few decades.

  3. Epidemiology of amyotrophic lateral sclerosis.

    PubMed

    Kurtzke, J F

    1982-01-01

    Motor neuron disease (MND) is used in this paper as the generic label, encompassing the clinical variants of amyotrophic lateral sclerosis (ALS), progressive myelopathic muscular atrophy (PMMA), and progressive bulbar palsy (PBP). ALS is limited to instances of anterior horn cell plus pyramidal tract involvement. When only anterior horn cell lesions are inferred, either PMMA or PBP is used, depending on the levels of involvement; when both cord and brain stem are affected. PBP is the designation. Mortality data on MND have been available for a number of countries since 1949. The coding used under international rules has varied considerably over this interval. Before 1969, hereditary muscular atrophies were included. Since 1979, no subdivision by type of MND is possible. International death rates for MND have all been rather close to 1 per 100,000 population per year, though perhaps nearer to 1.4 on the average in recent years. There has been an increasing proportion of MND deaths coded to ALS between 1949 and 1977. There is no notable geographic variation among countries, nor within countries such as the U.S. and Denmark. A slight upward trend in death rates over time in the U.S. is matched by a slight decrease in Denmark. Death rates from all sources indicate a male preponderance for ALS or MND as a whole, at about 1.5 to 1, male to female. There is also a consistent predilection by age, with few deaths under age 50 or so and a clear maximum in age-specific death rates at about age 70. This holds for both sexes. In the U.S., there is also a white-nonwhite difference, with a ratio of about 1.6:1 but with age and sex differences similar to whites. Average annual incidence rates from among white occidental populations range mostly between 0.6 and 1.8 per 100,000 population for MND and about 0.8 and 1.5 per 100,000 for ALS. Again a male predilection is seen. There is a clear maximum in age-specific incidence rates at about age 65 in all surveys except that of

  4. A perspective on stem cell modeling of amyotrophic lateral sclerosis

    PubMed Central

    de Boer, A Sophie; Eggan, Kevin

    2015-01-01

    Amyotrophic lateral sclerosis is a complex neurodegenerative disease. Limitations in animal models have impeded progress in studying disease pathology and potential drug discovery. Here, we will review recent advances in the development of stem cell models for the study of ALS. Additionally, we will discuss the progress toward therapeutic development derived from these stem cell based assays. PMID:26505672

  5. Amyotrophic lateral sclerosis: the role of exercise.

    PubMed

    Lisle, Stuart; Tennison, Matthew

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a chronic progressive neurodegenerative disease affecting both the upper and lower motor neurons. Given the deterioration of skeletal muscle function, historically there has been concern regarding exercise and its affect on ALS. This article reviews and explains current research, helping patients, caregivers, and providers be equipped better to make decisions regarding the treatment of ALS with exercise.

  6. Clinical Psychology and Amyotrophic Lateral Sclerosis

    PubMed Central

    Pagnini, Francesco; Rossi, Gabriella; Lunetta, Christian; Banfi, Paolo; Corbo, Massimo

    2010-01-01

    Amyotrophic lateral sclerosis is a fatal and progressive disease, characterized by progressive muscles weakness, with consequent loss of physical capacities. Psychologists can play an important role in ALS care, by providing clinical activities in every step of the disease, including support and counseling activities directed to patients, their caregivers and to physicians. PMID:21833203

  7. Mitochondrial dysfunction in blood cells from amyotrophic lateral sclerosis patients.

    PubMed

    Ehinger, Johannes K; Morota, Saori; Hansson, Magnus J; Paul, Gesine; Elmér, Eskil

    2015-06-01

    Mitochondrial dysfunction is implicated in amyotrophic lateral sclerosis, where the progressive degeneration of motor neurons results in muscle atrophy, paralysis and death. Abnormalities in both central nervous system and muscle mitochondria have previously been demonstrated in patient samples, indicating systemic disease. In this case-control study, venous blood samples were acquired from 24 amyotrophic lateral sclerosis patients and 21 age-matched controls. Platelets and peripheral blood mononuclear cells were isolated and mitochondrial oxygen consumption measured in intact and permeabilized cells with additions of mitochondrial substrates, inhibitors and titration of an uncoupler. Respiratory values were normalized to cell count and for two markers of cellular mitochondrial content, citrate synthase activity and mitochondrial DNA, respectively. Mitochondrial function was correlated with clinical staging of disease severity. Complex IV (cytochrome c-oxidase)-activity normalized to mitochondrial content was decreased in platelets from amyotrophic lateral sclerosis patients both when normalized to citrate synthase activity and mitochondrial DNA copy number. In mononuclear cells, complex IV-activity was decreased when normalized to citrate synthase activity. Mitochondrial content was increased in amyotrophic lateral sclerosis patient platelets. In mononuclear cells, complex I activity declined and mitochondrial content increased progressively with advancing disease stage. The findings are, however, based on small subsets of patients and need to be confirmed. We conclude that when normalized to mitochondria-specific content, complex IV-activity is reduced in blood cells from amyotrophic lateral sclerosis patients and that there is an apparent compensatory increase in cellular mitochondrial content. This supports systemic involvement in amyotrophic lateral sclerosis and suggests further study of mitochondrial function in blood cells as a future biomarker for the

  8. Evaluation and management of amyotrophic lateral sclerosis.

    PubMed

    Valadi, Nojan

    2015-06-01

    Motor neuron diseases can cause progressive impairment of voluntary muscles of movement, respiration, speech, and swallowing. This review discusses the most common motor neuron disease, amyotrophic lateral sclerosis (ALS). It reviews the evaluation, diagnosis, and management of ALS, and its epidemiology, pathophysiology, and management. A coordinated approach by the primary care physician and neurologist is necessary with a focus on treatment options, durable medical equipment needs, and end-of-life discussions.

  9. Psychiatric disorders prior to amyotrophic lateral sclerosis

    PubMed Central

    Goldacre, Raph; Talbot, Kevin; Goldacre, Michael J.

    2016-01-01

    It is recognized that neuropsychiatric conditions are overrepresented in amyotrophic lateral sclerosis (ALS) patient kindreds and psychiatric symptoms may precede the onset of motor symptoms. Using a hospital record linkage database, hospitalization with a diagnosis of schizophrenia, bipolar disorder, depression, or anxiety was significantly associated with a first diagnosis of ALS within the following year. This is likely to specifically reflect the clinicopathological overlap of ALS with frontotemporal dementia. A diagnosis of depression was significantly associated with a first record of ALS ≥5 years later, in keeping with growing evidence for major depressive disorder as an early marker of cerebral neurodegeneration. Ann Neurol 2016;80:935–938 PMID:27761925

  10. Pemphigus vulgaris and amyotrophic lateral sclerosis

    PubMed Central

    Mokhtari, Fatemeh; Matin, Marzieh; Rajati, Fatemeh

    2016-01-01

    Pemphigus vulgaris (PV) is an autoimmune bullous and erosive mucocutaneous disease. Rarely, it occurs in patients with other autoimmune disease. The relation between PV and neurological disorders is unclear and needs to be more studied. Here, we report a case of amyotrophic lateral sclerosis (ALS), followed by dermatologic involvement. Histopathological evidence and direct immunofluorescence are consistent with PV. Systemic corticosteroid and azathioprine were effective in the treatment of mucocutaneous lesions. PV seems to be accidentally associated with ALS. Expression of major histocompatibility complex Class II in autoimmune disease and production of autoantibodies have been proposed to describe the association of PV with ALS. PMID:28163728

  11. The changing scene of amyotrophic lateral sclerosis.

    PubMed

    Robberecht, Wim; Philips, Thomas

    2013-04-01

    Several recent breakthroughs have provided notable insights into the pathogenesis of amyotrophic lateral sclerosis (ALS), with some even shifting our thinking about this neurodegenerative disease and raising the question as to whether this disorder is a proteinopathy, a ribonucleopathy or both. In addition, these breakthroughs have revealed mechanistic links between ALS and frontotemporal dementia, as well as between ALS and other neurodegenerative diseases, such as the cerebellar atrophies, myotonic dystrophy and inclusion body myositis. Here, we summarize the new findings in ALS research, discuss what they have taught us about this disease and examine issues that are still outstanding.

  12. Amyotrophic lateral sclerosis: one or multiple causes?

    PubMed Central

    Bastos, Aline Furtado; Orsini, Marco; Machado, Dionis; Mello, Mariana Pimentel; Nader, Sergio; Silva, Júlio Guilherme; da Silva Catharino, Antonio M.; de Freitas, Marcos R.G.; Pereira, Alessandra; Pessoa, Luciane Lacerda; Sztajnbok, Flavio R.; Leite, Marco Araújo; Nascimento, Osvaldo J.M.; Bastos, Victor Hugo

    2011-01-01

    The Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease in the adulthood, and it is characterized by rapid and progressive compromise of the upper and lower motor neurons. The majority of the cases of ALS are classified as sporadic and, until now, a specific cause for these cases still is unknown. To present the different hypotheses on the etiology of ALS. It was carried out a search in the databases: Bireme, Scielo and Pubmed, in the period of 1987 to 2011, using the following keywords: Amyotrophic lateral sclerosis, motor neuron disease, etiology, causes and epidemiology and its similar in Portuguese and Spanish. It did not have consensus as regards the etiology of ALS. Researches demonstrates evidences as regards intoxication by heavy metals, environmental and occupational causes, genetic mutations (superoxide dismutase 1), certain viral infections and the accomplishment of vigorous physical activity for the development of the disease. There is still no consensus regarding the involved factors in the etiology of ALS. In this way, new research about these etiologies are necessary, for a better approach of the patients, promoting preventive programs for the disease and improving the quality of life of the patients. PMID:21785676

  13. High-fat and ketogenic diets in amyotrophic lateral sclerosis.

    PubMed

    Paganoni, Sabrina; Wills, Anne-Marie

    2013-08-01

    Amyotrophic lateral sclerosis is a fatal neurodegenerative disease. Epidemiologic data suggest that malnutrition is a common feature in amyotrophic lateral sclerosis and being overweight or obese confers a survival advantage in this patient population. In amyotrophic lateral sclerosis mouse models, a high-fat diet has been shown to lead to weight gain and prolonged survival. However, little research has been conducted to test whether nutritional interventions might ameliorate the disease course in humans. Here we review the currently available evidence supporting the potential role of dietary interventions as a therapeutic tool for amyotrophic lateral sclerosis. Ultimately, determining whether a high-fat or ketogenic diet could be beneficial in amyotrophic lateral sclerosis will require large randomized, placebo-controlled clinical trials.

  14. [Amyotrophic lateral sclerosis--diagnosis and treatment].

    PubMed

    Jung, H H; Neumann, M; Bloch, K E

    2012-07-04

    Amyotrophic lateral sclerosis (ALS) represents the most common motoneuron disorder in adulthood. It is characterized by selective degeneration of the motoneurons. About 10% of patients have a genetically determined ALS. Clinically, ALS is characterized by coexistence of signs of the first motoneuron, such as spasticity and hyperreflexia, as well as the second motoneuron, such as muscular atrophy and fasciculations. If such signs are present in at least three regions and if other possible causes have been excluded, a definite diagnosis of ALS can be made based on the revised El-Escorial criteria. Initial manifestations are often focalized and generalization develops during the course. The glutamate antagonist riluzole is worldwide the only approved ALS treatment. However, symptomatic treatments to ameliorate spasticity, drooling, speech and swallowing problems, and assisted ventilation to treat respiratory failure are essential.

  15. Amyotrophic lateral sclerosis associated with pregnancy.

    PubMed

    Tyagi, A; Sweeney, B J; Connolly, S

    2001-12-01

    Amyotrophic lateral sclerosis (ALS) is the most common, progressive motor neurone disease but is rare in the obstetric population. Only 4 cases have been described in the English literature since 1975. We describe a 29 year old woman who presented with ataxia, lower limb weakness and dysarthria 4 weeks after the birth of her first child. The symptoms had onset during the pregnancy but had not been considered remarkable. There were clinical features of upper and lower motor neurone involvement without any sensory loss. MRI of brain and spine was normal. CSF analysis was negative. EMG studies confirmed the presence of widespread anterior horn cell dysfunction compatible with ALS. The patient was commenced on Riluzole and has progressed clinically, at 12 months post diagnosis.

  16. Amyotrophic lateral sclerosis and environmental factors

    PubMed Central

    Bozzoni, Virginia; Pansarasa, Orietta; Diamanti, Luca; Nosari, Guido; Cereda, Cristina; Ceroni, Mauro

    2016-01-01

    Summary Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects central and peripheral motor neuron cells. Its etiology is unknown, although a relationship between genetic background and environmental factors may play a major role in triggering the neurodegeneration. In this review, we analyze the role of environmental factors in ALS: heavy metals, electromagnetic fields and electric shocks, pesticides, β-N-methylamino-L-alanine, physical activity and the controversial role of sports. The literature on the single issues is analyzed in an attempt to clarify, as clearly as possible, whether each risk factor significantly contributes to the disease pathogenesis. After summarizing conflicting observations and data, the authors provide a final synthetic statement. PMID:27027889

  17. Dysarthria in amyotrophic lateral sclerosis: A review.

    PubMed

    Tomik, Barbara; Guiloff, Roberto J

    2010-01-01

    Dysarthria is a motor disorder of speech characterized by abnormalities of the articulation and intelligibility of speech. Phonation and the rate of facial movements may also be affected. Understanding the nature and course of dysarthria in amyotrophic lateral sclerosis (ALS) is important because loss of communication prevents patients from participating in many activities, may lead to social isolation, and reduces the quality of life. The goal of management of dysarthria in ALS patients is to optimize communication effectiveness for as long as possible. The information about dysarthria in ALS is dispersed in physiological, pathological, speech therapy, otorhinolaringological and neurological publications. This review summarizes the current state of knowledge on the clinical features, differential diagnosis, pathophysiology, investigations and management of dysarthria in ALS patients. There is a need to compare the different methods used to assess dysarthria and for controlled clinical trials to assess therapeutic strategies.

  18. A comprehensive review of amyotrophic lateral sclerosis

    PubMed Central

    Zarei, Sara; Carr, Karen; Reiley, Luz; Diaz, Kelvin; Guerra, Orleiquis; Altamirano, Pablo Fernandez; Pagani, Wilfredo; Lodin, Daud; Orozco, Gloria; Chinea, Angel

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease affecting motor neurons with an incidence of about 1/100,000. Most ALS cases are sporadic, but 5–10% of the cases are familial ALS. Both sporadic and familial ALS (FALS) are associated with degeneration of cortical and spinal motor neurons. The etiology of ALS remains unknown. However, mutations of superoxide dismutase 1 have been known as the most common cause of FALS. In this study, we provide a comprehensive review of ALS. We cover all aspects of the disease including epidemiology, comorbidities, environmental risk factor, molecular mechanism, genetic factors, symptoms, diagnostic, treatment, and even the available supplement and management of ALS. This will provide the reader with an advantage of receiving a broad range of information about the disease. PMID:26629397

  19. Amyotrophic Lateral Sclerosis: New Perpectives and Update.

    PubMed

    Orsini, Marco; Oliveira, Acary Bulle; Nascimento, Osvaldo J M; Reis, Carlos Henrique Melo; Leite, Marco Antonio Araujo; de Souza, Jano Alves; Pupe, Camila; de Souza, Olivia Gameiro; Bastos, Victor Hugo; de Freitas, Marcos R G; Teixeira, Silmar; Bruno, Carlos; Davidovich, Eduardo; Smidt, Benny

    2015-09-24

    Amyotrophic lateral sclerosis (ALS), Charcot's disease or Lou Gehrig's disease, is a term used to cover the spetrum of syndromes caracterized by progressive degeneration of motor neurons, a paralytic disorder caused by motor neuron degeneration. Currently, there are approximately 25,000 patients with ALS in the USA, with an average age of onset of 55 years. The incidence and prevalence of ALS are 1-2 and 4-6 per 100,000 each year, respectively, with a lifetime ALS risk of 1/600 to 1/1000. It causes progressive and cumulative physical disabilities, and leads to eventual death due to respiratory muscle failure. ALS is diverse in its presentation, course, and progression. We do not yet fully understand the causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. In this chapter, we will discuss the diagnosis, treatment, and how to cope with impaired function and end of life based on of our experience, guidelines, and clinical trials. Nowadays ALS seems to be a more complex disease than it did two decades - or even one decade - ago, but new insights have been plentiful. Clinical trials should be seen more as experiments on pathogenic mechanisms. A medication or combination of medications that targets more than one pathogenic pathway may slow disease progression in an additive or synergistic fashion.

  20. Controversies and priorities in amyotrophic lateral sclerosis

    PubMed Central

    Turner, Martin R; Hardiman, Orla; Benatar, Michael; Brooks, Benjamin R; Chio, Adriano; de Carvalho, Mamede; Ince, Paul G; Lin, Cindy; Miller, Robert G; Mitsumoto, Hiroshi; Nicholson, Garth; Ravits, John; Shaw, Pamela J; Swash, Michael; Talbot, Kevin; Traynor, Bryan J; den Berg, Leonard H Van; Veldink, Jan H; Vucic, Steve; Kiernan, Matthew C

    2015-01-01

    Summary Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events. PMID:23415570

  1. Narrative discourse deficits in amyotrophic lateral sclerosis

    PubMed Central

    Menaged, Anna; Olm, Christopher; McMillan, Corey T.; Boller, Ashley; Irwin, David J.; McCluskey, Leo; Elman, Lauren; Grossman, Murray

    2014-01-01

    Objective: We examined narrative discourse in amyotrophic lateral sclerosis (ALS) to assess the role of executive functioning in support of language and the neuroanatomical basis for such support. Methods: We analyzed a semistructured speech sample in 26 patients with ALS and 19 healthy seniors for narrative discourse features of coherence. Regression analyses related a measure of discourse coherence (“local connectedness”) to gray matter atrophy and reduced white matter fractional anisotropy. Results: Patients with ALS were impaired relative to controls on measures of discourse adequacy, including local connectedness and maintenance of the theme. These discourse measures were related to measures of executive functioning but not to motor functioning. Regressions related local connectedness to gray matter atrophy in ventral and dorsal prefrontal regions and to reduced fractional anisotropy in white matter tracts mediating projections between prefrontal regions. Conclusion: Patients with ALS exhibit deficits in their ability to organize narrative discourse. These deficits appear to be related in part to executive limitations. Consistent with the hypothesis that ALS is a multisystem disorder, this deficit is related to disease in prefrontal regions. PMID:24991038

  2. Risk factors for amyotrophic lateral sclerosis

    PubMed Central

    Ingre, Caroline; Roos, Per M; Piehl, Fredrik; Kamel, Freya; Fang, Fang

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. It is typically fatal within 2–5 years of symptom onset. The incidence of ALS is largely uniform across most parts of the world, but an increasing ALS incidence during the last decades has been suggested. Although recent genetic studies have substantially improved our understanding of the causes of ALS, especially familial ALS, an important role of non-genetic factors in ALS is recognized and needs further study. In this review, we briefly discuss several major genetic contributors to ALS identified to date, followed by a more focused discussion on the most commonly examined non-genetic risk factors for ALS. We first review factors related to lifestyle choices, including smoking, intake of antioxidants, physical fitness, body mass index, and physical exercise, followed by factors related to occupational and environmental exposures, including electromagnetic fields, metals, pesticides, β-methylamino-L-alanine, and viral infection. Potential links between ALS and other medical conditions, including head trauma, metabolic diseases, cancer, and inflammatory diseases, are also discussed. Finally, we outline several future directions aiming to more efficiently examine the role of non-genetic risk factors in ALS. PMID:25709501

  3. Epidemiologic correlates of sporadic amyotrophic lateral sclerosis

    SciTech Connect

    Armon, C.; Kurland, L.T.; Daube, J.R.; O'Brien, P.C. )

    1991-07-01

    The authors evaluated 74 selected patients with amyotrophic lateral sclerosis (ALS) and 201 matched controls for risk factors for ALS by a case-control design and a sequential questionnaire/interview technique to quantitate biographic data. They analyzed occupational and recreational data only for 47 male patients and 47 corresponding patient controls; data for women were insufficient. They used nonparametric analyses to evaluate five primary comparisons of ALS patients with controls: (1) more hard physical labor, p not significant (NS); (2) greater frequency of neurodegenerative disease in family members, p NS; (3) greater exposure to lead, p less than 0.05; (4) more years lived in a rural community, p NS; and (5) more trauma or major surgery, p NS. Men with ALS had worked more frequently at blue-collar jobs (although not a statistically significant difference, p = 0.10) and at welding or soldering (p less than 0.01). These results suggest that there may be an association between ALS in men and exposure to lead vapor. The limited nature of the association favors a multifactorial etiologic mechanism of ALS.

  4. Rodent Models of Amyotrophic Lateral Sclerosis.

    PubMed

    Philips, Thomas; Rothstein, Jeffrey D

    2015-06-01

    Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease affecting upper and lower motor neurons in the central nervous system. Patients with ALS develop extensive muscle wasting and atrophy leading to paralysis and death 3 to 5 years after disease onset. The condition may be familial (fALS 10%) or sporadic ALS (sALS, 90%). The large majority of fALS cases are due to genetic mutations in the Superoxide dismutase 1 gene (SOD1, 15% of fALS) and repeat nucleotide expansions in the gene encoding C9ORF72 (∼ 40% to 50% of fALS and ∼ 10% of sALS). Studies suggest that ALS is mediated through aberrant protein homeostasis (i.e., ER stress and autophagy) and/or changes in RNA processing (as in all non-SOD1-mediated ALS). In all of these cases, animal models suggest that the disorder is mediated non-cell autonomously, i.e., not only motor neurons are involved, but glial cells including microglia, astrocytes, and oligodendrocytes, and other neuronal subpopulations are also implicated in the pathogenesis. Provided in this unit is a review of ALS rodent models, including discussion of their relative advantages and disadvantages. Emphasis is placed on correlating the model phenotype with the human condition and the utility of the model for defining the disease process. Information is also presented on RNA processing studies in ALS research, with particular emphasis on the newest ALS rodent models.

  5. Decisional Capacity in Amyotrophic Lateral Sclerosis.

    PubMed

    Khin Khin, Eindra; Minor, Darlinda; Holloway, Amanda; Pelleg, Ayla

    2015-06-01

    The cognitive and behavioral changes that can be observed in the neurodegenerative terminal disease amyotrophic lateral sclerosis (ALS), once characterized as purely a motor neuron disease, have become increasingly recognized over the past century. Detecting cognitive deficits earlier and identifying continued changes at regular intervals can lead to improved care, proactive treatments, and earlier discussions about end-of-life wishes. Although medical decisional capacity is required for every treatment decision made, its importance becomes paramount when making decisions on complex medical treatments that will invariably and significantly affect quality of life or life itself. In this review, we conducted a critical analysis of the evidence-based literature on the cognitive and behavioral impairments in ALS that can compromise medical decisional capacity. We review specific ALS-related clinical scenarios in which decisional capacity is of utmost importance and discuss a practical framework for cognitive and behavioral assessment that can be routinely and efficiently used, while being mindful of the confounding factors associated with ALS. Finally, we review models for preserving patient choices that can be used in patients with ALS to help safeguard autonomy and retain dignity toward the end of life.

  6. Amyotrophic Lateral Sclerosis: New Perpectives and Update

    PubMed Central

    Orsini, Marco; Oliveira, Acary Bulle; Nascimento, Osvaldo J.M.; Reis, Carlos Henrique Melo; Leite, Marco Antonio Araujo; de Souza, Jano Alves; Pupe, Camila; de Souza, Olivia Gameiro; Bastos, Victor Hugo; de Freitas, Marcos R.G.; Teixeira, Silmar; Bruno, Carlos; Davidovich, Eduardo; Smidt, Benny

    2015-01-01

    Amyotrophic lateral sclerosis (ALS), Charcot’s disease or Lou Gehrig’s disease, is a term used to cover the spetrum of syndromes caracterized by progressive degeneration of motor neurons, a paralytic disorder caused by motor neuron degeneration. Currently, there are approximately 25,000 patients with ALS in the USA, with an average age of onset of 55 years. The incidence and prevalence of ALS are 1-2 and 4-6 per 100,000 each year, respectively, with a lifetime ALS risk of 1/600 to 1/1000. It causes progressive and cumulative physical disabilities, and leads to eventual death due to respiratory muscle failure. ALS is diverse in its presentation, course, and progression. We do not yet fully understand the causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. In this chapter, we will discuss the diagnosis, treatment, and how to cope with impaired function and end of life based on of our experience, guidelines, and clinical trials. Nowadays ALS seems to be a more complex disease than it did two decades – or even one decade – ago, but new insights have been plentiful. Clinical trials should be seen more as experiments on pathogenic mechanisms. A medication or combination of medications that targets more than one pathogenic pathway may slow disease progression in an additive or synergistic fashion. PMID:26487927

  7. Selective attention impairment in amyotrophic lateral sclerosis.

    PubMed

    Volpato, Chiara; Prats Sedano, Maria Angeles; Silvoni, Stefano; Segato, Nicoletta; Cavinato, Marianna; Merico, Antonio; Piccione, Francesco; Palmieri, Arianna; Birbaumer, Niels

    2016-01-01

    Objective of this study was to evaluate attentional control mechanisms in amyotrophic lateral sclerosis (ALS) using an auditory event-related potentials (ERPs) paradigm. Fifteen mild to moderate ALS patients and 15 healthy controls were administered a brief neuropsychological test battery and an ERPs paradigm assessing selective attention. Four types of auditory stimuli were presented in random order: short standard (200 Hz, 200 ms), long standard (200 Hz, 500 ms), short deviant (1000 Hz, 200 ms) and long deviant (1000 Hz, 500 ms). Participants had to respond to the long deviant stimuli only. During the task the electroencephalogram (EEG) was recorded. The N200, P300 and re-orienting negativity (RON) ERP components were analysed. Compared to controls ALS patients showed reduced amplitudes and delayed latencies of N200, P300 and RON. These results could be attributable to both an alteration in change detection resulting in a reduction of the allocation and re-orientation of attentional resources or a general slowing or reduction of neural processing efficiency in the same system. The ERPs results support the hypothesis that ALS involves extramotor cognitive functions including auditory attentional processing at all processing stages, early (200 ms) and late (300-600 ms). These data prove the usefulness and sensitivity of the auditory ERPs in detection of cognitive functions in ALS patients.

  8. Respiratory exercise in amyotrophic lateral sclerosis.

    PubMed

    Pinto, Susana; Swash, Michael; de Carvalho, Mamede

    2012-01-01

    We have evaluated the potential role of respiratory exercise by implementing specific inspiratory muscle training in a selected population of early-affected amyotrophic lateral sclerosis (ALS) patients. We studied 26 patients with ALS with normal respiratory function using two groups of patients in a parallel, control-group, randomized, delayed-start design. Patients in the first group (G1) started the active inspiratory exercise programme at entry and were followed for eight months, while the second group (G2) of patients followed a placebo exercise programme for the first four months and then active exercise for the second four-month period. The primary outcome measure was the ALSFRS. Respiratory tests, neurophysiological measurements, fatigue and quality of life scales were secondary outcomes. Analysis of covariance was used to compare changes between and within groups. Results showed that there was no significant difference between the two patient groups. Within-group analysis suggested that inspiratory exercise promotes a transient improvement in the respiratory subscore and in the maximal voluntary ventilation, peak expiratory flow, and sniff inspiratory pressure. In conclusion, there was no clear positive or negative outcome of the respiratory exercise protocol we have proposed, but we cannot rule out a minor positive effect. Exercise regimes merit more detailed clinical evaluation in ALS.

  9. Immune system alterations in amyotrophic lateral sclerosis.

    PubMed

    Hovden, H; Frederiksen, J L; Pedersen, S W

    2013-11-01

    Amyotrophic lateral sclerosis is a disease of which the underlying cause and pathogenesis are unknown. Cumulatative data clearly indicates an active participation by the immune system in the disease. An increasingly recognized theory suggests a non-cell autonomous mechanism, meaning that multiple cells working together are necessary for the pathogenesis of the disease. Observed immune system alterations could indicate an active participation in this mechanism. Damaged motor neurons are able to activate microglia, astrocytes and the complement system, which further can influence each other and contribute to neurodegeneration. Infiltrating peripheral immune cells appears to correlate with disease progression, but their significance and composition is unclear. The deleterious effects of this collaborating system of cells appear to outweigh the protective aspects, and revealing this interplay might give more insight into the disease. Markers from the classical complement pathway are elevated where its initiator C1q appears to derive primarily from motor neurons. Activated microglia and astrocytes are found in close proximity to dying motor neurons. Their activation status and proliferation seemingly increases with disease progression. Infiltrating monocytes, macrophages and T cells are associated with these areas, although with mixed reports regarding T cell composition. This literature review will provide evidence supporting the immune system as an important part of ALS disease mechanism and present a hypothesis to direct the way for further studies.

  10. Characteristics of pain in amyotrophic lateral sclerosis

    PubMed Central

    Hanisch, Frank; Skudlarek, Anika; Berndt, Janine; Kornhuber, Malte E

    2015-01-01

    Background Pain is an often underestimated and neglected symptom in amyotrophic lateral sclerosis (ALS). Methods In a cross-sectional survey, 46 patients with ALS, 46 age- and gender matched population-based controls, and 23 diseased controls with myotonic dystrophy type 2 (DM2) were screened for occurrence, type, distribution, and treatment of pain and cramps. Data were collected with the use of the short form brief pain inventory (BPI). Results Pain was reported in 78% of ALS patients,79% of DM2 patients, and 54% of controls (P < 0.05). More ALS patients than controls reported moderate to severe pain (42% vs. 20%). Pain in ALS patients interfered significantly more with daily activities than in controls (median pain interference score: 3.0 vs. 1.2, P < 0.05), especially enjoyment of life (5.0 vs. 1.0) and mood (3.0 vs. 1.0). There was no correlation between the duration of the disease and the severity of pain. Movement-induced cramps were reported in 63% of ALS patients, mostly in the distal extremities. There was no difference in the duration of ALS disease between patients reporting cramps and those who did not. Discussion Our study showed that pain was a relatively frequent symptom which had an important impact on the quality of life. Pain that requires treatment can occur at every stage of ALS. PMID:25642388

  11. Alterations in the hypothalamic melanocortin pathway in amyotrophic lateral sclerosis.

    PubMed

    Vercruysse, Pauline; Sinniger, Jérôme; El Oussini, Hajer; Scekic-Zahirovic, Jelena; Dieterlé, Stéphane; Dengler, Reinhard; Meyer, Thomas; Zierz, Stephan; Kassubek, Jan; Fischer, Wilhelm; Dreyhaupt, Jens; Grehl, Torsten; Hermann, Andreas; Grosskreutz, Julian; Witting, Anke; Van Den Bosch, Ludo; Spreux-Varoquaux, Odile; Ludolph, Albert C; Dupuis, Luc

    2016-04-01

    Amyotrophic lateral sclerosis, the most common adult-onset motor neuron disease, leads to death within 3 to 5 years after onset. Beyond progressive motor impairment, patients with amyotrophic lateral sclerosis suffer from major defects in energy metabolism, such as weight loss, which are well correlated with survival. Indeed, nutritional intervention targeting weight loss might improve survival of patients. However, the neural mechanisms underlying metabolic impairment in patients with amyotrophic lateral sclerosis remain elusive, in particular due to the lack of longitudinal studies. Here we took advantage of samples collected during the clinical trial of pioglitazone (GERP-ALS), and characterized longitudinally energy metabolism of patients with amyotrophic lateral sclerosis in response to pioglitazone, a drug with well-characterized metabolic effects. As expected, pioglitazone decreased glycaemia, decreased liver enzymes and increased circulating adiponectin in patients with amyotrophic lateral sclerosis, showing its efficacy in the periphery. However, pioglitazone did not increase body weight of patients with amyotrophic lateral sclerosis independently of bulbar involvement. As pioglitazone increases body weight through a direct inhibition of the hypothalamic melanocortin system, we studied hypothalamic neurons producing proopiomelanocortin (POMC) and the endogenous melanocortin inhibitor agouti-related peptide (AGRP), in mice expressing amyotrophic lateral sclerosis-linked mutant SOD1(G86R). We observed lower Pomc but higher Agrp mRNA levels in the hypothalamus of presymptomatic SOD1(G86R) mice. Consistently, numbers of POMC-positive neurons were decreased, whereas AGRP fibre density was elevated in the hypothalamic arcuate nucleus of SOD1(G86R) mice. Consistent with a defect in the hypothalamic melanocortin system, food intake after short term fasting was increased in SOD1(G86R) mice. Importantly, these findings were replicated in two other amyotrophic

  12. A case-control study of amyotrophic lateral sclerosis.

    PubMed

    Savettieri, G; Salemi, G; Arcara, A; Cassata, M; Castiglione, M G; Fierro, B

    1991-01-01

    A retrospective case-control study was conducted using 46 patients affected by amyotrophic lateral sclerosis and 92 closely matched healthy controls. Cases were ascertained through typical clinical and instrumental findings. Putative risk factors (bone fractures or major trauma, exposure to domestic animals, surgical operations, disease among first degree relatives and others) were investigated anamnestically using a standard questionnaire. Using Mantel-Haenzsel estimates of the odds ratio, no association was found between amyotrophic lateral sclerosis and the investigated variables.

  13. Therapeutic progress in amyotrophic lateral sclerosis-beginning to learning.

    PubMed

    Kumar, Vijay; Islam, Asimul; Hassan, Md Imtaiyaz; Ahmad, Faizan

    2016-10-04

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, muscle weakness, paralysis and finally death. The proposed mechanisms of ALS include glutamate excitotoxicity, oxidative stress, inflammation, mitochondrial dysfunction, apoptosis and proteasomal dysfunction. Although numerous pathological mechanisms have been explained, ALS remains incurable disease because of failure of clinical trials and lack of any effective therapy. The rapid advancement in genetic discoveries in ALS emphasizes the point that ALS is a multi-subtype syndrome rather than a single disease. This can be argued as one of the single reason why many previous therapeutic drug trials have failed. Efforts to develop novel ALS treatments which target specific pathomechanisms are currently being pursued. Herein, we review the recent discovery and preclinical characterization of neuroprotective compounds and compare their effects on disease onset, duration and survival. Furthermore, the structure-activity relationships of these agents are analyzed with the overall goal of developing a screening strategy for future clinical applications.

  14. Percutaneous gastrojejunostomy in amyotrophic lateral sclerosis.

    PubMed

    Strong, M J; Rowe, A; Rankin, R N

    1999-10-31

    We have performed a retrospective review of the use of a percutaneous gastrojejunostomy in patients with amyotrophic lateral sclerosis (ALS). Forty-one patients with initial bulbar manifestations of ALS and 32 patients with initial limb manifestations underwent a percutaneous gastrojejunostomy under fluoroscopic control using the Rankin gastrojejunostomy tube. Survival characteristics were compared with 86 bulbar onsetting and 207 limb onsetting ALS patients who did not require nutritional support. The 30-day mortality rate was 9.6% (respiratory death in three bulbar onsetting patients and four limb onsetting patients) and the 30 day morbidity rate was 4.1% (one operative site infection and intraperitoneal leakage in two patients). The most frequent long-term complication was the requirement for tube changing (blockage in six; dislodgment in two). Gastric reflux was not described amongst the treated patients. Overall survivorship (symptom onset to death) was less in the bulbar onsetting patients receiving a gastrojejunostomy tube than in the control population (median survival 22.0 vs. 33.7 months, respectively, P=0.005). As a group, the median survivorship for limb onsetting patients was not different for those receiving a gastrojejunostomy than for those who did not. However, a significant reduction in survival was observed in limb onsetting patients receiving a gastrojejunostomy early in the course of their disease (P=0.001) compared to those with a longer duration prior to the procedure. This was not observed in the bulbar onsetting patients. In both patient populations, no relationship was observed between survival post-gastrojejunostomy and the severity of pulmonary involvement at the time of the intervention, serum chloride, or age at onset. These studies demonstrate that a percutaneous gastrojejunostomy is a well-tolerated and safe alternative technique for enteral nutritional support in ALS patients. It also offers the advantage of not requiring either a

  15. Amyotrophic lateral sclerosis treatment with ultramicronized palmitoylethanolamide: a case report.

    PubMed

    Clemente, Simonetta

    2012-11-01

    Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons which leads to muscular atrophy, paralysis and death in 3-5 years from starting symptoms. This disorder is accompanied by noteworthy spinal inflammation mediated in particular by microglia and mast cells. No effective therapy is available. This report describes the effects of administering the anti-inflammatory agent palmitoylethanolamide in a case of sporadic amyotrophic lateral sclerosis. Palmitoylethanolamide treatment led to an improved clinical picture, as evidenced by electromyographic analysis and pulmonary function. Conceivably, the action of palmitoylethanolamide could result, in part, from its ability to dampen mast cell and microglia activation.

  16. Spatiotemporal Coupling of the Tongue in Amyotrophic Lateral Sclerosis

    ERIC Educational Resources Information Center

    Kuruvilla, Mili S.; Green, Jordan R.; Yunusova, Yana; Hanford, Kathy

    2012-01-01

    Purpose: The primary aim of the investigation was to identify deficits in spatiotemporal coupling between tongue regions in amyotrophic lateral sclerosis (ALS). The relations between disease-related changes in tongue movement patterns and speech intelligibility were also determined. Methods: The authors recorded word productions from 11…

  17. Amyotrophic Lateral Sclerosis: An Introduction to Psychosocial and Behavioral Adaptations.

    ERIC Educational Resources Information Center

    Hoffman, R. Leigh; Decker, Thomas W.

    1993-01-01

    Defines amyotrophic lateral sclerosis (ALS) as motor-neuron disease that is terminal. Discusses symptoms associated with ALS and identifies treatment options. Reviews psychological and behavioral adaptations in regard to ALS clients, their families, and professionals who work with them. Discusses support groups as method of reducing stress for ALS…

  18. Amyotrophic Lateral Sclerosis Patients' Perspectives on Use of Mechanical Ventilation.

    ERIC Educational Resources Information Center

    Young, Jenny M.; And Others

    1994-01-01

    Interviewed 13 amyotrophic lateral sclerosis patients. All believed that they alone should make decision regarding use of mechanical ventilation. Factors they considered important were quality of life, severity of disability, availability of ventilation by means of nasal mask, possible admission to long-term care facility, ability to discontinue…

  19. Incidence of amyotrophic lateral sclerosis in Rhineland-Palatinate, Germany.

    PubMed

    Wolf, Joachim; Wöhrle, Johannes C; Palm, Frederick; Nix, Wilfred A; Maschke, Matthias; Safer, Anton; Becher, Heiko; Grau, Armin J

    2014-06-01

    There is a lack of prospective and population based epidemiological data on amyotrophic lateral sclerosis in Germany to date. The ALS registry Rhineland-Palatinate was established to investigate the incidence, course and phenotypic variety of ALS in this south-west German state of about 4 million inhabitants. During the period 2010-2011, consecutive incident patients with amyotrophic lateral sclerosis according to the revised El Escorial criteria were included and followed up using multiple overlapping sources of case ascertainment. One hundred and forty-six patients were enrolled. The annual crude incidence for amyotrophic lateral sclerosis in Rhineland-Palatinate was 1.8/100,000 person-years (95% CI 1.6-2.2). Male to female ratio was 1.1:1. Incidence increased with age reaching a peak in the 70-74 years age group and declined thereafter. Late-onset ALS (≥ 75 years) was found in 14.4% of patients. About 32% of patients presented with bulbar onset. In conclusion, incidence rate of amyotrophic lateral sclerosis in Rhineland-Palatinate is within the range of other prospective population based registers in Europe and North America. Gender ratio is nearly balanced.

  20. 38 CFR 3.318 - Presumptive service connection for amyotrophic lateral sclerosis.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... connection for amyotrophic lateral sclerosis. 3.318 Section 3.318 Pensions, Bonuses, and Veterans' Relief... sclerosis. (a) Except as provided in paragraph (b) of this section, the development of amyotrophic lateral... under this section: (1) If there is affirmative evidence that amyotrophic lateral sclerosis was...

  1. 38 CFR 3.318 - Presumptive service connection for amyotrophic lateral sclerosis.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... connection for amyotrophic lateral sclerosis. 3.318 Section 3.318 Pensions, Bonuses, and Veterans' Relief... sclerosis. (a) Except as provided in paragraph (b) of this section, the development of amyotrophic lateral... under this section: (1) If there is affirmative evidence that amyotrophic lateral sclerosis was...

  2. Apo-Ferritin as a Therapeutic Treatment for Amyotrophic Lateral Sclerosis

    DTIC Science & Technology

    2012-09-01

    for Amyotrophic Lateral Sclerosis PRINCIPAL INVESTIGATOR: James R. Connor, Ph.D...August 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Apo-Ferritin as a Therapeutic Treatment for Amyotrophic Lateral Sclerosis 5b. GRANT NUMBER...accumulation and deposition have been reported in patients with amyotrophic lateral sclerosis (ALS). Previous work in mutant SOD1 mice mouse models of ALS

  3. 38 CFR 3.318 - Presumptive service connection for amyotrophic lateral sclerosis.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... connection for amyotrophic lateral sclerosis. 3.318 Section 3.318 Pensions, Bonuses, and Veterans' Relief... sclerosis. (a) Except as provided in paragraph (b) of this section, the development of amyotrophic lateral... under this section: (1) If there is affirmative evidence that amyotrophic lateral sclerosis was...

  4. 38 CFR 3.318 - Presumptive service connection for amyotrophic lateral sclerosis.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... connection for amyotrophic lateral sclerosis. 3.318 Section 3.318 Pensions, Bonuses, and Veterans' Relief... sclerosis. (a) Except as provided in paragraph (b) of this section, the development of amyotrophic lateral... under this section: (1) If there is affirmative evidence that amyotrophic lateral sclerosis was...

  5. A case of amyotrophic lateral sclerosis presented as oropharyngeal Dysphagia.

    PubMed

    Noh, Eun Ji; Park, Moo In; Park, Seun Ja; Moon, Won; Jung, Hyun Joo

    2010-07-01

    Amyotrophic lateral sclerosis is a rare disease. It is a fatal neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons which leads to muscle weakness and muscle wasting. Respiratory failure limits survival to 2-5 years after disease onset. Several clinical manifestations including dysphagia can result in reductions in both the quality of life and life expectancy. Dysphagia occurs at onset in about one third of case, although generally it occurs in later stage of the disease. Evaluation of dysphagia includes video-fluoroscopic swallow study, radiological esophagogram, flexible endoscopic examination, ultrasound examination, conventional manometry and electromyography. We report a case of amyotrophic lateral sclerosis in a 54-year-old man presenting oropharyngeal dysphagia which was diagnosed by high resolution esophageal manometry presenting abnormality of the upper esophageal sphincter.

  6. Potential Environmental Factors in Amyotrophic Lateral Sclerosis

    PubMed Central

    Oskarsson, Björn; Horton, D. Kevin; Mitsumoto, Hiroshi

    2015-01-01

    Summary The current state of research in environmental risk factors of ALS has provided many intriguing possible associations. Yet only one-smoking is at this time firmly established. The methodologic difficulties with studying a rare disease that occurs late in life, which could be related to exposures many decades ago, make relationships dauntingly difficult to prove. Despite continued improvement in methodology, significant challenges remain. The diagnostic criteria for ALS are complicated and there are continued efforts to improve them. As they are, the criteria do not yet capture all people with ALS, which further complicates epidemiologic studies. It is hoped that larger datasets with better characterization of different clinical features and laboratory markers will provide more robust estimates of risk factors in ALS in the years to come. A better understanding of environmental risk factors could help reduce exposures and it is hoped markedly reduce ALS incidence over time. Epidemiologic research is critical to advance this field, but the relative rarity of ALS and the current notion that exposures may affect the risk of ALS only decades later make such projects complex with many challenges. One US project of great potential is the National ALS Registry. It is a congressionally-mandated prospective population-based registry encompassing the entire US population. In addition to quantifying the incidence, prevalence, and demographics of ALS in the US, another main goal of the Registry is to examine the risk factors for the disease through online risk factor modules. There are currently 17 different risk factor modules that persons with ALS can complete including, but not limited to, cigarette smoking, alcohol consumption, military service history, occupational history, and a family history of ALS. Since the Registry's launch in October 2010, over 45,000 online risk factor modules have been completed. To our knowledge, this is the largest and most

  7. Non-invasive ventilation in amyotrophic lateral sclerosis.

    PubMed

    Vrijsen, Bart; Testelmans, Dries; Belge, Catharina; Robberecht, Wim; Van Damme, Philip; Buyse, Bertien

    2013-03-01

    Abstract Non-invasive ventilation (NIV) is widely used to improve alveolar hypoventilation in amyotrophic lateral sclerosis. Several studies indicate a better survival when NIV is used, certainly in patients with none to moderate bulbar dysfunction. Data on quality of life (QoL) are rather disputable. Overall QoL is shown to be equivalent in patients with or without NIV, although health-related QoL is shown to be increased in patients with none to moderate bulbar dysfunction. NIV improves sleep quality, although patient-ventilator asynchronies are demonstrated. FVC < 50%, seated or supine, has been widely applied as threshold to initiate NIV. Today, measurements of respiratory muscle strength, nocturnal gas exchange and symptomatic complaints are used as indicators to start NIV. Being compliant with NIV therapy increases QoL and survival. Cough augmentation has an important role in appropriate NIV. Patients have today more technical options and patients with benefit from these advances are growing in number. Tracheal ventilation needs to be discussed when NIV seems impossible or becomes insufficient.

  8. Ethical considerations in the management of amyotrophic lateral sclerosis.

    PubMed

    Eisen, Andrew; Krieger, Charles

    2013-11-01

    This article examines some of the ethical concerns relevant for the management of amyotrophic lateral sclerosis (ALS). We emphasize the importance for providing a competent assessment of the clinical deficit to correctly identify the disease and to avoid incorrect diagnoses. Conveying the diagnosis to the patient and their family requires empathy and it is important to remain supportive and positive, even in the face of this incurable disease. The essence of care in ALS is to permit the patient to have optimal function for their level of ability. This may require the use of gastrostomy and non-invasive or permanent ventilation. Employment of a multi-disciplinary team will permit optimization of patient care to achieve a good quality of life for as long as possible. The patient should also be informed of the risks associated with unproven therapies and the risks and potential benefits of therapeutic trials. The wishes of patients in regard to gastrostomy, long-term ventilation and end-of life decisions must be considered in an unbiased fashion. Recent advances in the genetics of familial ALS (FALS) have demonstrated some overlap between FALS, sporadic ALS and fronto-temporal lobar dementia (FTLD). The interpretation and dissemination of the results of genetic testing although important can induce confusion, considerable anxiety and guilt in patients and their families and proper counseling is imperative.

  9. Intraspinal Stem Cell Transplantation for Amyotrophic Lateral Sclerosis

    PubMed Central

    Chen, Kevin S.; Sakowski, Stacey A.; Feldman, Eva L.

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder in which the loss of upper and lower motor neurons produces progressive weakness and eventually death. In the decades since the approval of riluzole, the only FDA approved medication to moderately slow progression of ALS, no new therapeutics have arisen to alter the course of the disease. This is partly due to our incomplete understanding of the complex pathogenesis of motor neuron degeneration. Stem cells have emerged as an attractive option in treating ALS since they come armed with equally complex cellular machinery and may modulate the local microenvironment in many ways to rescue diseased motor neurons. While various stem cell types are being evaluated in preclinical and early clinical applications, here we review the preclinical strategies and advances supporting the recent clinical translation of neural progenitor cell therapy for ALS. Specifically, we focus on the use of spinal cord neural progenitor cells and the pipeline starting from preclinical studies to the designs of the Phase I and IIa clinical trials involving direct intraspinal transplantation in humans. PMID:26696091

  10. Current view and perspectives in amyotrophic lateral sclerosis

    PubMed Central

    Mathis, Stéphane; Couratier, Philippe; Julian, Adrien; Corcia, Philippe; Le Masson, Gwendal

    2017-01-01

    Amyotrophic lateral sclerosis (ALS), identified as a distinct clinical entity by Charcot since the end of the nineteenth century, is a devastating and fatal neurodegenerative disorder that affects motor neurons in the brain, brainstem and spinal cord. Survival of patients with ALS is associated with several factors such as clinical phenotype, age at onset, gender, early presence of respiratory failure, weight loss and treatment with Riluzole (the only disease-modifying drug approved for this disease). Nowadays, there is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. Nevertheless, the scientific knowledge in the field of ALS motor neuron degeneration is growing, with the prospect of new treatments. Based on this physiopathological knowledge, several new therapeutic targets are being studied, involving various mechanisms such as excitotoxicity, neuroinflammation, mitochondrial dysfunction, oxidative stress, RNA metabolism and other attractive concepts. Moreover, it is also important to identify reliable biomarkers that will be essential components for future therapeutic development and study design in ALS. In this review, we present the main recent advances and promising therapeutics and biomarkers in the field of ALS.

  11. The Puzzling Case of Hyperexcitability in Amyotrophic Lateral Sclerosis

    PubMed Central

    Bae, Jong Seok; Simon, Neil G.; Menon, Parvathi; Vucic, Steve

    2013-01-01

    The development of hyperexcitability in amyotrophic lateral sclerosis (ALS) is a well-known phenomenon. Despite controversy as to the underlying mechanisms, cortical hyperexcitability appears to be closely related to the interplay between excitatory corticomotoneurons and inhibitory interneurons. Hyperexcitability is not a static phenomenon but rather shows a pattern of progression in a spatiotemporal aspect. Cortical hyperexcitability may serve as a trigger to the development of anterior horn cell degeneration through a 'dying forward' process. Hyperexcitability appears to develop during the early disease stages and gradually disappears in the advanced stages of the disease, linked to the destruction of corticomotorneuronal pathways. As such, a more precise interpretation of these unique processes may provide new insight regarding the pathophysiology of ALS and its clinical features. Recently developed technologies such as threshold tracking transcranial magnetic stimulation and automated nerve excitability tests have provided some clues about underlying pathophysiological processes linked to hyperexcitability. Additionally, these novel techniques have enabled clinicians to use the specific finding of hyperexcitability as a useful diagnostic biomarker, enabling clarification of various ALS-mimic syndromes, and the prediction of disease development in pre-symptomatic carriers of familial ALS. In terms of nerve excitability tests for peripheral nerves, an increase in persistent Na+ conductances has been identified as a major determinant of peripheral hyperexcitability in ALS, inversely correlated with the survival in ALS. As such, the present Review will focus primarily on the puzzling theory of hyperexcitability in ALS and summarize clinical and pathophysiological implications for current and future ALS research. PMID:23626643

  12. Dynamic markers of altered gait rhythm in amyotrophic lateral sclerosis

    NASA Technical Reports Server (NTRS)

    Hausdorff, J. M.; Lertratanakul, A.; Cudkowicz, M. E.; Peterson, A. L.; Kaliton, D.; Goldberger, A. L.

    2000-01-01

    Amyotrophic lateral sclerosis (ALS) is a disorder marked by loss of motoneurons. We hypothesized that subjects with ALS would have an altered gait rhythm, with an increase in both the magnitude of the stride-to-stride fluctuations and perturbations in the fluctuation dynamics. To test for this locomotor instability, we quantitatively compared the gait rhythm of subjects with ALS with that of normal controls and with that of subjects with Parkinson's disease (PD) and Huntington's disease (HD), pathologies of the basal ganglia. Subjects walked for 5 min at their usual pace wearing an ankle-worn recorder that enabled determination of the duration of each stride and of stride-to-stride fluctuations. We found that the gait of patients with ALS is less steady and more temporally disorganized compared with that of healthy controls. In addition, advanced ALS, HD, and PD were associated with certain common, as well as apparently distinct, features of altered stride dynamics. Thus stride-to-stride control of gait rhythm is apparently compromised with ALS. Moreover, a matrix of markers based on gait dynamics may be useful in characterizing certain pathologies of motor control and, possibly, in quantitatively monitoring disease progression and evaluating therapeutic interventions.

  13. Epidemiology of amyotrophic lateral sclerosis: A review of literature.

    PubMed

    Couratier, P; Corcia, P; Lautrette, G; Nicol, M; Preux, P-M; Marin, B

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons, resulting in worsening weakness of voluntary muscles until death occurs from respiratory failure. The incidence of ALS in European populations is two to three people per year per 100,000 of the general population. In Europe, crude prevalences range from 1.1/100,000 population in Yugoslavia to 8.2/100,000 in the Faroe Islands. Major advances have been made in our understanding of the genetic causes of ALS, whereas the contribution of environmental factors has been more difficult to assess and large-scale studies have not yet revealed a replicable, definitive environmental risk factor. The only established risk factors to date are older age, male gender and a family history of ALS. Median survival time from onset to death is usually 3 years from the first appearance of symptoms. Older age and bulbar onset are consistently reported to have poorer outcomes. However, there are conflicting data regarding gender, diagnostic delay and El Escorial criteria. The rate of symptom progression has been revealed to be an independent prognostic factor. Psychosocial factors and impaired cognitive function are negatively related to ALS outcome, while nutritional status and respiratory function are also related to ALS prognosis. The effect of enteral nutrition on survival is still unclear, although noninvasive positive pressure ventilation (NIPPV) has been found to improve survival. These findings have relevant implications for the design of future trials.

  14. The interaction between breathing and swallowing in amyotrophic lateral sclerosis.

    PubMed

    Erdem, Nazan Simsek; Karaali, Kamil; Ünal, Ali; Kızılay, Ferah; Öğüş, Candan; Uysal, Hilmi

    2016-12-01

    The aim of the study is to determine the association between respiratory swallow patterns in amyotrophic lateral sclerosis (ALS) patients. Furthermore, it aims to clarify the role of the dysphagia limit in defining the relationship between swallowing disorders and respiratory disorders. Functional rating scales were used to describe swallowing and respiratory function. Swallowing was observed using the dysphagia limit. Dysphagia limit is the volume at which a second or more swallows are required to swallow the whole bolus. Laryngeal and chest movement sensors, pulmonary function tests, submental, and diaphragm electromyography activity were used to evaluate the relationship between swallowing and respiratory phase. Of the 27 patients included in the study, 14 were dysphagic and 13 were non-dysphagic. Tests showed normal respiratory function in 11 of the non-dysphagic patients and 3 of the dysphagic patients. There was a high correlation between the dysphagia limit and Amyotrophic Lateral Sclerosis Functional Rating Scale swallowing parameters. Non-dysphagic patients were able to swallow during inspiration but only six patients in the dysphagic group were able to swallow during inspiration. The occurrence of dysphagia in ALS is related to piecemeal deglutition and respiration consistency during swallowing. Detecting the timing of disturbances in the relationship between swallowing and respiration may be a way of identifying dysphagia. Dysphagia limit may be a useful, complementary test for assessing swallowing disturbances in amyotrophic lateral sclerosis.

  15. [Research in amyotrophic lateral sclerosis: what is new in 2009?].

    PubMed

    Pradat, P-F; Attarian, S; Camdessanché, J-P; Carluer, L; Cintas, P; Corcia, P; Echaniz-Laguna, A; Gonzalez-Bermejo, J; Guy, N; Nicolas, G; Perez, T; Soriani, M-H; Vandenberghe, N; Verschueren, A

    2010-01-01

    This paper, written by French amyotrophic lateral sclerosis (ALS) center experts, presents an update of recent advances in fundamental, epidemiological and clinical research in ALS based on a review of the literature between September 2008 and November 2009. Among other pathophysiological mechanisms, the role of stress of the endoplasmic reticulum and the importance of energetic metabolic disturbances have been underscored. In the field of genetics, research has been advanced through the identification of mutations of the gene FUsed in Sarcoma/Translated in LipoSarcoma (FUS/TLS) in individuals with familial and sporadic ALS. This gene is involved in the regulation of transcription, splicing and RNA transport, and has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration. A report showed that mice expressing a mutant form of human TDP-43 develop a progressive and fatal neurodegenerative disease reminiscent of both ALS and frontotemporal lobar degeneration with ubiquitin aggregates (FTLD-U), providing a new animal model that may help to better understand the pathophysiology and test new therapeutics. Beside genetic studies, several epidemiologic studies have investigated the role of environmental factors. A recent study suggests that smoking is a risk factor for developing ALS and it is hypothesized that this could occur through lipid peroxidation via formaldehyde exposure. From a neuroprotective perspective, trials with IGF-1, sodium valproate, coenzyme Q or glatiramer acetate have failed to demonstrate any beneficial effect. A study published in 2008 argued that lithium may have a neuroprotective effect in ALS mice and also in patients. However, two preclinical studies failed to replicate the neuroprotective effect of lithium in ALS mice. Therapeutic trials have been performed or are currently ongoing in Europe and North America. Their results have not yet been published.

  16. Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants.

    PubMed

    Saberi, Shahram; Stauffer, Jennifer E; Schulte, Derek J; Ravits, John

    2015-11-01

    The neuropathologic molecular signature common to almost all sporadic amyotrophic lateral sclerosis (ALS) and most familial ALS is TDP-43 immunoreactive neuronal cytoplasmic inclusions. The neuropathologic and molecular neuropathologic features of ALS variants, primarily lateral sclerosis and progressive muscular atrophy, are less certain but also seem to share the primary features of ALS. Genetic causes, including mutations in SOD1, TDP-43, FUS, and C9orf72, all have distinctive molecular neuropathologic signatures. Neuropathology will continue to play an increasingly key role in solving the puzzle of ALS pathogenesis.

  17. Mutant SOD1 mediated pathogenesis of Amyotrophic Lateral Sclerosis.

    PubMed

    Kaur, Simran J; McKeown, Stephanie R; Rashid, Shazia

    2016-02-15

    Amyotrophic lateral sclerosis (ALS) is a neural disorder that causes death of the motor neurons in the brain and spinal cord; this affects the voluntary muscles and gradually leads to paralysis of the whole body. Most ALS cases are sporadic, though about 5-10% are familial. ALS is caused by multiple factors including mutation in any one of a number of specific genes, one of the most frequently affected is superoxide dismutase (SOD) 1. Alterations in SOD 1 have been linked with several variants of familial ALS. SOD 1 is a powerful antioxidant enzyme that protects cells from the damaging effects of superoxide radicals. The enzyme binds both copper and zinc ions that are directly involved in the deactivation of toxic superoxide radicals. Mutated SOD1 gene can acquire both gain and loss of function mutations. The most commonly identified mutations in SOD1 that affect protein activity are D90A, A4V and G93A. Deleterious mutations have been shown to modify SOD1 activity, which leads to the accumulation of highly toxic hydroxyl radicals. Accumulation of these free radicals causes degradation of both nuclear and mitochondrial DNA and protein misfolding, features which can be used as pathological indicators associated with ALS. Numerous clinical trials have been carried out over last few years with limited success. In some patients advanced techniques like gene and stem cell therapy have been trialed. However no definitive treatment option can provide a cure and currently ALS is managed by drugs and other supportive therapies. Consequently there is a need to identify new approaches for treatment of this ultimately fatal disease.

  18. Targeted Riluzole Delivery by Antioxidant Nanovectors for Treating Amyotrophic Lateral Sclerosis

    DTIC Science & Technology

    2013-10-01

    treating amyotrophic lateral sclerosis . PRINCIPAL INVESTIGATOR: Raymond J. Grill CONTRACTING ORGANIZATION: University of Texas Health...treating Amyotrophic lateral sclerosis 5a. CONTRACT NUMBER W 5b. GRANT NUMBER W81XWH-12-1-0612 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...survival in a mouse model of amyotrophic lateral sclerosis . This project involves work performed at both UT-Health and Rice University; combining the

  19. [Anesthetic management of a patient with amyotrophic lateral sclerosis].

    PubMed

    Mashio, H; Ito, Y; Yanagita, Y; Fujisawa, E; Hada, K; Goda, Y; Kawahigashi, H

    2000-02-01

    A 49-year-old male with amyotrophic lateral sclerosis (ALS) was scheduled for gastrectomy. Anesthetic management was performed under general anesthesia with sevoflurane and epidural anesthesia with lidocaine. He showed increased response to vecuronium under monitoring of neuromuscular block. But he responded favorably to anticholineesterase. He had little pain and showed no progress in neurological symptoms in the postoperative period. Neuromuscular monitoring is essential in administrating non-depolarizing neuromuscular blocking agents to patients with ALS, and epidural anesthesia may be useful for perioperative management of patients with ALS.

  20. [Amyotrophic lateral sclerosis in totally locked-in state].

    PubMed

    Oyanagi, Kiyomitsu; Mochizuki, Yoko; Nakayama, Yuki; Hayashi, Kentaro; Shimizu, Toshio; Nagao, Masahiro; Hashimoto, Tomoyo; Yamazaki, Mineo; Matsubara, Shiro; Komori, Takashi

    2013-01-01

    Seven autopsy patients with amyotrophic lateral sclerosis (ALS) in totally locked-in state (TLS) were examined neuropathologically. The patients were composed of 4 males and 3 females, and 3 with familial, 1 sporadic but with mutation in SOD1 gene, and 3 sporadic patients with unremarkable gene mutation. The brains weighed 715, 783, 1,019, 1,050, 1,170, 1,190 or 1,233 g. The tegmentum of the brain stem was markedly degenerated in every patient, and the tracts relating to the somatic sensory and auditory were involved in the lesions.

  1. An Autopsy Case of Amyotrophic Lateral Sclerosis with Diaphragm Pacing

    PubMed Central

    Ito, Hisashi; Kamei, Tetsumasa; Odake, Sanae; Nakano, Masayuki; Okeda, Riki; Kohriki, Shunsaku; Kawachi, Jun; Onders, Raymond P.; Yoshii, Fumihito

    2016-01-01

    Respiratory insufficiency is a critical problem in amyotrophic lateral sclerosis (ALS) patients. We herein present the case of an autopsied patient with sporadic ALS who underwent diaphragm pacing (DP). The pathology showed several localized adhesions with a markedly atrophied diaphragm. A marked loss of motor neurons with Bunina bodies and phosphorylated TDP-43 positive inclusions was found in the spinal cord and primary motor cortex. Mild hyalinization and a few multinucleated giant cells were present around the electrode tracks in the diaphragm. However, no infiltration of inflammatory cells was detected. Our findings suggest that full-time DP might not cause severe damage to adjacent diaphragm tissue. PMID:27904119

  2. Ensuring continued progress in biomarkers for amyotrophic lateral sclerosis

    PubMed Central

    Turner, Martin R; Benatar, Michael

    2015-01-01

    Multiple candidate biomarkers for amyotrophic lateral sclerosis (ALS) have emerged across a range of platforms. Replication of results, however, has been absent in all but a few cases, and the range of control samples has been limited. If progress toward clinical translation is to continue, the specific biomarker needs of ALS, which differ from those of other neurodegenerative disorders, as well as the challenges inherent to longitudinal ALS biomarker cohorts, must be understood. Appropriate application of multimodal approaches, international collaboration, presymptomatic studies, and biomarker integration into future therapeutic trials are among the essential priorities going forward. PMID:25288265

  3. An Autopsy Case of Amyotrophic Lateral Sclerosis with Diaphragm Pacing.

    PubMed

    Ito, Hisashi; Kamei, Tetsumasa; Odake, Sanae; Nakano, Masayuki; Okeda, Riki; Kohriki, Shunsaku; Kawachi, Jun; Onders, Raymond P; Yoshii, Fumihito

    Respiratory insufficiency is a critical problem in amyotrophic lateral sclerosis (ALS) patients. We herein present the case of an autopsied patient with sporadic ALS who underwent diaphragm pacing (DP). The pathology showed several localized adhesions with a markedly atrophied diaphragm. A marked loss of motor neurons with Bunina bodies and phosphorylated TDP-43 positive inclusions was found in the spinal cord and primary motor cortex. Mild hyalinization and a few multinucleated giant cells were present around the electrode tracks in the diaphragm. However, no infiltration of inflammatory cells was detected. Our findings suggest that full-time DP might not cause severe damage to adjacent diaphragm tissue.

  4. Widespread grey matter pathology dominates the longitudinal cerebral MRI and clinical landscape of amyotrophic lateral sclerosis.

    PubMed

    Menke, Ricarda A L; Körner, Sonja; Filippini, Nicola; Douaud, Gwenaëlle; Knight, Steven; Talbot, Kevin; Turner, Martin R

    2014-09-01

    Diagnosis, stratification and monitoring of disease progression in amyotrophic lateral sclerosis currently rely on clinical history and examination. The phenotypic heterogeneity of amyotrophic lateral sclerosis, including extramotor cognitive impairments is now well recognized. Candidate biomarkers have shown variable sensitivity and specificity, and studies have been mainly undertaken only cross-sectionally. Sixty patients with sporadic amyotrophic lateral sclerosis (without a family history of amyotrophic lateral sclerosis or dementia) underwent baseline multimodal magnetic resonance imaging at 3 T. Grey matter pathology was identified through analysis of T1-weighted images using voxel-based morphometry. White matter pathology was assessed using tract-based spatial statistics analysis of indices derived from diffusion tensor imaging. Cross-sectional analyses included group comparison with a group of healthy controls (n = 36) and correlations with clinical features, including regional disability, clinical upper motor neuron signs and cognitive impairment. Patients were offered 6-monthly follow-up MRI, and the last available scan was used for a separate longitudinal analysis (n = 27). In cross-sectional study, the core signature of white matter pathology was confirmed within the corticospinal tract and callosal body, and linked strongly to clinical upper motor neuron burden, but also to limb disability subscore and progression rate. Localized grey matter abnormalities were detected in a topographically appropriate region of the left motor cortex in relation to bulbar disability, and in Broca's area and its homologue in relation to verbal fluency. Longitudinal analysis revealed progressive and widespread changes in the grey matter, notably including the basal ganglia. In contrast there was limited white matter pathology progression, in keeping with a previously unrecognized limited change in individual clinical upper motor neuron scores, despite advancing disability

  5. Chitotriosidase - a putative biomarker for sporadic amyotrophic lateral sclerosis

    PubMed Central

    2013-01-01

    Background Potential biomarkers to aid diagnosis and therapy need to be identified for Amyotrophic Lateral Sclerosis, a progressive motor neuronal degenerative disorder. The present study was designed to identify the factor(s) which are differentially expressed in the cerebrospinal fluid (CSF) of patients with sporadic amyotrophic lateral sclerosis (SALS; ALS-CSF), and could be associated with the pathogenesis of this disease. Results Quantitative mass spectrometry of ALS-CSF and control-CSF (from orthopaedic surgical patients undergoing spinal anaesthesia) samples showed upregulation of 31 proteins in the ALS-CSF, amongst which a ten-fold increase in the levels of chitotriosidase-1 (CHIT-1) was seen compared to the controls. A seventeen-fold increase in the CHIT-1 levels was detected by ELISA, while a ten-fold elevated enzyme activity was also observed. Both these results confirmed the finding of LC-MS/MS. CHIT-1 was found to be expressed by the Iba-1 immunopositive microglia. Conclusion Elevated CHIT-1 levels in the ALS-CSF suggest a definitive role for the enzyme in the disease pathogenesis. Its synthesis and release from microglia into the CSF may be an aligned event of neurodegeneration. Thus, high levels of CHIT-1 signify enhanced microglial activity which may exacerbate the process of neurodegeneration. In view of the multifold increase observed in ALS-CSF, it can serve as a potential CSF biomarker for the diagnosis of SALS. PMID:24295388

  6. Anthropometry of Arm: Nutritional Risk Indicator in Amyotrophic Lateral Sclerosis.

    PubMed

    Salvioni, Cristina Cleide Dos Santos; Stanich, Patricia; Oliveira, Acary Souza Bulle; Orsini, Marco

    2015-12-29

    The aim of the paper is to examine the correlation between clinical data, nutritional, respiratory and functional parameters in amyotrophic lateral sclerosis (ALS). This is a descriptive study of 111 ALS patients [91 spinal onset (GS) and 20 bulbar onset (GB)] carried on using nutritional and respiratory parameters and amyotrophic lateral sclerosis functional rating scale (ALSFRS). ALSFRS was analyzed in the main domains (D1, D2 and D3). Forced vital capacity and anthropometric measurements, there was significant association for GS and GB, and in GS there was positive correlation with midarm circumference (MAC) (r=0.30; P=0.020), midarm muscle circumference (r=0.29; P=0.026), arm muscle area (r=0.28; P=0.033) and protein-caloric malnutrition score (r=0.27; P=0.039), while for GB only with body weight (r=0.64; P=0.024). On correlation of nutritional parameters and ALSFRS for GS patients we observed that MAC and %MAC presented positive association with both issues of D1 and D2. For GB, the total score in addition to correlate positively with anthropometric parameters related to lean body mass also presented negative association with a parameter associated with body fat. In summary, it is suggested that the application of anthropometry of arm could be useful in routine monitoring of ALS patients.

  7. Case-control study of amyotrophic lateral sclerosis

    SciTech Connect

    Deapen, D.M.; Henderson, B.E.

    1986-05-01

    The authors conducted a study of 518 amyotrophic lateral sclerosis patients identified between 1977 and 1979 and 518 controls to investigate putative risk factors for this disease. Occupations at risk of electrical exposure were reported more often by patients (odds ratio (OR) = 3.8, 95% confidence interval (CI) = 1.4-13.0) as were electrical shocks producing unconsciousness (OR = 2.8, 95% CI = 1.0-9.9). Although an overall excess of physical trauma associated with unconsciousness was observed in the amyotrophic lateral sclerosis patients (OR = 1.6, 95% CI = 1.0-2.4), the effect was inversely associated with duration of the unconscious episodes, suggesting an effect of recall bias. Only slight differences were found for surgical traumata to the nervous system. Parkinsonism was reported more often among first degree relatives of cases (OR = 2.7, 95% CI = 1.1-7.6). The frequencies of prior poliomyelitis or other central nervous system diseases were similar for patients and controls. Occupational exposure to selected toxic substances was similar for patients and controls except for the manufacture of plastics (OR = 3.7, 95% CI = 1.0-20.5), although few details of these exposures were provided. No differences in occupations with exposure to animal skins or hides were observed.

  8. Anthropometry of Arm: Nutritional Risk Indicator in Amyotrophic Lateral Sclerosis

    PubMed Central

    Stanich, Patricia; Oliveira, Acary Souza Bulle; Orsini, Marco

    2015-01-01

    The aim of the paper is to examine the correlation between clinical data, nutritional, respiratory and functional parameters in amyotrophic lateral sclerosis (ALS). This is a descriptive study of 111 ALS patients [91 spinal onset (GS) and 20 bulbar onset (GB)] carried on using nutritional and respiratory parameters and amyotrophic lateral sclerosis functional rating scale (ALSFRS). ALSFRS was analyzed in the main domains (D1, D2 and D3). Forced vital capacity and anthropometric measurements, there was significant association for GS and GB, and in GS there was positive correlation with midarm circumference (MAC) (r=0.30; P=0.020), midarm muscle circumference (r=0.29; P=0.026), arm muscle area (r=0.28; P=0.033) and protein-caloric malnutrition score (r=0.27; P=0.039), while for GB only with body weight (r=0.64; P=0.024). On correlation of nutritional parameters and ALSFRS for GS patients we observed that MAC and %MAC presented positive association with both issues of D1 and D2. For GB, the total score in addition to correlate positively with anthropometric parameters related to lean body mass also presented negative association with a parameter associated with body fat. In summary, it is suggested that the application of anthropometry of arm could be useful in routine monitoring of ALS patients. PMID:26788263

  9. The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey

    PubMed Central

    Turner, Martin R; Swash, Michael

    2015-01-01

    Recent advances in understanding amyotrophic lateral sclerosis (ALS) have delivered new questions. Disappointingly, the initial enthusiasm for transgenic mouse models of the disease has not been followed by rapid advances in therapy or prevention. Monogenic models may have inadvertently masked the true complexity of the human disease. ALS has evolved into a multisystem disorder, involving a final common pathway accessible via multiple upstream aetiological tributaries. Nonetheless, there is a common clinical core to ALS, as clear today as it was to Charcot and others. We stress the continuing relevance of clinical observations amid the increasing molecular complexity of ALS. PMID:25644224

  10. [Non-invasive mechanical ventilation with a facial interface during sedation for a percutaneous endoscopic gastrostomy in a patient with amyotrophic lateral sclerosis].

    PubMed

    González-Frasquet, M C; García-Covisa, N; Vidagany-Espert, L; Herranz-Gordo, A; Llopis-Calatayud, J E

    2015-11-01

    Amyotrophic lateral sclerosis is a chronic neurodegenerative disease of the central nervous system which affects the motor neurons and produces a progressive muscle weakness, leading to atrophy and muscle paralysis, and ultimately death. Performing a percutaneous endoscopic gastrostomy with sedation in patients with amyotrophic lateral sclerosis can be a challenge for the anesthesiologist. The case is presented of a 76-year-old patient who suffered from advanced stage amyotrophic lateral sclerosis, ASA III, in which a percutaneous endoscopic gastrostomy was performed with deep sedation, for which non-invasive ventilation was used as a respiratory support to prevent hypoventilation and postoperative respiratory complications.

  11. 76 FR 78823 - Schedule for Rating Disabilities; Evaluation of Amyotrophic Lateral Sclerosis

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-20

    ... Sclerosis AGENCY: Department of Veterans Affairs. ACTION: Final rule. SUMMARY: The Department of Veterans... criterion provided for amyotrophic lateral sclerosis (ALS) to provide an evaluation of 100 percent for any... revise the evaluation criterion for amyotrophic lateral sclerosis (ALS) in the VA Schedule for...

  12. Association between alcohol consumption and amyotrophic lateral sclerosis: a meta-analysis of five observational studies.

    PubMed

    E, Meng; Yu, Sufang; Dou, Jianrui; Jin, Wu; Cai, Xiang; Mao, Yiyang; Zhu, Daojian; Yang, Rumei

    2016-08-01

    The purpose of this study is to examine the association between alcohol consumption and amyotrophic lateral sclerosis. Published literature on the association between alcohol consumption and amyotrophic lateral sclerosis was retrieved from the PubMed and Embase databases. Two authors independently extracted the data. The quality of the identified studies was evaluated according to the Newcastle-Ottawa scale. Subgroup and sensitivity analyses were performed and publication bias was assessed. Five articles, including one cohort study and seven case-control studies, and a total of 431,943 participants, were identified. The odds ratio for the association between alcohol consumption and amyotrophic lateral sclerosis was 0.57 (95 % confidence interval 0.51-0.64). Subgroup and sensitivity analyses confirmed the result. Evidence for publication bias was detected. Alcohol consumption reduced the risk of developing amyotrophic lateral sclerosis compared with non-drinking. Alcohol, therefore, has a potentially neuroprotective effect on the development of amyotrophic lateral sclerosis.

  13. Diagnosis and treatment of bulbar symptoms in amyotrophic lateral sclerosis.

    PubMed

    Kühnlein, Peter; Gdynia, Hans-Jürgen; Sperfeld, Anne-Dorte; Lindner-Pfleghar, Beate; Ludolph, Albert Christian; Prosiegel, Mario; Riecker, Axel

    2008-07-01

    Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. Bulbar symptoms such as dysphagia and dysarthria are frequent features of ALS and can result in reductions in life expectancy and quality of life. These dysfunctions are assessed by clinical examination and by use of instrumented methods such as fiberendoscopic evaluation of swallowing and videofluoroscopy. Laryngospasm, another well-known complication of ALS, commonly comes to light during intubation and extubation procedures in patients undergoing surgery. Laryngeal and pharyngeal complications are treated by use of an array of measures, including body positioning, compensatory techniques, voice and breathing exercises, communication devices, dietary modifications, various safety strategies, and neuropsychological assistance. Meticulous monitoring of clinical symptoms and close cooperation within a multidisciplinary team (physicians, speech and language therapists, occupational therapists, dietitians, caregivers, the patients and their relatives) are vital.

  14. Rehabilitation in amyotrophic lateral sclerosis: why it matters.

    PubMed

    Majmudar, Salony; Wu, Jason; Paganoni, Sabrina

    2014-07-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in a constellation of problematic symptoms and a high patient and caregiver burden. Multidisciplinary care includes rehabilitation interventions that have the goal of assisting people to teach their fullest potential despite the presence of a disabling disease. Given the progressive nature of ALS, the clinician must be aware of the expected disease trajectory and apply appropriate interventions at each stage. This review will present rehabilitation strategies that can be utilized to maximize patient independence, function, safety, and quality of life, and to minimize disease-related symptoms. The role of bracing, exercise, assistive devices, and adaptive equipment will be discussed. At each disease stage, an experienced rehabilitation team is well positioned to make a significant impact on the life of ALS patients.

  15. Comprehensive care of amyotrophic lateral sclerosis patients: a care model.

    PubMed

    Güell, Maria Rosa; Antón, Antonio; Rojas-García, Ricardo; Puy, Carmen; Pradas, Jesus

    2013-12-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that presents with muscle weakness, causing progressive difficulty in movement, communication, eating and ultimately, breathing, creating a growing dependence on family members and other carers. The ideal way to address the problems associated with the disease, and the decisions that must be taken, is through multidisciplinary teams. The key objectives of these teams are to optimise medical care, facilitate communication between team members, and thus to improve the quality of care. In our centre, we have extensive experience in the care of patients with ALS through an interdisciplinary team whose aim is to ensure proper patient care from the hospital to the home setting. In this article, we describe the components of the team, their roles and our way of working.

  16. Elastic head support for persons with amyotrophic lateral sclerosis.

    PubMed

    Hansen, Andrew; Bedore, Beau; Nickel, Eric; Hanowski, Kristin; Tangen, Sonya; Goldish, Gary

    2014-01-01

    This article describes an inexpensive elastic head support for persons with amyotrophic lateral sclerosis (ALS) and neck muscle weakness and also presents a case series to examine its effectiveness. The device offers support to the head while the user is seated, standing, and walking, providing support for persons in various stages of ALS. The head support system was tested in seven male patients with ALS. Before and after the 2 wk trial, the subjects answered questions related to their communication efficacy, difficulty swallowing, level of neck discomfort, number of hours being upright before neck discomfort, comfort in social settings, and rating of perceived dyspnea. Subjects also answered specific questions related to the elastic head support after the 2 wk trial. The results suggested that the elastic head support is useful for some, but not all, patients.

  17. Current Therapy of Drugs in Amyotrophic Lateral Sclerosis

    PubMed Central

    Lu, Haiyan; Le, Wei Dong; Xie, Ya-Ying; Wang, Xiao-Ping

    2016-01-01

    Amyotrophic lateral sclerosis (ALS), commonly termed as motor neuron disease (MND) in UK, is a chronically lethal disorder among the neurodegenerative diseases, meanwhile. ALS is basically irreversible and progressive deterioration of upper and lower motor neurons in the motor cortex, brain stem and medulla spinalis. Riluzole, used for the treatment of ALS, was demonstrated to slightly delay the initiation of respiratory dysfunction and extend the median survival of patients by a few months. In this study, the key biochemical defects were discussed, such as: mutant Cu/Zn superoxide dismutase, mitochondrial protectants, and anti-excitotoxic/ anti-oxidative / anti-inflammatory/ anti-apoptotic agents, so the related drug candidates that have been studied in ALS models would possibly be further used in ALS patients. PMID:26786249

  18. Projected increase in amyotrophic lateral sclerosis from 2015 to 2040

    PubMed Central

    Arthur, Karissa C.; Calvo, Andrea; Price, T. Ryan; Geiger, Joshua T.; Chiò, Adriano; Traynor, Bryan J.

    2016-01-01

    Although amyotrophic lateral sclerosis (ALS) is relatively rare, the socioeconomic significance of the disease is extensive. It is therefore vital to project the epidemiologic trend of ALS. To date, there have been few published studies attempting to estimate the number and distribution of ALS cases in the upcoming years. Here we show that the number of ALS cases across the globe will increase from 222,801 in 2015 to 376,674 in 2040, representing an increase of 69%. This increase is predominantly due to ageing of the population, particularly among developing nations. This projection is likely an underestimate due to improving healthcare and economic conditions. The results should be used to inform healthcare policy to more efficiently allocate healthcare resources. PMID:27510634

  19. Autoimmunity in Amyotrophic Lateral Sclerosis: Past and Present

    PubMed Central

    Pagani, Mario Rafael; Gonzalez, Laura Elisabeth; Uchitel, Osvaldo Daniel

    2011-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting particularly motor neurons for which no cure or effective treatment is available. Although the cause of ALS remains unknown, accumulative evidence suggests an autoimmune mechanism of pathogenesis. In this paper, we will summarize the current research related to autoimmunity in the sporadic form of ALS and discuss the potential underlying pathogenic mechanisms and perspectives. Presented data supports the view that humoral immune responses against motor nerve terminals can initiate a series of physiological changes leading to alteration of calcium homeostasis. In turn, loss of calcium homeostasis may induce neuronal death through apoptotic signaling pathways. Additional approaches identifying specific molecular features of this hypothesis are required, which will hopefully allow us to develop techniques of early diagnosis and effective therapies. PMID:21826267

  20. Therapeutic applications of mesenchymal stem cells for amyotrophic lateral sclerosis

    PubMed Central

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the neuromuscular system and does not have a known singular cause. Genetic mutations, extracellular factors, non-neuronal support cells, and the immune system have all been shown to play varied roles in clinical and pathological disease progression. The therapeutic plasticity of mesenchymal stem cells (MSCs) may be well matched to this complex disease pathology, making MSCs strong candidates for cellular therapy in ALS. In this review, we summarize a variety of explored mechanisms by which MSCs play a role in ALS progression, including neuronal and non-neuronal cell replacement, trophic factor delivery, and modulation of the immune system. Currently relevant techniques for applying MSC therapy in ALS are discussed, focusing in particular on delivery route and cell source. We include examples from in vitro, preclinical, and clinical investigations to elucidate the remaining progress that must be made to understand and apply MSCs as a treatment for ALS. PMID:25157751

  1. Amyotrophic Lateral Sclerosis and Metabolomics: Clinical Implication and Therapeutic Approach

    PubMed Central

    Kumar, Alok; Ghosh, Devlina; Singh, R. L.

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is one of the most common motor neurodegenerative disorders, primarily affecting upper and lower motor neurons in the brain, brainstem, and spinal cord, resulting in paralysis due to muscle weakness and atrophy. The majority of patients die within 3–5 years of symptom onset as a consequence of respiratory failure. Due to relatively fast progression of the disease, early diagnosis is essential. Metabolomics offer a unique opportunity to understand the spatiotemporal metabolic crosstalks through the assessment of body fluids and tissue. So far, one of the most challenging issues related to ALS is to understand the variation of metabolites in body fluids and CNS with the progression of disease. In this paper we will review the changes in metabolic profile in response to disease progression condition and also see the therapeutic implication of various drugs in ALS patients. PMID:26317018

  2. Cerebrovascular injury as a risk factor for amyotrophic lateral sclerosis

    PubMed Central

    Turner, Martin R; Goldacre, Raph; Talbot, Kevin; Goldacre, Michael J

    2016-01-01

    Objective To use an unbiased method to test a previously reported association between cerebral arteriovenous malformation (AVM) embolisation and the subsequent development of amyotrophic lateral sclerosis (ALS). Methods A hospital record linkage database was used to create cohorts of individuals coded as having cerebral and peripheral vessel AVMs, stroke (separately for haemorrhagic and ischaemic), transient ischaemic attack (TIA) and subarachnoid haemorrhage (SAH). The rate ratio for subsequent ALS was compared to a reference cohort. Results An increased rate ratio for ALS was found in relation to prior AVM (2.69; p=0.005), all strokes (1.38; p<0.001), and TIA (1.47; p<0.001). Conclusions Cerebrovascular injury from a variety of causes, rather than the presence of AVM or the associated embolisation procedure per se, may be a risk factor for ALS within the context of a more complex multiple-hit model of pathogenesis. PMID:26260352

  3. Age, gender, kinship and caregiver burden in amyotrophic lateral sclerosis.

    PubMed

    Tramonti, Francesco; Bongioanni, Paolo; Leotta, Rebecca; Puppi, Irene; Rossi, Bruno

    2015-01-01

    Amyotrophic lateral sclerosis is a neurodegenerative disease that affects the motor neurons and causes progressive physical impairment. Also, other functions, such as breathing, swallowing and speech are compromised, and the loss of independence makes caregiver burden extremely high. The present study aimed at evaluating the differences in the caregiver burden due to age, gender and kinship. Women reported a higher physical and social burden than men, and partners scored higher in several dimensions of the caregiver burden when compared to sons and daughters. With respect to adult child caregivers, daughters reported higher levels of developmental burden than sons. Age has a significant impact on the caregiver burden, especially for the time dedicated to assistance and physical burden; disease severity is significantly related to the physical burden as well, and also with the developmental burden.

  4. Myostatin as a therapeutic target in Amyotrophic lateral sclerosis.

    PubMed

    Walsh, Frank S; Rutkowski, Julia Lynn

    2012-11-01

    Amyotrophic Lateral Sclerosis is a devastating neurological disease that is inevitably fatal after 3-5years duration. Treatment options are minimal and as such new therapeutic modalities are required. In this review, we discuss the role of the myostatin pathway as a modulator of skeletal muscle mass and therapeutic approaches using biological based therapies. Both monoclonal antibodies to myostatin and a soluble receptor decoy to its high affinity receptor have been used in clinical trials of neuromuscular diseases and while there have been efficacy signals with the latter approach there have also been safety issues. Our approach is to target the high affinity receptor-binding site on myostatin and to develop a next generation set of therapeutic reagents built on a novel protein scaffold. This is the natural single domain VNAR found in sharks which is extremely versatile and has the ability to develop products with superior properties compared to existing therapeutics.

  5. Amyotrophic lateral sclerosis: increased solubility of skin collagen

    NASA Technical Reports Server (NTRS)

    Ono, S.; Yamauchi, M.

    1992-01-01

    We studied the solubility of skin collagen from six patients with amyotrophic lateral sclerosis (ALS) and six controls. The amount of collagen extracted with neutral salt solution was significantly greater in patients with ALS than in controls. In addition, there was a statistically significant increase in the proportion of collagen extracted from ALS patients with increased duration of illness. The collagen solubilized by pepsin and cyanogen bromide treatments was significantly higher in ALS patients than in controls, and its proportion was positively and significantly associated with duration of illness in ALS patients. These results indicate that the metabolism of skin collagen may be affected in the disease process of ALS, causing an increase in immature soluble collagen in the tissue, which is the opposite to that which occurs in the normal aging process.

  6. Comprehensive Rehabilitative Care Across the Spectrum of Amyotrophic Lateral Sclerosis

    PubMed Central

    Paganoni, Sabrina; Karam, Chafic; Joyce, Nanette; Bedlack, Richard; Carter, Gregory T

    2016-01-01

    Background Amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) is a neurodegenerative disease that results in progressive muscle weakness and wasting. There is no known cure and the disease is uniformly fatal. Purpose This review discusses current concepts in ALS care, from breaking the diagnosis to end-of-life care. People with ALS have several multidisciplinary needs due to a complex and dynamic disease process. They benefit from rehabilitation interventions that are individualized and have the goal of optimizing independence, function, and safety. These strategies also help minimize symptomatic burden and maximize quality of life. Conclusion Patient-centered, multidisciplinary care has a significant impact on the life of people with ALS and is the current standard of care for this patient population. PMID:26409693

  7. Alternative Fuels in Epilepsy and Amyotrophic Lateral Sclerosis.

    PubMed

    Tefera, Tesfaye W; Tan, Kah Ni; McDonald, Tanya S; Borges, Karin

    2016-11-21

    This review summarises the recent findings on metabolic treatments for epilepsy and Amyotrophic Lateral Sclerosis (ALS) in honour of Professor Ursula Sonnewald. The metabolic impairments in rodent models of these disorders as well as affected patients are being discussed. In both epilepsy and ALS, there are defects in glucose uptake and reduced tricarboxylic acid (TCA) cycling, at least in part due to reduced amounts of C4 TCA cycle intermediates. In addition there are impairments in glycolysis in ALS. A reduction in glucose uptake can be addressed by providing the brain with alternative fuels, such as ketones or medium-chain triglycerides. As anaplerotic fuels, such as the triglyceride of heptanoate, triheptanoin, refill the TCA cycle C4/C5 intermediate pool that is deficient, they are ideal to boost TCA cycling and thus the oxidative metabolism of all fuels.

  8. Impact of Expiratory Strength Training in Amyotrophic Lateral Sclerosis

    PubMed Central

    Plowman, Emily K.; Watts, Stephanie A.; Tabor, Lauren; Robison, Raele; Gaziano, Joy; Domer, Amanda S.; Richter, Joel; Vu, Tuan; Gooch, Clifton

    2016-01-01

    Introduction We evaluated the feasibility and impact of Expiratory Muscle Strength Training (EMST) on respiratory and bulbar function in persons with amyotrophic lateral sclerosis (ALS). Methods 25 ALS patients participated in this delayed intervention open-label clinical trial. Following a lead-in period, patients completed a 5-week EMST protocol. Outcome measures included: maximum expiratory pressure (MEP), physiologic measures of swallow and cough, and Penetration-Aspiration Scale (PAS) scores. Results Of those participants who entered the active phase of the study (n=15), EMST was well tolerated and led to significant increases in MEPs and maximum hyoid displacement during swallowing post-EMST (P<0.05). No significant differences were observed for PAS scores or cough spirometry measures. Discussion EMST was feasible and well tolerated in this small cohort of ALS patients and led to improvements in expiratory force-generating pressures and swallow kinematics. Further investigation is warranted to confirm these preliminary findings. PMID:26599236

  9. Apoptosis signals in sporadic amyotrophic lateral sclerosis: an immunocytochemical study.

    PubMed

    Embacher, N; Kaufmann, W A; Beer, R; Maier, H; Jellinger, K A; Poewe, W; Ransmayr, G

    2001-11-01

    Sporadic amyotrophic lateral sclerosis (sALS) is a neurodegenerative disorder of unknown cause characterized by selective loss of both upper and lower motor neurons. Whether neuronal death in sALS is due to apoptosis has so far not been clarified. In this study, the expression and distribution patterns of pro- and anti-apoptotic bcl-2 family members as well as the executioner caspase-3 were investigated in post-mortem CNS tissue of eight sALS patients and seven age-matched controls. Sparse motor neurons were immunoreactive for bcl-2, bax, bak, and CM1 on serial sections through the spinal cord and motor cortex of individual sALS patients and controls. However, there was no obvious difference in the numbers of immunoreactive (IR) neurons between the two groups. The study did not find evidence for apoptosis as a major mechanism of motor neuronal cell death in sALS.

  10. REHABILITATION IN AMYOTROPHIC LATERAL SCLEROSIS: WHY IT MATTERS

    PubMed Central

    MAJMUDAR, SALONY; WU, JASON; PAGANONI, SABRINA

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in a constellation of problematic symptoms and a high patient and caregiver burden. Multidisciplinary care includes rehabilitation interventions that have the goal of assisting people to teach their fullest potential despite the presence of a disabling disease. Given the progressive nature of ALS, the clinician must be aware of the expected disease trajectory and apply appropriate interventions at each stage. This review will present rehabilitation strategies that can be utilized to maximize patient independence, function, safety, and quality of life, and to minimize disease-related symptoms. The role of bracing, exercise, assistive devices, and adaptive equipment will be discussed. At each disease stage, an experienced rehabilitation team is well positioned to make a significant impact on the life of ALS patients. PMID:24510737

  11. Current Therapy of Drugs in Amyotrophic Lateral Sclerosis.

    PubMed

    Lu, Haiyan; Le, Wei Dong; Xie, Ya-Ying; Wang, Xiao-Ping

    2016-01-01

    Amyotrophic lateral sclerosis (ALS), commonly termed as motor neuron disease (MND) in UK, is a chronically lethal disorder among the neurodegenerative diseases, meanwhile. ALS is basically irreversible and progressive deterioration of upper and lower motor neurons in the motor cortex, brain stem and medulla spinalis. Riluzole, used for the treatment of ALS, was demonstrated to slightly delay the initiation of respiratory dysfunction and extend the median survival of patients by a few months. In this study, the key biochemical defects were discussed, such as: mutant Cu/Zn superoxide dismutase, mitochondrial protectants, and anti-excitotoxic/ anti-oxidative / antiinflammatory/ anti-apoptotic agents, so the related drug candidates that have been studied in ALS models would possibly be further used in ALS patients.

  12. [A specific phobia of amyotrophic lateral sclerosis (ALS phobia)].

    PubMed

    Levitskiĭ, G N; Gilod, V M; Levin, O S

    2012-01-01

    A specific phobia of amyotrophic lateral sclerosis (ALS phobia) was not previously described in the literature. We examined 21 patients, 11 men and 10 women, aged 28-72 years, with symptoms of this phobia. Only 23% of patients had a history of the psychiatric disorder in the past. The duration of phobia symptoms was significantly higher in patients with moderate and severe phobia than in mild cases (1.5±0.6 and 5.0±1.1 months respectively; р<0.05). The severity of ALS phobia was correlated with its duration (r= -0.5; p=0.004). The primary character of phobia was established in 52.4% of patients basing on the regression of phobia symptoms assessed by the Hamilton anxiety scale after psychotherapy and pharmacotherapy (17±4 and 3±1 scores before and 3 months after treatment, respectively; p<0.05).

  13. Amyotrophic Lateral Sclerosis: What Nurses Need to Know.

    PubMed

    Bellomo, Tamara L; Cichminski, Lucille

    2017-03-01

    A MOTHER OF THREE teenage children, Mrs. S, 49, presented to her healthcare provider with bilateral leg twitching and weakness, difficulty swallowing, and fatigue that's worsened over the past few weeks. While she was on her daily morning walk, she tripped and fell. She experienced a small laceration to her leg, prompting her visit to the healthcare facility. Her husband said that she'd had periods of slurred speech over the past few months as well. She was alert and oriented, and her vital signs were all within normal limits.After an exam, her healthcare provider referred her to a neurologist who ordered magnetic resonance imaging (MRI), an electromyogram, and a full bloodwork panel. After multiple visits to rule out other causes, Mrs. S received the devastating diagnosis of amyotrophic lateral sclerosis (ALS).

  14. A patient with amyotrophic lateral sclerosis and atypical clinical and electrodiagnostic features: a case report

    PubMed Central

    2011-01-01

    Introduction Amyotrophic lateral sclerosis is a rapidly progressive, fatal neurodegenerative disorder for which there is no effective treatment. The diagnosis is dependent on the clinical presentation and consistent electrodiagnostic studies. Typically, there is a combination of upper and lower motor neuron signs as well as electrodiagnostic studies indicative of diffuse motor axonal injury. The presentation of amyotrophic lateral sclerosis, however, may be variable. At the same time, the diagnosis is essential for patient prognosis and management. It is therefore important to appreciate the range of possible presentations of amyotrophic lateral sclerosis. Case presentation We present the case of a 57-year-old Caucasian man with pathological findings on postmortem examination consistent with amyotrophic lateral sclerosis but atypical clinical and electrodiagnostic features. He died after a rapid course of progressive weakness. The patient did not respond to immunosuppressive therapy. Conclusion Amyotrophic lateral sclerosis should be considered in patients with a rapidly progressive, unexplained neuropathic process. This should be true even if there are atypical clinical and electrodiagnostic findings. Absence of response to therapy and the development of upper motor neuron signs should reinforce the possibility that amyotrophic lateral sclerosis may be present. Since amyotrophic lateral sclerosis is a fatal illness, however, the possibility of this disease in patients with atypical clinical features should not diminish the need for a thorough diagnostic evaluation and treatment trials. PMID:22047468

  15. Is SOD1 loss of function involved in amyotrophic lateral sclerosis?

    PubMed

    Saccon, Rachele A; Bunton-Stasyshyn, Rosie K A; Fisher, Elizabeth M C; Fratta, Pietro

    2013-08-01

    Mutations in the gene superoxide dismutase 1 (SOD1) are causative for familial forms of the neurodegenerative disease amyotrophic lateral sclerosis. When the first SOD1 mutations were identified they were postulated to give rise to amyotrophic lateral sclerosis through a loss of function mechanism, but experimental data soon showed that the disease arises from a--still unknown--toxic gain of function, and the possibility that loss of function plays a role in amyotrophic lateral sclerosis pathogenesis was abandoned. Although loss of function is not causative for amyotrophic lateral sclerosis, here we re-examine two decades of evidence regarding whether loss of function may play a modifying role in SOD1-amyotrophic lateral sclerosis. From analysing published data from patients with SOD1-amyotrophic lateral sclerosis, we find a marked loss of SOD1 enzyme activity arising from almost all mutations. We continue to examine functional data from all Sod1 knockout mice and we find obvious detrimental effects within the nervous system with, interestingly, some specificity for the motor system. Here, we bring together historical and recent experimental findings to conclude that there is a possibility that SOD1 loss of function may play a modifying role in amyotrophic lateral sclerosis. This likelihood has implications for some current therapies aimed at knocking down the level of mutant protein in patients with SOD1-amyotrophic lateral sclerosis. Finally, the wide-ranging phenotypes that result from loss of function indicate that SOD1 gene sequences should be screened in diseases other than amyotrophic lateral sclerosis.

  16. The split hand syndrome in amyotrophic lateral sclerosis.

    PubMed

    Eisen, Andrew; Kuwabara, Satoshi

    2012-04-01

    In amyotrophic lateral sclerosis (ALS), hand muscle wasting preferentially affects the 'thenar (lateral) hand', including the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) muscles, with relative sparing of the hypothenar muscles (the abductor digiti minimi (ADM)). This peculiar pattern of dissociated atrophy of the intrinsic hand muscles is termed the 'split hand' and is rarely seen in diseases other than ALS. The muscles involved in the split hand are innervated through the same spinal segments (C8 and T1), and FDI and ADM, which are differentially affected, are both ulnar nerve innervated. The physiological mechanisms underlying the split hand in ALS are incompletely understood but both cortical and spinal/peripheral mechanisms are probably involved. Motor potentials evoked by magnetic stimulation are significantly smaller when recorded from the thenar complex, compared with the hypothenar muscles, supporting a cortical mechanism. But peripheral axonal excitability studies have suggested that APB/FDI motor axons have more prominent persistent sodium currents than ADM axons, leading to higher axonal excitability and thereby more ready degeneration. Pincer or precision grip is vital to human hand function, and frequent use of thenar complex muscles may lead to greater oxidative stress and metabolic demands at both upper and lower motoneurons innervating the APB and FDI. The split hand is a useful diagnostic sign in early ALS, and recent objective studies indicate that the sign has a high degree of specificity.

  17. Canine degenerative myelopathy: a model of human amyotrophic lateral sclerosis.

    PubMed

    Nardone, Raffaele; Höller, Yvonne; Taylor, Alexandra C; Lochner, Piergiorgio; Tezzon, Frediano; Golaszewski, Stefan; Brigo, Francesco; Trinka, Eugen

    2016-02-01

    Canine degenerative myelopathy (CDM) represents a unique naturally occurring animal model for human amyotrophic lateral sclerosis (ALS) because of similar clinical signs, neuropathologic findings, and involvement of the superoxide dismutase 1 (SOD1) mutation. A definitive diagnosis can only be made postmortem through microscopic detection of axonal degeneration, demyelination and astroglial proliferation, which is more severe in the dorsal columns of the thoracic spinal cord and in the dorsal portion of the lateral funiculus. Interestingly, the muscle acetylcholine receptor complexes are intact in CDM prior to functional impairment, thus suggesting that muscle atrophy in CDM does not result from physical denervation. Moreover, since sensory involvement seems to play an important role in CDM progression, a more careful investigation of the sensory pathology in ALS is also warranted. The importance of SOD1 expression remains unclear, while oxidative stress and denatured ubiquinated proteins appear to play a crucial role in the pathogenesis of CDM. In this updated narrative review we performed a systematic search of the published studies on CDM that may shed light on the pathophysiological mechanisms of human ALS. A better understanding of the factors that determine the disease progression in CDM may be beneficial for the development of effective treatments for ALS.

  18. Oropharyngeal dysphagia in amyotrophic lateral sclerosis alters quality of life.

    PubMed

    Paris, G; Martinaud, O; Petit, A; Cuvelier, A; Hannequin, D; Roppeneck, P; Verin, E

    2013-03-01

    Dysphagia is one of the most important complications encountered in amyotrophic lateral sclerosis (ALS). Our aim was to determine whether oropharyngeal dysphagia impacted the quality of life (QoL) of patients with ALS. Thirty consecutive patients were recruited (31-82 years, 18 men). Swallowing function was evaluated using a standardised videofluoroscopic barium swallow. All the patients completed a specific questionnaire on quality of life in dysphagia (SWAL-QoL) immediately after the videofluoroscopy. The results of dysphagia outcome severity scale separated 14 patients with oropharyngeal dysphagia and 16 with normal swallowing function. There was no difference in the average age, weight and body mass index of the two groups (dysphagic patients: 68 ± 11 kg versus non-dysphagic patients: 69 ± 14 kg). Most of the dysphagic patients had a bulbar affection based on their Norris scores which determine the importance of cranial nerves illness (20 ± 8), significantly lower than those of the non-dysphagic patients (35 ± 5) (P < 0·0001). There was no difference in the neurological peripheral symptoms evaluated by Amyotrophic Lateral Sclerosis Functional Rating Scale scores (dysphagic patients: 26 ± 7 versus non-dysphagic patients: 27 ± 8) (ns). The swallowing quality of life questionnaire revealed that the dysphagic patients had significant burden (P < 0·001). They were affected by the necessity to applied a food selection (P < 0·01), by the increase in eating duration (P < 0·05) and described a decrease in eating desire (P < 0·05). They complained of fear regarding the risk of dysphagia (P < 0·05). They also described difficulties with oral communication (P < 0·001). All of those complained about dysphagia which impacted directly mental health (P < 0·05) and social life (P < 0·05). In conclusion, oropharyngeal dysphagia is a common symptom accompanying ALS, which alters the patient's QoL, especially social health.

  19. Application of botulinum toxin to treat sialorrhea in amyotrophic lateral sclerosis patients: a literature review

    PubMed Central

    de Oliveira, Ademar Francisco; Silva, Gêssyca Adryene de Menezes; Almeida, Débora Milenna Xavier

    2016-01-01

    ABSTRACT Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease characterized by the degeneration of motor neurons, which are the central nervous system cells that control voluntary muscle movements. The excessive salivation (sialorrhea) is present in approximately 50% of amyotrophic lateral sclerosis cases. Thus, some alternative therapeutic methods are sought, such as anticholinergic drugs and surgery. Recently the use of botulinum toxin applied at a midpoint of the salivary glands, often guided by ultrasound, have demonstrated positive results. The objective was to review the literature to demonstrate an alternative method to treatments of sialorrhea in patients with amyotrophic lateral sclerosis. In recent studies, the efficacy of botulinum toxin is confirmed, although new applications are required. Since the side effects are negligible, this is an alternative to treat amyotrophic lateral sclerosis, and other patients with diseases that present sialorrhea. PMID:27759834

  20. Defective cholesterol metabolism in amyotrophic lateral sclerosis[S

    PubMed Central

    Abdel-Khalik, Jonas; Yutuc, Eylan; Crick, Peter J.; Gustafsson, Jan-Åke; Warner, Margaret; Roman, Gustavo; Talbot, Kevin; Gray, Elizabeth; Turner, Martin R.; Wang, Yuqin

    2017-01-01

    As neurons die, cholesterol is released in the central nervous system (CNS); hence, this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS), in which altered cholesterol levels have been linked to prognosis. More than 40 different sterols were quantified in serum and cerebrospinal fluid (CSF) from ALS patients and healthy controls. In CSF, the concentration of cholesterol was found to be elevated in ALS samples. When CSF metabolite levels were normalized to cholesterol, the cholesterol metabolite 3β,7α-dihydroxycholest-5-en-26-oic acid, along with its precursor 3β-hydroxycholest-5-en-26-oic acid and product 7α-hydroxy-3-oxocholest-4-en-26-oic acid, were reduced in concentration, whereas metabolites known to be imported from the circulation into the CNS were not found to differ in concentration between groups. Analysis of serum revealed that (25R)26-hydroxycholesterol, the immediate precursor of 3β-hydroxycholest-5-en-26-oic acid, was reduced in concentration in ALS patients compared with controls. We conclude that the acidic branch of bile acid biosynthesis, known to be operative in-part in the brain, is defective in ALS, leading to a failure of the CNS to remove excess cholesterol, which may be toxic to neuronal cells, compounded by a reduction in neuroprotective 3β,7α-dihydroxycholest-5-en-26-oic acid. PMID:27811233

  1. Widespread temporo-occipital lobe dysfunction in amyotrophic lateral sclerosis

    PubMed Central

    Loewe, Kristian; Machts, Judith; Kaufmann, Jörn; Petri, Susanne; Heinze, Hans-Jochen; Borgelt, Christian; Harris, Joseph Allen; Vielhaber, Stefan; Schoenfeld, Mircea Ariel

    2017-01-01

    Recent studies suggest that amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) lie on a single clinical continuum. However, previous neuroimaging studies have found only limited involvement of temporal lobe regions in ALS. To better delineate possible temporal lobe involvement in ALS, the present study aimed to examine changes in functional connectivity across the whole brain, particularly with regard to extra-motor regions, in a group of 64 non-demented ALS patients and 38 healthy controls. To assess between-group differences in connectivity, we computed edge-level statistics across subject-specific graphs derived from resting-state functional MRI data. In addition to expected ALS-related decreases in functional connectivity in motor-related areas, we observed extensive changes in connectivity across the temporo-occipital cortex. Although ALS patients with comorbid FTD were deliberately excluded from this study, the pattern of connectivity alterations closely resembles patterns of cerebral degeneration typically seen in FTD. This evidence for subclinical temporal dysfunction supports the idea of a common pathology in ALS and FTD. PMID:28067298

  2. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

    PubMed Central

    McLaughlin, Russell L.; Schijven, Dick; van Rheenen, Wouter; van Eijk, Kristel R.; O'Brien, Margaret; Kahn, René S.; Ophoff, Roel A.; Goris, An; Bradley, Daniel G.; Al-Chalabi, Ammar; van den Berg, Leonard H.; Luykx, Jurjen J.; Hardiman, Orla; Veldink, Jan H.; Shatunov, Aleksey; Dekker, Annelot M.; Diekstra, Frank P.; Pulit, Sara L.; van der Spek, Rick A. A.; van Doormaal, Perry T. C.; Sproviero, William; Jones, Ashley R.; Nicholson, Garth A.; Rowe, Dominic B.; Pamphlett, Roger; Kiernan, Matthew C.; Bauer, Denis; Kahlke, Tim; Williams, Kelly; Eftimov, Filip; Fogh, Isabella; Ticozzi, Nicola; Lin, Kuang; Millecamps, Stéphanie; Salachas, François; Meininger, Vincent; de Carvalho, Mamede; Pinto, Susana; Mora, Jesus S.; Rojas-García, Ricardo; Polak, Meraida; Chandran, Siddharthan; Colville, Shuna; Swingler, Robert; Morrison, Karen E.; Shaw, Pamela J.; Hardy, John; Orrell, Richard W.; Pittman, Alan; Sidle, Katie; Fratta, Pietro; Malaspina, Andrea; Petri, Susanne; Abdulla, Susanna; Drepper, Carsten; Sendtner, Michael; Meyer, Thomas; Wiedau-Pazos, Martina; Lomen-Hoerth, Catherine; Van Deerlin, Vivianna M.; Trojanowski, John Q.; Elman, Lauren; McCluskey, Leo; Basak, Nazli; Meitinger, Thomas; Lichtner, Peter; Blagojevic-Radivojkov, Milena; Andres, Christian R.; Maurel, Cindy; Bensimon, Gilbert; Landwehrmeyer, Bernhard; Brice, Alexis; Payan, Christine A. M.; Saker-Delye, Safa; Dürr, Alexandra; Wood, Nicholas; Tittmann, Lukas; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Cichon, Sven; Nöuthen, Markus M.; Amouyel, Philippe; Tzourio, Christophe; Dartigues, Jean- François; Uitterlinden, Andre G.; Rivadeneira, Fernando; Estrada, Karol; Hofman, Albert; Curtis, Charles; van der Kooi, Anneke J.; de Visser, Marianne; Weber, Markus; Shaw, Christopher E.; Smith, Bradley N.; Pansarasa, Orietta; Cereda, Cristina; Del Bo, Roberto; Comi, Giacomo P.; D'Alfonso, Sandra; Bertolin, Cinzia; Sorarù, Gianni; Mazzini, Letizia; Pensato, Viviana; Gellera, Cinzia; Tiloca, Cinzia; Ratti, Antonia; Calvo, Andrea; Moglia, Cristina; Brunetti, Maura; Arcuti, Simon; Capozzo, Rosa; Zecca, Chiara; Lunetta, Christian; Penco, Silvana; Riva, Nilo; Padovani, Alessandro; Filosto, Massimiliano; Blair, Ian; Leigh, P Nigel; Casale, Federico; Chio, Adriano; Beghi, Ettore; Pupillo, Elisabetta; Tortelli, Rosanna; Logroscino, Giancarlo; Powell, John; Ludolph, Albert C.; Weishaupt, Jochen H.; Robberecht, Wim; Van Damme, Philip; Brown, Robert H.; Glass, Jonathan; Landers, John E.; Andersen, Peter M.; Corcia, Philippe; Vourc'h, Patrick; Silani, Vincenzo; van Es, Michael A.; Pasterkamp, R Jeroen; Lewis, Cathryn M.; Breen, Gerome; Ripke, Stephan; Neale, Benjamin M.; Corvin, Aiden; Walters, James T. R.; Farh, Kai-How; Holmans, Peter A; Lee, Phil; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A.; Begemann, Martin; Belliveau, Richard A.; Bene, Judit; Bergen, Sarah E.; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Catts, Stanley V.; Chambert, Kimberley D.; Chan, Raymond C. K.; Chan, Ronald Y. L.; Chen, Eric Y. H.; Cheng, Wei; Cheung, Eric F. C.; Chong, Siow Ann; Cloninger, C Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crowley, James J.; Curtis, David; Davidson, Michael; Davis, Kenneth L.; Degenhardt, Franziska; Del Favero, Jurgen; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Durmishi, Naser; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H.; Farrell, Martilias S.; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B.; Friedl, Marion; Friedman, Joseph I.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Giegling, Ina; Giusti-Rodríguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I.; Golimbet, Vera; Gopal, Srihari; Gratten, Jacob; de Haan, Lieuwe; Hammer, Christian; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Henskens, Frans A.; Herms, Stefan; Hirschhorn, Joel N.; Hoffmann, Per; Hofman, Andrea; Hollegaard, Mads V.; Hougaard, David M.; Ikeda, Masashi; Joa, Inge; Julià, Antonio; Kalaydjieva, Luba; Karachanak-Yankova, Sena; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C.; Kennedy, James L.; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Knowles, James A.; Konte, Bettina; Kucinskas, Vaidutis; Kucinskiene, Zita Ausrele; Kuzelova-Ptackova, Hana; Kähler, Anna K.; Laurent, Claudine; Lee, Jimmy; Lee, S Hong; Legge, Sophie E.; Lerer, Bernard; Li, Miaoxin; Li, Tao; Liang, Kung-Yee; Lieberman, Jeffrey; Limborska, Svetlana; Loughland, Carmel M.; Lubinski, Jan; Lönnqvist, Jouko; Macek, Milan; Magnusson, Patrik K. E.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W.; McDonald, Colm; McIntosh, Andrew M.; Meier, Sandra; Meijer, Carin J.; Melegh, Bela; Melle, Ingrid; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W.; Mors, Ole; Murphy, Kieran C.; Murray, Robin M.; Myin-Germeys, Inez; Müller-Myhsok, Bertram; Nelis, Mari; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nikitina-Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; O'Callaghan, Eadbhard; O'Dushlaine, Colm; O'Neill, F Anthony; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; Van Os, Jim; Pantelis, Christos; Papadimitriou, George N.; Papiol, Sergi; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Pejovic-Milovancevic, Milica; Perkins, Diana O.; Pietiläinen, Olli; Pimm, Jonathan; Pocklington, Andrew J.; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Rasmussen, Henrik B.; Reichenberg, Abraham; Reimers, Mark A.; Richards, Alexander L.; Roffman, Joshua L.; Roussos, Panos; Ruderfer, Douglas M.; Salomaa, Veikko; Sanders, Alan R.; Schall, Ulrich; Schubert, Christian R.; Schulze, Thomas G.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Rodney J.; Seidman, Larry J.; Shi, Jianxin; Sigurdsson, Engilbert; Silagadze, Teimuraz; Silverman, Jeremy M.; Sim, Kang; Slominsky, Petr; Smoller, Jordan W.; So, Hon-Cheong; Spencer, Chris C. A.; Stahl, Eli A.; Stefansson, Hreinn; Steinberg, Stacy; Stogmann, Elisabeth; Straub, Richard E.; Strengman, Eric; Strohmaier, Jana; Stroup, T Scott; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Söderman, Erik; Thirumalai, Srinivas; Toncheva, Draga; Tosato, Sarah; Veijola, Juha; Waddington, John; Walsh, Dermot; Wang, Dai; Wang, Qiang; Webb, Bradley T.; Weiser, Mark; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wong, Emily H. M.; Wormley, Brandon K.; Xi, Hualin Simon; Zai, Clement C.; Zheng, Xuebin; Zimprich, Fritz; Wray, Naomi R.; Stefansson, Kari; Visscher, Peter M.; Adolfsson, Rolf; Andreassen, Ole A.; Blackwood, Douglas H. R.; Bramon, Elvira; Buxbaum, Joseph D.; Børglum, Anders D.; Darvasi, Ariel; Domenici, Enrico; Ehrenreich, Hannelore; Esko, Tõnu; Gejman, Pablo V.; Gill, Michael; Gurling, Hugh; Hultman, Christina M.; Iwata, Nakao; Jablensky, Assen V.; Jönsson, Erik G.; Kendler, Kenneth S.; Kirov, George; Knight, Jo; Lencz, Todd; Levinson, Douglas F.; Li, Qingqin S.; Liu, Jianjun; Malhotra, Anil K.; McCarroll, Steven A.; McQuillin, Andrew; Moran, Jennifer L.; Mortensen, Preben B.; Mowry, Bryan J.; Owen, Michael J.; Palotie, Aarno; Pato, Carlos N.; Petryshen, Tracey L.; Posthuma, Danielle; Riley, Brien P.; Rujescu, Dan; Sham, Pak C.; Sklar, Pamela; St Clair, David; Weinberger, Daniel R.; Wendland, Jens R.; Werge, Thomas; Daly, Mark J.; Sullivan, Patrick F.; O'Donovan, Michael C.

    2017-01-01

    We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies. PMID:28322246

  3. INSPIRATIonAL--INSPIRAtory muscle training in amyotrophic lateral sclerosis.

    PubMed

    Cheah, Benjamin C; Boland, Robert A; Brodaty, Nina E; Zoing, Margie C; Jeffery, Sandra E; McKenzie, David K; Kiernan, Matthew C

    2009-01-01

    Respiratory impairment, due to respiratory muscle weakness, is a major cause of morbidity and mortality in patients with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). Threshold loading may strengthen the inspiratory muscles and thereby improve patient prognosis. A phase II, double-blind, randomized-controlled trial was undertaken to determine whether a 12-week inspiratory muscle training programme attenuated the decline in respiratory function and inspiratory muscle strength in patients with ALS/MND. Nine patients were randomized to inspiratory muscle training and 10 to sham training. Primary endpoints were respiratory function (forced vital capacity, vital capacity), lung volumes and inspiratory muscle strength. Patients were assessed before, during and immediately after a 12-week training period, and at eight weeks follow-up. While improvements in inspiratory muscle strength were observed in both treatment arms, there was a non-significant increase in maximum inspiratory pressure of 6.1% in the experimental group compared to controls (standard error of mean, 6.93%; 95% confidence interval -8.58 -20.79; p=0.39). The gains in inspiratory muscle strength were partially reversed during a period of training cessation. In conclusion, inspiratory muscle training may potentially strengthen the inspiratory muscles and slow the decline in respiratory function in patients with ALS/MND.

  4. CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

    PubMed Central

    Williams, Kelly L.; Topp, Simon; Yang, Shu; Smith, Bradley; Fifita, Jennifer A.; Warraich, Sadaf T.; Zhang, Katharine Y.; Farrawell, Natalie; Vance, Caroline; Hu, Xun; Chesi, Alessandra; Leblond, Claire S.; Lee, Albert; Rayner, Stephanie L.; Sundaramoorthy, Vinod; Dobson-Stone, Carol; Molloy, Mark P.; van Blitterswijk, Marka; Dickson, Dennis W.; Petersen, Ronald C.; Graff-Radford, Neill R.; Boeve, Bradley F.; Murray, Melissa E.; Pottier, Cyril; Don, Emily; Winnick, Claire; McCann, Emily P.; Hogan, Alison; Daoud, Hussein; Levert, Annie; Dion, Patrick A.; Mitsui, Jun; Ishiura, Hiroyuki; Takahashi, Yuji; Goto, Jun; Kost, Jason; Gellera, Cinzia; Gkazi, Athina Soragia; Miller, Jack; Stockton, Joanne; Brooks, William S.; Boundy, Karyn; Polak, Meraida; Muñoz-Blanco, José Luis; Esteban-Pérez, Jesús; Rábano, Alberto; Hardiman, Orla; Morrison, Karen E.; Ticozzi, Nicola; Silani, Vincenzo; de Belleroche, Jacqueline; Glass, Jonathan D.; Kwok, John B. J.; Guillemin, Gilles J.; Chung, Roger S.; Tsuji, Shoji; Brown, Robert H.; García-Redondo, Alberto; Rademakers, Rosa; Landers, John E.; Gitler, Aaron D.; Rouleau, Guy A.; Cole, Nicholas J.; Yerbury, Justin J.; Atkin, Julie D.; Shaw, Christopher E.; Nicholson, Garth A.; Blair, Ian P.

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase complex (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration. PMID:27080313

  5. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia.

    PubMed

    McLaughlin, Russell L; Schijven, Dick; van Rheenen, Wouter; van Eijk, Kristel R; O'Brien, Margaret; Kahn, René S; Ophoff, Roel A; Goris, An; Bradley, Daniel G; Al-Chalabi, Ammar; van den Berg, Leonard H; Luykx, Jurjen J; Hardiman, Orla; Veldink, Jan H

    2017-03-21

    We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

  6. Peripherin partially localizes in Bunina bodies in amyotrophic lateral sclerosis.

    PubMed

    Mizuno, Yuji; Fujita, Yukio; Takatama, Masamitsu; Okamoto, Koichi

    2011-03-15

    Peripherin is a type III intermediate filament protein expressed with low levels in spinal motor neurons. Amyotrophic lateral sclerosis (ALS) is characterized by the presence of Bunina bodies, skein-like inclusions, and Lewy body-like inclusions (LBLIs) in the remaining anterior horn cells, where the first and third structures are detected by Hematoxylin-Eosin (H & E) staining. We examined paraffin sections of lumbar spinal cords from six ALS patients, using H & E staining and immunostaining for human peripherin. The results demonstrated that there were a total of 73 anterior horn cells containing one or more Bunina bodies, and that twelve of these cells (approximately 16.4%) demonstrated peripherin-positive Bunina bodies. In fact, some part of chain-like Bunina bodies showed peripherin-positive reaction, although there were a much higher number of non-immunoreacitive Bunina bodies in each neuron. LBLIs were clearly immunostained for peripherin corresponding to the core, while some of them showed different types of immunoreactivities due to oblique cutting of inclusions. Our findings suggest that although the mechanisms underlying peripherin co-localization in Bunina bodies are unknown, peripherin could be involved in forming these inclusions. Furthermore, following cystatin C and transferrin, peripherin is the third most prevalent protein that partially localizes in Bunina bodies.

  7. A(a)LS: Ammonia-induced amyotrophic lateral sclerosis

    PubMed Central

    Parekh, Bhavin

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a dreadful, devastating and incurable motor neuron disease. Aetiologically, it is a multigenic, multifactorial and multiorgan disease. Despite intense research, ALS pathology remains unexplained. Following extensive literature review, this paper posits a new integrative explanation. This framework proposes that ammonia neurotoxicity is a main player in ALS pathogenesis. According to this explanation, a combination of impaired ammonia removal— mainly because of impaired hepatic urea cycle dysfunction—and increased ammoniagenesis— mainly because of impaired glycolytic metabolism in fast twitch skeletal muscle—causes chronic hyperammonia in ALS. In the absence of neuroprotective calcium binding proteins (calbindin, calreticulin and parvalbumin), elevated ammonia—a neurotoxin—damages motor neurons. Ammonia-induced motor neuron damage occurs through multiple mechanisms such as macroautophagy-endolysosomal impairment, endoplasmic reticulum (ER) stress, CDK5 activation, oxidative/nitrosative stress, neuronal hyperexcitability and neuroinflammation. Furthermore, the regional pattern of calcium binding proteins’ loss, owing to either ER stress and/or impaired oxidative metabolism, determines clinical variability of ALS. Most importantly, this new framework can be generalised to explain other neurodegenerative disorders such as Huntington’s disease and Parkinsonism. PMID:27785351

  8. Identification of new mutations in familial amyotrophic lateral sclerosis

    SciTech Connect

    Siddique, T.; Deng, H.X.; Hentati, A.

    1994-09-01

    Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease due to motor neuron death in the cortex, brain stem and spinal cord. Ten percent of ALS cases are familial (FALS). Previously a subset of FALS families have been mapped to chromosome 21 and mutations in the Cu,Zn superoxide dismutase gene have been identified in those families. Nineteen different mutations at 16 distinct codons have been documented, of which 12 different mutations were identified in our 29 FALS families. These mutations account for about twenty percent of all FALS families screened. The mutations identified in our FALS families are A4V, A4T, G37R, G41D, H43R, G85R, G93A, E100G, L106V, I113T, L144F, and V148G. Mutation A4V is the most frequent one which occurred in 14 out of our 29 FALS families. In further screening of our FALS families, two new mutations, V14M and L84V, have been identified. Thus a total of 21 different mutations at 18 distinct codon sites have been identified in SOD1.

  9. Emerging molecular biomarker targets for amyotrophic lateral sclerosis.

    PubMed

    Costa, Júlia; de Carvalho, Mamede

    2016-04-01

    Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects upper (UMN) and lower motor (LMN) neurons. It is associated with a short survival and there is no effective treatment, in spite of a large number of clinical trials. Strong efforts have been made to identify novel disease biomarkers to support diagnosis, provide information on prognosis, to measure disease progression in trials and increase our knowledge on disease pathogenesis. Electromyography by testing the function of the LMN can be used as a biomarker of its dysfunction. A number of electrophysiological and neuroimaging methods have been explored to identify a reliable marker of UMN degeneration. Recently, strong evidence from independent groups, large cohorts of patients and multicenter studies indicate that neurofilaments are very promising diagnostic biomarkers, in particular cerebrospinal fluid and blood levels of phosphoneurofilament heavy chain and neurofilament light chain. Furthermore, their increased levels are associated with poor prognosis. Additional studies have been performed aiming to identify other biomarkers, which alone or in combination with neurofilaments could increase the sensitivity and the specificity of the assays. Emerging molecular marker targets are being discovered, but more studies with standardized methods are required in larger cohorts of ALS patients.

  10. The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis.

    PubMed

    Loeffler, Jean-Philippe; Picchiarelli, Gina; Dupuis, Luc; Gonzalez De Aguilar, Jose-Luis

    2016-03-01

    Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease primarily characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. It is increasingly accepted that the pathological process leading to ALS is the result of multiple disease mechanisms that operate within motor neurons and other cell types both inside and outside the central nervous system. The implication of skeletal muscle has been the subject of a number of studies conducted on patients and related animal models. In this review, we describe the features of ALS muscle pathology and discuss on the contribution of muscle to the pathological process. We also give an overview of the therapeutic strategies proposed to alleviate muscle pathology or to deliver curative agents to motor neurons. ALS muscle mainly suffers from oxidative stress, mitochondrial dysfunction and bioenergetic disturbances. However, the way by which the disease affects different types of myofibers depends on their contractile and metabolic features. Although the implication of muscle in nourishing the degenerative process is still debated, there is compelling evidence suggesting that it may play a critical role. Detailed understanding of the muscle pathology in ALS could, therefore, lead to the identification of new therapeutic targets.

  11. Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis.

    PubMed

    Pryce, Gareth; Baker, David

    2015-01-01

    There are numerous reports that people with multiple sclerosis (MS) have for many years been self-medicating with illegal street cannabis or more recently medicinal cannabis to alleviate the symptoms associated with MS and also amyotrophic lateral sclerosis (ALS). These anecdotal reports have been confirmed by data from animal models and more recently clinical trials on the ability of cannabinoids to alleviate limb spasticity, a common feature of progressive MS (and also ALS) and neurodegeneration. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have efficacy, not only in symptom relief but also as neuroprotective agents which may slow disease progression and thus delay the onset of symptoms. This review discusses what we now know about the endocannabinoid system as it relates to MS and ALS and also the therapeutic potential of cannabinoid therapeutics as disease-modifying or symptom control agents, as well as future therapeutic strategies including the potential for slowing disease progression in MS and ALS.

  12. Longitudinal changes in discourse production in amyotrophic lateral sclerosis.

    PubMed

    Roberts-South, Angela; Findlater, Kate; Strong, Michael J; Orange, J B

    2012-02-01

    Amyotrophic lateral sclerosis (ALS) is a multisystem disease that significantly impacts communication as a function of changes in motor speech, cognition, and language skills. Although discourse tasks have been used to assess language in a variety of acquired disorders, little work to date has been published on changes in discourse in ALS and even less work has evaluated these changes with disease progression. In the present study, discourse samples (gained from a picture description task) as well as standardized language test measures obtained from 16 individuals with ALS without dementia and 12 healthy controls (collected over a duration of 24 months). Discourse samples were analyzed for both productivity and content. Results indicate that there were no differences for ALS versus controls for any of the standardized language tests. However, findings suggest that discourse analysis methods may be more sensitive for identifying subtle language deficits in ALS. Overall, discourse productivity appears less impaired than discourse content for individuals with ALS. Although there was a general trend for decline in language performance over the study duration, there was the suggestion of subgroups of language performance among ALS participants. The results suggest that subtle cognitive language deficits that affect discourse emerge early in ALS and progress with disease progression.

  13. Mitochondrial Disorders May Mimic Amyotrophic Lateral Sclerosis at Onset

    PubMed Central

    Finsterer, Josef; Zarrouk-Mahjoub, Sinda

    2016-01-01

    Similarities between a mitochondrial disorder (MID) and amyotrophic lateral sclerosis (ALS) fade with disease progression and the development of mitochondrial multiple organ dysfunction syndrome (MIMODS). However, with mild MIMODS, a MID may still be misinterpreted as ALS. We report a 48-year-old male who presented to the Neurological Hospital Rosenhügel, Vienna, Austria, in February 2001 with slowly progressive weakness, wasting and left upper limb fasciculations which spread to the shoulder girdle and lower limbs. Additionally, he developed tetraspasticity and bulbar involvement. He had been diagnosed with ALS a year previously due to electrophysiological investigations indicative of a chronic neurogenic lesion. However, a muscle biopsy revealed morphological features of a MID and a combined complex-II/III defect. Nerve conduction studies were performed over subsequent years until February 2011. This case demonstrates that MIDs may mimic ALS at onset and begin as a mono-organ disorder but develop into a multi-organ disease with long-term progression. A combined complex II/III defect may manifest with bulbar involvement. PMID:26909222

  14. The pre-clinical discovery of Amyotrophic Lateral Sclerosis Drugs

    PubMed Central

    Glicksman, Marcie A.

    2012-01-01

    Introduction Amyotrophic Lateral Sclerosis, also referred to as Lou Gehrig’s disease is characterized by the progressive loss of cells in the brain and spinal cord that leads to debilitation and death in 3–5 years. Only one therapeutic drug, Riluzole, has been approved for ALS and that drug improves survival by 2–3 months. The need for new therapeutics, either that can postpone or slow the progression of the motor deficits and prolong survival, is still a strong unmet medical need. Areas Covered Although there are a number of drugs currently in clinical trials for ALS, this review provides an overview of the most promising biological targets and preclinical strategies that are currently being developed and deployed. The list of targets for ALS was compiled from a variety of websites including: individual companies that have ALS programs, and the author’s experience. Expert Opinion Progress is being made in the identification of possible new therapeutics for ALS with recent efforts in: understanding the genetic causes of the disease, susceptibility factors, and the development of additional preclinical animal models. However, many challenges remain in the identification of new ALS therapeutics including: the use of relevant biomarkers, the need for earlier diagnosis of the disease, and additional animal models. Multiple strategies need to be tested, in the clinic, in order to determine what will be effective in patients. PMID:22646982

  15. Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

    PubMed Central

    Dodge, James C.; Treleaven, Christopher M.; Pacheco, Joshua; Cooper, Samantha; Bao, Channa; Abraham, Marissa; Cromwell, Mandy; Sardi, S. Pablo; Chuang, Wei-Lien; Sidman, Richard L.; Cheng, Seng H.; Shihabuddin, Lamya S.

    2015-01-01

    Recent genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases including hereditary spastic paraplegia, hereditary sensory neuropathy type 1, and non-5q spinal muscular atrophy. Here, we investigated whether altered glycosphingolipid metabolism is a modulator of disease course in amyotrophic lateral sclerosis (ALS). Levels of ceramide, glucosylceramide, galactocerebroside, lactosylceramide, globotriaosylceramide, and the gangliosides GM3 and GM1 were significantly elevated in spinal cords of ALS patients. Moreover, enzyme activities (glucocerebrosidase-1, glucocerebrosidase-2, hexosaminidase, galactosylceramidase, α-galactosidase, and β-galactosidase) mediating glycosphingolipid hydrolysis were also elevated up to threefold. Increased ceramide, glucosylceramide, GM3, and hexosaminidase activity were also found in SOD1G93A mice, a familial model of ALS. Inhibition of glucosylceramide synthesis accelerated disease course in SOD1G93A mice, whereas infusion of exogenous GM3 significantly slowed the onset of paralysis and increased survival. Our results suggest that glycosphingolipids are likely important participants in pathogenesis of ALS and merit further analysis as potential drug targets. PMID:26056266

  16. Percutaneous nocturnal oximetry in amyotrophic lateral sclerosis: periodic desaturation.

    PubMed

    de Carvalho, Mamede; Costa, João; Pinto, Susana; Pinto, Anabela

    2009-06-01

    Percutaneous nocturnal oximetry (PNO) is useful to screen respiratory function in amyotrophic lateral sclerosis (ALS). PNO recordings of some patients disclose a periodical pattern of O(2) desaturation (PP), whose significance is unknown. We aimed to characterize PP pattern, and we used a prospective study enrolling 261 consecutive ALS patients. Clinical, pulmonary and neurophysiological tests performed included: ALS functional rating scale, forced vital capacity (FVC), maximal inspiratory pressure (PImax), mouth occlusion pressure (MOP), phrenic nerve motor response, needle electromyography of the diaphragm, PNO, and sleep study. A total of 837 PNO recordings were analysed (3.2 recordings/patient) and 45 patients showed typical PP (17.2%). Four were excluded, 13 had normal diaphragm (group 1, G1), and in 28 the diaphragm was abnormal (G2). The two groups were comparable, apart from respiratory score, FVC and PImax which were lower in G2. In G1, REM sleep was absent and hypoventilation occurred at slow-wave sleep. Five patients in G1 were very spastic, had low MOP/FVC and a short survival. This study identified a subgroup of ALS patients (G1) with marked signs of upper motor neuron lesion, strong respiratory muscles, PP, low MOP/FVC ratio and poor prognosis. We speculate that they have a central respiratory dysfunction and deserve special care.

  17. Roles of Vascular Endothelial Growth Factor in Amyotrophic Lateral Sclerosis

    PubMed Central

    Pronto-Laborinho, Ana Catarina; Pinto, Susana; de Carvalho, Mamede

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal devastating neurodegenerative disorder, involving progressive degeneration of motor neurons in spinal cord, brainstem, and motor cortex. Riluzole is the only drug approved in ALS but it only confers a modest improvement in survival. In spite of a high number of clinical trials no other drug has proved effectiveness. Recent studies support that vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, also plays a key role in the nervous system, including neurogenesis, neuronal survival, neuronal migration, and axon guidance. VEGF has been used in exploratory clinical studies with promising results in ALS and other neurological disorders. Although VEGF is a very promising compound, translating the basic science breakthroughs into clinical practice is the major challenge ahead. VEGF-B, presenting a single safety profile, protects motor neurons from degeneration in ALS animal models and, therefore, it will be particularly interesting to test its effects in ALS patients. In the present paper the authors make a brief description of the molecular properties of VEGF and its receptors and review its different features and therapeutic potential in the nervous system/neurodegenerative disease, particularly in ALS. PMID:24987705

  18. Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes.

    PubMed

    Jones, Ashley R; Troakes, Claire; King, Andrew; Sahni, Vibhu; De Jong, Simone; Bossers, Koen; Papouli, Efterpi; Mirza, Muddassar; Al-Sarraj, Safa; Shaw, Christopher E; Shaw, Pamela J; Kirby, Janine; Veldink, Jan H; Macklis, Jeffrey D; Powell, John F; Al-Chalabi, Ammar

    2015-05-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons resulting in progressive paralysis. Gene expression studies of ALS only rarely identify the same gene pathways as gene association studies. We hypothesized that analyzing tissues by matching on degree of disease severity would identify different patterns of gene expression from a traditional case-control comparison. We analyzed gene expression changes in 4 postmortem central nervous system regions, stratified by severity of motor neuron loss. An overall comparison of cases (n = 6) and controls (n = 3) identified known ALS gene, SOX5, as showing differential expression (log2 fold change = 0.09, p = 5.5 × 10(-5)). Analyses stratified by disease severity identified expression changes in C9orf72 (p = 2.77 × 10(-3)), MATR3 (p = 3.46 × 10(-3)), and VEGFA (p = 8.21 × 10(-4)), all implicated in ALS through genetic studies, and changes in other genes in pathways involving RNA processing and immune response. These findings suggest that analysis of gene expression stratified by disease severity can identify major ALS genes and may be more efficient than traditional case-control comparison.

  19. Mitochondria and endoplasmic reticulum crosstalk in amyotrophic lateral sclerosis.

    PubMed

    Manfredi, Giovanni; Kawamata, Hibiki

    2016-06-01

    Physical and functional interactions between mitochondria and the endoplasmic reticulum (ER) are crucial for cell life. These two organelles are intimately connected and collaborate to essential processes, such as calcium homeostasis and phospholipid biosynthesis. The connections between mitochondria and endoplasmic reticulum occur through structures named mitochondria associated membranes (MAMs), which contain lipid rafts and a large number of proteins, many of which serve multiple functions at different cellular sites. Growing evidence strongly suggests that alterations of ER-mitochondria interactions are involved in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), a devastating and rapidly fatal motor neuron disease. Mutations in proteins that participate in ER-mitochondria interactions and MAM functions are increasingly being associated with genetic forms of ALS and other neurodegenerative diseases. This evidence strongly suggests that, rather than considering the two organelles separately, a better understanding of the disease process can derive from studying the alterations in their crosstalk. In this review we discuss normal and pathological ER-mitochondria interactions and the evidence that link them to ALS.

  20. A neurophysiological analysis of working memory in amyotrophic lateral sclerosis.

    PubMed

    Hammer, Anke; Vielhaber, Stefan; Rodriguez-Fornells, Antoni; Mohammadi, Bahram; Münte, Thomas F

    2011-11-03

    Frontal lobe functions, in particular working memory (WM) and verbal fluency, have been found to be deficient in amyotrophic lateral sclerosis (ALS). To study the neural correlates of WM-impairment, ALS patients and healthy age-matched controls were subjected to two working memory tasks following the 2-back paradigm, one requiring the storage of figural information, the other storage of spatial information. A significant proportion of ALS patients were unable to perform the WM-tasks. Those who could showed worse performance in the spatial task than the controls. Event-related brain potentials recorded during the task revealed a topographical change of the working memory effect in the ALS patients. Thus, behavioral and electrophysiological data suggest an alteration of working memory, in particular for spatial information, in ALS. Additionally, the patients also took part in two Go/Nogo tasks (spatial, figural) using the same stimulus material but defining targets prior to the experiment instead of a working memory manipulation. Here, an anteriorization of the nogo-P3 was found which has been established as an index of impaired inhibitory functions.

  1. Abnormalities of cortical inhibitory neurons in amyotrophic lateral sclerosis.

    PubMed

    Enterzari-Taher, M; Eisen, A; Stewart, H; Nakajima, M

    1997-01-01

    We have used peristimulus time histograms to study how paired, transcranial magnetic stimulation alters the firing of single motor units and the magnitude of unitary excitatory postsynaptic potentials (EPSPs) recorded from the extensor digitorum communis muscle. With stimulus intensity at threshold and an interstimulus interval of 30 ms, normal subjects (n = 20) demonstrated marked inhibition with a mean test/conditioning EPSP ratio of 13.8% (range 0-51%) and in 7 subjects the ratio was 0 (100% inhibition). In amyotrophic lateral sclerosis (ALS) the ratio was 133% (range 64-267%), P < 0.001. Fifty percent of patients had a test/conditioning EPSP ratio greater than 100% (0 inhibition). The abnormalities were independent of disease severity, bulbar versus spinal ALS, more prominent upper versus lower motor neuron findings, and disease duration. Normal inhibition occurred in 3 individuals, 1 each with multiple sclerosis, Kennedy's syndrome, and monomelic amyotrophy. We speculate that the marked loss of inhibition seen in all patients with ALS, which may be unique to this disorder, reflects loss of inhibitory modulation of the corticomotoneuron and could result in their chronic excitatory drive and eventual demise.

  2. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

    NASA Astrophysics Data System (ADS)

    McLaughlin, Russell L.; Schijven, Dick; van Rheenen, Wouter; van Eijk, Kristel R.; O'Brien, Margaret; Kahn, René S.; Ophoff, Roel A.; Goris, An; Bradley, Daniel G.; Al-Chalabi, Ammar; van den Berg, Leonard H.; Luykx, Jurjen J.; Hardiman, Orla; Veldink, Jan H.; Shatunov, Aleksey; Dekker, Annelot M.; Diekstra, Frank P.; Pulit, Sara L.; van der Spek, Rick A. A.; van Doormaal, Perry T. C.; Sproviero, William; Jones, Ashley R.; Nicholson, Garth A.; Rowe, Dominic B.; Pamphlett, Roger; Kiernan, Matthew C.; Bauer, Denis; Kahlke, Tim; Williams, Kelly; Eftimov, Filip; Fogh, Isabella; Ticozzi, Nicola; Lin, Kuang; Millecamps, Stéphanie; Salachas, François; Meininger, Vincent; de Carvalho, Mamede; Pinto, Susana; Mora, Jesus S.; Rojas-García, Ricardo; Polak, Meraida; Chandran, Siddharthan; Colville, Shuna; Swingler, Robert; Morrison, Karen E.; Shaw, Pamela J.; Hardy, John; Orrell, Richard W.; Pittman, Alan; Sidle, Katie; Fratta, Pietro; Malaspina, Andrea; Petri, Susanne; Abdulla, Susanna; Drepper, Carsten; Sendtner, Michael; Meyer, Thomas; Wiedau-Pazos, Martina; Lomen-Hoerth, Catherine; van Deerlin, Vivianna M.; Trojanowski, John Q.; Elman, Lauren; McCluskey, Leo; Basak, Nazli; Meitinger, Thomas; Lichtner, Peter; Blagojevic-Radivojkov, Milena; Andres, Christian R.; Maurel, Cindy; Bensimon, Gilbert; Landwehrmeyer, Bernhard; Brice, Alexis; Payan, Christine A. M.; Saker-Delye, Safa; Dürr, Alexandra; Wood, Nicholas; Tittmann, Lukas; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Cichon, Sven; Nöuthen, Markus M.; Amouyel, Philippe; Tzourio, Christophe; Dartigues, Jean-François; Uitterlinden, Andre G.; Rivadeneira, Fernando; Estrada, Karol; Hofman, Albert; Curtis, Charles; van der Kooi, Anneke J.; de Visser, Marianne; Weber, Markus; Shaw, Christopher E.; Smith, Bradley N.; Pansarasa, Orietta; Cereda, Cristina; Del Bo, Roberto; Comi, Giacomo P.; D'Alfonso, Sandra; Bertolin, Cinzia; Sorarù, Gianni; Mazzini, Letizia; Pensato, Viviana; Gellera, Cinzia; Tiloca, Cinzia; Ratti, Antonia; Calvo, Andrea; Moglia, Cristina; Brunetti, Maura; Arcuti, Simon; Capozzo, Rosa; Zecca, Chiara; Lunetta, Christian; Penco, Silvana; Riva, Nilo; Padovani, Alessandro; Filosto, Massimiliano; Blair, Ian; Leigh, P. Nigel; Casale, Federico; Chio, Adriano; Beghi, Ettore; Pupillo, Elisabetta; Tortelli, Rosanna; Logroscino, Giancarlo; Powell, John; Ludolph, Albert C.; Weishaupt, Jochen H.; Robberecht, Wim; van Damme, Philip; Brown, Robert H.; Glass, Jonathan; Landers, John E.; Andersen, Peter M.; Corcia, Philippe; Vourc'h, Patrick; Silani, Vincenzo; van Es, Michael A.; Pasterkamp, R. Jeroen; Lewis, Cathryn M.; Breen, Gerome; Ripke, Stephan; Neale, Benjamin M.; Corvin, Aiden; Walters, James T. R.; Farh, Kai-How; Holmans, Peter A.; Lee, Phil; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A.; Begemann, Martin; Belliveau, Richard A.; Bene, Judit; Bergen, Sarah E.; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Catts, Stanley V.; Chambert, Kimberley D.; Chan, Raymond C. K.; Chan, Ronald Y. L.; Chen, Eric Y. H.; Cheng, Wei; Cheung, Eric F. C.; Chong, Siow Ann; Cloninger, C. Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crowley, James J.; Curtis, David; Davidson, Michael; Davis, Kenneth L.; Degenhardt, Franziska; Del Favero, Jurgen; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Durmishi, Naser; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H.; Farrell, Martilias S.; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B.; Friedl, Marion; Friedman, Joseph I.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Giegling, Ina; Giusti-Rodríguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I.; Golimbet, Vera; Gopal, Srihari; Gratten, Jacob; de Haan, Lieuwe; Hammer, Christian; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Henskens, Frans A.; Herms, Stefan; Hirschhorn, Joel N.; Hoffmann, Per; Hofman, Andrea; Hollegaard, Mads V.; Hougaard, David M.; Ikeda, Masashi; Joa, Inge; Julià, Antonio; Kalaydjieva, Luba; Karachanak-Yankova, Sena; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C.; Kennedy, James L.; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Knowles, James A.; Konte, Bettina; Kucinskas, Vaidutis; Kucinskiene, Zita Ausrele; Kuzelova-Ptackova, Hana; Kähler, Anna K.; Laurent, Claudine; Lee, Jimmy; Lee, S. Hong; Legge, Sophie E.; Lerer, Bernard; Li, Miaoxin; Li, Tao; Liang, Kung-Yee; Lieberman, Jeffrey; Limborska, Svetlana; Loughland, Carmel M.; Lubinski, Jan; Lönnqvist, Jouko; Macek, Milan; Magnusson, Patrik K. E.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W.; McDonald, Colm; McIntosh, Andrew M.; Meier, Sandra; Meijer, Carin J.; Melegh, Bela; Melle, Ingrid; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W.; Mors, Ole; Murphy, Kieran C.; Murray, Robin M.; Myin-Germeys, Inez; Müller-Myhsok, Bertram; Nelis, Mari; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nikitina-Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; O'Callaghan, Eadbhard; O'Dushlaine, Colm; O'Neill, F. Anthony; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; van Os, Jim; Pantelis, Christos; Papadimitriou, George N.; Papiol, Sergi; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Pejovic-Milovancevic, Milica; Perkins, Diana O.; Pietiläinen, Olli; Pimm, Jonathan; Pocklington, Andrew J.; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Rasmussen, Henrik B.; Reichenberg, Abraham; Reimers, Mark A.; Richards, Alexander L.; Roffman, Joshua L.; Roussos, Panos; Ruderfer, Douglas M.; Salomaa, Veikko; Sanders, Alan R.; Schall, Ulrich; Schubert, Christian R.; Schulze, Thomas G.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Rodney J.; Seidman, Larry J.; Shi, Jianxin; Sigurdsson, Engilbert; Silagadze, Teimuraz; Silverman, Jeremy M.; Sim, Kang; Slominsky, Petr; Smoller, Jordan W.; So, Hon-Cheong; Spencer, Chris C. A.; Stahl, Eli A.; Stefansson, Hreinn; Steinberg, Stacy; Stogmann, Elisabeth; Straub, Richard E.; Strengman, Eric; Strohmaier, Jana; Stroup, T. Scott; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Söderman, Erik; Thirumalai, Srinivas; Toncheva, Draga; Tosato, Sarah; Veijola, Juha; Waddington, John; Walsh, Dermot; Wang, Dai; Wang, Qiang; Webb, Bradley T.; Weiser, Mark; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wong, Emily H. M.; Wormley, Brandon K.; Xi, Hualin Simon; Zai, Clement C.; Zheng, Xuebin; Zimprich, Fritz; Wray, Naomi R.; Stefansson, Kari; Visscher, Peter M.; Adolfsson, Rolf; Andreassen, Ole A.; Blackwood, Douglas H. R.; Bramon, Elvira; Buxbaum, Joseph D.; Børglum, Anders D.; Darvasi, Ariel; Domenici, Enrico; Ehrenreich, Hannelore; Esko, Tõnu; Gejman, Pablo V.; Gill, Michael; Gurling, Hugh; Hultman, Christina M.; Iwata, Nakao; Jablensky, Assen V.; Jönsson, Erik G.; Kendler, Kenneth S.; Kirov, George; Knight, Jo; Lencz, Todd; Levinson, Douglas F.; Li, Qingqin S.; Liu, Jianjun; Malhotra, Anil K.; McCarroll, Steven A.; McQuillin, Andrew; Moran, Jennifer L.; Mortensen, Preben B.; Mowry, Bryan J.; Owen, Michael J.; Palotie, Aarno; Pato, Carlos N.; Petryshen, Tracey L.; Posthuma, Danielle; Riley, Brien P.; Rujescu, Dan; Sham, Pak C.; Sklar, Pamela; St Clair, David; Weinberger, Daniel R.; Wendland, Jens R.; Werge, Thomas; Daly, Mark J.; Sullivan, Patrick F.; O'Donovan, Michael C.

    2017-03-01

    We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6 P=1 × 10-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

  3. Widespread temporo-occipital lobe dysfunction in amyotrophic lateral sclerosis

    NASA Astrophysics Data System (ADS)

    Loewe, Kristian; Machts, Judith; Kaufmann, Jörn; Petri, Susanne; Heinze, Hans-Jochen; Borgelt, Christian; Harris, Joseph Allen; Vielhaber, Stefan; Schoenfeld, Mircea Ariel

    2017-01-01

    Recent studies suggest that amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) lie on a single clinical continuum. However, previous neuroimaging studies have found only limited involvement of temporal lobe regions in ALS. To better delineate possible temporal lobe involvement in ALS, the present study aimed to examine changes in functional connectivity across the whole brain, particularly with regard to extra-motor regions, in a group of 64 non-demented ALS patients and 38 healthy controls. To assess between-group differences in connectivity, we computed edge-level statistics across subject-specific graphs derived from resting-state functional MRI data. In addition to expected ALS-related decreases in functional connectivity in motor-related areas, we observed extensive changes in connectivity across the temporo-occipital cortex. Although ALS patients with comorbid FTD were deliberately excluded from this study, the pattern of connectivity alterations closely resembles patterns of cerebral degeneration typically seen in FTD. This evidence for subclinical temporal dysfunction supports the idea of a common pathology in ALS and FTD.

  4. Acceptance of brain-computer interfaces in amyotrophic lateral sclerosis.

    PubMed

    Geronimo, Andrew; Stephens, Helen E; Schiff, Steven J; Simmons, Zachary

    2015-06-01

    Brain-computer interfaces (BCI) have the potential to permit patients with amyotrophic lateral sclerosis (ALS) to communicate even when locked in. Although as many as half of patients with ALS develop cognitive or behavioral dysfunction, the impact of these factors on acceptance of and ability to use a BCI has not been studied. We surveyed patients with ALS and their caregivers about BCIs used as assistive communication tools. The survey focused on the features of a BCI system, the desired end-use functions, and requirements. Functional, cognitive, and behavioral data were collected from patients and analyzed for their influence over decisions about BCI device use. Results showed that behavioral impairment was associated with decreased receptivity to the use of BCI technology. In addition, the operation of a BCI system during a pilot study altered patients' opinions of the utility of the system, generally in line with their perceived performance at controlling the device. In conclusion, these two findings have implications for the engineering design and clinical care phases of assistive device deployment.

  5. Gene discovery in amyotrophic lateral sclerosis: implications for clinical management.

    PubMed

    Al-Chalabi, Ammar; van den Berg, Leonard H; Veldink, Jan

    2017-02-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease predominantly affecting upper and lower motor neurons. The disease leads to relentlessly progressive weakness of voluntary muscles, with death typically resulting from diaphragmatic failure within 2-5 years. Since the discovery of mutations in SOD1, which account for ∼2% of ALS cases, increasing efforts have been made to understand the genetic component of ALS risk, with the expectation that this insight will not only aid diagnosis and classification, but also guide personalized treatment and reveal the mechanisms that cause motor neuron death. In this Review, we outline previous and current efforts to characterize genes that are associated with ALS, describe current knowledge about the genetic architecture of ALS - including the relevance of family history - and the probable nature of future gene discoveries, and explore how our understanding of ALS genetics affects present and future clinical decisions. We observe that many gene variants associated with ALS have effect sizes between those of mutations that greatly increase risk and those of common variants that have a small effect on risk, and combine this observation with insights from next-generation sequencing to explore the implications for genetic counselling.

  6. S-nitrosothiol depletion in amyotrophic lateral sclerosis.

    PubMed

    Schonhoff, Christopher M; Matsuoka, Masaaki; Tummala, Hemachand; Johnson, Michael A; Estevéz, Alvaro G; Wu, Rui; Kamaid, Andrés; Ricart, Karina C; Hashimoto, Yuichi; Gaston, Benjamin; Macdonald, Timothy L; Xu, Zuoshang; Mannick, Joan B

    2006-02-14

    Recent data suggest that either excessive or deficient levels of protein S-nitrosylation may contribute to disease. Disruption of S-nitrosothiol (SNO) homeostasis may result not only from altered nitric oxide (NO) synthase activity but also from alterations in the activity of denitrosylases that remove NO groups. A subset of patients with familial amyotrophic lateral sclerosis (ALS) have mutations in superoxide dismutase 1 (SOD1) that increase the denitrosylase activity of SOD1. Here, we show that the increased denitrosylase activity of SOD1 mutants leads to an aberrant decrease in intracellular protein and peptide S-nitrosylation in cell and animal models of ALS. Deficient S-nitrosylation is particularly prominent in the mitochondria of cells expressing SOD1 mutants. Our results suggest that SNO depletion disrupts the function and/or subcellular localization of proteins that are regulated by S-nitrosylation such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and thereby contributes to ALS pathogenesis. Repletion of intracellular SNO levels with SNO donor compounds rescues cells from mutant SOD1-induced death. These results suggest that aberrant depletion of intracellular SNOs contributes to motor neuron death in ALS, and raises the possibility that deficient S-nitrosylation is a general mechanism of disease pathogenesis. SNO donor compounds may provide new therapeutic options for diseases such as ALS that are associated with deficient S-nitrosylation.

  7. Action verb comprehension in amyotrophic lateral sclerosis and Parkinson's disease.

    PubMed

    York, Collin; Olm, Christopher; Boller, Ashley; McCluskey, Leo; Elman, Lauren; Haley, Jenna; Seltzer, Emily; Chahine, Lama; Woo, John; Rascovsky, Katya; McMillan, Corey; Grossman, Murray

    2014-06-01

    Patients with amyotrophic lateral sclerosis (ALS) have a motor disorder and cognitive difficulties, including difficulty with action verbs. However, the basis for the action verb impairment is unknown. Thirty-six participants with ALS and 22 with Parkinson's disease (PD) were assessed on a simple, two-alternative forced-choice associativity judgment task, where performance was untimed and did not depend on motor functioning. We probed 120 frequency-matched action verbs, cognition verbs, concrete nouns and abstract nouns. Performance was related to T1 MRI imaging of gray matter atrophy. Patients with ALS were significantly impaired relative to healthy senior control participants only for action verbs. Patients with PD did not differ from controls for all word categories. Regression analyses related action verb performance in ALS to motor-associated cortices, but action verb judgments in PD were not related to cortical atrophy. These findings are consistent with the hypothesis that action verb difficulty in ALS is related in part to the degradation of action-related conceptual knowledge represented in motor-associated cortex.

  8. AMPK Signalling and Defective Energy Metabolism in Amyotrophic Lateral Sclerosis.

    PubMed

    Perera, Nirma D; Turner, Bradley J

    2016-03-01

    Amyotrophic lateral sclerosis (ALS) is caused by selective loss of upper and lower motor neurons by complex mechanisms that are incompletely understood. Motor neurons are large, highly polarised and excitable cells with unusually high energetic demands to maintain resting membrane potential and propagate action potentials. This leads to higher ATP consumption and mitochondrial metabolism in motor neurons relative to other cells. Here, we review increasing evidence that defective energy metabolism and homeostasis contributes to selective vulnerability and degeneration of motor neurons in ALS. Firstly, we provide a brief overview of major energetic pathways in the CNS, including glycolysis, oxidative phosphorylation and the AMP-activated protein kinase (AMPK) signalling pathway, while highlighting critical metabolic interactions between neurons and astrocytes. Next, we review evidence from ALS patients and transgenic mutant SOD1 mice for weight loss, hypermetabolism, hyperlipidemia and mitochondrial dysfunction in disease onset and progression. Genetic and therapeutic modifiers of energy metabolism in mutant SOD1 mice will also be summarised. We also present evidence that additional ALS-linked proteins, TDP-43 and FUS, lead to energy disruption and mitochondrial defects in motor neurons. Lastly, we review emerging evidence including our own that dysregulation of the AMPK signalling cascade in motor neurons is an early and common event in ALS pathogenesis. We suggest that an imbalance in energy metabolism should be considered an important factor in both progression and potential treatment of ALS.

  9. [Amyotrophic lateral sclerosis: is the astrocyte the cell primarily involved?].

    PubMed

    Sica, Roberto E

    2013-01-01

    So far, amyotrophic lateral sclerosis (ALS) is thought as due to a primary insult of the motor neurons. None of its pathogenic processes proved to be the cause of the illness, nor can be blamed environmental agents. Motor neurons die by apoptosis, leaving the possibility that their death might be due to an unfriendly environment, unable to sustain their health, rather than being directly targeted themselves. These reasons justify an examination of the astrocytes, because they have the most important role controlling the neurons' environment. It is known that astrocytes are plastic, enslaving their functions to the requirements of the neurons to which they are related. Each population of astrocytes is unique, and if it were affected the consequences would reach the neurons that it normally sustains. In regard to the motor neurons, this situation would lead to a disturbed production and release of astrocytic neurotransmitters and transporters, impairing nutritional and trophic support as well. For explaining the spreading of muscle symptoms in ALS, correlated with the type of spreading observed at the cortical and spinal motor neurons pools, the present hypotheses suggests that the illness-causing process is spreading among astrocytes, through their gap junctions, depriving the motor neurons of their support. Also it is postulated that a normal astrocytic protein becomes misfolded and infectious, inducing the misfolding of its wild type, travelling from one protoplasmatic astrocyte to another and to the fibrous astrocytes encircling the pyramidal pathway which joints the upper and lower motoneurones.

  10. Amyotrophic lateral sclerosis: mechanisms and therapeutics in the epigenomic era.

    PubMed

    Paez-Colasante, Ximena; Figueroa-Romero, Claudia; Sakowski, Stacey A; Goutman, Stephen A; Feldman, Eva L

    2015-05-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor neurons, which results in weakness and atrophy of voluntary skeletal muscles. Treatments do not modify the disease trajectory effectively, and only modestly improve survival. A complex interaction between genes, environmental exposure and impaired molecular pathways contributes to pathology in patients with ALS. Epigenetic mechanisms control the hereditary and reversible regulation of gene expression without altering the basic genetic code. Aberrant epigenetic patterns-including abnormal microRNA (miRNA) biogenesis and function, DNA modifications, histone remodeling, and RNA editing-are acquired throughout life and are influenced by environmental factors. Thus, understanding the molecular processes that lead to epigenetic dysregulation in patients with ALS might facilitate the discovery of novel therapeutic targets and biomarkers that could reduce diagnostic delay. These achievements could prove crucial for successful disease modification in patients with ALS. We review the latest findings regarding the role of miRNA modifications and other epigenetic mechanisms in ALS, and discuss their potential as therapeutic targets.

  11. Regionality of disease progression predicts prognosis in amyotrophic lateral sclerosis.

    PubMed

    van der Kleij, Lisa A; Jones, Ashley R; Steen, I Nick; Young, Carolyn A; Shaw, Pamela J; Shaw, Christopher E; Leigh, P Nigel; Turner, Martin R; Al-Chalabi, Ammar

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurological syndrome in which motor neurons degenerate relentlessly. Although the site of onset and the rate of spread have been studied extensively, little is known about whether focal as opposed to diffuse disease affects prognosis. We therefore tested the hypothesis that regionality of disease burden is a prognostic factor in ALS. We analysed clinical data from two large multicentre, longitudinal trials. Regionality was defined as the difference in progression rates in three domains as measured by the revised ALS Functional Rating Scale, omitting the respiratory domain from analysis. We used death by trial end as the outcome variable and tested this by logistic regression against predictor variables including regionality and overall rate of disease progression. There were 561 patients. Regionality of disease was independently associated with significantly higher chance of death by study end (odds ratio most diffuse against most focal category 0.354 (0.191, 0.657), p = 0.001), with a direct relationship between degree of regionality and odds of death. We have shown using clinical trial data that focal disease is associated with a worse prognosis in ALS. Measures of regionality warrant further independent consideration in the development of future prognostic models.

  12. Dissociated lower limb muscle involvement in amyotrophic lateral sclerosis.

    PubMed

    Simon, Neil G; Lee, Michael; Bae, Jong Seok; Mioshi, Eneida; Lin, Cindy S-Y; Pfluger, Casey M; Henderson, Robert D; Vucic, Steve; Swash, Michael; Burke, David; Kiernan, Matthew C

    2015-06-01

    It has been suggested that corticomotoneuronal drive to ankle dorsiflexors is greater than to ankle plantar flexor muscles, despite the finding that plantar flexors are no less active than TA during walking and standing. The present study was undertaken to determine whether there was differential involvement of distal lower limb muscles in amyotrophic lateral sclerosis (ALS), to elucidate pathophysiological mechanisms of selective muscle involvement. Prospective studies were undertaken in 52 ALS patients, including clinical assessment, disease staging (revised ALS functional rating scale), Medical Research Council sum score, and a scale of upper motor neurone (UMN) dysfunction. Motor unit number estimates (MUNE) and compound muscle action potentials (CMAP) from ankle dorsiflexors and plantar flexors were used to provide objective measures. A novel 'split leg index' was calculated as follows: SLI = CMAPDF ÷ CMAPPF. In ALS, there was significantly greater reduction of MUNE and CMAP amplitude recorded from plantar flexors when compared to dorsiflexors, suggesting preferential involvement of plantar flexor muscles, underpinning a 'split leg' appearance. The SLI correlated with clinical plantar flexor strength (R= -0.56, p < 0.001). In no patient did the SLI suggest preferential dorsiflexor involvement. In subgroup analyses, mean SLI was greatest in lower limb-onset ALS. In conclusion, the present study has established dissociated involvement of muscles acting around the ankle in ALS. We suggest this reflects underlying differences in cortical, descending or local spinal modulation of these muscles.

  13. Smads as muscle biomarkers in amyotrophic lateral sclerosis

    PubMed Central

    Si, Ying; Cui, Xianqin; Kim, Soojin; Wians, Robert; Sorge, Robert; Oh, Shin J; Kwan, Thaddeus; AlSharabati, Mohammad; Lu, Liang; Claussen, Gwen; Anderson, Tina; Yu, Shaohua; Morgan, Dylan; Kazamel, Mohamed; King, Peter H

    2014-01-01

    Objective To identify molecular signatures in muscle from patients with amyotrophic lateral sclerosis (ALS) that could provide insight into the disease process and serve as biomarkers. Methods RNA sequencing was performed on ALS and control muscle samples to identify Smad family members as potential markers of disease. Validation studies were performed in a cohort of 27 ALS patients and 33 controls. The markers were assessed in the G93A superoxide dismutase (SOD)1 mouse at different stages of disease and in a model of sciatic nerve injury. Results Smad8, and to a lesser extent Smad1 and 5, mRNAs were significantly elevated in human ALS muscle samples. The markers displayed a remarkably similar pattern in the G93A SOD1 mouse model of ALS with increases detected at preclinical stages. Expression at the RNA and protein levels as well as protein activation (phosphorylation) significantly increased with disease progression in the mouse. The markers were also elevated to a lesser degree in gastrocnemius muscle following sciatic nerve injury, but then reverted to baseline during the muscle reinnervation phase. Interpretation These data indicate that Smad1, 5, 8 mRNA and protein levels, as well as Smad phosphorylation, are elevated in ALS muscle and could potentially serve as markers of disease progression or regression. PMID:25493269

  14. Meta-analysis of social cognition in amyotrophic lateral sclerosis.

    PubMed

    Bora, Emre

    2017-03-01

    Amyotrophic lateral sclerosis (ALS) is associated with executive dysfunction and behavioural impairment. Recent studies suggested that social cognitive deficits might also be a prominent feature of ALS. Current meta-analysis aimed to summarize available evidence for deficits in social cognition including theory of mind (ToM) and emotion recognition in ALS. In this meta-analysis of 15 studies, facial emotion recognition and ToM performances of 389 patients with ALS and 471 healthy controls were compared. ALS was associated with significant impairments with medium effect sizes in ToM (d = .65) and facial emotion recognition (d = .69). Among individual emotions recognition of disgust and surprise were particularly impaired. Deficits in perspective taking (d = .73) aspects of ToM (ToM-PT) was more pronounced in comparison to decoding (d = .28) aspects of ToM (ToM-decoding). The severity of social cognitive impairment was similar to level of executive dysfunction and there was a significant relationship between social cognition and executive dysfunction. Deficits in social cognition are part of the cognitive phenotype of ALS.

  15. c-jun-N-Terminal Kinase (JNK) for the Treatment of Amyotrophic Lateral Sclerosis

    DTIC Science & Technology

    2013-10-01

    Treatment of Amyotrophic Lateral Sclerosis ” PRINCIPAL INVESTIGATOR: Dr. Philip LoGrasso CONTRACTING ORGANIZATION: The Scripps Research... Lateral Sclerosis ” 5a. CONTRACT NUMBER W81XWH-12-1-0431 5b. GRANT NUMBER W81XWH-12-1-0431 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Philip...Annual 3. DATES COVERED 30September2012-29September2013 4. TITLE AND SUBTITLE “c-jun-N-Terminal Kinase (JNK) for the Treatment of Amyotrophic

  16. c-jun-N-Terminal Kinase (JNK) for the Treatment of Amyotrophic Lateral Sclerosis

    DTIC Science & Technology

    2015-03-01

    1 AWARD NUMBER: W81XWH-12-1-0431 TITLE: “c-jun-N- Terminal Kinase (JNK) for the Treatment of Amyotrophic Lateral Sclerosis” PRINCIPAL...TITLE AND SUBTITLE “c-jun-N- Terminal Kinase (JNK) for the Treatment of Amyotrophic Lateral Scelerosis” 5a. CONTRACT NUMBER 5b. GRANT NUMBER...ABSTRACT Abstract: 250 aminopyrazoles, a new class of c-jun-N- terminal kinase (JNK) inhibitors, have been synthesized and the biochemical IC50 has

  17. Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis

    PubMed Central

    Liu, Kevin X.; Edwards, Benjamin; Lee, Sheena; Finelli, Mattéa J.; Davies, Ben

    2015-01-01

    Amyotrophic lateral sclerosis is a devastating neurodegenerative disorder characterized by the progressive loss of spinal motor neurons. While the aetiological mechanisms underlying the disease remain poorly understood, oxidative stress is a central component of amyotrophic lateral sclerosis and contributes to motor neuron injury. Recently, oxidation resistance 1 (OXR1) has emerged as a critical regulator of neuronal survival in response to oxidative stress, and is upregulated in the spinal cord of patients with amyotrophic lateral sclerosis. Here, we tested the hypothesis that OXR1 is a key neuroprotective factor during amyotrophic lateral sclerosis pathogenesis by crossing a new transgenic mouse line that overexpresses OXR1 in neurons with the SOD1G93A mouse model of amyotrophic lateral sclerosis. Interestingly, we report that overexpression of OXR1 significantly extends survival, improves motor deficits, and delays pathology in the spinal cord and in muscles of SOD1G93A mice. Furthermore, we find that overexpression of OXR1 in neurons significantly delays non-cell-autonomous neuroinflammatory response, classic complement system activation, and STAT3 activation through transcriptomic analysis of spinal cords of SOD1G93A mice. Taken together, these data identify OXR1 as the first neuron-specific antioxidant modulator of pathogenesis and disease progression in SOD1-mediated amyotrophic lateral sclerosis, and suggest that OXR1 may serve as a novel target for future therapeutic strategies. PMID:25753484

  18. Microstructural Correlates of Emotional Attribution Impairment in Non-Demented Patients with Amyotrophic Lateral Sclerosis

    PubMed Central

    Cerami, Chiara; Dodich, Alessandra; Canessa, Nicola; Iannaccone, Sandro; Corbo, Massimo; Lunetta, Christian; Falini, Andrea; Cappa, Stefano F.

    2016-01-01

    Impairments in the ability to recognize and attribute emotional states to others have been described in amyotrophic lateral sclerosis patients and linked to the dysfunction of key nodes of the emotional empathy network. Microstructural correlates of such disorders are still unexplored. We investigated the white-matter substrates of emotional attribution deficits in a sample of amyotrophic lateral sclerosis patients without cognitive decline. Thirteen individuals with either probable or definite amyotrophic lateral sclerosis and 14 healthy controls were enrolled in a Diffusion Tensor Imaging study and administered the Story-based Empathy Task, assessing the ability to attribute mental states to others (i.e., Intention and Emotion attribution conditions). As already reported, a significant global reduction of empathic skills, mainly driven by a failure in Emotion Attribution condition, was found in amyotrophic lateral sclerosis patients compared to healthy subjects. The severity of this deficit was significantly correlated with fractional anisotropy along the forceps minor, genu of corpus callosum, right uncinate and inferior fronto-occipital fasciculi. The involvement of frontal commissural fiber tracts and right ventral associative fronto-limbic pathways is the microstructural hallmark of the impairment of high-order processing of socio-emotional stimuli in amyotrophic lateral sclerosis. These results support the notion of the neurofunctional and neuroanatomical continuum between amyotrophic lateral sclerosis and frontotemporal dementia. PMID:27513746

  19. Microstructural Correlates of Emotional Attribution Impairment in Non-Demented Patients with Amyotrophic Lateral Sclerosis.

    PubMed

    Crespi, Chiara; Cerami, Chiara; Dodich, Alessandra; Canessa, Nicola; Iannaccone, Sandro; Corbo, Massimo; Lunetta, Christian; Falini, Andrea; Cappa, Stefano F

    2016-01-01

    Impairments in the ability to recognize and attribute emotional states to others have been described in amyotrophic lateral sclerosis patients and linked to the dysfunction of key nodes of the emotional empathy network. Microstructural correlates of such disorders are still unexplored. We investigated the white-matter substrates of emotional attribution deficits in a sample of amyotrophic lateral sclerosis patients without cognitive decline. Thirteen individuals with either probable or definite amyotrophic lateral sclerosis and 14 healthy controls were enrolled in a Diffusion Tensor Imaging study and administered the Story-based Empathy Task, assessing the ability to attribute mental states to others (i.e., Intention and Emotion attribution conditions). As already reported, a significant global reduction of empathic skills, mainly driven by a failure in Emotion Attribution condition, was found in amyotrophic lateral sclerosis patients compared to healthy subjects. The severity of this deficit was significantly correlated with fractional anisotropy along the forceps minor, genu of corpus callosum, right uncinate and inferior fronto-occipital fasciculi. The involvement of frontal commissural fiber tracts and right ventral associative fronto-limbic pathways is the microstructural hallmark of the impairment of high-order processing of socio-emotional stimuli in amyotrophic lateral sclerosis. These results support the notion of the neurofunctional and neuroanatomical continuum between amyotrophic lateral sclerosis and frontotemporal dementia.

  20. Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis.

    PubMed

    Liu, Kevin X; Edwards, Benjamin; Lee, Sheena; Finelli, Mattéa J; Davies, Ben; Davies, Kay E; Oliver, Peter L

    2015-05-01

    Amyotrophic lateral sclerosis is a devastating neurodegenerative disorder characterized by the progressive loss of spinal motor neurons. While the aetiological mechanisms underlying the disease remain poorly understood, oxidative stress is a central component of amyotrophic lateral sclerosis and contributes to motor neuron injury. Recently, oxidation resistance 1 (OXR1) has emerged as a critical regulator of neuronal survival in response to oxidative stress, and is upregulated in the spinal cord of patients with amyotrophic lateral sclerosis. Here, we tested the hypothesis that OXR1 is a key neuroprotective factor during amyotrophic lateral sclerosis pathogenesis by crossing a new transgenic mouse line that overexpresses OXR1 in neurons with the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Interestingly, we report that overexpression of OXR1 significantly extends survival, improves motor deficits, and delays pathology in the spinal cord and in muscles of SOD1(G93A) mice. Furthermore, we find that overexpression of OXR1 in neurons significantly delays non-cell-autonomous neuroinflammatory response, classic complement system activation, and STAT3 activation through transcriptomic analysis of spinal cords of SOD1(G93A) mice. Taken together, these data identify OXR1 as the first neuron-specific antioxidant modulator of pathogenesis and disease progression in SOD1-mediated amyotrophic lateral sclerosis, and suggest that OXR1 may serve as a novel target for future therapeutic strategies.

  1. Amyotrophic Lateral Sclerosis 2-Deficiency Leads to Neuronal Degeneration in Amyotrophic Lateral Sclerosis through Altered AMPA Receptor Trafficking

    PubMed Central

    Lai, Chen; Xie, Chengsong; McCormack, Stefanie G.; Chiang, Hsueh-Cheng; Michalak, Marta K.; Lin, Xian; Chandran, Jayanth; Shim, Hoon; Shimoji, Mika; Cookson, Mark R.; Huganir, Richard L.; Rothstein, Jeffrey D.; Price, Donald L.; Wong, Philip C.; Martin, Lee J.; Zhu, J. Julius; Cai, Huaibin

    2008-01-01

    Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease is caused by a selective loss of motor neurons. One form of juvenile onset autosomal recessive ALS (ALS2) has been linked to the loss of function of the ALS2 gene. The pathogenic mechanism of ALS2-deficiency, however, remains unclear. To further understand the function of alsin that is encoded by the full-length ALS2 gene, we screened proteins interacting with alsin. Here, we report that alsin interacted with glutamate receptor interacting protein 1 (GRIP1) both in vitro and in vivo, and colocalized with GRIP1 in neurons. In support of the physiological interaction between alsin and GRIP1, the subcellular distribution of GRIP1 was altered in ALS2-/- spinal motor neurons, which correlates with a significant reduction of AMPA-type glutamate receptor subunit 2 (GluR2) at the synaptic/cell surface of ALS2-/- neurons. The decrease of calcium-impermeable GluR2-containing AMPA receptors at the cell/synaptic surface rendered ALS2-/- neurons more susceptible to glutamate receptor-mediated neurotoxicity. Our findings reveal a novel function of alsin in AMPA receptor trafficking and provide a novel pathogenic link between ALS2-deficiency and motor neuron degeneration, suggesting a protective role of alsin in maintaining the survival of motor neurons. PMID:17093100

  2. Identification of Epigenetically Altered Genes in Sporadic Amyotrophic Lateral Sclerosis

    PubMed Central

    Bender, Diane E.; Delaney, Colin E.; Cataldo, Michael D.; Smith, Andrea L.; Yung, Raymond; Ruden, Douglas M.; Callaghan, Brian C.; Feldman, Eva L.

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a terminal disease involving the progressive degeneration of motor neurons within the motor cortex, brainstem and spinal cord. Most cases are sporadic (sALS) with unknown causes suggesting that the etiology of sALS may not be limited to the genotype of patients, but may be influenced by exposure to environmental factors. Alterations in epigenetic modifications are likely to play a role in disease onset and progression in ALS, as aberrant epigenetic patterns may be acquired throughout life. The aim of this study was to identify epigenetic marks associated with sALS. We hypothesize that epigenetic modifications may alter the expression of pathogenesis-related genes leading to the onset and progression of sALS. Using ELISA assays, we observed alterations in global methylation (5 mC) and hydroxymethylation (5 HmC) in postmortem sALS spinal cord but not in whole blood. Loci-specific differentially methylated and expressed genes in sALS spinal cord were identified by genome-wide 5mC and expression profiling using high-throughput microarrays. Concordant direction, hyper- or hypo-5mC with parallel changes in gene expression (under- or over-expression), was observed in 112 genes highly associated with biological functions related to immune and inflammation response. Furthermore, literature-based analysis identified potential associations among the epigenes. Integration of methylomics and transcriptomics data successfully revealed methylation changes in sALS spinal cord. This study represents an initial identification of epigenetic regulatory mechanisms in sALS which may improve our understanding of sALS pathogenesis for the identification of biomarkers and new therapeutic targets. PMID:23300739

  3. Systemic inflammatory response and neuromuscular involvement in amyotrophic lateral sclerosis

    PubMed Central

    Lu, Ching-Hua; Allen, Kezia; Oei, Felicia; Leoni, Emanuela; Kuhle, Jens; Tree, Timothy; Fratta, Pietro; Sharma, Nikhil; Sidle, Katie; Howard, Robin; Orrell, Richard; Fish, Mark; Greensmith, Linda; Pearce, Neil; Gallo, Valentina

    2016-01-01

    Objective: To evaluate the combined blood expression of neuromuscular and inflammatory biomarkers as predictors of disease progression and prognosis in amyotrophic lateral sclerosis (ALS). Methods: Logistic regression adjusted for markers of the systemic inflammatory state and principal component analysis were carried out on plasma levels of creatine kinase (CK), ferritin, and 11 cytokines measured in 95 patients with ALS and 88 healthy controls. Levels of circulating biomarkers were used to study survival by Cox regression analysis and correlated with disease progression and neurofilament light chain (NfL) levels available from a previous study. Cytokines expression was also tested in blood samples longitudinally collected for up to 4 years from 59 patients with ALS. Results: Significantly higher levels of CK, ferritin, tumor necrosis factor (TNF)–α, and interleukin (IL)–1β, IL-2, IL-8, IL-12p70, IL-4, IL-5, IL-10, and IL-13 and lower levels of interferon (IFN)–γ were found in plasma samples from patients with ALS compared to controls. IL-6, TNF-α, and IFN-γ were the most highly regulated markers when all explanatory variables were jointly analyzed. High ferritin and IL-2 levels were predictors of poor survival. IL-5 levels were positively correlated with CK, as was TNF-α with NfL. IL-6 was strongly associated with CRP levels and was the only marker showing increasing expression towards end-stage disease in the longitudinal analysis. Conclusions: Neuromuscular pathology in ALS involves the systemic regulation of inflammatory markers mostly active on T-cell immune responses. Disease stratification based on the prognostic value of circulating inflammatory markers could improve clinical trials design in ALS. PMID:27308305

  4. Apelin Deficiency Accelerates the Progression of Amyotrophic Lateral Sclerosis

    PubMed Central

    Kasai, Atsushi; Kinjo, Toshihiko; Ishihara, Rie; Sakai, Ikumi; Ishimaru, Yuki; Yoshioka, Yasuhiro; Yamamuro, Akiko; Ishige, Kumiko; Ito, Yoshihisa; Maeda, Sadaaki

    2011-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Recent studies have implicated that chronic hypoxia and insufficient vascular endothelial growth factor (VEGF)-dependent neuroprotection may lead to the degeneration of motor neurons in ALS. Expression of apelin, an endogenous ligand for the G protein-coupled receptor APJ, is regulated by hypoxia. In addition, recent reports suggest that apelin protects neurons against glutamate-induced excitotoxicity. Here, we examined whether apelin is an endogenous neuroprotective factor using SOD1G93A mouse model of ALS. In mouse CNS tissues, the highest expressions of both apelin and APJ mRNAs were detected in spinal cord. APJ immunoreactivity was observed in neuronal cell bodies located in gray matter of spinal cord. Although apelin mRNA expression in the spinal cord of wild-type mice was not changed from 4 to 18 weeks age, that of SOD1G93A mice was reduced along with the paralytic phenotype. In addition, double mutant apelin-deficient and SOD1G93A displayed the disease phenotypes earlier than SOD1G93A littermates. Immunohistochemical observation revealed that the number of motor neurons was decreased and microglia were activated in the spinal cord of the double mutant mice, indicating that apelin deficiency pathologically accelerated the progression of ALS. Furthermore, we showed that apelin enhanced the protective effect of VEGF on H2O2-induced neuronal death in primary neurons. These results suggest that apelin/APJ system in the spinal cord has a neuroprotective effect against the pathogenesis of ALS. PMID:21887354

  5. Amyotrophic lateral sclerosis among cross-country skiers in Sweden.

    PubMed

    Fang, Fang; Hållmarker, Ulf; James, Stefan; Ingre, Caroline; Michaëlsson, Karl; Ahlbom, Anders; Feychting, Maria

    2016-03-01

    A highly increased risk of amyotrophic lateral sclerosis (ALS) has been suggested among professional athletes. We aimed to examine whether long distance cross-country skiers have also a higher risk of ALS and whether the increased risk was modified by skiing performance. We followed 212,246 cross-country skiers in the Swedish Vasaloppet cohort and a random selection of 508,176 general Swedes not participating in the Vasaloppet during 1989-2010. The associations between cross-country skiing as well as skiing performance (i.e., type of race, finishing time and number of races) and the consequent risk of ALS were estimated through hazard ratios (HRs) derived from Cox model. During the study, 39 cases of ALS were ascertained among the skiers. The fastest skiers (100-150% of winner time) had more than fourfold risk of ALS (HR 4.31, 95% confidence interval [CI] 1.78-10.4), as compared to skiers that finished at >180% of winner time. Skiers who participated >4 races during this period had also a higher risk (HR 3.13, 95% CI 1.37-7.17) than those participated only one race. When compared to the non-skiers, the fastest skiers still had a higher risk (HR 2.08, 95% CI 1.12-3.84), as skiers who had >4 races (HR 1.88, 95% CI 1.05-3.35), but those finishing at >180% of winner time had a lower risk (HR 0.46, 95% CI 0.24-0.87). In conclusion, long distance cross-country skiing is associated with a higher risk of ALS, but only among the best skiers; recreational skiers appear to have a largely reduced risk.

  6. [Respiratory domain of revised amyotrophic lateral sclerosis. Functional Rating Scale].

    PubMed

    Lima, Sandra E; Pessolano, Fernando A; Monteiro, Sergio G; De Vito, Eduardo L

    2009-01-01

    Virtually all patients with amyotrophic lateral sclerosis will complain of dyspnea, which is perhaps the most distressing symptom of this devastating disease. The objective was to correlate respiratory domain of ALSFRS-R with forced vital capacity and maximal static pressures in the mouth. We designed a prospective study in 20 consecutive patients without dyspnea during 24 months. The global decline of ALSFRS-R was from 34.3 +/- 10.3 to 22.1 +/- 8.0 (p = 0.0325), the contribution of respiratory domain was irrelevant. Those who referred dyspnea (n: 12), forced vital capacity fell 41 +/- 21% of the initial value but with similar value of fall (46 +/- 23%) 8 patients did not referred dyspnea. Total score of ALSFRS-R correlated with forced vital capacity (litres), r: 0.73, p = 0.0016 and maximal inspiratory pressure (cm H2O), r: 0.84, p = 0.0038, but the fall of the forced vital capacity (%) did not correlate with dyspnea (r(s): 0.23, p = 0.1400). There was a moderate correlation between dyspnea and maximal inspiratory pressure (%), r(s): 0.58, p = 0.0300 and between dyspnea and maximal expiratory pressure (%), r(s): 0.49, p = 0.0400. We concluded that the respiratory functional deterioration could not be predicted using respiratory domain of ALSFRS-R. This suggests that respiratory domain of this scale does not replace to respiratory function testing measurements and, due to the respiratory insufficiency could not be clinically evident; performing pulmonary function tests provides an objective view and permit to make anticipatory actions.

  7. Alzheimer disease and amyotrophic lateral sclerosis: An etiopathogenic connection

    PubMed Central

    Wang, Xiaochuan; Blanchard, Julie; Grundke-Iqbal, Inge; Wegiel, Jerzy; Deng, Han-Xiang; Siddique, Teepu; Iqbal, Khalid

    2013-01-01

    The etiopathogenesis of neither the sporadic form of Alzheimer disease (AD) nor of amyotrophic lateral sclerosis (ALS) are well understood. The activity of protein phosphatase-2A (PP2A), which regulates the phosphorylation of tau and neurofilaments, is negatively regulated by the myeloid leukemia-associated protein SET, also known as inhibitor-2 of PP2A, I2PP2A. In AD brain PP2A activity is compromised, probably because I2PP2A is overexpressed and is selectively cleaved at asparagine 175 into an N-terminal fragment, I2NTF, and a C-terminal fragment, I2CTF, and both fragments inhibit PP2A. Here we analyzed the spinal cords from ALS and control cases for I2PP2A cleavage and PP2A activity. As observed in AD brain, we found a selective increase in the cleavage of I2PP2A into I2NTF and I2CTF and inhibition of the activity and not the expression of PP2A in the spinal cords of ALS cases. To test the hypothesis that both AD and ALS could be triggered by I2CTF, a cleavage product of I2PP2A, we transduced by intracerebroventricular injections newborn rats with adeno-associated virus serotype 1 (AAV1) containing human I2CTF. AAV1- I2CTF produced reference memory impairment and tau pathology, and intraneuronal accumulation of Aβ by 5–8 months, and motor deficit and hyperphosphorylation and proliferation of neurofilaments, tau and TDP-43 pathologies, degeneration and loss of motor neurons and axons in the spinal cord by 10–14 months in rats. These findings suggest a previously undiscovered etiopathogenic relationship between sporadic forms of AD and ALS that is linked to I2PP2A and the potential of I2PP2A-based therapeutics for these diseases. PMID:24136402

  8. Prospective study of chemical exposures and amyotrophic lateral sclerosis

    PubMed Central

    Weisskopf, MG; Morozova, N; O'Reilly, EJ; McCullough, ML; Calle, EE; Thun, MJ; Ascherio, A

    2009-01-01

    Background Although environmental toxins, including pesticides, are suspected of contributing to the risk of amyotrophic lateral sclerosis (ALS), no data exist from large prospective investigations. This study assessed the association between exposure to chemicals and risk of ALS in a prospective cohort study. Methods We prospectively assessed the relation between self-report of regular exposure to 11 different chemical classes or X-rays and ALS mortality among over 1 million participants in the American Cancer Society's Cancer Prevention Study II. Follow-up from 1989 through 2004 identified 617 deaths from ALS among men and 539 among women. We calculated adjusted rate ratios (RR) using Cox proportional hazards. Results The RR for ALS mortality among individuals exposed to pesticides/herbicides compared to the unexposed was 1.07 (95% confidence interval (CI): 0.79-1.44), but somewhat higher after excluding those with missing duration of pesticides exposure (RR: 1.44; 95% CI: 0.89-2.31; p=0.14). A non-significant increase in ALS mortality was found among individuals who reported exposure to formaldehyde (RR: 1.34; 95% CI: 0.93-1.92). Excluding those with missing duration of formaldehyde exposure, the RR was 2.47 (95% CI: 1.58-3.86), and there was a strongly significant dose-response relation with increasing years of exposure (p-trend=0.0004). Conclusions We found little evidence for an association between pesticides/herbicide exposure and ALS. In contrast, we found evidence suggesting an increased risk of ALS with formaldehyde exposure. Because of the longitudinal design, this result is unlikely to be due to bias, but it should nevertheless be interpreted cautiously and needs to be independently verified. PMID:19372290

  9. PHOSPHORYLATED TAU: CANDIDATE BIOMARKER FOR AMYOTROPHIC LATERAL SCLEROSIS

    PubMed Central

    Grossman, Murray; Elman, Lauren; McCluskey, Leo; McMillan, Corey T.; Boller, Ashley; Powers, John; Rascovsky, Katya; Hu, William; Shaw, Les; Irwin, David J.; Lee, Virginia M.-Y.; Trojanowski, John Q.

    2014-01-01

    IMPORTANCE An increasingly varied clinical spectrum of cases with amyotrophic lateral sclerosis (ALS) has been identified, and objective criteria for clinical trial eligibility is necessary. OBJECTIVE We sought to develop a cerebrospinal fluid (CSF) biomarker sensitive and specific for the diagnosis of ALS. DESIGN Case-control study. SETTING Academic medical center. PARTICIPANTS 51 individuals with ALS and 23 individuals with a disorder associated with a four-repeat tauopathy (4R-tau). MAIN OUTCOME MEASURE CSF level of tau phosophorylated at threonine 181 (ptau), and ratio of ptau to total tau (ttau). RESULTS Using a cross-validation prediction procedure, we found significantly reduced CSF levels of ptau and ptau:ttau in ALS relative to 4R-tau and to controls. In the validation cohort, the receiver operating characteristic area under the curve for the ptau:ttau ratio was 0.916, and the comparison of ALS to 4R-tau showed sensitivity=92% and specificity=91.7%. Correct classification based on low CSF ptau:ttau was confirmed in 18 (85.7%) of 21 cases with autopsy-proven or genetically-determined disease. In patients with available measures, ptau:ttau in ALS correlated with clinical measures of disease severity such as Mini Mental State Exam (n=51) and ALS Functional Rating Scale-Revised (n=42), and regression analyses related ptau:ttau to MRI (n=10) evidence of disease in the corticospinal tract and white matter projections involving prefrontal cortex. CONCLUSIONS AND RELEVANCE CSF ptau:ttau may be a candidate biomarker to provide objective support for the diagnosis of ALS. PMID:24492862

  10. Laryngeal Sensitivity in Patients with Amyotrophic Lateral Sclerosis

    PubMed Central

    Ruoppolo, Giovanni; Onesti, Emanuela; Gori, Maria Cristina; Schettino, Ilenia; Frasca, Vittorio; Biasiotta, Antonella; Giordano, Carla; Ceccanti, Marco; Cambieri, Chiara; Greco, Antonio; Buonopane, Costantino Eugenio; Cruccu, Giorgio; De Vincentiis, Marco; Inghilleri, Maurizio

    2016-01-01

    Recent studies have shown the involvement of the sensory nervous system in patients with amyotrophic lateral sclerosis (ALS). The aim of our study was to investigate the correlation between the laryngeal sensitivity deficit and the type of ALS onset (bulbar or spinal) in a large series of 114 consecutive ALS patients. Participants were subdivided into two groups, bulbar and spinal ALS, according to the clinical onset of disease and submitted to a clinical and instrumental evaluation of swallowing, including a fiber-optic endoscopic evaluation of swallowing with sensory testing. Dysphagia severity was scored using the Penetration–Aspiration Scale (PAS) and the Pooling score (P-score). In addition, three patients with laryngeal sensitivity deficit were submitted to a laryngeal biopsy to assess the status of the sensory innervation. All patients showed a normal glottal closure during phonation and volitional cough. Fifty-six subjects (49%), 14 spinal- and 42 bulbar-onset ALS, showed dysphagia at the first clinical observation (PAS score >1; P-score >5). Dysphagia resulted more frequently in bulbar-onset ALS (P < 0.01). Thirty-eight (33%) patients had a sensory deficit of the larynx. The sensory deficit of the larynx was significantly more frequent in bulbar-onset ALS (P < 0.01). The sensory deficit of the larynx among dysphagic patients was also significantly more frequent in bulbar-onset ALS (P = 0.02). Several abnormalities were found in all three subjects who underwent a laryngeal biopsy: in one patient, no intraepidermal fiber was found; in the other two, the fibers showed morphological changes. Our observations are important to consider for assessment and management of dysphagia in patients with ALS. PMID:27965622

  11. Alzheimer disease and amyotrophic lateral sclerosis: an etiopathogenic connection.

    PubMed

    Wang, Xiaochuan; Blanchard, Julie; Grundke-Iqbal, Inge; Wegiel, Jerzy; Deng, Han-Xiang; Siddique, Teepu; Iqbal, Khalid

    2014-02-01

    The etiopathogenesis of neither the sporadic form of Alzheimer disease (AD) nor of amyotrophic lateral sclerosis (ALS) is well understood. The activity of protein phosphatase-2A (PP2A), which regulates the phosphorylation of tau and neurofilaments, is negatively regulated by the myeloid leukemia-associated protein SET, also known as inhibitor-2 of PP2A, I2(PP2A). In AD brain, PP2A activity is compromised, probably because I2(PP2A) is overexpressed and is selectively cleaved at asparagine 175 into an N-terminal fragment, I2NTF, and a C-terminal fragment, I2CTF, and both fragments inhibit PP2A. Here, we analyzed the spinal cords from ALS and control cases for I2(PP2A) cleavage and PP2A activity. As observed in AD brain, we found a selective increase in the cleavage of I2(PP2A) into I2NTF and I2CTF and inhibition of the activity and not the expression of PP2A in the spinal cords of ALS cases. To test the hypothesis that both AD and ALS could be triggered by I2CTF, a cleavage product of I2(PP2A), we transduced by intracerebroventricular injections newborn rats with adeno-associated virus serotype 1 (AAV1) containing human I2CTF. AAV1-I2CTF produced reference memory impairment and tau pathology, and intraneuronal accumulation of Aβ by 5-8 months, and motor deficit and hyperphosphorylation and proliferation of neurofilaments, tau and TDP-43 pathologies, degeneration and loss of motor neurons and axons in the spinal cord by 10-14 months in rats. These findings suggest a previously undiscovered etiopathogenic relationship between sporadic forms of AD and ALS that is linked to I2(PP2A) and the potential of I2(PP2A)-based therapeutics for these diseases.

  12. Noninvasive ventilation reduces energy expenditure in amyotrophic lateral sclerosis

    PubMed Central

    2014-01-01

    Background Amyotrophic lateral sclerosis (ALS) leads to chronic respiratory failure. Diaphragmatic dysfunction, a major driver of dyspnea and mortality, is associated with a shift of the burden of ventilation to extradiaphragmatic inspiratory muscles, including neck muscles. Besides, energy expenditure is often abnormally high in ALS, and this is associated with a negative prognostic value. We hypothesized that noninvasive ventilation (NIV) would relieve inspiratory neck muscles and reduce resting energy expenditure (REE). Methods Using indirect calorimetry, we measured REE during spontaneous breathing (REESB) and NIV (REENIV) in 16 ALS patients with diaphragmatic dysfunction, during the first 3 months of NIV. Measured values were compared with predicted REE (REEpred)(Harris-Benedict equation). Results NIV abolished inspiratory neck muscle activity. Even though our patients were not hypermetabolic, on the contrary, with a REESB that was lower than REEpred (average 11%), NIV did reduce energy expenditure. Indeed, median REENIV, in this population with a mean body mass index of 21.4 kg.m-2, was 1149 kcal/24 h [interquartile 970-1309], lower than REESB (1197 kcal/24 h, 1054-1402; mean difference 7%; p = 0.03, Wilcoxon). REESB and REENIV were correlated with forced vital capacity and maximal inspiratory pressure. Conclusions NIV can reduce energy expenditure in ALS patients probably by alleviating the ventilatory burden imposed on inspiratory neck muscles to compensate diaphragm weakness. It remains to be elucidated whether or not, in which population, and to what extent, NIV can be beneficial in ALS through the corresponding reduction in energy expenditure. PMID:24507664

  13. Glial activation colocalizes with structural abnormalities in amyotrophic lateral sclerosis

    PubMed Central

    Alshikho, Mohamad J.; Zürcher, Nicole R.; Loggia, Marco L.; Cernasov, Paul; Chonde, Daniel B.; Izquierdo Garcia, David; Yasek, Julia E.; Akeju, Oluwaseun; Catana, Ciprian; Rosen, Bruce R.; Cudkowicz, Merit E.

    2016-01-01

    Objective: In this cross-sectional study, we aimed to evaluate brain structural abnormalities in relation to glial activation in the same cohort of participants. Methods: Ten individuals with amyotrophic lateral sclerosis (ALS) and 10 matched healthy controls underwent brain imaging using integrated MR/PET and the radioligand [11C]-PBR28. Diagnosis history and clinical assessments including Upper Motor Neuron Burden Scale (UMNB) were obtained from patients with ALS. Diffusion tensor imaging (DTI) analyses including tract-based spatial statistics and tractography were applied. DTI metrics including fractional anisotropy (FA) and diffusivities (mean, axial, and radial) were measured in regions of interest. Cortical thickness was assessed using surface-based analysis. The locations of structural changes, measured by DTI and the areas of cortical thinning, were compared to regional glial activation measured by relative [11C]-PBR28 uptake. Results: In this cohort of individuals with ALS, reduced FA and cortical thinning colocalized with regions demonstrating higher radioligand binding. [11C]-PBR28 binding in the left motor cortex was correlated with FA (r = −0.68, p < 0.05) and cortical thickness (r = −0.75, p < 0.05). UMNB was correlated with glial activation (r = +0.75, p < 0.05), FA (r = −0.77, p < 0.05), and cortical thickness (r = −0.75, p < 0.05) in the motor cortex. Conclusions: Increased uptake of the glial marker [11C]-PBR28 colocalizes with changes in FA and cortical thinning. This suggests a link between disease mechanisms (gliosis and inflammation) and structural changes (cortical thinning and white and gray matter changes). In this multimodal neuroimaging work, we provide an in vivo model to investigate the pathogenesis of ALS. PMID:27837005

  14. Is amyotrophic lateral sclerosis a primary astrocytic disease?

    PubMed

    Sica, Roberto E

    2012-12-01

    Amyotrophic lateral sclerosis (ALS) is thought to be due to primary involvement of motor neurons. Pathogenic mechanisms underlying its appearance are relatively well known and include inflammation, excitotoxicity, oxidative stress, endoplasmic reticulum stress, protein damage, genetic abnormalities and type of neuronal death. Although these processes have been investigated in detail in the past two decades none of them appear to be the cause of the illness. In addition several possible environmental agents have been investigated but the results, in every case, were conflicting and therefore inconclusive. However, since the motor neurons display the features of apoptosis in this illness, the possibility remains that the motor neurons die because of a hostile environment, one that is unable to sustain their health, rather than being directly targeted themselves. The above considerations lead to an examination of astrocytes, for these cells play a key role in controlling the environment of neurons. It is known that astrocytes are exquisitely plastic, adapting their metabolism and behaviour to the needs of the neurons they contact. Each population of astrocytes is therefore unique and, were one to be adversely affected at the start of a disease process, the consequences would extend to the neurons that it normally chaperoned. The disturbed relationship might involve inappropriate production and secretion of astrocytic neurotransmitters, defective transport of glutamate and impaired trophic and metabolic support of the motor neurons. In order to explain the spread of weakness and pyramidal signs in ALS patients, which is very often from one group of muscles to a neighbouring one, it is postulated that, within the spinal cord, the brainstem and the motor cortex, the disease-causing process is also spreading-in this case, from one group of astrocytes to its neighbours. A misfolded protein, possibly a prion-like protein, would be a candidate for this type of transmission.

  15. Lockhart Clarke’s contribution to the description of amyotrophic lateral sclerosis

    PubMed Central

    Turner, Martin R.; Swash, Michael; Ebers, George C.

    2011-01-01

    The definition of the clinicopathological entity of amyotrophic lateral sclerosis evolved over half a century. Although the definitive term amyotrophic lateral sclerosis that acknowledged both upper and lower motor neuron involvement was attributed to Jean-Martin Charcot in 1874, his initial case was published nearly a decade earlier; and it is accepted that, from at least the 1830s, several others (including Charles Bell, François-Amilcar Aran and Jean Cruveilhier) had already recognized a progressive lower motor neuron-only syndrome within a broader, clinically-defined group of disorders, termed progressive muscular atrophy. Although William Gowers first grouped the three phenotypes of amyotrophic lateral sclerosis, progressive muscular atrophy and progressive bulbar palsy together as part of the same syndrome, the term motor neuron disease, as an over-arching label, was not suggested until nearly a century later by W. Russell Brain. Augustus Jacob Lockhart Clarke (1817–80) is best known for his descriptions of spinal cord anatomy. However, in two detailed case reports from the 1860s, he carried out rigorous post-mortem neuropathological studies of what appear to be classical cases of amyotrophic lateral sclerosis. Furthermore, he recognized the additional involvement of the corticospinal tracts that distinguished this from progressive muscular atrophy. Several aspects of the exquisite clinical histories documented as part of both studies, one by Charles Bland Radcliffe, resonate with contemporary debates concerning the evolution of disease in amyotrophic lateral sclerosis. These ‘past masters’ still have much to teach us. PMID:20576696

  16. Riluzole exerts central and peripheral modulating effects in amyotrophic lateral sclerosis.

    PubMed

    Vucic, Steve; Lin, Cindy Shin-Yi; Cheah, Benjamin C; Murray, Jenna; Menon, Parvathi; Krishnan, Arun V; Kiernan, Matthew C

    2013-05-01

    Riluzole, a benzothiazole derivative, has been shown to be effective in prolonging survival in amyotrophic lateral sclerosis. The mechanisms by which riluzole exerts neuroprotective effects in amyotrophic lateral sclerosis remains to be fully elucidated, although inhibition of glutamatergic transmission and modulation of Na+ channel function have been proposed. In an attempt to determine the mechanisms by which riluzole exerts neuroprotective effects, in particular to dissect the relative contributions of inhibition of glutamatergic transmission and Na+ channel modulation, the present study utilized a combination of cortical and peripheral axonal excitability approaches to monitor changes in excitability and function in patients with amyotrophic lateral sclerosis. Cortical assessment was undertaken by utilising the threshold tracking transcranial magnetic stimulation (TMS) technique and combined with peripheral axonal excitability studies in 25 patients with amyotrophic lateral sclerosis. Studies were performed at baseline and repeated when patients were receiving riluzole 100 mg/day. At the time of second testing all patients were tolerating the medication well. Motor evoked potential and compound muscle action potential responses were recorded over the abductor pollicis brevis muscle. At baseline, features of cortical hyperexcitability were evident in patients with amyotrophic lateral sclerosis, indicated by marked reduction in short interval intracortical inhibition (P < 0.001) and cortical silent period duration (P < 0.001), as well as an increase in the motor evoked potential amplitude (P < 0.01). Riluzole therapy partially normalized cortical excitability by significantly increasing short interval intracortical inhibition (short interval intracortical inhibitionbaseline 0.5 ± 1.8%; short interval intracortical inhibitionON riluzole 7.9 ± 1.7%, P < 0.01). In contrast, riluzole did not exert any modulating effect on cortical silent period duration (P = 0

  17. Hyaluronic acid is increased in the skin and urine in patients with amyotrophic lateral sclerosis

    NASA Technical Reports Server (NTRS)

    Ono, S.; Imai, T.; Yamauchi, M.; Nagao, K.

    1996-01-01

    We performed morphological studies of skin and measured glycosaminoglycans in the urine from patients with sporadic amyotrophic lateral sclerosis (ALS) and control subjects. The wide spaces separating collagen bundles reacted strongly with alcian blue stain in ALS patients and stained more markedly as ALS progressed. Staining with alcian blue was virtually eliminated by Streptomyces hyaluronidase. The urinary excretion of hyaluronic acid (HA) (mg/day) was significantly increased (P < 0.01) in ALS patients compared with that of control subjects, and there was a significant positive correlation between the excreted amount of HA and the duration of illness in advanced ALS patients with a duration of more than 2 years from clinical onset (r = 0.72, P < 0.02). We suggest that sporadic ALS includes a metabolic disorder of HA in which an accumulation of HA in the skin is linked to an increased urinary excretion of HA.

  18. Cataract Surgery in a Patient with Amyotrophic Lateral Sclerosis: A Case Report

    PubMed Central

    Cenk Kohen, Maryo; Beril Kucumen, Raciha

    2011-01-01

    Abstract We report a cataract operation with complications in a patient with amyotrophic lateral sclerosis (ALS). The patient had a grade 4 mature brown cataract. Phacoemulsification with intraocular lens (IOL) implantation was planned; however, due to unexpected complications occurring during surgery, the operating technique was revised to an intracapsular cataract extraction. A very high vitreous pressure was found and therefore scleral fixating IOL was not implanted after anterior vitrectomy because of the possibility of choroidal effusion. The postoperative visual acuity improved sufficiently for the patient to communicate. Visual communication is of vital importance for an ALS patient and his caregivers. Therefore, surgery may be advisable in patients at a terminal stage with an advanced cataract, even if their general health condition may not seem appropriate for such an operation. Nevertheless, the intra- and postoperative course of the surgery may show unexpected complications and the surgeon should be prepared for such conditions. PMID:21886620

  19. Retraction: DNAJC6 variants in Parkinson's disease and amyotrophic lateral sclerosis.

    PubMed

    Jiang, Teng; Zhang, Ying-Dong; Tan, Lan; Yu, Jin-Tai

    2016-04-04

    The above Letter to the Editor from Annals of Neurology, published online as an Accepted Article on 4th April 2016 on Wiley Online Library (wileyonlinelibrary.com), has been withdrawn at the request of the authors with agreement from the journal editor, Clifford B. Saper, and Wiley Periodicals, Inc. The withdrawal has been agreed due to an acknowledgement from the authors that they inappropriately implied that material from the PD Gene and ALS Gene public databases and a figure from the Max Planck Society for the Advancement of Science was their own work. Reference Jiang, T., Zhang, Y-D., Tan, L., and Yu, J-T (2016) DNAJC6 variants in Parkinson's disease and amyotrophic lateral sclerosis. Ann Neurol. doi: 10.1002/ana.24658.

  20. Ethical considerations in disease management of amyotrophic lateral sclerosis: a cross-cultural, worldwide perspective.

    PubMed

    Russell, J A

    1998-08-01

    Amyotrophic lateral sclerosis (ALS) is universally fatal. Technological advances have provided a means to impact upon, without radically improving, the natural history of the disease. In addition, we now have the capability of potentially identifying patients who are pre-symptomatic carriers of the rare heritable forms of the disease. These capabilities provide the basis for the numerous ethical dilemmas that face patients, physicians, and agencies responsible for health care expenditures; dilemmas that can only be amplified between cultures. This paper attempts to address some of the major ethical issues germane to the care of ALS patients. It discusses the emergence of autonomy as the reigning principle of medical ethics in the United States and its potential conflict with the ethical dilemma of limited resource allocation. Finally, it attempts to compare and contrast, in an admittedly anecdotal and fragmentary fashion, the perspective of other cultures regarding the care of ALS patients.

  1. Anti-Ganglioside Antibodies in Amyotrophic Lateral Sclerosis Revisited

    PubMed Central

    Kollewe, Katja; Wurster, Ulrich; Sinzenich, Thomas; Körner, Sonja; Dengler, Reinhard; Mohammadi, Bahram; Petri, Susanne

    2015-01-01

    Background Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder with typical onset in the 5th- 6th decade of life. The hypothesis of an autoimmune origin of ALS receives less attention today, but immunological phenomena still seem to be involved and mechanisms such as protective autoimmunity may be important. Detection of antibodies against a variety of gangliosides has been repeatedly described in ALS-patients by several authors, but widely differing frequencies and titres have been reported. Therefore, we investigated the presence of six common antibodies with a commercially available test panel for GA1, GM1, GM2, GD1a, GD1b and GQ1b in a large group of clinically well-characterized ALS patients and compared them to a collective of 200 healthy blood donors. Methods IgG and IgM antibodies to the six gangliosides asialoGM1 (GA1), GM1, GM2, GD1a, GD1b, GQ1b were determined by GanglioCombi ELISA in sera of 84 ALS patients. Results were expressed as a %-ratio of a highly positive control and categorized as negative (<30%), borderline (30–50%), moderately (50–100%) and strongly positive (>100%). The values obtained from 200 Swiss blood donors served as a reference group. Results In twenty-two (26.2%) ALS-patients elevated anti-ganglioside antibodies could be detected: Taking all subspecific antibodies together, IgG antibodies were found in 9/84 (10.7%) and IgM in 15/84 (17.9%) patients. There was no correlation between age, gender, site of onset or survival and anti-ganglioside-positive/-negative titres in ALS-patients. No statistically significant difference in the frequency of anti-ganglioside antibodies compared to the group of healthy blood donors was found. Conclusion Even with this more comprehensive approach, anti-ganglioside antibody frequencies and patterns in our ALS cohort closely resembled the values measured in healthy controls. In accordance with other studies, we did not observe any association of a distinct ALS phenotype

  2. Amyotrophic lateral sclerosis and occupational exposure to electromagnetic fields

    SciTech Connect

    Davanipour, Z.; Sobel, E.; Bowman, J.D.; Qian, Z.; Will, A.D.

    1997-03-01

    In an hypothesis-generating case-control study of amyotrophic lateral sclerosis, lifetime occupational histories were obtained. The patients (n = 28) were clinic based. The occupational exposure of interest in this report is electromagnetic fields (EMFs). This is the first and so far the only exposure analyzed in this study. Occupational exposure up to 2 years prior to estimated disease symptom onset was used for construction of exposure indices for cases. Controls (n = 32) were blood and nonblood relatives of cases. Occupational exposure for controls was through the same age as exposure for the corresponding cases. Twenty (71%) cases and 28 (88%) controls had at least 20 years of work experience covering the exposure period. The occupational history and task data were used to classify blindly each occupation for each subject as having high, medium/high, medium, medium/low, or low EMF exposure, based primarily on data from an earlier and unrelated study designed to obtain occupational EMF exposure information on workers in ``electrical`` and ``nonelectrical`` jobs. By using the length of time each subject spent in each occupation through the exposure period, two indices of exposure were constructed: total occupational exposure (E{sub 1}) and average occupational exposure (E{sub 2}). For cases and controls with at least 20 years of work experience, the odds ratio (OR) for exposure at the 75th percentile of the E{sub 1} case exposure data relative to minimum exposure was 7.5 (P < 0.02; 95% CI, 1.4--38.1) and the corresponding OR for E{sub 2} was 5.5 (P < 0.02; 95% CI, 1.3--22.5). For all cases and controls, the ORs were 2.5 (P < 0.1; 95% CI, 0.9--8.1) for E{sub 1} and 2.3 (P = 0.12; 95% CI, 0.8--6.6) for E{sub 2}. This study should be considered an hypothesis-generating study. Larger studies, using incident cases and improved exposure assessment, should be undertaken.

  3. Novel cases of amyotrophic lateral sclerosis after treatment of cerebral arteriovenous malformationss.

    PubMed

    Linnebank, Michael; McDougall, Cameron G; Krueger, Stefanie; Biskup, Saskia; Neumann, Manuela; Weller, Michael; Valavanis, Antonios; Prudlo, Johannes

    2016-01-01

    Previous case studies reported nine patients with cerebral arteriovenous malformations (AVM) who developed amyotrophic lateral sclerosis (ALS) after AVM embolisation. Here, we describe three novel cases of ALS which developed 13-34 years after treatment, including embolisation, of cerebral AVM. This study provides further arguments supporting the thesis that embolisation of cerebral AVM might influence the risk of later ALS development.

  4. Side of limb-onset predicts laterality of gray matter loss in amyotrophic lateral sclerosis.

    PubMed

    Zhang, Qiuli; Mao, Cuiping; Jin, Jiaoting; Niu, Chen; Bai, Lijun; Dang, Jingxia; Zhang, Ming

    2014-01-01

    Conflicting findings have been reported regarding the lateralized brain abnormality in patients with amyotrophic lateral sclerosis (ALS). In this study, we aimed to investigate the probable lateralization of gray matter (GM) atrophy in ALS patients. We focused on the relationship between the asymmetry in decreased GM volume and the side of disease onset in patients with limb-onset. Structural imaging evaluation of normalized atrophy (SIENAX) and voxel-based morphometry (VBM) were used to assess differences in global and local brain regions in patients with heterogeneous body onset and subgroups with different side of limb-onset. We found global brain atrophy and GM losses in the frontal and parietal areas in each patient group as well as left predominant GM losses in the total cohort. The intriguing findings in subgroup analyses demonstrated that the motor cortex in the contralateral hemisphere of the initially involved limb was most affected. We also found that regional brain atrophy was related to disease progression rate. Our observations suggested that side of limb-onset can predict laterality of GM loss in ALS patients and disease progression correlates with the extent of cortical abnormality.

  5. Dietary BMAA Exposure in an Amyotrophic Lateral Sclerosis Cluster from Southern France

    PubMed Central

    Masseret, Estelle; Banack, Sandra; Boumédiène, Farid; Abadie, Eric; Brient, Luc; Pernet, Fabrice; Juntas-Morales, Raoul; Pageot, Nicolas; Metcalf, James; Cox, Paul; Camu, William

    2013-01-01

    Background Dietary exposure to the cyanotoxin BMAA is suspected to be the cause of amyotrophic lateral sclerosis in the Western Pacific Islands. In Europe and North America, this toxin has been identified in the marine environment of amyotrophic lateral sclerosis clusters but, to date, only few dietary exposures have been described. Objectives We aimed at identifying cluster(s) of amyotrophic lateral sclerosis in the Hérault district, a coastal district from Southern France, and to search, in the identified area(s), for the existence of a potential dietary source of BMAA. Methods A spatio-temporal cluster analysis was performed in the district, considering all incident amyotrophic lateral sclerosis cases identified from 1994 to 2009 by our expert center. We investigated the cluster area with serial collections of oysters and mussels that were subsequently analyzed blind for BMAA concentrations. Results We found one significant amyotrophic lateral sclerosis cluster (p = 0.0024), surrounding the Thau lagoon, the most important area of shellfish production and consumption along the French Mediterranean coast. BMAA was identified in mussels (1.8 µg/g to 6.0 µg/g) and oysters (0.6 µg/g to 1.6 µg/g). The highest concentrations of BMAA were measured during summer when the highest picocyanobacteria abundances were recorded. Conclusions While it is not possible to ascertain a direct link between shellfish consumption and the existence of this ALS cluster, these results add new data to the potential association of BMAA with sporadic amyotrophic lateral sclerosis, one of the most severe neurodegenerative disorder. PMID:24349504

  6. The extracellular domain of neurotrophin receptor p75 as a candidate biomarker for amyotrophic lateral sclerosis.

    PubMed

    Shepheard, Stephanie R; Chataway, Tim; Schultz, David W; Rush, Robert A; Rogers, Mary-Louise

    2014-01-01

    Objective biomarkers for amyotrophic lateral sclerosis would facilitate the discovery of new treatments. The common neurotrophin receptor p75 is up regulated and the extracellular domain cleaved from injured neurons and peripheral glia in amyotrophic lateral sclerosis. We have tested the hypothesis that urinary levels of extracellular neurotrophin receptor p75 serve as a biomarker for both human motor amyotrophic lateral sclerosis and the SOD1(G93A) mouse model of the disease. The extracellular domain of neurotrophin receptor p75 was identified in the urine of amyotrophic lateral sclerosis patients by an immuno-precipitation/western blot procedure and confirmed by mass spectrometry. An ELISA was established to measure urinary extracellular neurotrophin receptor p75. The mean value for urinary extracellular neurotrophin receptor p75 from 28 amyotrophic lateral sclerosis patients measured by ELISA was 7.9±0.5 ng/mg creatinine and this was significantly higher (p<0.001) than 12 controls (2.6±0.2 ng/mg creatinine) and 19 patients with other neurological disease (Parkinson's disease and Multiple Sclerosis; 4.1±0.2 ng/mg creatinine). Pilot data of disease progression rates in 14 MND patients indicates that p75NTR(ECD) levels were significantly higher (p = 0.0041) in 7 rapidly progressing patients as compared to 7 with slowly progressing disease. Extracellular neurotrophin receptor p75 was also readily detected in SOD1(G93A) mice by immuno-precipitation/western blot before the onset of clinical symptoms. These findings indicate a significant relation between urinary extracellular neurotrophin receptor p75 levels and disease progression and suggests that it may be a useful marker of disease activity and progression in amyotrophic lateral sclerosis.

  7. Characteristics of fasciculations in amyotrophic lateral sclerosis and the benign fasciculation syndrome.

    PubMed

    Mills, Kerry R

    2010-11-01

    The aim of this study was to determine first, if benign fasciculations and those in amyotrophic lateral sclerosis can de distinguished on the basis of their waveforms or firing characteristics, and second to determine how fasciculation parameters evolved with progression of amyotrophic lateral sclerosis. Fasciculation potentials recorded from 63 muscles of 28 patients with definite amyotrophic lateral sclerosis were compared with those from 21 muscles of 11 patients with the benign fasciculation syndrome. In each muscle, at a single site, up to 15 identifiable fasciculation potentials could be recognized. Thus the characteristics of 430 fasciculations from patients with amyotrophic lateral sclerosis and 191 benign fasciculations were analysed. Fasciculation potential amplitude, area, turns, duration, firing interval, indices of waveform variability, evidence of axonal conduction block, evidence of axonal conduction variability and propensity to produce double fasciculations were measured. The waveforms of fasciculations in amyotrophic lateral sclerosis were on average of shorter duration and had a greater number of turns than benign fasciculations, but, although irregular in both conditions, the firing rate in amyotrophic lateral sclerosis was significantly higher. In both conditions, there was evidence of multifocal distal generation of fasciculations, axonal conduction block in the motor unit arborization and of variable axonal conduction. When severe weakness and marked chronic neurogenic change were present on electromyography, the firing rate of fasciculations in amyotrophic lateral sclerosis was higher but fasciculation potential amplitude, area and indices of waveform variability were little changed. Double fasciculations in which the waveforms of the two potentials were the same occurred in both conditions. The intervals were in two bands: an early band with 4-10 ms intervals showed identical waveforms of the two potentials, indicating the region of

  8. Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers.

    PubMed

    Freischmidt, Axel; Müller, Kathrin; Zondler, Lisa; Weydt, Patrick; Volk, Alexander E; Božič, Anže Lošdorfer; Walter, Michael; Bonin, Michael; Mayer, Benjamin; von Arnim, Christine A F; Otto, Markus; Dieterich, Christoph; Holzmann, Karlheinz; Andersen, Peter M; Ludolph, Albert C; Danzer, Karin M; Weishaupt, Jochen H

    2014-11-01

    Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.

  9. High and Low Contrast Visual Acuity Are Not Affected in Amyotrophic Lateral Sclerosis.

    PubMed

    Moss, Heather E; Samelson, Monica; Mohan, Girish; Jiang, Qin Li

    2016-01-01

    The afferent visual system may be affected by neuro-degeneration in amyotrophic lateral sclerosis (ALS) based on observations of visual function impairment and retinal inclusions on histopathology in ALS patients. To test the hypothesis that visual acuity is impaired in ALS, we compared three measures of visual acuity in ALS patients (n = 25) attending a multidisciplinary ALS clinic and age matched control subjects (n = 25). Bilateral monocular and binocular visual acuities were assessed using high contrast (black letters on white background) and low contrast (2.5%, 1.25% grey letters on white background) visual acuity charts under controlled lighting conditions following refraction. Binocular summation was calculated as the difference between binocular and best monocular acuity scores. There were no associations between binocular or monocular high contrast visual acuity or low contrast visual acuity and amyotrophic lateral sclerosis diagnosis (generalized estimating equation models accounting for age). Binocular summation was similar in both amyotrophic lateral sclerosis and control subjects. There was a small magnitude association between increased duration of ALS symptoms and reduced 1.25% low contrast visual acuity. This study does not confirm prior observations of impaired visual acuity in patients with amyotrophic lateral sclerosis and does not support this particular measure of visual function for use in broad scale assessment of visual pathway involvement in ALS patients.

  10. High and Low Contrast Visual Acuity Are Not Affected in Amyotrophic Lateral Sclerosis

    PubMed Central

    Samelson, Monica; Mohan, Girish; Jiang, Qin Li

    2016-01-01

    The afferent visual system may be affected by neuro-degeneration in amyotrophic lateral sclerosis (ALS) based on observations of visual function impairment and retinal inclusions on histopathology in ALS patients. To test the hypothesis that visual acuity is impaired in ALS, we compared three measures of visual acuity in ALS patients (n = 25) attending a multidisciplinary ALS clinic and age matched control subjects (n = 25). Bilateral monocular and binocular visual acuities were assessed using high contrast (black letters on white background) and low contrast (2.5%, 1.25% grey letters on white background) visual acuity charts under controlled lighting conditions following refraction. Binocular summation was calculated as the difference between binocular and best monocular acuity scores. There were no associations between binocular or monocular high contrast visual acuity or low contrast visual acuity and amyotrophic lateral sclerosis diagnosis (generalized estimating equation models accounting for age). Binocular summation was similar in both amyotrophic lateral sclerosis and control subjects. There was a small magnitude association between increased duration of ALS symptoms and reduced 1.25% low contrast visual acuity. This study does not confirm prior observations of impaired visual acuity in patients with amyotrophic lateral sclerosis and does not support this particular measure of visual function for use in broad scale assessment of visual pathway involvement in ALS patients. PMID:28033389

  11. Methods of Communication at End of Life for the Person with Amyotrophic Lateral Sclerosis

    ERIC Educational Resources Information Center

    Brownlee, Alisa; Bruening, Lisa M.

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in loss of most motor functions by the time of death. Most persons with ALS experience a dysarthria that eventually renders oral/vocal communication unintelligible. This article reviews the communication needs of persons with ALS and the range of communication…

  12. 38 CFR 3.318 - Presumptive service connection for amyotrophic lateral sclerosis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... under this section: (1) If there is affirmative evidence that amyotrophic lateral sclerosis was not incurred during or aggravated by active military, naval, or air service; (2) If there is affirmative... sclerosis manifested at any time after discharge or release from active military, naval, or air service...

  13. 78 FR 72573 - Specially Adapted Housing Eligibility for Amyotrophic Lateral Sclerosis Beneficiaries

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-03

    ... AFFAIRS 38 CFR Part 3 RIN 2900-AO84 Specially Adapted Housing Eligibility for Amyotrophic Lateral... housing (SAH). The amendment authorizes automatic issuance of a certificate of eligibility for SAH to all... indicate that they are submitted in response to ``RIN 2900-AO84--Specially Adapted Housing Eligibility...

  14. Ethnic and demographic incidence of amyotrophic lateral sclerosis (ALS) in Brazil: A population based study.

    PubMed

    Moura, Mirian Conceicao; Casulari, Luiz Augusto; Carvalho Garbi Novaes, Maria Rita

    2016-01-01

    Our objectives were to examine demographic and ethnic factors associated with amyotrophic lateral sclerosis in Brazil. The method used was a retrospective study of death certificates performed in June 2015, identifying the incidence of amyotrophic lateral sclerosis over 10 years, from January 2004 to December 2013, related to gender, age and race. Results revealed 8942 death certificates with 8152 as the underlying cause and 790 as a secondary cause. The average age was 62.7 ± 13.2 years, with a predominance of males (1·3:1). The adjusted mortality rate over 20 years was 0.61 to 0.89/100,000 person-years, and over 45 years was 1.77 to 2.3/100,000 person-years. There was a predominance of amyotrophic lateral sclerosis in Caucasians compared to the general population above 20 years (2010 Census), with an odds ratio (OR) of 2.92 (95% CI 2.78-3.07). The OR in blacks was 0.04 (95% CI: 0.03-0.04), in mestizos was 0.05 (0.04-0.07), and in Indians was 0.02 (0.01-0.04). The mean age was lower than in European populations (48.5 ± 12.3 years) (p < 0.0001). In conclusion, the incidence of amyotrophic lateral sclerosis in Brazil is close to other Latin American populations, with a lower age at death and clear predominance in Caucasians.

  15. Is There a Role for Exercise in the Management of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis?

    ERIC Educational Resources Information Center

    Plowman, Emily K.

    2015-01-01

    Purpose: The role of exercise in the management of people with amyotrophic lateral sclerosis (PALS) is controversial and currently unclear. The purpose of this review article is to review literature examining the impact of limb, respiratory, and oral motor exercise on function, disease progression, and survival in PALS and the transgenic ALS…

  16. Characteristics of Speaking Rate in the Dysarthria Associated with Amyotrophic Lateral Sclerosis.

    ERIC Educational Resources Information Center

    Turner, Greg S.; Weismer, Gary

    1993-01-01

    The ability to alter speaking rate was studied in nine adult subjects with amyotrophic lateral sclerosis and nine control subjects. Results suggest that the relationship between speaking rate, articulation rate, pause duration, and pause frequency remained largely intact for the dysarthric speakers. Data showed greater dependence on pausing by the…

  17. Speech Intelligibility and Marital Communication in Amyotrophic Lateral Sclerosis: An Exploratory Study

    ERIC Educational Resources Information Center

    Joubert, Karin; Bornman, Juan; Alant, Erna

    2011-01-01

    Amyotrophic lateral sclerosis (ALS), a rapidly progressive neuromuscular disease, has a devastating impact not only on individuals diagnosed with ALS but also their spouses. Speech intelligibility, often compromised as a result of dysarthria, affects the couple's ability to maintain effective, intimate communication. The purpose of this…

  18. Protein disulphide isomerase protects against protein aggregation and is S-nitrosylated in amyotrophic lateral sclerosis.

    PubMed

    Walker, Adam K; Farg, Manal A; Bye, Chris R; McLean, Catriona A; Horne, Malcolm K; Atkin, Julie D

    2010-01-01

    Amyotrophic lateral sclerosis is a rapidly progressing fatal neurodegenerative disease characterized by the presence of protein inclusions within affected motor neurons. Endoplasmic reticulum stress leading to apoptosis was recently recognized to be an important process in the pathogenesis of sporadic human amyotrophic lateral sclerosis as well as in transgenic models of mutant superoxide dismutase 1-linked familial amyotrophic lateral sclerosis. Endoplasmic reticulum stress occurs early in disease, indicating a critical role in pathogenesis, and involves upregulation of an important endoplasmic reticulum chaperone, protein disulphide isomerase. We aimed to investigate the involvement of protein disulphide isomerase in endoplasmic reticulum stress induction, protein aggregation, inclusion formation and toxicity in amyotrophic lateral sclerosis. Motor neuron-like NSC-34 cell lines were transfected with superoxide dismutase 1 and protein disulphide isomerase encoding vectors and small interfering RNA, and examined by immunocytochemistry and immunoblotting. Expression of mutant superoxide dismutase 1 induced endoplasmic reticulum stress, predominantly in cells bearing mutant superoxide dismutase 1 inclusions but also in a proportion of cells expressing mutant superoxide dismutase 1 without visible inclusions. Over-expression of protein disulphide isomerase decreased mutant superoxide dismutase 1 aggregation, inclusion formation, endoplasmic reticulum stress induction and toxicity, whereas small interfering RNA targeting protein disulphide isomerase increased mutant superoxide dismutase 1 inclusion formation, indicating a protective role for protein disulphide isomerase against superoxide dismutase 1 misfolding. Aberrant modification of protein disulphide isomerase by S-nitrosylation of active site cysteine residues has previously been shown as an important process in neurodegeneration in Parkinson's and Alzheimer's disease brain tissue, but has not been described in

  19. Eye tracking communication devices in amyotrophic lateral sclerosis: impact on disability and quality of life.

    PubMed

    Caligari, Marco; Godi, Marco; Guglielmetti, Simone; Franchignoni, Franco; Nardone, Antonio

    2013-12-01

    People with amyotrophic lateral sclerosis (PwALS) show progressive loss of voluntary muscle strength. In advanced disease, motor and phonatory impairments seriously hinder the patient's interpersonal communication. High-tech devices such as eye tracking communication devices (ETCDs) are used to aid communication in the later stages of ALS. We sought to evaluate the effect of ETCDs on patient disability, quality of life (QoL), and user satisfaction, in a group of 35 regular ETCD users in late-stage ALS with tetraplegia and anarthria. The following scales were administered: 1) the Individually Prioritized Problem Assessment (IPPA) scale, in three conditions: without device, with ETCD and, when applicable, with an Eye Transfer (ETRAN) board; 2) the Psychosocial Impact of Assistive Devices Scale (PIADS); and 3) the Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST 2.0). With ETRAN, IPPA showed an increase in communicative abilities with respect to the condition without device, but ETCD produced a further significant increase. PIADS evidenced a large increase of QoL, and QUEST 2.0 showed high user satisfaction with ETCD use. In conclusion, ETCDs should be considered in late-stage ALS with tetraplegia and anarthria, since in these patients they can reduce communication disability and improve QoL.

  20. Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria.

    PubMed

    Strong, Michael J; Abrahams, Sharon; Goldstein, Laura H; Woolley, Susan; Mclaughlin, Paula; Snowden, Julie; Mioshi, Eneida; Roberts-South, Angie; Benatar, Michael; HortobáGyi, Tibor; Rosenfeld, Jeffrey; Silani, Vincenzo; Ince, Paul G; Turner, Martin R

    2017-01-05

    This article presents the revised consensus criteria for the diagnosis of frontotemporal dysfunction in amyotrophic lateral sclerosis (ALS) based on an international research workshop on frontotemporal dementia (FTD) and ALS held in London, Canada in June 2015. Since the publication of the Strong criteria, there have been considerable advances in the understanding of the neuropsychological profile of patients with ALS. Not only is the breadth and depth of neuropsychological findings broader than previously recognised - - including deficits in social cognition and language - but mixed deficits may also occur. Evidence now shows that the neuropsychological deficits in ALS are extremely heterogeneous, affecting over 50% of persons with ALS. When present, these deficits significantly and adversely impact patient survival. It is the recognition of this clinical heterogeneity in association with neuroimaging, genetic and neuropathological advances that has led to the current re-conceptualisation that neuropsychological deficits in ALS fall along a spectrum. These revised consensus criteria expand upon those of 2009 and embrace the concept of the frontotemporal spectrum disorder of ALS (ALS-FTSD).

  1. Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43

    PubMed Central

    Uchida, Azusa; Sasaguri, Hiroki; Kimura, Nobuyuki; Tajiri, Mio; Ohkubo, Takuya; Ono, Fumiko; Sakaue, Fumika; Kanai, Kazuaki; Hirai, Takashi; Sano, Tatsuhiko; Shibuya, Kazumoto; Kobayashi, Masaki; Yamamoto, Mariko; Yokota, Shigefumi; Kubodera, Takayuki; Tomori, Masaki; Sakaki, Kyohei; Enomoto, Mitsuhiro; Hirai, Yukihiko; Kumagai, Jiro; Yasutomi, Yasuhiro; Mochizuki, Hideki; Kuwabara, Satoshi; Uchihara, Toshiki; Mizusawa, Hidehiro

    2012-01-01

    Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and

  2. Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43.

    PubMed

    Uchida, Azusa; Sasaguri, Hiroki; Kimura, Nobuyuki; Tajiri, Mio; Ohkubo, Takuya; Ono, Fumiko; Sakaue, Fumika; Kanai, Kazuaki; Hirai, Takashi; Sano, Tatsuhiko; Shibuya, Kazumoto; Kobayashi, Masaki; Yamamoto, Mariko; Yokota, Shigefumi; Kubodera, Takayuki; Tomori, Masaki; Sakaki, Kyohei; Enomoto, Mitsuhiro; Hirai, Yukihiko; Kumagai, Jiro; Yasutomi, Yasuhiro; Mochizuki, Hideki; Kuwabara, Satoshi; Uchihara, Toshiki; Mizusawa, Hidehiro; Yokota, Takanori

    2012-03-01

    Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and

  3. Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study

    PubMed Central

    Al-Chalabi, Ammar; Calvo, Andrea; Chio, Adriano; Colville, Shuna; Ellis, Cathy M; Hardiman, Orla; Heverin, Mark; Howard, Robin S; Huisman, Mark H B; Keren, Noa; Leigh, P Nigel; Mazzini, Letizia; Mora, Gabriele; Orrell, Richard W; Rooney, James; Scott, Kirsten M; Scotton, William J; Seelen, Meinie; Shaw, Christopher E; Sidle, Katie S; Swingler, Robert; Tsuda, Miho; Veldink, Jan H; Visser, Anne E; van den Berg, Leonard H; Pearce, Neil

    2014-01-01

    Summary Background Amyotrophic lateral sclerosis shares characteristics with some cancers, such as onset being more common in later life, progression usually being rapid, the disease affecting a particular cell type, and showing complex inheritance. We used a model originally applied to cancer epidemiology to investigate the hypothesis that amyotrophic lateral sclerosis is a multistep process. Methods We generated incidence data by age and sex from amyotrophic lateral sclerosis population registers in Ireland (registration dates 1995–2012), the Netherlands (2006–12), Italy (1995–2004), Scotland (1989–98), and England (2002–09), and calculated age and sex-adjusted incidences for each register. We regressed the log of age-specific incidence against the log of age with least squares regression. We did the analyses within each register, and also did a combined analysis, adjusting for register. Findings We identified 6274 cases of amyotrophic lateral sclerosis from a catchment population of about 34 million people. We noted a linear relationship between log incidence and log age in all five registers: England r2=0·95, Ireland r2=0·99, Italy r2=0·95, the Netherlands r2=0·99, and Scotland r2=0·97; overall r2=0·99. All five registers gave similar estimates of the linear slope ranging from 4·5 to 5·1, with overlapping confidence intervals. The combination of all five registers gave an overall slope of 4·8 (95% CI 4·5–5·0), with similar estimates for men (4·6, 4·3–4·9) and women (5·0, 4·5–5·5). Interpretation A linear relationship between the log incidence and log age of onset of amyotrophic lateral sclerosis is consistent with a multistage model of disease. The slope estimate suggests that amyotrophic lateral sclerosis is a six-step process. Identification of these steps could lead to preventive and therapeutic avenues. Funding UK Medical Research Council; UK Economic and Social Research Council; Ireland Health Research Board; The

  4. MTHFSD and DDX58 are novel RNA-binding proteins abnormally regulated in amyotrophic lateral sclerosis.

    PubMed

    MacNair, Laura; Xiao, Shangxi; Miletic, Denise; Ghani, Mahdi; Julien, Jean-Pierre; Keith, Julia; Zinman, Lorne; Rogaeva, Ekaterina; Robertson, Janice

    2016-01-01

    Tar DNA-binding protein 43 (TDP-43) is an RNA-binding protein normally localized to the nucleus of cells, where it elicits functions related to RNA metabolism such as transcriptional regulation and alternative splicing. In amyotrophic lateral sclerosis, TDP-43 is mislocalized from the nucleus to the cytoplasm of diseased motor neurons, forming ubiquitinated inclusions. Although mutations in the gene encoding TDP-43, TARDBP, are found in amyotrophic lateral sclerosis, these are rare. However, TDP-43 pathology is common to over 95% of amyotrophic lateral sclerosis cases, suggesting that abnormalities of TDP-43 play an active role in disease pathogenesis. It is our hypothesis that a loss of TDP-43 from the nucleus of affected motor neurons in amyotrophic lateral sclerosis will lead to changes in RNA processing and expression. Identifying these changes could uncover molecular pathways that underpin motor neuron degeneration. Here we have used translating ribosome affinity purification coupled with microarray analysis to identify the mRNAs being actively translated in motor neurons of mutant TDP-43(A315T) mice compared to age-matched non-transgenic littermates. No significant changes were found at 5 months (presymptomatic) of age, but at 10 months (symptomatic) the translational profile revealed significant changes in genes involved in RNA metabolic process, immune response and cell cycle regulation. Of 28 differentially expressed genes, seven had a ≥ 2-fold change; four were validated by immunofluorescence labelling of motor neurons in TDP-43(A315T) mice, and two of these were confirmed by immunohistochemistry in amyotrophic lateral sclerosis cases. Both of these identified genes, DDX58 and MTHFSD, are RNA-binding proteins, and we show that TDP-43 binds to their respective mRNAs and we identify MTHFSD as a novel component of stress granules. This discovery-based approach has for the first time revealed translational changes in motor neurons of a TDP-43 mouse model

  5. Executive deficits, not processing speed relates to abnormalities in distinct prefrontal tracts in amyotrophic lateral sclerosis.

    PubMed

    Pettit, Lewis D; Bastin, Mark E; Smith, Colin; Bak, Thomas H; Gillingwater, Thomas H; Abrahams, Sharon

    2013-11-01

    Cognitive impairment in amyotrophic lateral sclerosis is characterized by deficits on tests of executive function; however, the contribution of abnormal processing speed is unknown. Methods are confounded by tasks that depend on motor speed in patients with physical disability. Structural and functional magnetic resonance imaging studies have revealed multi-system cerebral involvement, with evidence of reduced white matter volume and integrity in predominant frontotemporal regions. The current study has two aims. First, to investigate whether cognitive impairments in amyotrophic lateral sclerosis are due to executive dysfunction or slowed processing speed using methodology that accommodates motor disability. This is achieved using a dual-task paradigm and tasks that manipulate stimulus presentation times and do not rely on response motor speed. Second, to identify relationships between specific cognitive impairments and the integrity of distinct white matter tracts. Thirty patients with amyotrophic lateral sclerosis and 30 age- and education-matched control subjects were administered an experimental dual-task procedure that combined a visual inspection time task and digit recall. In addition, measures of executive function (including letter fluency) and processing speed (visual inspection time and rapid serial letter identification) were administered. Integrity of white matter tracts was determined using region of interest analyses of diffusion tensor magnetic resonance imaging data. Patients with amyotrophic lateral sclerosis did not show impairments on tests of processing speed, but executive deficits were revealed once visual inspection time was combined with digit recall (dual-task) and in letter fluency. In addition to the corticospinal tracts, significant differences in fractional anisotropy and mean diffusivity were found between groups in a number of prefrontal and temporal white matter tracts including the anterior cingulate, anterior thalamic radiation

  6. Amyotrophic lateral sclerosis (ALS): three letters that change the people's life. For ever.

    PubMed

    Oliveira, Acary Souza Bulle; Pereira, Roberto Dias Batista

    2009-09-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor nervous system. It causes progressive and cumulative physical disabilities in patients, and leads to eventual death due to respiratory muscle failure. The disease is diverse in its presentation, course, and progression. We do not yet fully understand the cause or causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. Currently, we rely on a multidisciplinary approach to symptomatically manage and care for patients who have ALS. Although amyotrophic lateral sclerosis and its variants are readily recognized by neurologists, about 10% of patients are misdiagnosed, and delays in diagnosis are common. Prompt diagnosis, sensitive communication of the diagnosis, the involvement of the patient and their family, and a positive care plan are prerequisites for good clinical management. A multidisciplinary, palliative approach can prolong survival and maintain quality of life. Treatment with Riluzole improves survival but has a marginal effect on the rate of functional deterioration, whereas non-invasive ventilation prolongs survival and improves or maintains quality of life. In this review, we discuss the diagnosis, management, and how to cope with impaired function and end of life on the basis of our experience, the opinions of experts, existing guidelines, and clinical trials. Multiple problems require a multidisciplinary approach including aggressive symptomatic management, rehabilitation to maintain motor function, nutritional support (enteric feeding, gastrostomy), respiratory support (non invasive home ventilation, invasive ventilation, tracheotomy), augmentative communication devices, palliative care, psychological support for both patients and families (because family members so often play a central role in management and care), communication between the care team, the patient and his or her family, and recognition of

  7. Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis

    PubMed Central

    Fee, Lanette; Tao, Yazhong; Redler, Rachel L.; Fay, James M.; Zhang, Yuliang; Lv, Zhengjian; Mercer, Ian P.; Deshmukh, Mohanish; Lyubchenko, Yuri L.; Dokholyan, Nikolay V.

    2016-01-01

    Since the linking of mutations in the Cu,Zn superoxide dismutase gene (sod1) to amyotrophic lateral sclerosis (ALS) in 1993, researchers have sought the connection between SOD1 and motor neuron death. Disease-linked mutations tend to destabilize the native dimeric structure of SOD1, and plaques containing misfolded and aggregated SOD1 have been found in the motor neurons of patients with ALS. Despite advances in understanding of ALS disease progression and SOD1 folding and stability, cytotoxic species and mechanisms remain unknown, greatly impeding the search for and design of therapeutic interventions. Here, we definitively link cytotoxicity associated with SOD1 aggregation in ALS to a nonnative trimeric SOD1 species. We develop methodology for the incorporation of low-resolution experimental data into simulations toward the structural modeling of metastable, multidomain aggregation intermediates. We apply this methodology to derive the structure of a SOD1 trimer, which we validate in vitro and in hybridized motor neurons. We show that SOD1 mutants designed to promote trimerization increase cell death. Further, we demonstrate that the cytotoxicity of the designed mutants correlates with trimer stability, providing a direct link between the presence of misfolded oligomers and neuron death. Identification of cytotoxic species is the first and critical step in elucidating the molecular etiology of ALS, and the ability to manipulate formation of these species will provide an avenue for the development of future therapeutic strategies. PMID:26719414

  8. Writing errors as a result of frontal dysfunction in Japanese patients with amyotrophic lateral sclerosis.

    PubMed

    Tsuji-Akimoto, Sachiko; Hamada, Shinsuke; Yabe, Ichiro; Tamura, Itaru; Otsuki, Mika; Kobashi, Syoji; Sasaki, Hidenao

    2010-12-01

    Loss of communication is a critical problem for advanced amyotrophic lateral sclerosis (ALS) patients. This loss of communication is mainly caused by severe dysarthria and disability of the dominant hand. However, reports show that about 50% of ALS patients have mild cognitive dysfunction, and there are a considerable number of case reports on Japanese ALS patients with agraphia. To clarify writing disabilities in non-demented ALS patients, eighteen non-demented ALS patients and 16 controls without neurological disorders were examined for frontal cognitive function and writing ability. To assess writing errors statistically, we scored them on their composition ability with the original writing error index (WEI). The ALS and control groups did not differ significantly with regard to age, years of education, or general cognitive level. Two patients could not write a letter because of disability of the dominant hand. The WEI and results of picture arrangement tests indicated significant impairment in the ALS patients. Auditory comprehension (Western Aphasia Battery; WAB IIC) and kanji dictation also showed mild impairment. Patients' writing errors consisted of both syntactic and letter-writing mistakes. Omission, substitution, displacement, and inappropriate placement of the phonic marks of kana were observed; these features have often been reported in Japanese patients with agraphia resulted from a frontal lobe lesion. The most frequent type of error was an omission of kana, the next most common was a missing subject. Writing errors might be a specific deficit for some non-demented ALS patients.

  9. Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

    PubMed

    Nicholson, Katharine A; Cudkowicz, Merit E; Berry, James D

    2015-04-01

    The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS.

  10. Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum.

    PubMed

    Ji, Ai-Ling; Zhang, Xia; Chen, Wei-Wei; Huang, Wen-Juan

    2017-03-01

    Recent genetic discoveries have dramatically changed our understanding of two major neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are common, devastating diseases of the brain. For decades, ALS and FTD were classified as movement and cognitive disorders, respectively, due to their distinct clinical phenotypes. The recent identification of chromosome 9 open reading frame 72 (C9orf72) as the major gene causative of familial forms of ALS and FTD uncovered a new reality of a continuous FTD/ALS spectrum. The finding that up to 50% of all patients present some degree of ALS and FTD phenotypes supports this ALS/FTD continuum. Now >100 genes are known to contribute to ALS/FTD, with a few major contributors that are reviewed below. The low penetrance of C9orf72 mutations, its contribution to sporadic cases, and its combination with other genes support an oligogenic model where two or more genes contribute to disease risk, onset, progression and phenotype: from 'pure' ALS or FTD to combined ALS/FTD. These advances in the genetics of ALS/FTD will soon lead to a better mechanistic understanding of the pathobiology of the disease, which should result in the development of effective therapies in the near future.

  11. Worming forward: amyotrophic lateral sclerosis toxicity mechanisms and genetic interactions in Caenorhabditis elegans

    PubMed Central

    Therrien, Martine; Parker, J. Alex

    2014-01-01

    Neurodegenerative diseases share pathogenic mechanisms at the cellular level including protein misfolding, excitotoxicity and altered RNA homeostasis among others. Recent advances have shown that the genetic causes underlying these pathologies overlap, hinting at the existence of a genetic network for neurodegeneration. This is perhaps best illustrated by the recent discoveries of causative mutations for amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Once thought to be distinct entities, it is now recognized that these diseases exist along a genetic spectrum. With this wealth of discoveries comes the need to develop new genetic models of ALS and FTD to investigate not only pathogenic mechanisms linked to causative mutations, but to uncover potential genetic interactions that may point to new therapeutic targets. Given the conservation of many disease genes across evolution, Caenorhabditis elegans is an ideal system to investigate genetic interactions amongst these genes. Here we review the use of C. elegans to model ALS and investigate a putative genetic network for ALS/FTD that may extend to other neurological disorders. PMID:24860590

  12. Effects of chronic caffeine intake in a mouse model of amyotrophic lateral sclerosis.

    PubMed

    Potenza, Rosa Luisa; Armida, Monica; Ferrante, Antonella; Pèzzola, Antonella; Matteucci, Alessandra; Puopolo, Maria; Popoli, Patrizia

    2013-04-01

    Caffeine is a nonselective adenosine receptor antagonist; chronic consumption has proved protective toward neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. The present study was designed to determine whether caffeine intake affected survival and/or motor performance in a transgenic model of amyotrophic lateral sclerosis (ALS). SOD1(G93A) mice received caffeine through drinking water from 70 days of age until death. Body weight, motor performance and survival were evaluated. Furthermore, the expression of adenosine A(2A) receptors (A(2A) Rs), glial glutamate transporter (GLT1), and glial fibrillar acidic protein (GFAP) were evaluated by Western blotting. The results showed that caffeine intake significantly shortened the survival of SOD1(G93A) mice (log rank test, P = 0.01) and induced a nonsignificant advancing of disease onset. The expression of A(2A) R, GLT1, and GFAP was altered in the spinal cords of ALS mice, but caffeine did not influence their expression in either wild-type or SOD1(G93) mice. These data indicate that adenosine receptors may play an important role in ALS.

  13. Neuroimaging to Investigate Multisystem Involvement and Provide Biomarkers in Amyotrophic Lateral Sclerosis

    PubMed Central

    Pradat, Pierre-François; El Mendili, Mohamed-Mounir

    2014-01-01

    Neuroimaging allows investigating the extent of neurological systems degeneration in amyotrophic lateral sclerosis (ALS). Advanced MRI methods can detect changes related to the degeneration of upper motor neurons but have also demonstrated the participation of other systems such as the sensory system or basal ganglia, demonstrating in vivo that ALS is a multisystem disorder. Structural and functional imaging also allows studying dysfunction of brain areas associated with cognitive signs. From a biomarker perspective, numerous studies using diffusion tensor imaging showed a decrease of fractional anisotropy in the intracranial portion of the corticospinal tract but its diagnostic value at the individual level remains limited. A multiparametric approach will be required to use MRI in the diagnostic workup of ALS. A promising avenue is the new methodological developments of spinal cord imaging that has the advantage to investigate the two motor system components that are involved in ALS, that is, the lower and upper motor neuron. For all neuroimaging modalities, due to the intrinsic heterogeneity of ALS, larger pooled banks of images with standardized image acquisition and analysis procedures are needed. In this paper, we will review the main findings obtained with MRI, PET, SPECT, and nuclear magnetic resonance spectroscopy in ALS. PMID:24949452

  14. [Utility of muscle ultrasonography for the diagnosis of amyotrophic lateral sclerosis].

    PubMed

    Misawa, Sonoko

    2014-03-01

    The diagnosis of amyotrophic lateral sclerosis (ALS) is frequently challenging, because motor neuron involvement is usually focal at disease onset and many syndromes mimic ALS. Neurological examination and needle EMG are important in the diagnosis of ALS, and patients with early-stage ALS usually undergo several EMG examinations before the diagnosis is confirmed. Ultrasonography has recently been used for the non-invasive assessment of neuromuscular disorders. This review discusses the recent advances in ultrasonography for ALS diagnosis. Ultrasonography could help detect lower motor neuron involvement by evaluating muscle volume, echo intensity, and fasciculations. Previous reports have documented the diagnostic values of all these parameters. In particular, fasciculations are characteristic features of ALS that can be easily and reliably visualized using ultrasonography. Moreover, the combined use of ultrasonography and EMG to detect fasciculations could substantially increase the diagnostic sensitivity of Awaji criteria for ALS. Attempts to utilize ultrasonography for ALS diagnosis have started only recently, and the technique used is yet to be standardized. However, ultrasonography has a major advantage over EMG in that it is non-invasive. Further studies are needed to understand the use of ultrasound as a novel non-invasive tool for ALS diagnosis.

  15. End-of-life management in patients with amyotrophic lateral sclerosis.

    PubMed

    Connolly, Sheelah; Galvin, Miriam; Hardiman, Orla

    2015-04-01

    Most health-care professionals are trained to promote and maintain life and often have difficulty when faced with the often rapid decline and death of people with terminal illnesses such as amyotrophic lateral sclerosis (ALS). By contrast, data suggest that early and open discussion of end-of-life issues with patients and families allows time for reflection and planning, can obviate the introduction of unwanted interventions or procedures, can provide reassurance, and can alleviate fear. Patients' perspectives regarding end-of-life interventions and use of technologies might differ from those of the health professionals involved in their care, and health-care professionals should recognise this and respect the patient's autonomy. Advance care directives can preserve autonomy, but their legal validity and use varies between countries. Clinical management of the end of life should aim to maximise quality of life of both the patient and caregiver and, when possible, incorporate appropriate palliation of distressing physical, psychosocial, and existential distress. Training of health-care professionals should include the development of communication skills that help to sensitively manage the inevitability of death. The emotional burden for health-care professionals caring for people with terminal neurological disease should be recognised, with structures and procedures developed to address compassion, fatigue, and the moral and ethical challenges related to providing end-of-life care.

  16. Molecular Chaperones in the Pathogenesis of Amyotrophic Lateral Sclerosis: The Role of HSPB1

    PubMed Central

    Capponi, Simona; Geuens, Thomas; Geroldi, Alessandro; Origone, Paola; Verdiani, Simonetta; Cichero, Elena; Adriaenssens, Elias; De Winter, Vicky; Bandettini di Poggio, Monica; Barberis, Marco; Chiò, Adriano; Fossa, Paola; Mandich, Paola; Bellone, Emilia

    2016-01-01

    ABSTRACT Genetic discoveries in amyotrophic lateral sclerosis (ALS) have a significant impact on deciphering molecular mechanisms of motor neuron degeneration but, despite recent advances, the etiology of most sporadic cases remains elusive. Several cellular mechanisms contribute to the motor neuron degeneration in ALS, including RNA metabolism, cellular interactions between neurons and nonneuronal cells, and seeding of misfolded protein with prion‐like propagation. In this scenario, the importance of protein turnover and degradation in motor neuron homeostasis gained increased recognition. In this study, we evaluated the role of the candidate gene HSPB1, a molecular chaperone involved in several proteome‐maintenance functions. In a cohort of 247 unrelated Italian ALS patients, we identified two variants (c.570G>C, p.Gln190His and c.610dupG, p.Ala204Glyfs*6). Functional characterization of the p.Ala204Glyfs*6 demonstrated that the mutant protein alters HSPB1 dynamic equilibrium, sequestering the wild‐type protein in a stable dimer and resulting in a loss of chaperone‐like activity. Our results underline the relevance of identifying rare but pathogenic variations in sporadic neurodegenerative diseases, suggesting a possible correlation between specific pathomechanisms linked to HSPB1 mutations and the associated neurological phenotype. Our study provides additional lines of evidence to support the involvement of HSPB1 in the pathogenesis of sporadic ALS. PMID:27492805

  17. Speech Movement Measures as Markers of Bulbar Disease in Amyotrophic Lateral Sclerosis

    PubMed Central

    Shellikeri, Sanjana; Green, Jordan R.; Kulkarni, Madhura; Rong, Panying; Martino, Rosemary; Zinman, Lorne

    2016-01-01

    Purpose The goal of this study was to identify the effects of amyotrophic lateral sclerosis (ALS) on tongue and jaw control, both cross-sectionally and longitudinally. The data were examined in the context of their utility as a diagnostic marker of bulbar disease. Method Tongue and jaw movements were recorded cross-sectionally (n = 33 individuals with ALS, 13 controls) and longitudinally (n = 10 individuals with ALS) using a three-dimensional electromagnetic articulography system during the production of the sentence Buy Bobby a puppy. The movements were examined for evidence of changes in size, speed, and duration and with respect to disease severity and time in the study. Results Maximum speed of tongue movements and movement durations were significantly different only at an advanced stage of bulbar ALS compared with the healthy control group. The longitudinal analysis revealed a reduction in tongue movement size and speed with time at early stages of disease, which was not seen cross-sectionally. As speaking rate declined, tongue movements decreased in maximum speed, whereas jaw movements increased in maximum speed. Conclusions Longitudinal analyses of sentence-level kinematic data show their sensitivity to early bulbar impairment. A change in articulatory kinematics can serve as a useful diagnostic marker for bulbar ALS and to track bulbar disease progression in a clinical setting. PMID:27679842

  18. Clinicopathologic variability of the GRN A9D mutation, including amyotrophic lateral sclerosis

    PubMed Central

    Cannon, Ashley; Fujioka, Shinsuke; Rutherford, Nicola J.; Ferman, Tanis J.; Broderick, Daniel F.; Boylan, Kevin B.; Graff-Radford, Neill R.; Uitti, Ryan J.; Rademakers, Rosa; Wszolek, Zbigniew K.

    2013-01-01

    Objective: We examined the clinical and pathologic phenotypes of GRN mutation carriers with the pathogenic A9D (g.26C>A) missense mutation. Methods: Three patients with GRN A9D mutations were evaluated clinically and came to autopsy with subsequent neuropathologic examination. Results: The clinical diagnoses of patients with GRN A9D mutations were amyotrophic lateral sclerosis, atypical extrapyramidal disorder, and behavioral variant frontotemporal dementia. Immunohistochemistry for TAR DNA-binding protein 43 (TDP-43) revealed variability in morphology and distribution of pathology. One patient had notable involvement of motor neurons in the spinal cord as well as type B TDP-43, whereas 2 other patients had type A TDP-43. Conclusions: The clinical presentation of the GRN A9D missense mutation is not restricted to behavioral variant frontotemporal dementia and may include aphasia, extrapyramidal features, and, notably, amyotrophic lateral sclerosis. PMID:23596077

  19. [Diagnostic Criteria for Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex in the Kii Peninsula, Japan].

    PubMed

    Kokubo, Yasumasa

    2015-07-01

    The diagnostic criteria for amyotrophic lateral sclerosis/parkinsonism-dementia complex in the Kii peninsula of Japan (Kii ALS/PDC) have been proposed. Muro disease has been considered an endemic neurodegenerative disease in the southern part of the Kii peninsula. Recent intensive and comprehensive research has revealed it to be a complex and genetically heterogeneous disease. At present, there are four subtypes of Muro disease: sporadic amyotrophic lateral sclerosis (ALS), Kii ALS/PDC with tauopathy, ALS with C9orf72 gene mutation, and ALS with optineurin gene mutation. The present criteria are applicable to only one of these subtypes, Kii ALS/PDC with tauopathy, which is quite similar to ALS/PDC in Guam.

  20. A journey of suffering: living with amyotrophic lateral sclerosis in South Korea.

    PubMed

    Oh, Hyunjin; Schepp, Karen G; McGrath, Barbara B

    2014-06-01

    Amyotrophic lateral sclerosis presents significant challenges for patients because of the devastating disease characteristics and the fact that there is no treatment available. In this article, we explored the illness experiences from the perspectives of patients with amyotrophic lateral sclerosis in the sociocultural context of South Korea. Fifteen patients were observed and interviewed between September 2009 and July 2010 in the metropolitan area of South Korea. We used an ethnographic approach for data collection and analysis. The meta-theme generated was "a journey of suffering," and three themes emerged: (a) off the course, (b) drifting, and (c) on a new boat. Participants experienced multidimensional suffering as the disease progressed. Healthcare professionals should understand that, for many patients, this disease is a process or a series of experiences rather than a single diagnosis. This knowledge would allow healthcare providers to help patients prepare for those needs that arise as the disease worsens.

  1. Targeted Riluzole Delivery by Antioxidant Nanovectors for Treating Amyotrophic Lateral Sclerosis

    DTIC Science & Technology

    2015-06-01

    murine model of amyotrophic lateral sclerosis. HCCs were produced by Dr. James Tour of Rice University and provided to Dr. Grill to assess in his... Rice University. The goal of this proposal was to determine whether functionalized PEG-HCCs could alone, or in combination with riluzole, enhance...Homozygous subjects were grafted with osmotic minipumps filled with either PEG-HCCs (condition A) created and provided by the Tour lab of Rice

  2. Psychological wellbeing and quality of life in amyotrophic lateral sclerosis: a review.

    PubMed

    Pagnini, Francesco

    2013-01-01

    Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with a progressive and rapid course that, so far, cannot be stopped or reversed. The psychological impact of the disease is huge, on both patients and caregivers. This review summarizes studies that have investigated quality of life, depression, anxiety, pain, spiritual and existential issues, hope, and hopelessness in the ALS field, with attention to both patients and their caregivers. Psychological support and the possible role of psychologists in the ALS field are also discussed.

  3. Amyotrophic lateral sclerosis and Alzheimer's disease--clinical and neuropathological considerations in two cases.

    PubMed

    Rusina, R; Sheardová, K; Rektorová, I; Ridzon, P; Kulist'ák, P; Matej, R

    2007-07-01

    Amyotrophic lateral sclerosis (ALS) may be accompanied by cognitive impairment; when present, it is mainly in the form of frontotemporal impairment. We report on two cases with clinically defined ALS that subsequently developed dementia. Neuropathological examination showed not only the typical neuropathological hallmarks characteristic of ALS but, surprisingly, also showed neurofibrillary tangles and neuritic plaques in sufficient numbers to fulfill the diagnostic criteria of definite Alzheimer's disease.

  4. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.

    PubMed

    Bannwarth, Sylvie; Ait-El-Mkadem, Samira; Chaussenot, Annabelle; Genin, Emmanuelle C; Lacas-Gervais, Sandra; Fragaki, Konstantina; Berg-Alonso, Laetitia; Kageyama, Yusuke; Serre, Valérie; Moore, David G; Verschueren, Annie; Rouzier, Cécile; Le Ber, Isabelle; Augé, Gaëlle; Cochaud, Charlotte; Lespinasse, Françoise; N'Guyen, Karine; de Septenville, Anne; Brice, Alexis; Yu-Wai-Man, Patrick; Sesaki, Hiromi; Pouget, Jean; Paquis-Flucklinger, Véronique

    2014-08-01

    Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these

  5. Efficacy of peptide nucleic acid and selected conjugates against specific cellular pathologies of amyotrophic lateral sclerosis.

    PubMed

    Browne, Elisse C; Parakh, Sonam; Duncan, Luke F; Langford, Steven J; Atkin, Julie D; Abbott, Belinda M

    2016-04-01

    Cellular studies have been undertaken on a nonamer peptide nucleic acid (PNA) sequence, which binds to mRNA encoding superoxide dismutase 1, and a series of peptide nucleic acids conjugated to synthetic lipophilic vitamin analogs including a recently prepared menadione (vitamin K) analog. Reduction of both mutant superoxide dismutase 1 inclusion formation and endoplasmic reticulum stress, two of the key cellular pathological hallmarks in amyotrophic lateral sclerosis, by two of the prepared PNA oligomers is reported for the first time.

  6. Masticatory muscle pain and progressive mouth opening limitation caused by amyotrophic lateral sclerosis: a case report.

    PubMed

    Pang, Kang Mi; Park, Ji Woon

    2015-01-01

    This article reports a case of masticatory muscle pain and progressive limited mouth opening secondary to amyotrophic lateral sclerosis (ALS), popularly known as Lou Gehrig's disease. The symptoms were first mistaken as those of temporomandibular disorders, before fatty degeneration of all masticatory muscles were discovered on magnetic resonance imaging (MRI). ALS should be considered in the differential diagnosis process when the patient presents with longstanding progressive mouth opening limitation associated with pain. MRI could facilitate the diagnostic process.

  7. Diffusion tensor imaging analysis of sequential spreading of disease in amyotrophic lateral sclerosis confirms patterns of TDP-43 pathology.

    PubMed

    Kassubek, Jan; Müller, Hans-Peter; Del Tredici, Kelly; Brettschneider, Johannes; Pinkhardt, Elmar H; Lulé, Dorothée; Böhm, Sarah; Braak, Heiko; Ludolph, Albert C

    2014-06-01

    Diffusion tensor imaging can identify amyotrophic lateral sclerosis-associated patterns of brain alterations at the group level. Recently, a neuropathological staging system for amyotrophic lateral sclerosis has shown that amyotrophic lateral sclerosis may disseminate in a sequential regional pattern during four disease stages. The objective of the present study was to apply a new methodological diffusion tensor imaging-based approach to automatically analyse in vivo the fibre tracts that are prone to be involved at each neuropathological stage of amyotrophic lateral sclerosis. Two data samples, consisting of 130 diffusion tensor imaging data sets acquired at 1.5 T from 78 patients with amyotrophic lateral sclerosis and 52 control subjects; and 55 diffusion-tensor imaging data sets at 3.0 T from 33 patients with amyotrophic lateral sclerosis and 22 control subjects, were analysed by a tract of interest-based fibre tracking approach to analyse five tracts that become involved during the course of amyotrophic lateral sclerosis: the corticospinal tract (stage 1); the corticorubral and the corticopontine tracts (stage 2); the corticostriatal pathway (stage 3); the proximal portion of the perforant path (stage 4); and two reference pathways. The statistical analyses of tracts of interest showed differences between patients with amyotrophic lateral sclerosis and control subjects for all tracts. The significance level of the comparisons at the group level was lower, the higher the disease stage with corresponding involved fibre tracts. Both the clinical phenotype as assessed by the amyotrophic lateral sclerosis functional rating scale-revised and disease duration correlated significantly with the resulting staging scheme. In summary, the tract of interest-based technique allowed for individual analysis of predefined tract structures, thus making it possible to image in vivo the disease stages in amyotrophic lateral sclerosis. This approach can be used not only for

  8. Novel Neuroprotective Multicomponent Therapy for Amyotrophic Lateral Sclerosis Designed by Networked Systems.

    PubMed

    Herrando-Grabulosa, Mireia; Mulet, Roger; Pujol, Albert; Mas, José Manuel; Navarro, Xavier; Aloy, Patrick; Coma, Mireia; Casas, Caty

    2016-01-01

    Amyotrophic Lateral Sclerosis is a fatal, progressive neurodegenerative disease characterized by loss of motor neuron function for which there is no effective treatment. One of the main difficulties in developing new therapies lies on the multiple events that contribute to motor neuron death in amyotrophic lateral sclerosis. Several pathological mechanisms have been identified as underlying events of the disease process, including excitotoxicity, mitochondrial dysfunction, oxidative stress, altered axonal transport, proteasome dysfunction, synaptic deficits, glial cell contribution, and disrupted clearance of misfolded proteins. Our approach in this study was based on a holistic vision of these mechanisms and the use of computational tools to identify polypharmacology for targeting multiple etiopathogenic pathways. By using a repositioning analysis based on systems biology approach (TPMS technology), we identified and validated the neuroprotective potential of two new drug combinations: Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine. In addition, we estimated their molecular mechanisms of action in silico and validated some of these results in a well-established in vitro model of amyotrophic lateral sclerosis based on cultured spinal cord slices. The results verified that Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine promote neuroprotection of motor neurons and reduce microgliosis.

  9. Novel Neuroprotective Multicomponent Therapy for Amyotrophic Lateral Sclerosis Designed by Networked Systems

    PubMed Central

    Herrando-Grabulosa, Mireia; Mulet, Roger; Pujol, Albert; Mas, José Manuel; Navarro, Xavier; Aloy, Patrick; Coma, Mireia; Casas, Caty

    2016-01-01

    Amyotrophic Lateral Sclerosis is a fatal, progressive neurodegenerative disease characterized by loss of motor neuron function for which there is no effective treatment. One of the main difficulties in developing new therapies lies on the multiple events that contribute to motor neuron death in amyotrophic lateral sclerosis. Several pathological mechanisms have been identified as underlying events of the disease process, including excitotoxicity, mitochondrial dysfunction, oxidative stress, altered axonal transport, proteasome dysfunction, synaptic deficits, glial cell contribution, and disrupted clearance of misfolded proteins. Our approach in this study was based on a holistic vision of these mechanisms and the use of computational tools to identify polypharmacology for targeting multiple etiopathogenic pathways. By using a repositioning analysis based on systems biology approach (TPMS technology), we identified and validated the neuroprotective potential of two new drug combinations: Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine. In addition, we estimated their molecular mechanisms of action in silico and validated some of these results in a well-established in vitro model of amyotrophic lateral sclerosis based on cultured spinal cord slices. The results verified that Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine promote neuroprotection of motor neurons and reduce microgliosis. PMID:26807587

  10. Information-seeking Behavior and Information Needs in Patients With Amyotrophic Lateral Sclerosis: Analyzing an Online Patient Community.

    PubMed

    Oh, Juyeon; Kim, Jung A

    2017-02-22

    A few studies have examined the specific informational needs of the population with amyotrophic lateral sclerosis. The aims of this study were to describe the information-seeking behavior and information needs of patients with amyotrophic lateral sclerosis and their families in Korea by analyzing messages from an online patient community. A total of 1047 messages from the question and answer forum of the "Lou Gehrig's Disease Network" (http://cafe.daum.net/alsfree) from January 2010 to September 2015 were collected. The word frequency, main questions, and asker of the messages were analyzed and coded. Terms such as "hospital," "mother," "father," "gastrostomy," and "ALS" were most frequently identified. The most commonly mentioned main topic was about disease-specific information, while the most frequent subcategory was symptoms or management of symptoms. Other prominent categories concerned information about treatment, rehabilitation, and the medical system. The people who wrote the questions were mostly the son/daughter of patients with amyotrophic lateral sclerosis. Patients with amyotrophic lateral sclerosis and their family members commonly obtained information by posting their inquiries online and have a variety of questions regarding amyotrophic lateral sclerosis in this study. The findings of this study can be used as a base of information for developing educational programs and resources for patients with amyotrophic lateral sclerosis and their families.

  11. The ratio of N-acetyl aspartate to glutamate correlates with disease duration of amyotrophic lateral sclerosis.

    PubMed

    Sako, Wataru; Abe, Takashi; Izumi, Yuishin; Harada, Masafumi; Kaji, Ryuji

    2016-05-01

    Glutamate (Glu)-induced excitotoxicity has been implicated in the neuronal loss of amyotrophic lateral sclerosis. To test the hypothesis that Glu in the primary motor cortex contributes to disease severity and/or duration, the Glu level was investigated using MR spectroscopy. Seventeen patients with amyotrophic lateral sclerosis were diagnosed according to the El Escorial criteria for suspected, possible, probable or definite amyotrophic lateral sclerosis, and enrolled in this cross-sectional study. We measured metabolite concentrations, including N-acetyl aspartate (NAA), creatine, choline, inositol, Glu and glutamine, and performed partial correlation between each metabolite concentration or NAA/Glu ratio and disease severity or duration using age as a covariate. Considering our hypothesis that Glu is associated with neuronal cell death in amyotrophic lateral sclerosis, we investigated the ratio of NAA to Glu, and found a significant correlation between NAA/Glu and disease duration (r=-0.574, p=0.02). The "suspected" amyotrophic lateral sclerosis patients showed the same tendency as possible, probable and definite amyotrophic lateral sclerosis patients in regard to correlation of NAA/Glu ratio with disease duration. The other metabolites showed no significant correlation. Our findings suggested that glutamatergic neurons are less vulnerable compared to other neurons and this may be because inhibitory receptors are mainly located presynaptically, which supports the notion of Glu-induced excitotoxicity.

  12. Soluble RAGE Treatment Delays Progression of Amyotrophic Lateral Sclerosis in SOD1 Mice

    PubMed Central

    Juranek, Judyta K.; Daffu, Gurdip K.; Geddis, Matthew S.; Li, Huilin; Rosario, Rosa; Kaplan, Benjamin J.; Kelly, Lauren; Schmidt, Ann Marie

    2016-01-01

    The etiology of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized by progressive muscle weakness and spasticity, remains largely unknown. Approximately 5–10% of cases are familial, and of those, 15–20% are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Mutations of the SOD1 gene interrupt cellular homeostasis and contribute to cellular toxicity evoked by the presence of altered SOD1, along with other toxic species, such as advanced glycation end products (AGEs). AGEs trigger activation of their chief cell surface receptor, RAGE (receptor for advanced glycation end products), and induce RAGE-dependent cellular stress and inflammation in neurons, thereby affecting their function and leading to apoptosis. Here, we show for the first time that the expression of RAGE is higher in the SOD1 transgenic mouse model of ALS vs. wild-type mouse spinal cord. We tested whether pharmacological blockade of RAGE may delay the onset and progression of disease in this mouse model. Our findings reveal that treatment of SOD1 transgenic mice with soluble RAGE (sRAGE), a natural competitor of RAGE that sequesters RAGE ligands and blocks their interaction with cell surface RAGE, significantly delays the progression of ALS and prolongs life span compared to vehicle treatment. We demonstrate that in sRAGE-treated SOD1 transgenic animals at the final stage of the disease, a significantly higher number of neurons and lower number of astrocytes is detectable in the spinal cord. We conclude that RAGE antagonism may provide a novel therapeutic strategy for ALS intervention. PMID:27242430

  13. Autoimmune-like hepatitis during masitinib therapy in an amyotrophic lateral sclerosis patient

    PubMed Central

    Salvado, Maria; Vargas, Victor; Vidal, Marta; Simon-Talero, Macarena; Camacho, Jessica; Gamez, Josep

    2015-01-01

    We report a case of acute severe hepatitis resulting from masitinib in a young amyotrophic lateral sclerosis patient. Hepatotoxicity induced by masitinib, a tyrosine kinase inhibitor, is usually transient with mild elevation of transaminases, although acute hepatitis has been not reported to date. The hepatitis was resolved after masitinib was discontinued and a combination of prednisone and azathioprine was started. The transaminases returned to baseline normal values five months later. This is the first case in the hepatitis literature associated with masitinib. The autoimmune role of this drug-induced liver injury is discussed. Physicians should be aware of this potential complication. PMID:26420975

  14. Application of botulinum toxin to treat sialorrhea in amyotrophic lateral sclerosis patients: a literature review.

    PubMed

    Oliveira, Ademar Francisco de; Silva, Gêssyca Adryene de Menezes; Almeida, Débora Milenna Xavier

    2016-01-01

    Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease characterized by the degeneration of motor neurons, which are the central nervous system cells that control voluntary muscle movements. The excessive salivation (sialorrhea) is present in approximately 50% of amyotrophic lateral sclerosis cases. Thus, some alternative therapeutic methods are sought, such as anticholinergic drugs and surgery. Recently the use of botulinum toxin applied at a midpoint of the salivary glands, often guided by ultrasound, have demonstrated positive results. The objective was to review the literature to demonstrate an alternative method to treatments of sialorrhea in patients with amyotrophic lateral sclerosis. In recent studies, the efficacy of botulinum toxin is confirmed, although new applications are required. Since the side effects are negligible, this is an alternative to treat amyotrophic lateral sclerosis, and other patients with diseases that present sialorrhea. RESUMO Esclerose lateral amiotrófica é uma doença neurodegenerativa progressiva e fatal, caracterizada pela degeneração dos neurônios motores, as células do sistema nervoso central que controlam os movimentos voluntários dos músculos. A salivação excessiva (sialorreia) está presente em cerca de 50% dos casos de esclerose lateral amiotrófica. Dessa forma, surgem medidas terapêuticas alternativas como drogas anticolinérgicas e cirurgia, e recentemente, o uso da toxina botulínica, aplicada em um ponto central das glândulas salivares, muitas vezes guiado por ultrassonografia, demostrou resultados positivos. Objetivou-se revisar a literatura no intuito de demonstrar um método alternativo aos tratamentos de sialorreia em pacientes com esclerose lateral amiotrófica. Em estudos recentes, a eficácia do tratamento com toxina botulínica foi confirmada e, mesmo requerendo novas aplicações, os efeitos colaterais são ínfimos. Ela surge então como alternativa não só ao

  15. [Amyotrophic lateral sclerosis in literature, cinema and television].

    PubMed

    Collado-Vázquez, Susana; Carrillo, Jesús María

    2014-07-01

    Introduccion. La esclerosis lateral amiotrofica (ELA) es una enfermedad neurodegenerativa de curso progresivo que afecta a las motoneuronas corticoespinales y medulares, y que se manifiesta principalmente con debilidad muscular, amiotrofia e hiperreflexia. Su incidencia es de 0,4-2,4 casos/100.000 habitantes/año, y su prevalencia, de 4-6 casos/100.000 habitantes. Es mas frecuente en varones adultos mayores de 50 años. Se han mostrado diversas enfermedades neurologicas en la literatura, el cine y la television, entre ellas la ELA, que se ha presentado de forma correcta y realista. Objetivo. Analizar el abordaje que la literatura, el cine y la television han hecho de la ELA. Desarrollo. Existen diversas obras literarias que abordan la ELA, como El desencuentro, Lou Gehrig: the luckiest man o Martes con mi viejo profesor; el cine tambien ha reflejado esta enfermedad en titulos como El orgullo de los Yankees, My love beside me (closer to Heaven) o Derecho a morir; y en la television se ha mostrado esta enfermedad en series, documentales y telefilmes, como Martes con mi viejo profesor, Jenifer o Mi vida con Lou Gehrig. La mayor parte de las obras es de tipo biografico y de testimonio, y muestra la enfermedad con realismo, con la intencion de dar a conocer la ELA y de concienciar a la poblacion. Conclusion. La literatura, el cine y la television han mostrado la ELA de forma realista y creible, a diferencia de otras enfermedades de origen neurologico.

  16. Six important themes in amyotrophic lateral sclerosis (ALS) research, 1999.

    PubMed

    Rowland, L P

    2000-11-01

    My assignment was to identify the 6 most important ALS papers published in 1999 but, great to relate, there were too many excellent candidates. Rather than confining the search to individual papers, six major themes seemed appropriate for discussion: 1) The study of transgenic mice that carry a mutated human gene for superoxide dismutase-1 (SOD1) has led to many far-reaching advances in ALS research. The mice are regarded as the best test system to evaluate potential therapies, including creatine. Inconsistencies between efficacy in mice and people are noted, however. 2) Transgenic mice have also been used to evaluate the role of glutamate toxicity in the pathogenesis of ALS, a dominant theory. 3) The role of mitochondria in the pathogenesis of ALS is gathering increasing attention. 4) The role of neurofilaments in the pathogenesis of ALS has provided new twists in mice and people. 5) Motor neuropathy is the most important differential diagnosis of ALS. 6) Gene therapy, as exemplified by the use of stem cells, has been applied successfully to animal models of other inherited diseases of the central nervous system.

  17. Modelling and treating amyotrophic lateral sclerosis through induced-pluripotent stem cells technology.

    PubMed

    Bohl, Delphine; Pochet, Roland; Mitrecic, Dinko; Nicaise, Charles

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease affecting primarily the population of motor neurons, even though a non-cell autonomous component, involving neighbouring non-neuronal cells, is more and more described. Despite 140 years of disease experience, still no efficient treatment exists against ALS. The inability to readily obtain the faulty cell types relevant to ALS has impeded progress in drug discovery for decades. However, the pioneer work of Shinya Yamanaka in 2007 in the stem cell field was a real breakthrough. Recent advances in cell reprogramming now grant access to significant quantities of CNS disease-affected cells. Induced pluripotent stem cells (iPSc) have been recently derived from patients carrying mutations linked to familial forms of ALS as well as from sporadic patients. Precise and mature protocols allow now their differentiation into ALS-relevant cell subtypes; sustainable and renewable sources of human motor neurons or glia are being available for ALS disease modelling, drug screening or for the development of cell therapies. In few years, the proof-of-concept was made that ALS disease-related phenotypes can be reproduced with iPSc and despite some remaining challenges, we are now not so far to provide platforms for the investigation of ALS therapeutics. This paper also reviews the pioneering studies regarding the applicability of iPSc technology in ALS animal models. From modest slowing down of ALS progression to no severe adverse effects, iPSc-based cell therapy resulted in promising premises in ALS preclinical paradigms, although long-term surveys are highly recommended.

  18. Prognostic Factors in Amyotrophic Lateral Sclerosis: A Population-Based Study

    PubMed Central

    Moura, Mirian Conceicao; Novaes, Maria Rita Carvalho Garbi; Eduardo, Emanoel Junio; Zago, Yuri S. S. P.; Freitas, Ricardo Del Negro Barroso; Casulari, Luiz Augusto

    2015-01-01

    Objective To determine the prognostic factors associated with survival in amyotrophic lateral sclerosis at diagnosis. Methods This retrospective population-based study evaluated 218 patients treated with riluzole between 2005 and 2014 and described their clinical and demographic profiles after the analysis of clinical data and records from the mortality information system in the Federal District, Brazil. Cox multivariate regression analysis was conducted for the parameters found. Results The study sample consisted of 132 men and 86 women with a mean age at disease onset of 57.2±12.3 years; 77.6% of them were Caucasian. The mean periods between disease onset and diagnosis were 22.7 months among men and 23.5 months among women, and the mean survival periods were 45.7±47.0 months among men and 39.3±29.8 months among women. In addition, 80.3% patients presented non-bulbar-onset amyotrophic lateral sclerosis, and 19.7% presented bulbar-onset. Cox regression analysis indicated worse prognosis for body mass index (BMI) <25 kg/m2 (relative risk [RR]: 3.56, 95% confidence interval [CI]: 1.44–8.86), age >75 years (RR: 12.47, 95% CI: 3.51–44.26), and bulbar-onset (RR: 4.56, 95% CI: 2.06–10.12). Electromyography did not confirm the diagnosis in 55.6% of the suspected cases and in 27.9% of the bulbar-onset cases. Conclusions The factors associated with lower survival in amyotrophic lateral sclerosis were age >75 years, BMI <25 kg/m2, and bulbar-onset. PMID:26517122

  19. System xC- is a mediator of microglial function and its deletion slows symptoms in amyotrophic lateral sclerosis mice.

    PubMed

    Mesci, Pinar; Zaïdi, Sakina; Lobsiger, Christian S; Millecamps, Stéphanie; Escartin, Carole; Seilhean, Danielle; Sato, Hideyo; Mallat, Michel; Boillée, Séverine

    2015-01-01

    Amyotrophic lateral sclerosis is the most common adult-onset motor neuron disease and evidence from mice expressing amyotrophic lateral sclerosis-causing SOD1 mutations suggest that neurodegeneration is a non-cell autonomous process where microglial cells influence disease progression. However, microglial-derived neurotoxic factors still remain largely unidentified in amyotrophic lateral sclerosis. With excitotoxicity being a major mechanism proposed to cause motor neuron death in amyotrophic lateral sclerosis, our hypothesis was that excessive glutamate release by activated microglia through their system [Formula: see text] (a cystine/glutamate antiporter with the specific subunit xCT/Slc7a11) could contribute to neurodegeneration. Here we show that xCT expression is enriched in microglia compared to total mouse spinal cord and absent from motor neurons. Activated microglia induced xCT expression and during disease, xCT levels were increased in both spinal cord and isolated microglia from mutant SOD1 amyotrophic lateral sclerosis mice. Expression of xCT was also detectable in spinal cord post-mortem tissues of patients with amyotrophic lateral sclerosis and correlated with increased inflammation. Genetic deletion of xCT in mice demonstrated that activated microglia released glutamate mainly through system [Formula: see text]. Interestingly, xCT deletion also led to decreased production of specific microglial pro-inflammatory/neurotoxic factors including nitric oxide, TNFa and IL6, whereas expression of anti-inflammatory/neuroprotective markers such as Ym1/Chil3 were increased, indicating that xCT regulates microglial functions. In amyotrophic lateral sclerosis mice, xCT deletion surprisingly led to earlier symptom onset but, importantly, this was followed by a significantly slowed progressive disease phase, which resulted in more surviving motor neurons. These results are consistent with a deleterious contribution of microglial-derived glutamate during symptomatic

  20. Palliative Care Issues in Amyotrophic Lateral Sclerosis: An Evidenced-Based Review.

    PubMed

    Karam, Chafic Y; Paganoni, Sabrina; Joyce, Nanette; Carter, Gregory T; Bedlack, Richard

    2016-02-01

    As palliative care physicians become increasingly involved in the care of patients with amyotrophic lateral sclerosis (ALS), they will be asked to provide guidance regarding the use of supplements, diet, exercise, and other common preventive medicine interventions. Moreover, palliative care physicians have a crucial role assisting patients with ALS in addressing health care decisions to maximize quality of life and cope with a rapidly disabling disease. It is therefore important for palliative care physicians to be familiar with commonly encountered palliative care issues in ALS. This article provides an evidenced-based review of palliative care options not usually addressed in national and international ALS guidelines.

  1. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

    PubMed

    Neumann, Manuela; Sampathu, Deepak M; Kwong, Linda K; Truax, Adam C; Micsenyi, Matthew C; Chou, Thomas T; Bruce, Jennifer; Schuck, Theresa; Grossman, Murray; Clark, Christopher M; McCluskey, Leo F; Miller, Bruce L; Masliah, Eliezer; Mackenzie, Ian R; Feldman, Howard; Feiden, Wolfgang; Kretzschmar, Hans A; Trojanowski, John Q; Lee, Virginia M-Y

    2006-10-06

    Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

  2. Juvenile amyotrophic lateral sclerosis: Classical wine glass sign on magnetic resonance imaging

    PubMed Central

    Kumar, Saurabh; Aga, Pallavi; Gupta, Aakansha; Kohli, Neera

    2016-01-01

    Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease, is a chronic degenerative neurologic disease and is characterized by the selective involvement of the motor system. Usually, patients present with upper motor neuron (UMN) and lower motor neuron compromise. Degeneration of the UMN in the cerebral cortex is one of the main pathologic changes in ALS. These changes usually affect corticospinal tracts leading to degeneration of the fibers which show characteristic hyperintensities along the tracts leading to the “wine glass sign.” Patients with ALS usually present in the sixth decade of life; presentation in pediatric age in the form of juvenile ALS being rare. PMID:27195035

  3. [Structure of peripheral blood platelets surface in patients with amyotrophic lateral sclerosis and multiple sclerosis].

    PubMed

    Kiktenko, A I; Zlobina, G P; Brusov, O S; Zakharova, M N

    2005-01-01

    Using scanning electronic microscopy of peripheral blood platelets in 32 patients with amyotrophic lateral sclerosis (ALS) and 6 patients with multiple sclerosis (MS), platelets activation, emerging in pseudopodiums formation, aggregation and lysis, was found. Platelets activation was more pronounced in ALS than in MS. It was most markedly seen for quantitative evaluation of the above traits. The features of platelet activation found in the study support the evidence for considering ALS as a systemic disorder being characterized by a broad spectrum of alterations of biological processes.

  4. Amyotrophic Lateral Sclerosis and Organ Donation: Is There Risk of Disease Transmission?

    PubMed Central

    Holmes, Brandon B.; Diamond, Marc I.

    2013-01-01

    A new protocol suggests that patients with amyotrophic lateral sclerosis (ALS) are a viable source of tissue for organ transplantation. However, multiple lines of evidence suggest that many neurodegenerative diseases, including ALS, might progress due to transcellular propagation of protein aggregation among neurons. Transmission of the disease state from donor to host thus may be possible under the permissive circumstances of graft transplantation. We argue for careful patient selection and close longitudinal follow-up of recipients when harvesting organs from individuals with neurodegenerative disease, especially dominantly inherited forms. PMID:23280834

  5. Depression and disease progression in amyotrophic lateral sclerosis: A comprehensive meta-regression analysis.

    PubMed

    Pagnini, Francesco; Manzoni, Gian Mauro; Tagliaferri, Aurora; Gibbons, Chris J

    2015-08-01

    Depression in people with amyotrophic lateral sclerosis, a fatal and progressive neurodegenerative disorder, is a serious issue with important clinical consequences. However, physical impairment may confound the diagnosis when using generic questionnaires. We conducted a comprehensive review of literature. Mean scores from depression questionnaires were meta-regressed on study-level mean time since onset of symptoms. Data from 103 studies (3190 subjects) indicate that the Beck Depression Inventory and, to a lesser degree, the Hospital Anxiety and Depression Scale are influenced by the time since symptom onset, strongly related to physical impairment. Our results suggest that widely used depression scales overestimate depression due to confounding with physical symptoms.

  6. Evidence for a dopaminergic deficit in sporadic amyotrophic lateral sclerosis on positron emission scanning

    SciTech Connect

    Takahashi, Hirohide; Snow, B.J.; Bhatt, M.H.; Peppard, R.; Eisen, A.; Calne, D.B. )

    1993-10-23

    Although rare, the chronic neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and idiopathic parkinsonism coexist to a greater degree than expected by chance. This suggests that patients with ALS may have subclinical lesions of the nigrostriatal dopaminergic pathway. To study this hypothesis, the authors did positron emission tomography with 6-fluorodopa on 16 patients with sporadic ALS and without extrapyramidal disease, and compared the results with age-matched controls. They found a significant progressive fall in 6-fluorodopa uptake with time since diagnosis, and reduced dopaminergic function in 3 patients with ALS of long duration. This supports the hypothesis that ALS and IP may share pathogenesis, and, perhaps, etiology.

  7. Intraneuronal aluminum accumulation in amyotrophic lateral sclerosis and Parkinsonism-dementia of Guam

    SciTech Connect

    Perl, D.P.; Gajdusek, D.C.; Garruto, R.M.; Yanagihara, R.T.; Gibbs, C.J.

    1982-09-10

    Scanning electron microscopy with energy-dispersive x-ray spectrometry was used to analyze the elemental content of neurofibrillary tangle (NFT)-bearing and NFT-free neurons within the Sommer's sector (H1 region) of the hippocampus in Guamanian Chamorros with amyotrophic lateral sclerosis and parkinsonism-dementia and in neurologically normal controls. Preliminary data indicate prominent accumulation of aluminum within the nuclear region and perikaryal cytoplasm of NFT-bearing hippocampal neurons, regardless of the underlying neurological diagnosis. These findings further extend the association between intraneuronal aluminum and NFT formation and support the hypothesis that environmental factors are related to the neurodegenerative changes seen in the Chamorro population.

  8. Palliative Care Issues in Amyotrophic Lateral Sclerosis: An Evidenced-Based Review

    PubMed Central

    Karam, Chafic Y.; Paganoni, Sabrina; Joyce, Nanette; Carter, Gregory T.; Bedlack, Richard

    2015-01-01

    As palliative care physicians become increasingly involved in the care of patients with amyotrophic lateral sclerosis (ALS), they will be asked to provide guidance regarding the use of supplements, diet, exercise, and other common preventive medicine interventions. Moreover, palliative care physicians have a crucial role assisting patients with ALS in addressing health care decisions to maximize quality of life and cope with a rapidly disabling disease. It is therefore important for palliative care physicians to be familiar with commonly encountered palliative care issues in ALS. This article provides an evidenced-based review of palliative care options not usually addressed in national and international ALS guidelines. PMID:25202033

  9. Cronobacter sakazakii DNA Detection in Cerebrospinal Fluid of a Patient with Amyotrophic Lateral Sclerosis Mimic Syndrome

    PubMed Central

    Piombo, Marianna; Chiarello, Daniela; Corbetto, Marzia; Di Pino, Giovanni; Dicuonzo, Giordano; Angeletti, Silvia; Riva, Elisabetta; De Florio, Lucia; Capone, Fioravante; Di Lazzaro, Vincenzo

    2015-01-01

    A 45-year-old male noticed progressive weakness of the right lower limb with gait disturbance. Over the following months, motor deficits worsened, spreading to the right upper limb. Electromyography showed active denervation in the upper and lower limb muscles. A diagnosis of amyotrophic lateral sclerosis (ALS) was made. About 2 years after symptom onset, gradual improvement occurred. Cerebrospinal fluid analysis performed about 3 years after the beginning of symptoms identified Cronobacter sakazakii. Since no other possible causes were identified, we suggest that an almost completely reversible ALS-like syndrome had been triggered by Cronobacter infection in our immunocompetent patient. PMID:26955334

  10. Motor unit changes in thoracic paraspinal muscles in amyotrophic lateral sclerosis.

    PubMed

    de Carvalho, Mamede; Pinto, Susana; Swash, Michael

    2009-01-01

    In 38 amyotrophic lateral sclerosis (ALS) patients and 28 controls, we performed motor unit potential (MUP) analysis in the C-6 and T-5 paraspinal and biceps muscles. In ALS cases, we found similar abnormalities in MUPs in paraspinal and limb muscles. Fasciculation potentials (FPs) were more frequent in biceps than in paraspinal muscles, but fibrillation potentials and positive sharp waves (fibs-sw) were equally frequent in all three muscles. These results confirm the value of paraspinal MUP analysis in the diagnosis of ALS.

  11. A Bibliometric Assessment of Global Ice Bucket Challenge (Amyotrophic Lateral Sclerosis) Research

    PubMed Central

    Ram, Shri

    2016-01-01

    Background This study is a quantitative and qualitative assessment of the global research trends on amyotrophic lateral sclerosis (ALS) (popularly known as Ice Bucket Challenge), through related literatures retrieved from SCOPUS multidisciplinary database for the period 1974-2013. Purpose This study is aimed at analyzing the literature on ALS in terms of document type, language, annual growth, productive country, journal, authors, subject, and most cited articles. Methods The bibliographic data for this study was retrieved from the SCOPUS database using keywords ‘amyotrophic lateral sclerosis’, ‘motor neurone disease’, ‘Charcot disease’, ‘Lou Gehrig's disease’, ‘Ice Bucket Challenge’ available in title, abstract, and keyword fields of Scopus database from 1974 to 2013. Results The literature analysis included 21,750 articles during the period from 1974 to 2013 in different areas of ALS. USA was the most productive country in terms of literature produced, while Neurology was the most productive journal. Conclusion An intensive awareness created by ‘Ice Bucket Challenge’ has attracted masses, and an intensive growth of literature is pertinent on ALS. The results of this study are expressed in terms of growth of literature, output of individual countries, and authors, and will be helpful in collaborative research in future. PMID:27780988

  12. [An autopsy case of amyotrophic lateral sclerosis associated with cervical syringomyelia].

    PubMed

    Hamada, K; Sudoh, K; Fukaura, H; Yanagihara, T; Hamada, T; Tashiro, K; Isu, T

    1990-06-01

    An autopsied case of amyotrophic lateral sclerosis complicated by cervical syringomyelia was reported. The case was a 59-year-old man, who first noticed weakness of both lower extremities at 54-year-old. The weakness spread to both upper extremities within 2 years. Cervical myelography revealed multi-level cervical spondylosis and anterior fusion of C5-C7 was done. But the weakness and atrophy of proximal muscle, diminished deep tendon reflex on upper extremities, hyperreflexia and pathological reflexes on both legs, tongue fasciculation and respiratory muscle weakness developed successively, and the patient died of respiratory distress at 59-year-old. Autopsy revealed multiple independent four syrinxes located at the level between C2-C7. One of these syrinxes had ependymal cell lining and thought to be idiopathic syringomyelia. The other three syrinxes were considered to be the cavitation in association with cervical spondylotic myelopathy. Degeneration and decreasing of spinal anterior horn cells, atrophy of medullary pyramis and Bunina bodies were observed as features of typical amyotrophic lateral sclerosis. Cervical spondylosis as causative lesion of multiple syrinxes was discussed, and relationship between ALS and the syrinxes was not indicated clearly.

  13. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration

    PubMed Central

    Xu, Zihui; Poidevin, Mickael; Li, Xuekun; Li, Yujing; Shu, Liqi; Nelson, David L.; Li, He; Hales, Chadwick M.; Gearing, Marla; Wingo, Thomas S.; Jin, Peng

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share phenotypic and pathologic overlap. Recently, an expansion of GGGGCC repeats in the first intron of C9orf72 was found to be a common cause of both illnesses; however, the molecular pathogenesis of this expanded repeat is unknown. Here we developed both Drosophila and mammalian models of this expanded hexanucleotide repeat and showed that expression of the expanded GGGGCC repeat RNA (rGGGGCC) is sufficient to cause neurodegeneration. We further identified Pur α as the RNA-binding protein of rGGGGCC repeats and discovered that Pur α and rGGGGCC repeats interact in vitro and in vivo in a sequence-specific fashion that is conserved between mammals and Drosophila. Furthermore, overexpression of Pur α in mouse neuronal cells and Drosophila mitigates rGGGGCC repeat-mediated neurodegeneration, and Pur α forms inclusions in the fly eye expressing expanded rGGGGCC repeats, as well as in cerebellum of human carriers of expanded GGGGCC repeats. These data suggest that expanded rGGGGCC repeats could sequester specific RNA-binding protein from their normal functions, ultimately leading to cell death. Taken together, these findings suggest that the expanded rGGGGCC repeats could cause neurodegeneration, and that Pur α may play a role in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia. PMID:23553836

  14. Spatial Elucidation of Spinal Cord Lipid- and Metabolite- Regulations in Amyotrophic Lateral Sclerosis

    PubMed Central

    Hanrieder, Jörg; Ewing, Andrew G.

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressing disease of the central nervous system that is characterized by motor neuron degeneration in the brain stem and the spinal cord. We employed time of flight secondary ion mass spectrometry (ToF-SIMS) to profile spatial lipid- and metabolite- regulations in post mortem human spinal cord tissue from ALS patients to investigate chemical markers of ALS pathogenesis. ToF-SIMS scans and multivariate analysis of image and spectral data were performed on thoracic human spinal cord sections. Multivariate statistics of the image data allowed delineation of anatomical regions of interest based on their chemical identity. Spectral data extracted from these regions were compared using two different approaches for multivariate statistics, for investigating ALS related lipid and metabolite changes. The results show a significant decrease for cholesterol, triglycerides, and vitamin E in the ventral horn of ALS samples, which is presumably a consequence of motor neuron degeneration. Conversely, the biogenic mediator lipid lysophosphatidylcholine and its fragments were increased in ALS ventral spinal cord, pointing towards neuroinflammatory mechanisms associated with neuronal cell death. ToF-SIMS imaging is a promising approach for chemical histology and pathology for investigating the subcellular mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis. PMID:24919836

  15. Structures of the G85R Variant of SOD1 in Familial Amyotrophic Lateral Sclerosis

    SciTech Connect

    Cao, Xiaohang; Antonyuk, Svetlana V.; Seetharaman, Sai V.; Whitson, Lisa J.; Taylor, Alexander B.; Holloway, Stephen P.; Strange, Richard W.; Doucette, Peter A.; Valentine, Joan Selverstone; Tiwari, Ashutosh; Hayward, Lawrence J.; Padua, Shelby; Cohlberg, Jeffrey A.; Hasnain, S. Samar; Hart, P. John

    2008-07-21

    Mutations in the gene encoding human copper-zinc superoxide dismutase (SOD1) cause a dominant form of the progressive neurodegenerative disease amyotrophic lateral sclerosis. Transgenic mice expressing the human G85R SOD1 variant develop paralytic symptoms concomitant with the appearance of SOD1-enriched proteinaceous inclusions in their neural tissues. The process(es) through which misfolding or aggregation of G85R SOD1 induces motor neuron toxicity is not understood. Here we present structures of the human G85R SOD1 variant determined by single crystal x-ray diffraction. Alterations in structure of the metal-binding loop elements relative to the wild type enzyme suggest a molecular basis for the metal ion deficiency of the G85R SOD1 protein observed in the central nervous system of transgenic mice and in purified recombinant G85R SOD1. These findings support the notion that metal-deficient and/or disulfide-reduced mutant SOD1 species contribute to toxicity in SOD1-linked amyotrophic lateral sclerosis.

  16. Factors affecting longitudinal functional decline and survival in amyotrophic lateral sclerosis patients.

    PubMed

    Watanabe, Hazuki; Atsuta, Naoki; Nakamura, Ryoichi; Hirakawa, Akihiro; Watanabe, Hirohisa; Ito, Mizuki; Senda, Jo; Katsuno, Masahisa; Izumi, Yuishin; Morita, Mitsuya; Tomiyama, Hiroyuki; Taniguchi, Akira; Aiba, Ikuko; Abe, Koji; Mizoguchi, Kouichi; Oda, Masaya; Kano, Osamu; Okamoto, Koichi; Kuwabara, Satoshi; Hasegawa, Kazuko; Imai, Takashi; Aoki, Masashi; Tsuji, Shoji; Nakano, Imaharu; Kaji, Ryuji; Sobue, Gen

    2015-06-01

    Our objective was to elucidate the clinical factors affecting functional decline and survival in Japanese amyotrophic lateral sclerosis (ALS) patients. We constructed a multicenter prospective ALS cohort that included 451 sporadic ALS patients in the analysis. We longitudinally utilized the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) as the functional scale, and determined the timing of introduction of a tracheostomy for positive-pressure ventilation and death. A joint modelling approach was employed to identify prognostic factors for functional decline and survival. Age at onset was a common prognostic factor for both functional decline and survival (p < 0.001, p < 0.001, respectively). Female gender (p = 0.019) and initial symptoms, including upper limb weakness (p = 0.010), lower limb weakness (p = 0.008) or bulbar symptoms (p = 0.005), were related to early functional decline, whereas neck weakness as an initial symptom (p = 0.018), non-use of riluzole (p = 0.030) and proximal dominant muscle weakness in the upper extremities (p = 0.01) were related to a shorter survival time. A decline in the ALSFRS-R score was correlated with a shortened survival time (p < 0.001). In conclusion, the factors affecting functional decline and survival in ALS were common in part but different to some extent. This difference has not been previously well recognized but is informative in clinical practice and for conducting trials.

  17. Mutant SOD1 inhibits ER-Golgi transport in amyotrophic lateral sclerosis.

    PubMed

    Atkin, Julie D; Farg, Manal A; Soo, Kai Ying; Walker, Adam K; Halloran, Mark; Turner, Bradley J; Nagley, Phillip; Horne, Malcolm K

    2014-04-01

    Cu/Zn-superoxide dismutase is misfolded in familial and sporadic amyotrophic lateral sclerosis, but it is not clear how this triggers endoplasmic reticulum (ER) stress or other pathogenic processes. Here, we demonstrate that mutant SOD1 (mSOD1) is predominantly found in the cytoplasm in neuronal cells. Furthermore, we show that mSOD1 inhibits secretory protein transport from the ER to Golgi apparatus. ER-Golgi transport is linked to ER stress, Golgi fragmentation and axonal transport and we also show that inhibition of ER-Golgi trafficking preceded ER stress, Golgi fragmentation, protein aggregation and apoptosis in cells expressing mSOD1. Restoration of ER-Golgi transport by over-expression of coatomer coat protein II subunit Sar1 protected against inclusion formation and apoptosis, thus linking dysfunction in ER-Golgi transport to cellular pathology. These findings thus link several cellular events in amyotrophic lateral sclerosis into a single mechanism occurring early in mSOD1 expressing cells.

  18. Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis etiology and survival.

    PubMed

    Beard, John D; Kamel, Freya

    2015-01-01

    Rates of amyotrophic lateral sclerosis (ALS) have been reported to be higher among US military veterans, who currently number more than 21 million, but the causal factor(s) has not been identified. We conducted a review to examine the weight of evidence for associations between military service, deployments, and exposures and ALS etiology and survival. Thirty articles or abstracts published through 2013 were reviewed. Although the current evidence suggests a positive association with ALS etiology, it is too limited to draw firm conclusions regarding associations between military service and ALS etiology or survival. Some evidence suggests that deployment to the 1990-1991 Persian Gulf War may be associated with ALS etiology, but there is currently no strong evidence that any particular military exposure is associated with ALS etiology. Future studies should address the limitations of previous ones, such as reliance on mortality as a surrogate for incidence, a dearth of survival analyses, lack of clinical data, low statistical power, and limited exposure assessment. The Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis (GENEVA) Study is one such study, but additional research is needed to determine whether military-related factors are associated with ALS and to assess potential prevention strategies.

  19. Amyotrophic lateral sclerosis progression and stability of brain-computer interface communication.

    PubMed

    Silvoni, Stefano; Cavinato, Marianna; Volpato, Chiara; Ruf, Carolin A; Birbaumer, Niels; Piccione, Francesco

    2013-09-01

    Our objective was to investigate the relationship between brain-computer interface (BCI) communication skill and disease progression in amyotrophic lateral sclerosis (ALS). We sought also to assess stability of BCI communication performance over time and whether it is related to the progression of neurological impairment before entering the locked-in state. A three years follow-up, BCI evaluation in a group of ALS patients (n = 24) was conducted. For a variety of reasons only three patients completed the three years follow-up. BCI communication skill and disability level, using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, were assessed at admission and at each of the three follow-ups. Multiple non-parametric statistical methods were used to ensure reliability of the dependent variables: correlations, paired test and factor analysis of variance. Results demonstrated no significant relationship between BCI communication skill (BCI-CS) and disease evolution. The patients who performed the follow-up evaluations preserved their BCI-CS over time. Patients' age at admission correlated positively with the ability to achieve control over a BCI. In conclusion, disease evolution in ALS does not affect the ability to control a BCI for communication. BCI performance can be maintained in the different stages of the illness.

  20. A2A adenosine receptors are up-regulated in lymphocytes from amyotrophic lateral sclerosis patients.

    PubMed

    Vincenzi, Fabrizio; Corciulo, Carmen; Targa, Martina; Casetta, Ilaria; Gentile, Mauro; Granieri, Enrico; Borea, Pier Andrea; Popoli, Patrizia; Varani, Katia

    2013-09-01

    Adenosine, a purine nucleoside interacting with A1, A2A, A2B and A3 adenosine receptors (ARs), is a potent endogenous modulator of inflammatory and neuronal processes involved in the pathophysiology of several neurodegenerative diseases. In the present study, ARs were investigated in lymphocytes from patients with amyotrophic lateral sclerosis (ALS) and compared with age-matched healthy subjects. In ALS patients A2AARs were analysed by using RT-PCR, Western blotting and saturation binding experiments. The effect of A2AAR stimulation on cyclic AMP levels was evaluated in lymphocytes from ALS patients and healthy subjects. An up-regulation of A2AARs was observed in ALS patients with respect to healthy subjects while A1, A2B and A3AR affinity and density did not change. In ALS patients, the A2AAR density values correlated with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Furthermore, the stimulation of A2AARs mediated a significant increase in cyclic AMP levels in lymphocytes from ALS patients, with a higher potency than in lymphocytes from healthy subjects. In conclusion, the positive correlation between A2AAR density and ALSFRS-R scores could indicate a possible protective effect of this receptor subtype, representing an interesting starting point for the study of alternative therapeutic approaches for ALS based on A2AAR modulation.

  1. The Cyanobacteria Derived Toxin Beta-N-Methylamino-L-Alanine and Amyotrophic Lateral Sclerosis

    PubMed Central

    Banack, Sandra Anne; Caller, Tracie A.; Stommel, Elijah W.

    2010-01-01

    There is mounting evidence to suggest that environmental factors play a major role in the development of neurodegenerative diseases like ALS (Amyotrophic Lateral Sclerosis). The non-protein amino acid beta-N-methylamino-L-alanine (BMAA) was first associated with the high incidence of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) in Guam, and has been implicated as a potential environmental factor in ALS, Alzheimer’s disease, and other neurodegenerative diseases. BMAA has a number of toxic effects on motor neurons including direct agonist action on NMDA and AMPA receptors, induction of oxidative stress, and depletion of glutathione. As a non-protein amino acid, there is also the strong possibility that BMAA could cause intraneuronal protein misfolding, the hallmark of neurodegeneration. While an animal model for BMAA-induced ALS is lacking, there is substantial evidence to support a link between this toxin and ALS. The ramifications of discovering an environmental trigger for ALS are enormous. In this article, we discuss the history, ecology, pharmacology and clinical ramifications of this ubiquitous, cyanobacteria-derived toxin. PMID:22069578

  2. Military Service, Deployments, and Exposures in Relation to Amyotrophic Lateral Sclerosis Etiology and Survival

    PubMed Central

    Beard, John D.; Kamel, Freya

    2015-01-01

    Rates of amyotrophic lateral sclerosis (ALS) have been reported to be higher among US military veterans, who currently number more than 21 million, but the causal factor(s) has not been identified. We conducted a review to examine the weight of evidence for associations between military service, deployments, and exposures and ALS etiology and survival. Thirty articles or abstracts published through 2013 were reviewed. Although the current evidence suggests a positive association with ALS etiology, it is too limited to draw firm conclusions regarding associations between military service and ALS etiology or survival. Some evidence suggests that deployment to the 1990–1991 Persian Gulf War may be associated with ALS etiology, but there is currently no strong evidence that any particular military exposure is associated with ALS etiology. Future studies should address the limitations of previous ones, such as reliance on mortality as a surrogate for incidence, a dearth of survival analyses, lack of clinical data, low statistical power, and limited exposure assessment. The Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis (GENEVA) Study is one such study, but additional research is needed to determine whether military-related factors are associated with ALS and to assess potential prevention strategies. PMID:25365170

  3. Spatial Elucidation of Spinal Cord Lipid- and Metabolite- Regulations in Amyotrophic Lateral Sclerosis

    NASA Astrophysics Data System (ADS)

    Hanrieder, Jörg; Ewing, Andrew G.

    2014-06-01

    Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressing disease of the central nervous system that is characterized by motor neuron degeneration in the brain stem and the spinal cord. We employed time of flight secondary ion mass spectrometry (ToF-SIMS) to profile spatial lipid- and metabolite- regulations in post mortem human spinal cord tissue from ALS patients to investigate chemical markers of ALS pathogenesis. ToF-SIMS scans and multivariate analysis of image and spectral data were performed on thoracic human spinal cord sections. Multivariate statistics of the image data allowed delineation of anatomical regions of interest based on their chemical identity. Spectral data extracted from these regions were compared using two different approaches for multivariate statistics, for investigating ALS related lipid and metabolite changes. The results show a significant decrease for cholesterol, triglycerides, and vitamin E in the ventral horn of ALS samples, which is presumably a consequence of motor neuron degeneration. Conversely, the biogenic mediator lipid lysophosphatidylcholine and its fragments were increased in ALS ventral spinal cord, pointing towards neuroinflammatory mechanisms associated with neuronal cell death. ToF-SIMS imaging is a promising approach for chemical histology and pathology for investigating the subcellular mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis.

  4. Linking amyotrophic lateral sclerosis and spinal muscular atrophy through RNA-transcriptome homeostasis: a genomics perspective.

    PubMed

    Gama-Carvalho, Margarida; L Garcia-Vaquero, Marina; R Pinto, Francisco; Besse, Florence; Weis, Joachim; Voigt, Aaron; Schulz, Jörg B; De Las Rivas, Javier

    2017-04-01

    In this review, we present our most recent understanding of key biomolecular processes that underlie two motor neuron degenerative disorders, amyotrophic lateral sclerosis, and spinal muscular atrophy. We focus on the role of four multifunctional proteins involved in RNA metabolism (TDP-43, FUS, SMN, and Senataxin) that play a causal role in these diseases. Recent results have led to a novel scenario of intricate connections between these four proteins, bringing transcriptome homeostasis into the spotlight as a common theme in motor neuron degeneration. We review reported functional and physical interactions between these four proteins, highlighting their common association with nuclear bodies and small nuclear ribonucleoprotein particle biogenesis and function. We discuss how these interactions are turning out to be particularly relevant for the control of transcription and chromatin homeostasis, including the recent identification of an association between SMN and Senataxin required to ensure the resolution of DNA-RNA hybrid formation and proper termination by RNA polymerase II. These connections strongly support the existence of common pathways underlying the spinal muscular atrophy and amyotrophic lateral sclerosis phenotype. We also discuss the potential of genome-wide expression profiling, in particular RNA sequencing derived data, to contribute to unravelling the underlying mechanisms. We provide a review of publicly available datasets that have addressed both diseases using these approaches, and highlight the value of investing in cross-disease studies to promote our understanding of the pathways leading to neurodegeneration.

  5. [In search of unknown aetiopathogenesis: from Henry Louis ("Lou") Gehrig to Gianluca Signorini: history of the link between amyotrophic lateral sclerosis and sport].

    PubMed

    Cristani, Alessandro; Romagnoli, Elisa

    2006-01-01

    From "Lou" Gehirg to Gianluca Signorini: the history of almost 70 years of link between amyotrophic lateral sclerosis and sport. From first intuitions and assumptions to late epidemiological evidences supporting the possible relation between Italian soccer and amyotrophic lateral sclerosis; comparison among old and new aetiopathogenetic hypothesis.

  6. The mitochondrial calcium regulator cyclophilin D is an essential component of oestrogen-mediated neuroprotection in amyotrophic lateral sclerosis

    PubMed Central

    Kim, Hyun Jeong; Magranè, Jordi; Starkov, Anatoly A.

    2012-01-01

    Amyotrophic lateral sclerosis is a devastating neurodegenerative disorder that is more prevalent in males than in females. A similar gender difference has been reported in some strains of transgenic mouse models of familial amyotrophic lateral sclerosis harbouring the G93A mutation in CuZn superoxide dismutase. Mitochondrial damage caused by pathological alterations in Ca2+ accumulation is frequently involved in neurodegenerative diseases, including CuZn superoxide dismutase-related amyotrophic lateral sclerosis, but its association with gender is not firmly established. In this study, we examined the effects of genetic ablation of cyclophilin D on gender differences in mice expressing G93A mutant CuZn superoxide dismutase. Cyclophilin D is a mitochondrial protein that promotes mitochondrial damage from accumulated Ca2+. As anticipated, we found that cyclophilin D ablation markedly increased Ca2+ retention in brain mitochondria of both males and females. Surprisingly, cyclophilin D ablation completely abolished the phenotypic advantage of G93A females, with no effect on disease in males. We also found that the 17β-oestradiol decreased Ca2+ retention in brain mitochondria, and that cyclophilin D ablation abolished this effect. Furthermore, 17β-oestradiol protected G93A cortical neurons and spinal cord motor neurons against glutamate toxicity, but the protection was lost in neurons lacking cyclophilin D. Taken together, these results identify a novel mechanism of oestrogen-mediated neuroprotection in CuZn superoxide dismutase-related amyotrophic lateral sclerosis, whereby Ca2+ overload and mitochondrial damage are prevented in a cyclophilin D-dependent manner. Such a protective mechanism may contribute to the lower incidence and later onset of amyotrophic lateral sclerosis, and perhaps other chronic neurodegenerative diseases, in females. PMID:22961554

  7. Evidence for neuronal localisation of enteroviral sequences in motor neurone disease/amyotrophic lateral sclerosis by in situ hybridization.

    PubMed

    Woodall, C J; Graham, D I

    2004-01-01

    Sequences resembling those of human enterovirus type B sequences have been associated with motor neurone disease/amyotrophic lateral sclerosis. In a previous study we detected enteroviral sequences in spinal cord/brain stem from cases of motor neurone disease/amyotrophic lateral sclerosis, but not controls. Adjacent tissue sections to two of those strongly positive for these sequences by reverse-transcriptase polymerase chain reaction were analyzed by in situ hybridization with digoxigenin-labelled virus-specific antisense riboprobes. In one case, a female aged 83 showing 12 month rapid progressive disease, signal was specifically localized to cells identifiable as motor neurones of the anterior horn. In another case, a male aged 63 with a 60-month history of progressive muscle weakness, dysarthia, dyspnoea and increased tendon reflexes, signal was located to neurones in the gracile/cuneate nuclei of the brain stem tissue block that had been analyzed. This case showed loss of neurones in the anterior horn of the spinal cord by histopathologic examination which would account for clinical signs of motor neurone disease/amyotrophic lateral sclerosis. Dysfunction of the gracile/cuneate nuclei might have been masked by the paralytic disease. These structures are adjacent to the hypoglossal nuclei, and suggest either localised dissemination from hypoglossal nuclei or a possible route of dissemination of infection through the brainstem to the hypoglossal nuclei. These findings provide further evidence for the possible involvement of enteroviruses in motor neurone disease/amyotrophic lateral sclerosis.

  8. Expression of MicroRNAs in Human Post-mortem Amyotrophic Lateral Sclerosis Spinal Cords Provides Insight into Disease Mechanisms

    PubMed Central

    Lunn, J. Simon; Paez-Colasante, Ximena; Bender, Diane E.; Yung, Raymond; Sakowski, Stacey A.; Feldman, Eva L.

    2016-01-01

    Amyotrophic lateral sclerosis is a late-onset and terminal neurodegenerative disease. The majority of cases are sporadic with unknown causes and only a small number of cases are genetically linked. Recent evidence suggests that post-transcriptional regulation and epigenetic mechanisms, such as microRNAs, underlie the onset and progression of neurodegenerative disorders; therefore, altered microRNA expression may result in the dysregulation of key genes and biological pathways that contribute to the development of sporadic amyotrophic lateral sclerosis. Using systems biology analyses on postmortem human spinal cord tissue, we identified dysregulated mature microRNAs and their potential targets previously implicated in functional process and pathways associated with the pathogenesis of ALS. Furthermore, we report a global reduction of mature microRNAs, alterations in microRNA processing, and support for a role of the nucleotide binding protein, TAR DNA binding protein 43, in regulating sporadic amyotrophic lateral sclerosis-associated microRNAs, thereby offering a potential underlying mechanism for sporadic amyotrophic lateral sclerosis. PMID:26704906

  9. Expression of microRNAs in human post-mortem amyotrophic lateral sclerosis spinal cords provides insight into disease mechanisms.

    PubMed

    Figueroa-Romero, Claudia; Hur, Junguk; Lunn, J Simon; Paez-Colasante, Ximena; Bender, Diane E; Yung, Raymond; Sakowski, Stacey A; Feldman, Eva L

    2016-03-01

    Amyotrophic lateral sclerosis is a late-onset and terminal neurodegenerative disease. The majority of cases are sporadic with unknown causes and only a small number of cases are genetically linked. Recent evidence suggests that post-transcriptional regulation and epigenetic mechanisms, such as microRNAs, underlie the onset and progression of neurodegenerative disorders; therefore, altered microRNA expression may result in the dysregulation of key genes and biological pathways that contribute to the development of sporadic amyotrophic lateral sclerosis. Using systems biology analyses on postmortem human spinal cord tissue, we identified dysregulated mature microRNAs and their potential targets previously implicated in functional process and pathways associated with the pathogenesis of ALS. Furthermore, we report a global reduction of mature microRNAs, alterations in microRNA processing, and support for a role of the nucleotide binding protein, TAR DNA binding protein 43, in regulating sporadic amyotrophic lateral sclerosis-associated microRNAs, thereby offering a potential underlying mechanism for sporadic amyotrophic lateral sclerosis.

  10. Pseudo-ischaemic ECG in a patient with amyotrophic lateral sclerosis surviving for a decade

    PubMed Central

    Zhang, Jian; Yang, Shi-Wei; Wang, Zheng; Wei, Guang-Ru; Zhou, Yu-Jie

    2012-01-01

    A 58-year-old female with no history of heart disease was admitted to our hospital for abnormal ECG mimicking myocardial ischaemia. The ECG revealed persistent T-wave inversion in almost all leads, especially in precordial leads V2–V6. The patient had no complaints of chest pain, chest distress, short of breath or other atypical myocardial ischaemia symptoms. She had a history of amyotrophic lateral sclerosis (ALS) with a disease course more than 20 years. Examinations help rule out other diseases causing persistent T-wave inversion. Importantly, cardiac catheterisation showed nearly normal coronary arteries that could rule out myocardial ischaemia. Accordingly, the authors presumed that the pseudo-ischaemic ECG was associated with ALS in this patient. The findings of the present case provide new evidence that autonomic nervous system may involve in the pathophysiological progress of ALS. PMID:22665549

  11. An early history of Japanese amyotrophic lateral sclerosis (ALS) and the current significance.

    PubMed

    Abe, Koji

    2017-03-30

    The present review focuses an early history of Japanese amyotrophic lateral sclerosis (ALS) and the current significance in comparison to previously known and newly found reports on Japanese ALS. After a preliminary case report of ALS by Masamichi Hirai on 1890, 2 completed reports were simultaneously published within 2 weeks of 1891 by Momojiro Nakamura and Zenjiro Inoue, followed by Eikichi Watanabe's report on 1892. After Shonosuke Hasegawa's and Hiroshi Kawahara's case reports on 1894-1896, Aihiko Sata first reported an autopsy case of ALS on 1897. The great contribution of Kinnosuke Miura was also introduced for the naming and pathogenesis in the early stage of ALS history in Japan during 1893-1911.

  12. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

    PubMed

    Cirulli, Elizabeth T; Lasseigne, Brittany N; Petrovski, Slavé; Sapp, Peter C; Dion, Patrick A; Leblond, Claire S; Couthouis, Julien; Lu, Yi-Fan; Wang, Quanli; Krueger, Brian J; Ren, Zhong; Keebler, Jonathan; Han, Yujun; Levy, Shawn E; Boone, Braden E; Wimbish, Jack R; Waite, Lindsay L; Jones, Angela L; Carulli, John P; Day-Williams, Aaron G; Staropoli, John F; Xin, Winnie W; Chesi, Alessandra; Raphael, Alya R; McKenna-Yasek, Diane; Cady, Janet; Vianney de Jong, J M B; Kenna, Kevin P; Smith, Bradley N; Topp, Simon; Miller, Jack; Gkazi, Athina; Al-Chalabi, Ammar; van den Berg, Leonard H; Veldink, Jan; Silani, Vincenzo; Ticozzi, Nicola; Shaw, Christopher E; Baloh, Robert H; Appel, Stanley; Simpson, Ericka; Lagier-Tourenne, Clotilde; Pulst, Stefan M; Gibson, Summer; Trojanowski, John Q; Elman, Lauren; McCluskey, Leo; Grossman, Murray; Shneider, Neil A; Chung, Wendy K; Ravits, John M; Glass, Jonathan D; Sims, Katherine B; Van Deerlin, Vivianna M; Maniatis, Tom; Hayes, Sebastian D; Ordureau, Alban; Swarup, Sharan; Landers, John; Baas, Frank; Allen, Andrew S; Bedlack, Richard S; Harper, J Wade; Gitler, Aaron D; Rouleau, Guy A; Brown, Robert; Harms, Matthew B; Cooper, Gregory M; Harris, Tim; Myers, Richard M; Goldstein, David B

    2015-03-27

    Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.

  13. CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients.

    PubMed

    Chiò, Adriano; Mora, Gabriele; Sabatelli, Mario; Caponnetto, Claudia; Traynor, Bryan J; Johnson, Janel O; Nalls, Mike A; Calvo, Andrea; Moglia, Cristina; Borghero, Giuseppe; Monsurrò, Maria Rosaria; La Bella, Vincenzo; Volanti, Paolo; Simone, Isabella; Salvi, Fabrizio; Logullo, Francesco O; Nilo, Riva; Battistini, Stefania; Mandrioli, Jessica; Tanel, Raffaella; Murru, Maria Rita; Mandich, Paola; Zollino, Marcella; Conforti, Francesca L; Brunetti, Maura; Barberis, Marco; Restagno, Gabriella; Penco, Silvana; Lunetta, Christian

    2015-04-01

    Mutations in CHCHD10 have recently been described as a cause of frontotemporal dementia (FTD) comorbid with amyotrophic lateral sclerosis (ALS). The aim of this study was to assess the frequency and clinical characteristics of CHCHD10 mutations in Italian patients diagnosed with familial (n = 64) and apparently sporadic ALS (n = 224). Three apparently sporadic patients were found to carry c.100C>T (p.Pro34Ser) heterozygous variant in the exon 2 of CHCHD10. This mutation had been previously described in 2 unrelated French patients with FTD-ALS. However, our patients had a typical ALS, without evidence of FTD, cerebellar or extrapyramidal signs, or sensorineural deficits. We confirm that CHCHD10 mutations account for ∼ 1% of Italian ALS patients and are a cause of disease in subjects without dementia or other atypical clinical signs.

  14. Role of PET and SPECT in the Study of Amyotrophic Lateral Sclerosis

    PubMed Central

    Cuccurullo, Vincenzo; Pagani, Marco; Valentini, Maria Consuelo; Mansi, Luigi

    2014-01-01

    Amyotrophic lateral sclerosis has been defined as a “heterogeneous group of neurodegenerative syndromes characterized by progressive muscle paralysis caused by the degeneration of motor neurons allocated in primary motor cortex, brainstem, and spinal cord.” A comprehensive diagnostic workup for ALS usually includes several electrodiagnostic, clinical laboratory and genetic tests. Neuroimaging exams, such as computed tomography, magnetic resonance imaging and spinal cord myelogram, may also be required. Nuclear medicine, with PET and SPECT, may also play a role in the evaluation of patients with ALS, and provide additional information to the clinicians. This paper aims to offer to the reader a comprehensive review of the different radiotracers for the assessment of the metabolism of glucose (FDG), the measurement of cerebral blood flow (CBF), or the evaluation of neurotransmitters, astrocytes, and microglia by means of newer and not yet clinically diffuse radiopharmaceuticals. PMID:24818133

  15. Nuclear transport dysfunction: a common theme in amyotrophic lateral sclerosis and frontotemporal dementia.

    PubMed

    Jovičić, Ana; Paul, Joseph W; Gitler, Aaron D

    2016-08-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping genetic factors and pathology. On the cellular level, a majority of ALS and FTD cases are characterized by nuclear clearance and cytoplasmic aggregation of otherwise nuclear proteins, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma. Recent studies investigating cellular pathways perturbed by genetic risk factors for ALS/FTD converge on nucleocytoplasmic transport dysfunction as a mechanism leading to disease pathophysiology. We propose that mutations in FUS and hexanucleotide expansions in C9orf72 and aging all converge on the impairment of nucleocytoplasmic transport, which results in the hallmark pathological feature of ALS/FTD - cytoplasmic aggregation of TDP-43 or FUS.

  16. Tools and talk: an evolutionary perspective on the functional deficits associated with amyotrophic lateral sclerosis.

    PubMed

    Eisen, Andrew; Turner, Martin R; Lemon, Roger

    2014-04-01

    We propose that amyotrophic lateral sclerosis (ALS), and frontotemporal dementia may be viewed as a failure of interlinked functional complexes having their origins in key evolutionary adaptations. We discuss how hand-arm function, locomotion, brainstem function (involving vocalization/speech, swallowing and breathing), and cognitive impairment share complex, interdependent evolutionary adaptations that can be traced back several million years. Fine movements of the hand facilitated tool-making and use enhanced by development of bipedalism. Development of the larynx and integration of respiratory control were central to vocalization, which when combined with gesture are intermediary to human language. These adaptations were accompanied by progressive encephalization, with development of Theory of Mind to facilitate socialization. The varied clinical phenotypes of ALS can thus be understood in the context of inter-related functional complexes that subserve "Tools and Talk"; they have a long evolutionary history and are related to specific developmental neural and gene networks.

  17. Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations

    PubMed Central

    Tokuda, Eiichi; Furukawa, Yoshiaki

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease affecting both upper and lower motor neurons, and currently, there is no cure or effective treatment. Mutations in a gene encoding a ubiquitous antioxidant enzyme, Cu,Zn-superoxide dismutase (SOD1), have been first identified as a cause of familial forms of ALS. It is widely accepted that mutant SOD1 proteins cause the disease through a gain in toxicity but not through a loss of its physiological function. SOD1 is a major copper-binding protein and regulates copper homeostasis in the cell; therefore, a toxicity of mutant SOD1 could arise from the disruption of copper homeostasis. In this review, we will briefly review recent studies implying roles of copper homeostasis in the pathogenesis of SOD1-ALS and highlight the therapeutic interventions focusing on pharmacological as well as genetic regulations of copper homeostasis to modify the pathological process in SOD1-ALS. PMID:27136532

  18. Maple Syrup Decreases TDP-43 Proteotoxicity in a Caenorhabditis elegans Model of Amyotrophic Lateral Sclerosis (ALS).

    PubMed

    Aaron, Catherine; Beaudry, Gabrielle; Parker, J Alex; Therrien, Martine

    2016-05-04

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing death of the motor neurons. Proteotoxicity caused by TDP-43 protein is an important aspect of ALS pathogenesis, with TDP-43 being the main constituent of the aggregates found in patients. We have previously tested the effect of different sugars on the proteotoxicity caused by the expression of mutant TDP-43 in Caenorhabditis elegans. Here we tested maple syrup, a natural compound containing many active molecules including sugars and phenols, for neuroprotective activity. Maple syrup decreased several age-dependent phenotypes caused by the expression of TDP-43(A315T) in C. elegans motor neurons and requires the FOXO transcription factor DAF-16 to be effective.

  19. Multi-resolution entropy analysis of gait symmetry in neurological degenerative diseases and amyotrophic lateral sclerosis.

    PubMed

    Liao, Fuyuan; Wang, Jue; He, Ping

    2008-04-01

    Gait rhythm of patients with Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) has been studied focusing on the fractal and correlation properties of stride time fluctuations. In this study, we investigated gait asymmetry in these diseases using the multi-resolution entropy analysis of stance time fluctuations. Since stance time is likely to exhibit fluctuations across multiple spatial and temporal scales, the data series were decomposed into appropriate levels by applying stationary wavelet transform. The similarity between two corresponding wavelet coefficient series in terms of their regularities at each level was quantified based on a modified sample entropy method and a weighted sum was then used as gait symmetry index. We found that gait symmetry in subjects with PD and HD, especially with ALS is significantly disturbed. This method may be useful in characterizing certain pathologies of motor control and, possibly, in monitoring disease progression and evaluating the effect of an individual treatment.

  20. Multislice 1H magnetic resonance spectroscopic imaging: assessment of epilepsy, Alzheimer's disease, and amyotrophic lateral sclerosis

    NASA Astrophysics Data System (ADS)

    Weiner, Michael W.; Maudsley, Andrew A.; Schuff, Norbert; Soher, Brian J.; Vermathen, Peter P.; Fein, George; Laxer, Kenneth D.

    1998-07-01

    Proton magnetic resonance spectroscopic imaging (1H MRSI) with volume pre-selection (i.e. by PRESS) or multislice 1H MRSI was used to investigate changes in brain metabolites in Alzheimer's disease, epilepsy, and amyotrophic lateral sclerosis. Examples of results from several ongoing clinical studies are provided. Multislice 1H MRSI of the human brain, without volume pre-selection offers considerable advantages over previously available techniques. Furthermore, MRI tissue segmentation and completely automated spectra curve fitting greatly facilitate quantitative data analysis. Future efforts will be devoted to obtaining full brain coverage and data acquisition at short spin echo times (TE less than 30 ms) for the detection of metabolites with short T2 relaxation times.

  1. Collagen cross-linking of skin in patients with amyotrophic lateral sclerosis

    NASA Technical Reports Server (NTRS)

    Ono, S.; Yamauchi, M.

    1992-01-01

    Collagen cross-links of skin tissue (left upper arm) from 11 patients with amyotrophic lateral sclerosis (ALS) and 9 age-matched control subjects were quantified. It was found that patients with ALS had a significant reduction in the content of an age-related, stable cross-link, histidinohydroxylysinonorleucine, that was negatively correlated with the duration of illness. The contents of sodium borohydride-reducible labile cross-links, dehydro-hydroxylysinonorleucine and dehydro-histidinohydroxymerodesmosine, were significantly increased and were positively associated with the duration of illness (r = 0.703, p less than 0.05 and r = 0.684, p less than 0.05, respectively). The results clearly indicate that during the course of ALS, the cross-linking pathway of skin collagen runs counter to its normal aging, resulting in a "rejuvenation" phenomenon of skin collagen. Thus, cross-linking of skin collagen is affected in ALS.

  2. Glutamate and aspartate are decreased in the skin in amyotrophic lateral sclerosis

    NASA Technical Reports Server (NTRS)

    Ono, S.; Yamauchi, M.

    1992-01-01

    We measured the levels of amino acids in biopsied skin from eight patients with amyotrophic lateral sclerosis (ALS) and seven controls. The most conspicuous changes in ALS patients were as follows. First, the contents of the acidic amino acids glutamate and aspartate were significantly decreased in ALS, and were negatively and significantly associated with the duration of illness. Second, the levels of the collagen-associated amino acids hydroxyproline, proline, glycine, alanine, and hydroxylysine were significantly decreased in ALS, and correlated inversely with the duration of illness. These results suggest that there are abnormalities of acidic amino acids and collagen-associated amino acids in the skin of patients with ALS. These changes may underlie the pathogenesis of ALS.

  3. Elastin cross-linking in the skin from patients with amyotrophic lateral sclerosis

    NASA Technical Reports Server (NTRS)

    Ono, S.; Yamauchi, M.

    1994-01-01

    Two cross-links unique to elastin, desmosine and isodesmosine were measured and compared in skin tissue (left upper arm) from 10 patients with amyotrophic lateral sclerosis (ALS) and from seven age-matched controls. The contents of desmosine and isodesmosine were significantly decreased (p < 0.01 and p < 0.01, respectively) in patients with ALS compared with those of controls, and were negatively and significantly associated with duration of illness in ALS patients (r = -0.77, p < 0.01 and r = -0.65, p < 0.05, respectively). The decline in skin desmosine and isodesmosine is more rapid in ALS than in normal ageing. Thus cross-linking of skin elastin is affected in ALS.

  4. New ALS-Related Genes Expand the Spectrum Paradigm of Amyotrophic Lateral Sclerosis.

    PubMed

    Sabatelli, Mario; Marangi, Giuseppe; Conte, Amelia; Tasca, Giorgio; Zollino, Marcella; Lattante, Serena

    2016-03-01

    Amyotrophic Lateral Sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons. Clinical heterogeneity is a well-recognized feature of the disease as age of onset, site of onset and the duration of the disease can vary greatly among patients. A number of genes have been identified and associated to familial and sporadic forms of ALS but the majority of cases remains still unexplained. Recent breakthrough discoveries have demonstrated that clinical manifestations associated with ALS-related genes are not circumscribed to motor neurons involvement. In this view, ALS appears to be linked to different conditions over a continuum or spectrum in which overlapping phenotypes may be identified. In this review, we aim to examine the increasing number of spectra, including ALS/Frontotemporal Dementia and ALS/Myopathies spectra. Considering all these neurodegenerative disorders as different phenotypes of the same spectrum can help to identify common pathological pathways and consequently new therapeutic targets in these incurable diseases.

  5. Electrical Impedance Myography (EIM) in the Evaluation of the Tongue Musculature in Amyotrophic Lateral Sclerosis (ALS)

    PubMed Central

    Shellikeri, Sanjana; Yunusova, Yana; Green, Jordan R.; Pattee, Gary L.; Berry, James D.; Rutkove, Seward B.; Zinman, Lorne

    2015-01-01

    Introduction Electrical impedance myography (EIM) quantifies muscle health and is used as a biomarker of muscle abnormalities in neurogenic and myopathic diseases. EIM has yet to be evaluated in the tongue musculature in people with amyotrophic lateral sclerosis (ALS), who often show clinical bulbar signs. Methods The lingual musculature of 19 subjects with motor neuron disease and 21 of normal participants were assessed using EIM, strength and endurance testing, and clinical observation. Results Tongue musculature in the ALS group was characterized by significantly smaller phase (Ph) and larger resistance (R) when compared to the healthy cohort. Ph and tongue endurance were correlated in the ALS group. Discussion EIM of tongue musculature could distinguish people with ALS from healthy controls. The demonstrated relationship between tongue function and Ph supports further testing of EIM of the tongue as a potential biomarker in ALS. PMID:25580728

  6. Interaction between PON1 and population density in amyotrophic lateral sclerosis.

    PubMed

    Diekstra, Frank P; Beleza-Meireles, Ana; Leigh, Nigel P; Shaw, Christopher E; Al-Chalabi, Ammar

    2009-01-28

    Paraoxonase polymorphisms have been associated with amyotrophic lateral sclerosis (ALS). Paraoxonases are detoxifying enzymes involved in the metabolism of organophosphates. We tested the hypothesis that genetic variation within paraoxonase genes would interact with the environmental exposure to paraoxonase substrates. We used population density in the location of residence of ALS patients as a surrogate marker for environmental exposure. Paraoxonase genotypes at previously associated single nucleotide polymorphisms rs662, rs854560, rs6954345, and rs11981433 were studied in 98 patients from the South East England ALS population-based register. A case-only analysis was carried out and median population density was used to categorize patients into rural or urban environments. We found a significant interaction with population density for marker rs854560 (L55M) in ALS.

  7. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

    PubMed Central

    Cirulli, Elizabeth T.; Lasseigne, Brittany N.; Petrovski, Slavé; Sapp, Peter C.; Dion, Patrick A.; Leblond, Claire S.; Couthouis, Julien; Lu, Yi-Fan; Wang, Quanli; Krueger, Brian J.; Ren, Zhong; Keebler, Jonathan; Han, Yujun; Levy, Shawn E.; Boone, Braden E.; Wimbish, Jack R.; Waite, Lindsay L.; Jones, Angela L.; Carulli, John P.; Day-Williams, Aaron G.; Staropoli, John F.; Xin, Winnie W.; Chesi, Alessandra; Raphael, Alya R.; McKenna-Yasek, Diane; Cady, Janet; de Jong, J.M.B. Vianney; Kenna, Kevin P.; Smith, Bradley N.; Topp, Simon; Miller, Jack; Gkazi, Athina; Al-Chalabi, Ammar; van den Berg, Leonard H.; Veldink, Jan; Silani, Vincenzo; Ticozzi, Nicola; Shaw, Christopher E.; Baloh, Robert H.; Appel, Stanley; Simpson, Ericka; Lagier-Tourenne, Clotilde; Pulst, Stefan M.; Gibson, Summer; Trojanowski, John Q.; Elman, Lauren; McCluskey, Leo; Grossman, Murray; Shneider, Neil A.; Chung, Wendy K.; Ravits, John M.; Glass, Jonathan D.; Sims, Katherine B.; Van Deerlin, Vivianna M.; Maniatis, Tom; Hayes, Sebastian D.; Ordureau, Alban; Swarup, Sharan; Landers, John; Baas, Frank; Allen, Andrew S.; Bedlack, Richard S.; Harper, J. Wade; Gitler, Aaron D.; Rouleau, Guy A.; Brown, Robert; Harms, Matthew B.; Cooper, Gregory M.; Harris, Tim; Myers, Richard M.; Goldstein, David B.

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. Here we report the results of a moderate-scale sequencing study aimed at identifying new genes contributing to predisposition for ALS. We performed whole exome sequencing of 2,874 ALS patients and compared them to 6,405 controls. Several known ALS genes were found to be associated, and the non-canonical IκB kinase family TANK-Binding Kinase 1 (TBK1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention. PMID:25700176

  8. Can cannabinoids be a potential therapeutic tool in amyotrophic lateral sclerosis?

    PubMed Central

    Giacoppo, Sabrina; Mazzon, Emanuela

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. Over the last years, a growing interest was aimed to discovery new innovative and safer therapeutic approaches in the ALS treatment. In this context, the bioactive compounds of Cannabis sativa have shown antioxidant, anti-inflammatory and neuroprotective effects in preclinical models of central nervous system disease. However, most of the studies proving the ability of cannabinoids in delay disease progression and prolong survival in ALS were performed in animal model, whereas the few clinical trials that investigated cannabinoids-based medicines were focused only on the alleviation of ALS-related symptoms, not on the control of disease progression. The aim of this report was to provide a short but important overview of evidences that are useful to better characterize the efficacy as well as the molecular pathways modulated by cannabinoids. PMID:28197175

  9. The experience of meditation for people with amyotrophic lateral sclerosis and their caregivers - a qualitative analysis.

    PubMed

    Marconi, Anna; Gragnano, Gaia; Lunetta, Christian; Gatto, Ramona; Fabiani, Viviana; Tagliaferri, Aurora; Rossi, Gabriella; Sansone, Valeria; Pagnini, Francesco

    2016-09-01

    There is a lack of studies about psychological interventions for people with amyotrophic lateral sclerosis (ALS) and their caregivers. We investigated the experience of a meditation training program tailored for ALS needs. People with ALS (pALS) and their caregivers that joined a meditation program for ALS were interviewed at the end of the program. Verbatims were analyzed with a qualitative approach. Both pALS and their caregivers reported a positive impact on their psychological well-being, promoted by an increase in acceptance and non-judgmental attitude. Furthermore, coping strategies seem to improve, with a positive effect on resilience skills. The ALS meditation training program seems to be an effective psychological intervention for the promotion of well-being in pALS and their caregivers.

  10. Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations.

    PubMed

    Tokuda, Eiichi; Furukawa, Yoshiaki

    2016-04-28

    Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease affecting both upper and lower motor neurons, and currently, there is no cure or effective treatment. Mutations in a gene encoding a ubiquitous antioxidant enzyme, Cu,Zn-superoxide dismutase (SOD1), have been first identified as a cause of familial forms of ALS. It is widely accepted that mutant SOD1 proteins cause the disease through a gain in toxicity but not through a loss of its physiological function. SOD1 is a major copper-binding protein and regulates copper homeostasis in the cell; therefore, a toxicity of mutant SOD1 could arise from the disruption of copper homeostasis. In this review, we will briefly review recent studies implying roles of copper homeostasis in the pathogenesis of SOD1-ALS and highlight the therapeutic interventions focusing on pharmacological as well as genetic regulations of copper homeostasis to modify the pathological process in SOD1-ALS.

  11. Risk agents related to work and amyotrophic lateral sclerosis: An occupational medicine focus.

    PubMed

    Garzillo, Elpidio Maria; Miraglia, Nadia; Pedata, Paola; Feola, Daniela; Lamberti, Monica

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons. In recent years, in addition to several studies about genetic mechanisms leading to motor neurons damage, various epigenetic theories have been developed, involving the study of the patients' work and lifestyle. The work aims at focusing the role of occupational exposure related to ALS by literature data analysis. Articles, selected on the basis of keywords, year of publication and topics, are related to occupational exposure, suggesting an impact on ALS onset. The literature review shows that there are still a lot of biases in the studies design, which actually do not allow to draw unequivocal conclusions.

  12. Intraspinal Neural Stem Cell Transplantation in Amyotrophic Lateral Sclerosis: Phase 1 Trial Outcomes

    PubMed Central

    Feldman, Eva L; Boulis, Nicholas M; Hur, Junguk; Johe, Karl; Rutkove, Seward B; Federici, Thais; Polak, Meraida; Bordeau, Jane; Sakowski, Stacey A; Glass, Jonathan D

    2014-01-01

    Objective The US Food and Drug Administration–approved trial, “A Phase 1, Open-Label, First-in-Human, Feasibility and Safety Study of Human Spinal Cord-Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis, Protocol Number: NS2008-1,” is complete. Our overall objective was to assess the safety and feasibility of stem cell transplantation into lumbar and/or cervical spinal cord regions in amyotrophic lateral sclerosis (ALS) subjects. Methods Preliminary results have been reported on the initial trial cohort of 12 ALS subjects. Here, we describe the safety and functional outcome monitoring results for the final trial cohort, consisting of 6 ALS subjects receiving 5 unilateral cervical intraspinal neural stem cell injections. Three of these subjects previously received 10 total bilateral lumbar injections as part of the earlier trial cohort. All injections utilized a novel spinal-mounted stabilization and injection device to deliver 100,000 neural stem cells per injection, for a dosing range up to 1.5 million cells. Subject assessments included detailed pre- and postsurgical neurological outcome measures. Results The cervical injection procedure was well tolerated and disease progression did not accelerate in any subject, verifying the safety and feasibility of cervical and dual-targeting approaches. Analyses on outcome data revealed preliminary insight into potential windows of stem cell biological activity and identified clinical assessment measures that closely correlate with ALS Functional Rating Scale-Revised scores, a standard assessment for ALS clinical trials. Interpretation This is the first report of cervical and dual-targeted intraspinal transplantation of neural stem cells in ALS subjects. This approach is feasible and well-tolerated, supporting future trial phases examining therapeutic dosing and efficacy. PMID:24510776

  13. [An analysis of characteristics of nerve conduction in 154 cases of amyotrophic lateral sclerosis].

    PubMed

    Ren, Y T; Cui, F; Yang, F; Chen, Z H; Ling, L; Huang, X S

    2016-10-01

    Objective: To analyze the features of nerve conduction in patients with amyotrophic lateral sclerosis (ALS), and explore the correlation between compound muscle action potential (CMAP) amplitude and disease duration and revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R). Methods: Standard motor and sensory nerve conduction studies were performed in 154 patients with ALS. The following parameters were collected including CMAP amplitude, distal motor latency (DML), motor conduction velocity, sensory conduction velocity and sensory nerve action potential amplitude. Regression study was done to explore the correlation between CMAP amplitude and disease duration and ALSFRS-R. Results: Motor nerve conduction abnormalities were presented in a majority of the patients with prolonged DML in the tibial nerve, median nerve and ulnar nerve as the most common form (61.06%-81.42%), followed by decreased CMAP amplitude (30.12%-53.98%), decreased MCV (12.05%-16.81%) and absence of CMAP (2.65%-9.73%). Sensory nerve conduction abnormalities were detected in a small proportion of patients and the decreased SCV, decreased SNAP amplitude and absence of SNAP in the sural nerve, median nerve and ulnar nerve were found in 1.22%-2.73%, 0-1.82% and 0-1.22% patients respectively. No correlation was found between CMAP of the common peroneal nerve, tibial nerve, median nerve and ulnar nerve and the disease duration (P>0.05), while significant positive correlation was established between CMAP amplitude of the median nerve and ulnar nerve and ALSFRS-R (r=0.273, P=0.016; r=0.357, P=0.001). Conclusions: Motor nerve conduction is abnormal in a majority of ALS patients with prolonged DML as the most common form, while abnormal sensory nerve conduction is only found in a few of ALS patients. CMAP amplitude of the median nerve and ulnar nerve might be of certain clinical value in evaluating the severity of ALS.

  14. Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: assessed with [(11)C]-PBR28.

    PubMed

    Zürcher, Nicole R; Loggia, Marco L; Lawson, Robert; Chonde, Daniel B; Izquierdo-Garcia, David; Yasek, Julia E; Akeju, Oluwaseun; Catana, Ciprian; Rosen, Bruce R; Cudkowicz, Merit E; Hooker, Jacob M; Atassi, Nazem

    2015-01-01

    Evidence from human post mortem, in vivo and animal model studies implicates the neuroimmune system and activated microglia in the pathology of amyotrophic lateral sclerosis. The study aim was to further evaluate in vivo neuroinflammation in individuals with amyotrophic lateral sclerosis using [(11)C]-PBR28 positron emission tomography. Ten patients with amyotrophic lateral sclerosis (seven males, three females, 38-68 years) and ten age- and [(11)C]-PBR28 binding affinity-matched healthy volunteers (six males, four females, 33-65 years) completed a positron emission tomography scan. Standardized uptake values were calculated from 60 to 90 min post-injection and normalized to whole brain mean. Voxel-wise analysis showed increased binding in the motor cortices and corticospinal tracts in patients with amyotrophic lateral sclerosis compared to healthy controls (p FWE < 0.05). Region of interest analysis revealed increased [(11)C]-PBR28 binding in the precentral gyrus in patients (normalized standardized uptake value = 1.15) compared to controls (1.03, p < 0.05). In patients those values were positively correlated with upper motor neuron burden scores (r = 0.69, p < 0.05), and negatively correlated with the amyotrophic lateral sclerosis functional rating scale (r = -0.66, p < 0.05). Increased in vivo glial activation in motor cortices, that correlates with phenotype, complements previous histopathological reports. Further studies will determine the role of [(11)C]-PBR28 as a marker of treatments that target neuroinflammation.

  15. [A case of amyotrophic lateral sclerosis with bilateral vocal cord paralysis necessitating tracheotomy].

    PubMed

    Arai, Motomi; Endo, Shiori; Oshima, Goro; Yagi, Yuki

    2011-10-01

    Vocal cord movement disorders are increasingly recognized in patients with amyotrophic lateral sclerosis (ALS). We describe a patient with limb-onset ALS who developed vocal cord paralysis. A 74-year-old Japanese male consulted our clinic with a 6-month history of weakness in both arms. His family history was unremarkable. There were fasciculations and mild atrophy of the tongue and both arms. In the legs, muscle strength was almost normal but widespread fasciculations were present. All tendon reflexes were hypoactive and pathological reflexes were absent. Thereafter, he developed weakness of the legs and showed increased eating time. Babinski sign was positive bilaterally at this stage. The forced vital capacity dropped from 90% at the initial evaluation to 62% of the predicted value 14 months later. Two years after disease onset, the patient developed aspiration pneumonia with hoarseness and had difficulty clearing his throat of phlegm. Laryngoscopy demonstrated severe vocal cord paresis on both sides, particularly in the abductor muscles possibly leading to obstruction. Tracheotomy was performed because of the risk that the patient could choke to death. A review of the literature suggests that severe impairment of vocal cord abduction could be a prelude to sudden death in ALS. Follow up by laryngoscopic examination is necessary.

  16. Executive Dysfunctions and Event-Related Brain Potentials in Patients with Amyotrophic Lateral Sclerosis

    PubMed Central

    Seer, Caroline; Fürkötter, Stefanie; Vogts, Maj-Britt; Lange, Florian; Abdulla, Susanne; Dengler, Reinhard; Petri, Susanne; Kopp, Bruno

    2015-01-01

    A growing body of evidence implies psychological disturbances in amyotrophic lateral sclerosis (ALS). Specifically, executive dysfunctions occur in up to 50% of ALS patients. The recently shown presence of cytoplasmic aggregates (TDP-43) in ALS patients and in patients with behavioral variants of frontotemporal dementia suggests that these two disease entities form the extremes of a spectrum. The present study aimed at investigating behavioral and electrophysiological indices of conflict processing in patients with ALS. A non-verbal variant of the flanker task demanded two-choice responses to target stimuli that were surrounded by flanker stimuli which either primed the correct response or the alternative response (the latter case representing the conflict situation). Behavioral performance, event-related potentials (ERP), and lateralized readiness potentials (LRP) were analyzed in 21 ALS patients and 20 controls. In addition, relations between these measures and executive dysfunctions were examined. ALS patients performed the flanker task normally, indicating preserved conflict processing. In similar vein, ERP and LRP indices of conflict processing did not differ between groups. However, ALS patients showed enhanced posterior negative ERP waveform deflections, possibly indicating increased modulation of visual processing by frontoparietal networks in ALS. We also found that the presence of executive dysfunctions was associated with more error-prone behavior and enhanced LRP amplitudes in ALS patients, pointing to a prefrontal pathogenesis of executive dysfunctions and to a potential link between prefrontal and motor cortical functional dysregulation in ALS, respectively. PMID:26733861

  17. Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression.

    PubMed

    Bruneteau, Gaëlle; Simonet, Thomas; Bauché, Stéphanie; Mandjee, Nathalie; Malfatti, Edoardo; Girard, Emmanuelle; Tanguy, Marie-Laure; Behin, Anthony; Khiami, Frédéric; Sariali, Elhadi; Hell-Remy, Caroline; Salachas, François; Pradat, Pierre-François; Fournier, Emmanuel; Lacomblez, Lucette; Koenig, Jeanine; Romero, Norma Beatriz; Fontaine, Bertrand; Meininger, Vincent; Schaeffer, Laurent; Hantaï, Daniel

    2013-08-01

    Amyotrophic lateral sclerosis is a typically rapidly progressive neurodegenerative disorder affecting motor neurons leading to progressive muscle paralysis and death, usually from respiratory failure, in 3-5 years. Some patients have slow disease progression and prolonged survival, but the underlying mechanisms remain poorly understood. Riluzole, the only approved treatment, only modestly prolongs survival and has no effect on muscle function. In the early phase of the disease, motor neuron loss is initially compensated for by collateral reinnervation, but over time this compensation fails, leading to progressive muscle wasting. The crucial role of muscle histone deacetylase 4 and its regulator microRNA-206 in compensatory reinnervation and disease progression was recently suggested in a mouse model of amyotrophic lateral sclerosis (transgenic mice carrying human mutations in the superoxide dismutase gene). Here, we sought to investigate whether the microRNA-206-histone deacetylase 4 pathway plays a role in muscle compensatory reinnervation in patients with amyotrophic lateral sclerosis and thus contributes to disease outcome differences. We studied muscle reinnervation using high-resolution confocal imaging of neuromuscular junctions in muscle samples obtained from 11 patients with amyotrophic lateral sclerosis, including five long-term survivors. We showed that the proportion of reinnervated neuromuscular junctions was significantly higher in long-term survivors than in patients with rapidly progressive disease. We analysed the expression of muscle candidate genes involved in the reinnervation process and showed that histone deacetylase 4 upregulation was significantly greater in patients with rapidly progressive disease and was negatively correlated with the extent of muscle reinnervation and functional outcome. Conversely, the proposed regulator of histone deacetylase 4, microRNA-206, was upregulated in both patient groups, but did not correlate with disease

  18. Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

    PubMed Central

    Proudfoot, Malcolm; Rohenkohl, Gustavo; Quinn, Andrew; Colclough, Giles L.; Wuu, Joanne; Talbot, Kevin; Woolrich, Mark W.; Benatar, Michael

    2016-01-01

    Abstract Continuous rhythmic neuronal oscillations underpin local and regional cortical communication. The impact of the motor system neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) on the neuronal oscillations subserving movement might therefore serve as a sensitive marker of disease activity. Movement preparation and execution are consistently associated with modulations to neuronal oscillation beta (15–30 Hz) power. Cortical beta‐band oscillations were measured using magnetoencephalography (MEG) during preparation for, execution, and completion of a visually cued, lateralized motor task that included movement inhibition trials. Eleven “classical” ALS patients, 9 with the primary lateral sclerosis (PLS) phenotype, and 12 asymptomatic carriers of ALS‐associated gene mutations were compared with age‐similar healthy control groups. Augmented beta desynchronization was observed in both contra‐ and ipsilateral motor cortices of ALS patients during motor preparation. Movement execution coincided with excess beta desynchronization in asymptomatic mutation carriers. Movement completion was followed by a slowed rebound of beta power in all symptomatic patients, further reflected in delayed hemispheric lateralization for beta rebound in the PLS group. This may correspond to the particular involvement of interhemispheric fibers of the corpus callosum previously demonstrated in diffusion tensor imaging studies. We conclude that the ALS spectrum is characterized by intensified cortical beta desynchronization followed by delayed rebound, concordant with a broader concept of cortical hyperexcitability, possibly through loss of inhibitory interneuronal influences. MEG may potentially detect cortical dysfunction prior to the development of overt symptoms, and thus be able to contribute to the assessment of future neuroprotective strategies. Hum Brain Mapp 38:237–254, 2017. © 2016 Wiley Periodicals, Inc. PMID:27623516

  19. Structural and diffusion imaging versus clinical assessment to monitor amyotrophic lateral sclerosis

    PubMed Central

    Cardenas-Blanco, Arturo; Machts, Judith; Acosta-Cabronero, Julio; Kaufmann, Joern; Abdulla, Susanne; Kollewe, Katja; Petri, Susanne; Schreiber, Stefanie; Heinze, Hans-Jochen; Dengler, Reinhard; Vielhaber, Stefan; Nestor, Peter J.

    2016-01-01

    Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects upper and lower motor neurons. Observational and intervention studies can be tracked using clinical measures such as the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) but for a complete understanding of disease progression, objective in vivo biomarkers of both central and peripheral motor pathway pathology are highly desirable. The aim of this study was to determine the utility of structural and diffusion imaging as central nervous system biomarkers compared to the standard clinical measure, ALSFRS-R, to track longitudinal evolution using three time-point measurements. N = 34 patients with ALS were scanned and clinically assessed three times at a mean of three month time intervals. The MRI biomarkers were structural T1-weighted volumes for cortical thickness measurement as well as deep grey matter volumetry, voxel-based morphometry and diffusion tensor imaging (DTI). Cortical thickness focused specifically on the precentral gyrus while quantitative DTI biomarkers focused on the corticospinal tracts. The evolution of imaging biomarkers and ALSFRS-R scores over time were analysed using a mixed effects model that accounted for the scanning interval as a fixed effect variable, and, the initial measurements and time from onset as random variables. The mixed effects model showed a significant decrease in the ALSFRS-R score, (p < 0.0001, and an annual rate of change (AROC) of − 7.3 points). Similarly, fractional anisotropy of the corticospinal tract showed a significant decrease (p = 0.009, AROC = − 0.0066) that, in turn, was driven by a significant increase in radial diffusivity combined with a trend to decrease in axial diffusivity. No significant change in cortical thickness of the precentral gyrus was found (p > 0.5). In addition, deep grey matter volumetry and voxel-based morphometry also identified no significant changes. Furthermore, the

  20. Theory of Mind and Its Neuropsychological and Quality of Life Correlates in the Early Stages of Amyotrophic Lateral Sclerosis

    PubMed Central

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

    2016-01-01

    This study aims to explore the potential impairment of Theory of Mind (ToM; i.e., the ability to represent cognitive and affective mental states to both self and others) and the clinical, neuropsychological and Quality of Life (QoL) correlates of these cognitive abnormalities in the early stages of amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disease recently recognized as a part of the same clinical and pathological spectrum of frontotemporal lobar degeneration. Twenty-two consecutive, cognitively intact ALS patients, and 15 healthy controls, underwent assessment of executive, verbal comprehension, visuospatial, behavioral, and QoL measures, as well as of the ToM abilities by Emotion Attribution Task (EAT), Advanced Test of ToM (ATT), and Eyes Task (ET). ALS patients obtained significantly lower scores than controls on EAT and ET. No significant difference was found between the two groups on ATT. As regard to type of ALS onset, patients with bulbar onset performed worse than those with spinal onset on ET. Correlation analysis revealed that EAT and ET were positively correlated with education, memory prose, visuo-spatial performances, and “Mental Health” scores among QoL items. Our results suggest that not only “cognitive” but also “affective” subcomponents of ToM may be impaired in the early stages of ALS, with significant linkage to disease onset and dysfunctions of less executively demanding conditions, causing potential impact on patients’ “Mental Health.” PMID:28018269

  1. Defining peripheral nervous system dysfunction in the SOD-1G93A transgenic rat model of amyotrophic lateral sclerosis.

    PubMed

    Riva, Nilo; Chaabane, Linda; Peviani, Marco; Ungaro, Daniela; Domi, Teuta; Dina, Giorgia; Bianchi, Francesca; Spano, Giorgia; Cerri, Federica; Podini, Paola; Corbo, Massimo; Carro, Ubaldo Del; Comi, Giancarlo; Bendotti, Caterina; Quattrini, Angelo

    2014-07-01

    Growing evidence indicates that alterations within the peripheral nervous system (PNS) are involved at an early stage in the amyotrophic lateral sclerosis (ALS) pathogenetic cascade. In this study, magnetic resonance imaging (MRI), neurophysiologic analyses, and histologic analyses were used to monitor the extent of PNS damage in the hSOD-1 ALS rat model. The imaging signature of the disease was defined using in vivo MRI of the sciatic nerve. Initial abnormalities were detected in the nerves by an increase in T2 relaxation time before the onset of clinical disease; diffusion MRI showed a progressive increase in mean and radial diffusivity and reduction of fractional anisotropy at advanced stages of disease. Histologic analysis demonstrated early impairment of the blood-nerve barrier followed by acute axonal degeneration associated with endoneurial edema and macrophage response in motor nerve compartments. Progressive axonal degeneration and motor nerve fiber loss correlated with MRI and neurophysiologic changes. These functional and morphologic investigations of the PNS might be applied in following disease progression in preclinical therapeutic studies. This study establishes the PNS signature in this rat ALS model (shedding new light into pathogenesis) and provides a rationale for translating into future systematic MRI studies of PNS involvement in patients with ALS.

  2. Prospects for bone marrow cell therapy in amyotrophic lateral sclerosis: how far are we from a clinical treatment?

    PubMed Central

    Gubert, Fernanda; Satiago, Marcelo F.

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive muscular atrophy and death within 3–5 years after its onset. Despite the significant advances in knowledge of ALS pathology, no effective treatment is available. Therefore, it is imperative to search for new alternatives to treat ALS. Cell therapy, especially using bone-marrow cells, has showed to be very useful to protect the neural tissue in different brain disease or traumatic lesions. In ALS, most published results show beneficial effects of the use bone marrow cells, especially mesenchymal stromal cells. However, until now, the best outcome extends animal's lifespan by only a few weeks. It is essential to continue the search for a really effective therapy, testing different cells, routes and time-windows of administration. Studying the mechanisms that initiate and spread the degenerative process is also important to find out an effective therapy. Therefore, we discussed here some progresses that have been made using bone-marrow cell therapy as a therapeutic tool for ALS. PMID:27651758

  3. Shifting the balance: cell-based therapeutics as modifiers of the amyotrophic lateral sclerosis-specific neuronal microenvironment.

    PubMed

    Riley, Jonathan; Sweeney, Walter; Boulis, Nicholas

    2008-01-01

    Recent advances in the laboratory have improved the current understanding of neurobiological mechanisms underlying the initiating events and pathological progression observed in amyotrophic lateral sclerosis (ALS). Whereas initial studies have revealed the late-stage intracellular cascades contributing to neuronal dysfunction and cell death, more recently collected data have begun to elucidate the presence and importance of a "non-cell autonomous" component indicating that affected glial cell subtypes may serve distinct and required roles. Pharmacological interventions for ALS have largely been disappointing likely in part because they have failed to address either the proximate events contributing to neuronal dysfunction and death or the deleterious contributions of non-neuronal cells within the local microenvironment. Alternatively, cell-based therapeutics offer the potential of a multifaceted approach oriented toward the dual ends of protecting remaining viable neurons and attempting to restore neuronal function lost as a manifestation of disease progression. The authors review the evolving knowledge of disease initiation and progression, with specific emphasis on the role of affected glia as crucial contributors to the observed ALS phenotype. This basis is used to underscore the potential roles of cell-based therapeutics as modifiers of the ALS-specific microenvironment.

  4. Chromosomal localization of glutamate receptor genes: relationship to familial amyotrophic lateral sclerosis and other neurological disorders of mice and humans.

    PubMed Central

    Gregor, P; Reeves, R H; Jabs, E W; Yang, X; Dackowski, W; Rochelle, J M; Brown, R H; Haines, J L; O'Hara, B F; Uhl, G R

    1993-01-01

    Receptors for the major excitatory neurotransmitter glutamate may play key roles in neurodegeneration. The mouse Glur-5 gene maps to chromosome 16 between App and Sod-1. The homologous human GLUR5 gene maps to the corresponding region of human chromosome 21, which contains the locus for familial amyotrophic lateral sclerosis. This location, and other features, render GLUR5 a possible candidate gene for familial amyotrophic lateral sclerosis. In addition, dosage imbalance of GLUR5 may have a role in the trisomy 21 (Down syndrome). Further characterization of the murine glutamate receptor family includes mapping of Glur-1 to the same region as neurological mutants spasmodic, shaker-2, tipsy, and vibrator on chromosome 11; Glur-2 near spastic on chromosome 3; Glur-6 near waltzer and Jackson circler on chromosome 10; and Glur-7 near clasper on chromosome 4. Images Fig. 3 PMID:8464923

  5. Progression of hippocampal degeneration in amyotrophic lateral sclerosis with or without memory impairment: distinction from Alzheimer disease.

    PubMed

    Takeda, Takahiro; Uchihara, Toshiki; Arai, Nobutaka; Mizutani, Toshio; Iwata, Makoto

    2009-01-01

    The hippocampal involvement in amyotrophic lateral sclerosis (ALS) patients has been known for more than a decade, however, its relationship to clinical manifestations including memory deficits and topographical differentiation from Alzheimer disease (AD) remain unclear. In order to clarify the anatomopathological features in the hippocampus and their relevance to disease-specific memory deficits in ALS patients, topography and cytopathology of the hippocampal lesions along the perforant pathway were quantitatively and semiquantitatively surveyed in 14 ALS patients with extramotor involvement. These pathological findings were compared with clinical characteristics assessed from their clinical records. Cytoplasmic inclusions initially appear in the granular cells of the dentate gyrus (DG) and superficial small neurons of the transentorhinal cortex (TEC) with mild subicular degeneration (stage I: inclusion stage). Subsequent gliosis and neuronal loss of the TEC, concomitant with presynaptic degeneration of the outer molecular layer of the DG, suggests an extension of the degeneration through the perforant pathway (stage II: early perforant stage). In a more advanced stage, the presynaptic degeneration is more evident with moderate to severe neuronal loss in the TEC (stage III: advanced perforant stage). This advanced stage was associated with episodic memory deficits mimicking AD in some ALS patients. This ALS pathology initiated by cytoplasmic inclusions and neuronal loss in layer II-III of the TEC is different from neurofibrillary tangles of AD, dominant in layer II-III of the entorhinal cortex. Because this involvement of the TEC-molecular DG projection and subiculum is specific to ALS, it will provide a basis for clinical characterization of memory deficits of ALS, which could be distinct from those of AD.

  6. Amyotrophic lateral sclerosis presenting as upper limb weakness in a 35 year old female: a case report.

    PubMed

    Sigurdson, Leif A

    2011-09-01

    Chiropractors regularly assess and provide treatment for a variety of neuromuscular complaints. Many of these respond well to conservative care however some represent conditions that must be referred for further evaluation. This article chronicles the management of a patient who presented with upper limb weakness and was subsequently diagnosed with amyotrophic lateral sclerosis (ALS). Chiropractors should be informed of the nature and presentation of this disease to facilitate early diagnosis and treatment.

  7. Amyotrophic lateral sclerosis presenting as upper limb weakness in a 35 year old female: a case report

    PubMed Central

    Sigurdson, Leif A.

    2011-01-01

    Chiropractors regularly assess and provide treatment for a variety of neuromuscular complaints. Many of these respond well to conservative care however some represent conditions that must be referred for further evaluation. This article chronicles the management of a patient who presented with upper limb weakness and was subsequently diagnosed with amyotrophic lateral sclerosis (ALS). Chiropractors should be informed of the nature and presentation of this disease to facilitate early diagnosis and treatment. PMID:21886282

  8. The Use of Autologous Mesenchymal Stem Cells for Cell Therapy of Patients with Amyotrophic Lateral Sclerosis in Belarus.

    PubMed

    Rushkevich, Yu N; Kosmacheva, S M; Zabrodets, G V; Ignatenko, S I; Goncharova, N V; Severin, I N; Likhachev, S A; Potapnev, M P

    2015-08-01

    We studied a new method of treatment of amyotrophic lateral sclerosis with autologous mesenchymal stem cells. Autologous mesenchymal stem cells were injected intravenously (intact cells) or via lumbar puncture (cells committed to neuronal differentiation). Evaluation of the results of cell therapy after 12-month follow-up revealed slowing down of the disease progression in 10 patients in comparison with the control group consisting of 15 patients. The cell therapy was safe for the patients.

  9. An Autopsy Case of Amyotrophic Lateral Sclerosis with Waldenström Macroglobulinemia and Anti-MAG Gammopathy.

    PubMed

    Jurici, Snejana; Laquerrière, Annie; Bedat-Millet, Anne-Laure; Jardin, Fabrice; Musset, Lucile; Vallat, Jean-Michel; Hannequin, Didier; Martinaud, Olivier

    2011-09-01

    We report the case of a 71-year-old woman with typical signs of bulbar amyotrophic lateral sclerosis (ALS) associated with immunoglobulin M (IgM) monoclonal gammopathy and anti-MAG (myelin-associated glycoprotein) antibodies. This unusual association between ALS and anti-MAG antibodies has previously been reported in a single case. Our present case, at neuropathological examination, demonstrated no causative link between anti-MAG antibodies and ALS.

  10. Temporal trends and geographic clusters of mortality from amyotrophic lateral sclerosis in Japan, 1995-2004.

    PubMed

    Doi, Yuriko; Yokoyama, Testuji; Tango, Toshiro; Takahashi, Kunihiko; Fujimoto, Kenichi; Nakano, Imaharu

    2010-11-15

    The present study examined temporal trends and geographic clustering of amyotrophic lateral sclerosis (ALS) mortality in Japan, during 1995-2004, using vital statistics based on death certificates. ALS was usually diagnosed by neurologists according to clinical guidelines that complied with the El Escorial Criteria. The underlying cause of death for ALS was coded as G12.2A. Regression analysis was used to examine temporal trends. Spatial scan statistic was used to detect any area of elevated risk as a cluster. A total of 12,173 (6864 male and 5309 female) ALS deaths were reported. Annual crude mortality rate per 100,000 population was 1.07 (1.26 for males and 0.89 for females) in 2004. Although the overall temporal trend was stable, the trend increased in the 70+ years age group (p for trend, <0.001 in males and <0.05 in females), while it declined in the under 70 years age group (p for trend, <0.01 for both sexes). Male preponderance and M/F ratio remained nearly constant over time. Three clusters were detected: two (p<0.005 in males and p<0.05 in females) in northeast and one (p<0.05 in males) in west-central Japan. Further research is needed to clarify contributing factors for the observed trends and clusters in ALS mortality.

  11. Discriminative time-frequency kernels for gait analysis for amyotrophic lateral sclerosis.

    PubMed

    Sugavaneswaran, Lakshmi; Umapathy, Karthikeyan; Krishnan, Sridhar

    2011-01-01

    Many stochastic systems show certain trends which in turn govern their underlying non-stationary time varying behavior. In order to facilitate efficient quantification of such signals, their analysis necessitates the use of robust tools for discerning between different classes of data. Research show that, use of time-frequency techniques offer intelligible representations for non-stationary signals, along with facilitating computation of instantaneous parameters. Further, in order to obtain efficient discrimination machine learning (ML) modules are often used alongside suitable representation techniques. In this work, we exploit the concepts of ML-kernel functions directly by incorporating them in the ambiguity time-frequency (TF) space, thereby obtaining a one-step discrimination between different non-stationary patterns. The proposed technique is evaluated for quantification applications for gait signal analysis. An overall classification accuracy of 93.1% is reported for the neurological gait database consisting of signals from 16-control and 13-amyotrophic lateral sclerosis (ALS) subjects. Results indicate that this scheme offers great potential in designing robust tools for time-varying signal analysis.

  12. Physical Trauma and Amyotrophic Lateral Sclerosis: A Population-Based Study Using Danish National Registries

    PubMed Central

    Seals, Ryan M.; Hansen, Johnni; Gredal, Ole; Weisskopf, Marc G.

    2016-01-01

    Prior studies have suggested that physical trauma might be associated with the development of amyotrophic lateral sclerosis (ALS). We conducted a population-based, individually matched case-control study in Denmark to assess whether hospitalization for trauma is associated with a higher risk of developing ALS. There were 3,650 incident cases of ALS in the Danish National Patient Register from 1982 to 2009. We used risk-set sampling to match each case to 100 age- and sex-matched population controls alive on the date of the case's diagnosis. Odds ratios and 95% confidence intervals were calculated using a conditional logistic regression model. History of trauma diagnosis was also obtained from the Danish Patient Register. When traumas in the 5 years prior to the index date were excluded, there was a borderline association between any trauma and ALS (odds ratio (OR) = 1.09, 95% confidence interval (CI): 0.99, 1.19). A first trauma before age 55 years was associated with ALS (OR = 1.22, 95% CI: 1.08, 1.37), whereas first traumas at older ages were not (OR = 0.97, 95% CI: 0.85, 1.10). Our data suggest that physical trauma at earlier ages is associated with ALS risk. Age at first trauma could help explain discrepancies in results of past studies of trauma and ALS. PMID:26825926

  13. EEG functional network topology is associated with disability in patients with amyotrophic lateral sclerosis

    PubMed Central

    Fraschini, Matteo; Demuru, Matteo; Hillebrand, Arjan; Cuccu, Lorenza; Porcu, Silvia; Di Stefano, Francesca; Puligheddu, Monica; Floris, Gianluca; Borghero, Giuseppe; Marrosu, Francesco

    2016-01-01

    Amyotrophic Lateral Sclerosis (ALS) is one of the most severe neurodegenerative diseases, which is known to affect upper and lower motor neurons. In contrast to the classical tenet that ALS represents the outcome of extensive and progressive impairment of a fixed set of motor connections, recent neuroimaging findings suggest that the disease spreads along vast non-motor connections. Here, we hypothesised that functional network topology is perturbed in ALS, and that this reorganization is associated with disability. We tested this hypothesis in 21 patients affected by ALS at several stages of impairment using resting-state electroencephalography (EEG) and compared the results to 16 age-matched healthy controls. We estimated functional connectivity using the Phase Lag Index (PLI), and characterized the network topology using the minimum spanning tree (MST). We found a significant difference between groups in terms of MST dissimilarity and MST leaf fraction in the beta band. Moreover, some MST parameters (leaf, hierarchy and kappa) significantly correlated with disability. These findings suggest that the topology of resting-state functional networks in ALS is affected by the disease in relation to disability. EEG network analysis may be of help in monitoring and evaluating the clinical status of ALS patients. PMID:27924954

  14. Amyotrophic lateral sclerosis and denervation alter sphingolipids and up-regulate glucosylceramide synthase

    PubMed Central

    Henriques, Alexandre; Croixmarie, Vincent; Priestman, David A.; Rosenbohm, Angela; Dirrig-Grosch, Sylvie; D'Ambra, Eleonora; Huebecker, Mylene; Hussain, Ghulam; Boursier-Neyret, Claire; Echaniz-Laguna, Andoni; Ludolph, Albert C.; Platt, Frances M.; Walther, Bernard; Spedding, Michael; Loeffler, Jean-Philippe; Gonzalez De Aguilar, Jose-Luis

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. Growing evidence suggests a link between changes in lipid metabolism and ALS. Here, we used UPLC/TOF-MS to survey the lipidome in SOD1(G86R) mice, a model of ALS. Significant changes in lipid expression were evident in spinal cord and skeletal muscle before overt neuropathology. In silico analysis also revealed appreciable changes in sphingolipids including ceramides and glucosylceramides (GlcCer). HPLC analysis showed increased amounts of GlcCer and downstream glycosphingolipids (GSLs) in SOD1(G86R) muscle compared with wild-type littermates. Glucosylceramide synthase (GCS), the enzyme responsible for GlcCer biosynthesis, was up-regulated in muscle of SOD1(G86R) mice and ALS patients, and in muscle of wild-type mice after surgically induced denervation. Conversely, inhibition of GCS in wild-type mice, following transient peripheral nerve injury, reversed the overexpression of genes in muscle involved in oxidative metabolism and delayed motor recovery. GCS inhibition in SOD1(G86R) mice also affected the expression of metabolic genes and induced a loss of muscle strength and morphological deterioration of the motor endplates. These findings suggest that GSLs may play a critical role in ALS muscle pathology and could lead to the identification of new therapeutic targets. PMID:26483191

  15. Role of the Sigma-1 receptor in Amyotrophic Lateral Sclerosis (ALS)

    PubMed Central

    Mavlyutov, Timur A.; Guo, Lian-Wang; Epstein, Miles L.; Ruoho, Arnold E.

    2015-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease affecting spinal cord motoneurons (MN) with an associative connection to Frontotemporal Lobar Dementia (FTLD). The endoplasmic reticulum (ER) bound Sigma-1 Receptor (S1R) chaperone protein localizes to specialized ER cisternae within 10 nm of the plasma membrane in spinal cord ventral horn cholinergic post synaptic C-terminals. Removal of the S1R gene in the Superoxide Dismutase-1 (SOD-1) mouse model of ALS exacerbated the neurodegenerative condition and resulted in a significantly reduced longevity when compared to the SOD-1/S1R wild type (WT) mouse. The proposed amelioration of the ALS phenotype by the S1R is likely due to a “brake” on excitation of the MN as evidenced by a reduction in action potential generation in the MN of the WT when compared to the S1R KO mouse MN. Although the precise signal transduction pathway(s) regulated by the S1R in the MN has/have not been elucidated at present, it is likely that direct or indirect functional interactions occur between the S1R in the ER cisternae with voltage gated potassium channels and/or with muscarinic M2 receptor signaling in the post synaptic plasma membrane. Possible mechanisms for regulation of MN excitability by S1R are discussed. PMID:25704013

  16. Sumoylation of critical proteins in amyotrophic lateral sclerosis: emerging pathways of pathogenesis

    PubMed Central

    Foran, Emily; Rosenblum, Lauren; Bogush, Alexey I.; Trotti, Davide

    2013-01-01

    Emerging lines of evidence suggest a relationship between amyotrophic lateral sclerosis (ALS) and protein sumoylation. Multiple studies have demonstrated that several of the proteins involved in the pathogenesis of ALS, including superoxide dismutase 1 (SOD1), fused in liposarcoma (FUS), and TAR DNA binding protein 43 (TDP43), are substrates for sumoylation. Additionally, recent studies in cellular and animal models of ALS revealed that sumoylation of these proteins impact their localization, longevity and how they functionally perform in disease, providing novel areas for mechanistic investigations and therapeutics. In this article, we summarize the current literature examining the impact of sumoylation of critical proteins involved in ALS and discuss the potential impact for the pathogenesis of the disease. In addition, we report and discuss the implications of new evidence demonstrating that sumoylation of a fragment derived from the proteolytic cleavage of the astroglial glutamate transporter, EAAT2, plays a direct role in downregulating the expression levels of full length EAAT2 by binding to a regulatory region of its promoter. PMID:24062161

  17. The Mitochondrial Permeability Transition Pore: A Molecular Target for Amyotrophic Lateral Sclerosis Therapy

    PubMed Central

    Martin, Lee J.

    2009-01-01

    Effective therapies are needed for the treatment of amyotrophic lateral sclerosis (ALS), a fatal type of motor neuron disease. Morphological, biochemical, molecular genetic, and cell/animal model studies suggest that mitochondria have potentially diverse roles in neurodegenerative disease mechanisms and neuronal cell death. In human ALS, abnormalities have been found in mitochondrial structure, mitochondrial respiratory chain enzymes, and mitochondrial cell death proteins indicative of some non-classical form of programmed cell death. Mouse models of ALS are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria. This minireview summarizes work on the how malfunctioning mitochondria might contribute to neuronal death in ALS through the biophysical entity called the mitochondrial permeability pore (mPTP). The major protein components of the mPTP are enriched in mouse motor neurons. Early in the course of disease in ALS mice expressing human mutant superoxide dismutase-1, mitochondria in motor neurons undergo trafficking abnormalities and dramatic remodeling resulting in the formation of mega-mitochondria and coinciding with increased protein carbonyl formation and nitration of mPTP components. The genetic deletion of a major mPTP component, cyclophilin D, has robust effects in ALS mice by delaying disease onset and extending survival. Thus, attention should be directed to the mPTP as rational target for the development of drugs designed to treat ALS. PMID:19651206

  18. Geographic Variation of Amyotrophic Lateral Sclerosis Incidence in New Jersey, 2009-2011.

    PubMed

    Henry, Kevin A; Fagliano, Jerald; Jordan, Heather M; Rechtman, Lindsay; Kaye, Wendy E

    2015-09-15

    Few analyses in the United States have examined geographic variation and socioeconomic disparities in amyotrophic lateral sclerosis (ALS) incidence, because of lack of population-based incidence data. In this analysis, we used population-based ALS data to identify whether ALS incidence clusters geographically and to determine whether ALS risk varies by area-based socioeconomic status (SES). This study included 493 incident ALS cases diagnosed (via El Escorial criteria) in New Jersey between 2009 and 2011. Geographic variation and clustering of ALS incidence was assessed using a spatial scan statistic and Bayesian geoadditive models. Poisson regression was used to estimate the associations between ALS risk and SES based on census-tract median income while controlling for age, sex, and race. ALS incidence varied across and within counties, but there were no statistically significant geographic clusters. SES was associated with ALS incidence. After adjustment for age, sex, and race, the relative risk of ALS was significantly higher (relative risk (RR) = 1.37, 95% confidence interval (CI): 1.02, 1.82) in the highest income quartile than in the lowest. The relative risk of ALS was significantly lower among blacks (RR = 0.57, 95% CI: 0.39, 0.83) and Asians (RR = 0.63, 95% CI: 0.41, 0.97) than among whites. Our findings suggest that ALS incidence in New Jersey appears to be associated with SES and race.

  19. Power Wheelchair Use in Persons With Amyotrophic Lateral Sclerosis: Changes Over Time.

    PubMed

    Ward, Amber Lea; Hammond, Sara; Holsten, Scott; Bravver, Elena; Brooks, Benjamin Rix

    2015-01-01

    The objectives of this study were to survey persons with Amyotrophic Lateral Sclerosis (ALS) at 1 and 6 months after receiving power wheelchairs to determine long-term use, comfort, and function as well as the power wheelchair's impact on daily tasks and quality of life. A 33-question survey and Psychosocial Impact of Assistive Devices Scale (PIADS) were sent 1 month after getting a new power wheelchair; a follow-up survey was sent at 6 months. Based on satisfaction and feature use survey results, at 1 month, 81% of users found the power wheelchair overall comfort to be high, 88% found their overall mobility to be improved, and 95% found it easy to use. Their quality of life increased and pain decreased at 1 and 6 months. According to the PIADS, the power wheelchair gave users increased ability to participate and sense of competence. This study has important results for the ALS community, as it is the first to assess power wheelchair users at 1 and 6 months after power wheelchair procurement. The results demonstrate the impact the power wheelchair has on mobility, psychosocial issues, functional abilities, and quality of life for a person with ALS.

  20. Clinical epidemiology of amyotrophic lateral sclerosis in Liguria, Italy: An update of LIGALS register.

    PubMed

    Scialò, Carlo; Novi, Giovanni; Bandettini di Poggio, Monica; Canosa, Antonio; Sormani, Maria Pia; Mandich, Paola; Origone, Paola; Truffelli, Romina; Mancardi, Giovanni Luigi; Caponnetto, Claudia

    Our objectives were: (1) to assess amyotrophic lateral sclerosis (ALS) incidence and its trend over time in Liguria, an Italian north-western region, performing an analysis of data prospectively collected from 1 January 2009 to 31 December 2014; (2) to determine the mean and median survival in the 2009-2014 Ligurian ALS incident cases; and (3) to evaluate the presence of disease prognostic factors. The Liguria Register for ALS (LIGALS) is an ongoing, multicentre prospective register enrolling all ALS incident cases in Liguria. Cases were identified using several concurrent sources. ALS diagnosis was based on El Escorial revised criteria (EEC-R). Two hundred and ninety-eight patients were enrolled in this study. The mean annual crude incidence rate in the 2009-2014 period was 3.11/100,000 population (95% CI 2.77-3.49); the point prevalence at 31 December 2014 was 7.85/100,000 (95% CI 6.54-9.36) population. Survival analysis demonstrated a median survival from symptom onset of 37.0 months (95% CI 32.0-42.0). In conclusion, ALS crude incidence in Liguria is higher compared to other Italian regions. Clinical and epidemiological data are comparable with those of the Italian ALS population. Survival analysis showed that higher age at onset, bulbar onset, definite EEC-R diagnostic category and a shorter diagnostic delay are related with worse outcomes.

  1. Predictors of impaired communication in amyotrophic lateral sclerosis patients with tracheostomy-invasive ventilation.

    PubMed

    Nakayama, Yuki; Shimizu, Toshio; Mochizuki, Yoko; Hayashi, Kentaro; Matsuda, Chiharu; Nagao, Masahiro; Watabe, Kazuhiko; Kawata, Akihiro; Oyanagi, Kiyomitsu; Isozaki, Eiji; Nakano, Imaharu

    2015-01-01

    Predictors of communication impairment in patients with amyotrophic lateral sclerosis (ALS) using tracheostomy-invasive ventilation (TIV) were investigated. Seventy-six ALS patients using TIV were enrolled and classified into three subgroups of communication ability: patients who could communicate with communication devices (Stage I), patients who had difficulty with communication (Stage II, III, or IV), and patients who could not communicate by any means (Stage V). Predictors of communication impairment were analysed by the Cox proportional hazard model. Results demonstrated that there were no significant differences in disease duration between subgroups. Within 24 months after disease onset, patients who needed TIV and tube feeding, developed oculomotor impairment or became totally quadriplegic and progressed from Stage I to II and V significantly earlier. Multivariate analyses revealed that within 24 months from onset, the need for TIV and progression to total quadriplegia were significant events in patients who progressed to Stage II, whereas the development of oculomotor limitation was significant in patients who progressed to Stage V. In conclusion, TIV, impaired oculomotor movement and total quadriplegia are predictors of severe communication impairment. Rapid disease progression might indicate future communication impairment after the use of TIV. We highly recommend early detection of impaired communication and identification of the best methods of communication.

  2. Cardiovascular disease and diagnosis of amyotrophic lateral sclerosis: A population based study.

    PubMed

    Kioumourtzoglou, Marianthi-Anna; Seals, Ryan M; Gredal, Ole; Mittleman, Murray A; Hansen, Johnni; Weisskopf, Marc G

    Amyotrophic lateral sclerosis (ALS) is a rapidly fatal neurodegenerative disease of unknown etiology. We investigated the association between ALS diagnosis and prior cardiovascular disease (CVD), and CVD-specific, hospital admissions in the Danish population. We conducted a population based nested case-control study, including 3182 Danish residents diagnosed with ALS at age ≥20 years (1982-2009) and 100 randomly selected controls for each case, matched on age, gender and vital status. We estimated odds ratios (OR) associated with CVD, and CVD-specific hospital admissions, adjusting for socioeconomic and marital status, region of residence and past diabetes and obesity diagnoses. The estimated adjusted OR for any CVD admission at least three years prior to the date of ALS diagnosis was 1.15 (95% CI 1.04-1.27). Our results varied across cause-specific admissions; for atherosclerosis the OR was 1.36 (95% CI 1.02-1.80) and for ischemic heart disease 1.14 (95% CI 0.99-1.31), while we observed no association with hypertensive and cerebrovascular diseases. Adjusting for or stratifying by COPD status, a cigarette-smoking correlate, did not change our results. In conclusion, in our population based study we found evidence for a moderately elevated association with CVD that was stronger for specific conditions, such as atherosclerosis. Our findings may have important implications for ALS pathogenesis.

  3. The evaluation of pain in amyotrophic lateral sclerosis: a case controlled observational study.

    PubMed

    Wallace, Victoria C J; Ellis, Cathy M; Burman, Rachel; Knights, Catherine; Shaw, Christopher E; Al-Chalabi, Ammar

    2014-12-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder leading to progressive paralysis. ALS is complicated by a number of non-motor symptoms including pain. Pain in ALS has been poorly studied and poorly managed. This study aimed to collate information regarding pain in ALS using standardized pain questionnaires. Forty-two patients with ALS participated in the study. Control subjects included 41 age-matched healthy volunteers and 42 age-matched patients with neurological conditions other than ALS. Data on pain were collected using the The Brief Pain Inventory and The painDetect Questionnaire. Eighty-five percent of subjects with ALS reported pain versus 50% of neurology clinic controls and 35% of healthy controls (p < 0.01). Pain in ALS included cramping, aching, tiring, sharp and tender, and was non-neuropathic. Pain impacted significantly on mood, general activity, relationships and general enjoyment of life. Fifty-four percent of people with painful ALS used regular analgesia and 29% regular opioids. Other non-motor symptoms suffered included tiredness, constipation, urinary problems, itching and drowsiness. In conclusion, these data support the fact that pain is a significant symptom in ALS which impacts on quality of life. These data can be used to educate clinicians and patients to promote better multidisciplinary management of ALS symptoms and a better quality of life.

  4. Brain-computer interface (BCI) evaluation in people with amyotrophic lateral sclerosis.

    PubMed

    McCane, Lynn M; Sellers, Eric W; McFarland, Dennis J; Mak, Joseph N; Carmack, C Steve; Zeitlin, Debra; Wolpaw, Jonathan R; Vaughan, Theresa M

    2014-06-01

    Brain-computer interfaces (BCIs) might restore communication to people severely disabled by amyotrophic lateral sclerosis (ALS) or other disorders. We sought to: 1) define a protocol for determining whether a person with ALS can use a visual P300-based BCI; 2) determine what proportion of this population can use the BCI; and 3) identify factors affecting BCI performance. Twenty-five individuals with ALS completed an evaluation protocol using a standard 6 × 6 matrix and parameters selected by stepwise linear discrimination. With an 8-channel EEG montage, the subjects fell into two groups in BCI accuracy (chance accuracy 3%). Seventeen averaged 92 (± 3)% (range 71-100%), which is adequate for communication (G70 group). Eight averaged 12 (± 6)% (range 0-36%), inadequate for communication (L40 subject group). Performance did not correlate with disability: 11/17 (65%) of G70 subjects were severely disabled (i.e. ALSFRS-R < 5). All L40 subjects had visual impairments (e.g. nystagmus, diplopia, ptosis). P300 was larger and more anterior in G70 subjects. A 16-channel montage did not significantly improve accuracy. In conclusion, most people severely disabled by ALS could use a visual P300-based BCI for communication. In those who could not, visual impairment was the principal obstacle. For these individuals, auditory P300-based BCIs might be effective.

  5. Genetic Counseling Dilemmas for a Patient with Sporadic Amyotrophic Lateral Sclerosis, Frontotemporal Degeneration & Parkinson's Disease.

    PubMed

    Mantero, Vittorio; Tarlarini, Claudia; Aliprandi, Angelo; Lauria, Giuseppe; Rigamonti, Andrea; Abate, Lucia; Origone, Paola; Mandich, Paola; Penco, Silvana; Salmaggi, Andrea

    2017-03-01

    Amyotrophic lateral sclerosis (ALS), frontotemporal degeneration and Parkinson's disease may be different expressions of the same neurodegenerative disease. However, association between ALS and parkinsonism-dementia complex (ALS-PDC) has only rarely been reported apart from the cluster detected in Guam. We report a patient presenting with ALS-PDC in whom pathological mutations/expansions were investigated. No other family members were reported to have any symptoms of a neurological condition. Our case demonstrates that ALS-PDC can occur as a sporadic disorder, even though the coexistence of the three clinical features in one patient suggests a single underlying genetic cause. It is known that genetic testing should be preferentially offered to patients with ALS who have affected first or second-degree relatives. However, this case illustrates the importance of genetic counseling for family members of patients with sporadic ALC-PDC in order to provide education on the low recurrence risk. Here, we dicuss the ethical, psychological and practical consequences for patients and their relatives.

  6. Nutritional state, energy intakes and energy expenditure of amyotrophic lateral sclerosis (ALS) patients.

    PubMed

    Genton, L; Viatte, V; Janssens, J-P; Héritier, A-C; Pichard, C

    2011-10-01

    Amyotrophic lateral sclerosis (ALS) alters nutritional state, energy intake and energy expenditure. This article aims at reviewing present knowledge on these topics in order to determine energy requirements for maintaining a neutral energy balance in ALS patients. Maintaining a neutral energy balance prevents malnutrition and its complications and may improve physical functioning, quality of life and survival. Prevalence of malnutrition varies between 16 and 55% in ALS patients. Energy intakes are below recommended dietary allowances in 70% of ALS patients at least. These elements suggest a chronic negative energy balance with an imbalance between requirements and intakes. While insufficient intakes can be compensated with nutritional support, the energy requirements are unclear. Studies generally report hypermetabolism in ALS patients. Estimation of total energy expenditure and as a corollary energy needs, necessitates taking into account this hypermetabolism, physical activity and possibly mechanical ventilation. The review suggests a flow chart for optimal nutritional follow-up in clinics. Further studies are required to assess whether optimal nutritional follow-up improves outcome.

  7. Impact of disease, cognitive and behavioural factors on caregiver outcome in amyotrophic lateral sclerosis.

    PubMed

    Watermeyer, Tamlyn J; Brown, Richard G; Sidle, Katie C L; Oliver, David J; Allen, Christopher; Karlsson, Joanna; Ellis, Cathy; Shaw, Christopher E; Al-Chalabi, Ammar; Goldstein, Laura H

    2015-01-01

    Up to 50% of patients with amyotrophic lateral sclerosis (ALS) show mild to moderate cognitive-behavioural change alongside their progressive functional impairment. This study examines the relative impact of patients' disease symptoms, behavioural change and current executive function and social cognition abilities on psychosocial outcomes in spouse caregivers of people with ALS. Thirty-five spouse caregivers rated their own levels of depression and anxiety, subjective burden and marital satisfaction. Caregivers also rated their partner's everyday behaviour. The patients were assessed for disease severity and cognitive function, with composite scores derived for executive function and social cognition. Regression analyses revealed that caregiver burden was predicted by the severity of patients' limb involvement and behavioural problems. Depression was predicted by patients' limb involvement, while behavioural problems and patient age predicted caregiver anxiety. Current marital satisfaction was predicted by patient behavioural problems beyond the level of pre-illness marital satisfaction. In conclusion, the study highlights the potential impact of ALS patients' functional impairment and behavioural change on ALS caregivers' psychosocial functioning. Clinical communication with ALS families should emphasise both physical and psychological challenges presented by the disease.

  8. Active music therapy approach in amyotrophic lateral sclerosis: a randomized-controlled trial.

    PubMed

    Raglio, Alfredo; Giovanazzi, Elena; Pain, Debora; Baiardi, Paola; Imbriani, Chiara; Imbriani, Marcello; Mora, Gabriele

    2016-12-01

    This randomized controlled study assessed the efficacy of active music therapy (AMT) on anxiety, depression, and quality of life in amyotrophic lateral sclerosis (ALS). Communication and relationship during AMT treatment were also evaluated. Thirty patients were assigned randomly to experimental [AMT plus standard of care (SC)] or control (SC) groups. AMT consisted of 12 sessions (three times a week), whereas the SC treatment was based on physical and speech rehabilitation sessions, occupational therapy, and psychological support. ALS Functional Rating Scale-Revised, Hospital Anxiety and Depression Scale, McGill Quality of Life Questionnaire, and Music Therapy Rating Scale were administered to assess functional, psychological, and music therapy outcomes. The AMT group improved significantly in McGill Quality of Life Questionnaire global scores (P=0.035) and showed a positive trend in nonverbal and sonorous-music relationship during the treatment. Further studies involving larger samples in a longer AMT intervention are needed to confirm the effectiveness of this approach in ALS.

  9. Altered Thiol Chemistry in Human Amyotrophic Lateral Sclerosis-linked Mutants of Superoxide Dismutase 1*

    PubMed Central

    Solsona, Carles; Kahn, Thomas B.; Badilla, Carmen L.; Álvarez-Zaldiernas, Cristina; Blasi, Juan; Fernandez, Julio M.; Alegre-Cebollada, Jorge

    2014-01-01

    Neurodegenerative diseases share a common characteristic, the presence of intracellular or extracellular deposits of protein aggregates in nervous tissues. Amyotrophic Lateral Sclerosis (ALS) is a severe and fatal neurodegenerative disorder, which affects preferentially motoneurons. Changes in the redox state of superoxide dismutase 1 (SOD1) are associated with the onset and development of familial forms of ALS. In human SOD1 (hSOD1), a conserved disulfide bond and two free cysteine residues can engage in anomalous thiol/disulfide exchange resulting in non-native disulfides, a hallmark of ALS that is related to protein misfolding and aggregation. Because of the many competing reaction pathways, traditional bulk techniques fall short at quantifying individual thiol/disulfide exchange reactions. Here, we adapt recently developed single-bond chemistry techniques to study individual disulfide isomerization reactions in hSOD1. Mechanical unfolding of hSOD1 leads to the formation of a polypeptide loop held by the disulfide. This loop behaves as a molecular jump rope that brings reactive Cys-111 close to the disulfide. Using force-clamp spectroscopy, we monitor nucleophilic attack of Cys-111 at either sulfur of the disulfide and determine the selectivity of the reaction. Disease-causing mutations G93A and A4V show greatly altered reactivity patterns, which may contribute to the progression of familial ALS. PMID:25096579

  10. Neuroprotection for Amyotrophic Lateral Sclerosis: Role of Stem Cells, Growth Factors, and Gene Therapy

    PubMed Central

    Pandya, Rachna S.; Mao, Lilly L. J.; Zhou, Edward W.; Bowser, Robert; Zhu, Zhenglun; Zhu, Yongjin; Wang, Xin

    2014-01-01

    Various molecular mechanisms including apoptosis, inflammation, oxidative stress, and excitotoxicity have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), though the exact mechanisms have yet to be specified. Furthermore, the underlying restorative molecular mechanisms resulting in neuronal and/or non-neuronal regeneration have to be yet elucidated. Therapeutic agents targeting one or more of these mechanisms to combat either initiation or progression of the disease are under research. Novel treatments including stem cell therapy, growth factors, and gene therapy might prolong survival and delay progression of symptoms. Harnessing the regenerative potential of the central nervous system would be a novel approach for the treatment of motor neuron death resulting from ALS. Endogenous neural replacement, if augmented with administration of exogenous growth factors or with pharmaceuticals that increase the rate of neural progenitor formation, neural migration, and neural maturation could slow the rate of cell loss enough to result in clinical improvement. In this review, we discuss the impact of therapeutic treatment involving stem cell therapy, trophic factors, gene therapy, and combination therapy on disease onset and progression of ALS. In addition, we summarize human clinical trials of stem cell therapy, growth factor therapy, and gene therapy in individuals with ALS. PMID:22283698

  11. The potential of GPNMB as novel neuroprotective factor in amyotrophic lateral sclerosis

    PubMed Central

    Tanaka, Hirotaka; Shimazawa, Masamitsu; Kimura, Masataka; Takata, Masafumi; Tsuruma, Kazuhiro; Yamada, Mitsunori; Takahashi, Hitoshi; Hozumi, Isao; Niwa, Jun-ichi; Iguchi, Yohei; Nikawa, Takeshi; Sobue, Gen; Inuzuka, Takashi; Hara, Hideaki

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease characterized by the loss of motor neurons. Despite substantial research, the causes of ALS remain unclear. Glycoprotein nonmetastatic melanoma protein B (GPNMB) was identified as an ALS-related factor using DNA microarray analysis with mutant superoxide dismutase (SOD1G93A) mice. GPNMB was greatly induced in the spinal cords of ALS patients and a mouse model as the disease progressed. It was especially expressed in motor neurons and astrocytes. In an NSC34 cell line, glycosylation of GPNMB was inhibited by interaction with SOD1G93A, increasing motor neuron vulnerability, whereas extracellular fragments of GPNMB secreted from activated astrocytes attenuated the neurotoxicity of SOD1G93A in neural cells. Furthermore, GPNMB expression was substantial in the sera of sporadic ALS patients than that of other diseased patients. This study suggests that GPNMB can be a target for therapeutic intervention for suppressing motor neuron degeneration in ALS. PMID:22891158

  12. Neuromuscular Junction Protection for the Potential Treatment of Amyotrophic Lateral Sclerosis

    PubMed Central

    Krakora, Dan; Macrander, Corey; Suzuki, Masatoshi

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by the progressive degeneration of upper and lower motor neurons (MNs), leading to muscular atrophy and eventual respiratory failure. ALS research has primarily focused on mechanisms regarding MN cell death; however, degenerative processes in the skeletal muscle, particularly involving neuromuscular junctions (NMJs), are observed in the early stages of and throughout disease progression. According to the “dying-back” hypothesis, NMJ degeneration may not only precede, but actively cause upper and lower MN loss. The importance of NMJ pathology has relatively received little attention in ALS, possibly because compensatory mechanisms mask NMJ loss for prolonged periods. Many mechanisms explaining NMJ degeneration have been proposed such as the disruption of anterograde/retrograde axonal transport, irregular cellular metabolism, and changes in muscle gene and protein expression. Neurotrophic factors, which are known to have neuroprotective and regenerative properties, have been intensely investigated for their therapeutic potential in both the preclinical and clinical setting. Additional research should focus on the potential of preserving NMJs in order to delay or prevent disease progression PMID:22919482

  13. A Comprehensive Library of Familial Human Amyotrophic Lateral Sclerosis Induced Pluripotent Stem Cells

    PubMed Central

    Li, Ying; Balasubramanian, Umamahesw; Cohen, Devon; Zhang, Ping-Wu; Mosmiller, Elizabeth; Sattler, Rita; Maragakis, Nicholas J.; Rothstein, Jeffrey D.

    2015-01-01

    Amyotrophic lateral sclerosis is a progressive disease characterized by the loss of upper and lower motor neurons, leading to paralysis of voluntary muscles. About 10% of all ALS cases are familial (fALS), among which 15–20% are linked to Cu/Zn superoxide dismutase (SOD1) mutations, usually inherited in an autosomal dominant manner. To date only one FDA approved drug is available which increases survival moderately. Our understanding of ALS disease mechanisms is largely derived from rodent model studies, however due to the differences between rodents and humans, it is necessary to have humanized models for studies of disease pathogenesis as well as drug development. Therefore, we generated a comprehensive library of a total 22 of fALS patient-specific induced pluripotent stem cell (iPSC) lines. These cells were thoroughly characterized before being deposited into the library. The library of cells includes a variety of C9orf72 mutations, sod1 mutations, FUS, ANG and FIG4 mutations. Certain mutations are represented with more than one line, which allows for studies of variable genetic backgrounds. In addition, these iPSCs can be successfully differentiated to astroglia, a cell type known to play a critical role in ALS disease progression. This library represents a comprehensive resource that can be used for ALS disease modeling and the development of novel therapeutics. PMID:25760436

  14. Functional connectivity changes resemble patterns of pTDP-43 pathology in amyotrophic lateral sclerosis

    PubMed Central

    Schulthess, Ines; Gorges, Martin; Müller, Hans-Peter; Lulé, Dorothée; Del Tredici, Kelly; Ludolph, Albert C.; Kassubek, Jan

    2016-01-01

    ‘Resting-state’ fMRI allows investigation of alterations in functional brain organization that are associated with an underlying pathological process. We determine whether abnormal connectivity in amyotrophic lateral sclerosis (ALS) in a priori-defined intrinsic functional connectivity networks, according to a neuropathological staging scheme and its DTI-based tract correlates, permits recognition of a sequential involvement of functional networks. ‘Resting-state’ fMRI data from 135 ALS patients and 56 matched healthy controls were investigated for the motor network (corresponding to neuropathological stage 1), brainstem (stage 2), ventral attention (stage 3), default mode/hippocampal network (stage 4), and primary visual network (as the control network) in a cross-sectional analysis and longitudinally in a subgroup of 27 patients after 6 months. Group comparison from cross-sectional and longitudinal data revealed significantly increased functional connectivity (p < 0.05, corrected) in all four investigated networks (but not in the control network), presenting as a network expansion that was correlated with physical disability. Increased connectivity of functional networks, as investigated in a hypothesis-driven approach, is characterized by network expansions and resembled the pattern of pTDP-43 pathology in ALS. However, our data did not allow for the recognition of a sequential involvement of functional connectivity networks at the individual level. PMID:27929102

  15. Epidemiology and surveillance of amyotrophic lateral sclerosis in two large metropolitan areas in California

    PubMed Central

    Valle, Jhaqueline; Roberts, Eric; Paulukonis, Susan; Collins, Natalie; English, Paul; Kaye, Wendy

    2015-01-01

    Abstract Our objective was to provide demographic profiles and incidence estimates of amyotrophic lateral sclerosis (ALS) in two diverse California metropolitan areas: Los Angeles County (LA) and the San Francisco Bay Area (SFBA). Data were retrospectively collected from multiple sources. Case eligibility criteria included residency in SFBA or LA, and treatment for or diagnosis of ALS between 1 January 2009 and 31 December 2011. Overall incidence rates as well as age-, gender-, race- and ethnicity-specific rates were calculated. We identified 539 ALS cases in SFBA and 545 in LA; 618 were incident cases. Cases were more likely to be male and white. There were considerably more cases (p < 0.05) in LA who were foreign-born (LA, 22%; SFBA, 15%), black (LA, 10%; SFBA, 6%) or Hispanic (LA, 19%; SFBA, 10%). Conversely, the age adjusted incidence rates (per 100,000) were higher in SFBA for whites (LA, 1.40; SFBA, 2.49) and Hispanics (LA, 0.66; SFBA, 1.57) compared with LA. General case demographics and incidence rates in these two areas were similar to published studies. However, the differences between the two areas raise questions about how factors such as geography, access to care, and referral patterns may affect case ascertainment and diagnosis. PMID:25822003

  16. Survival and Cause of Death among a Cohort of Confirmed Amyotrophic Lateral Sclerosis Cases

    PubMed Central

    Paulukonis, Susan T.; Roberts, Eric M.; Valle, Jhaqueline P.; Collins, Natalie N.; English, Paul B.; Kaye, Wendy E.

    2015-01-01

    Introduction Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. Estimates of survival from disease onset range from 20 to 48 months and have been generated using clinical populations or death records alone. Methods Data on a cohort of ALS cases diagnosed between 2009–2011 were collected as part of the Los Angeles and San Francisco Bay Area Metropolitan ALS Surveillance projects; death records 2009–2013 were linked to these confirmed cases to determine survival post diagnosis and factors associated with survival time. Results There were 618 cases identified and 283 of these died during the follow up time period. Median age at death was 64.3 years, and median survival time post-diagnosis was 2.6 years. Age at diagnosis and year of diagnosis were predictors of survival time in adjusted models; those diagnosed at age 80 or older had shorter survival than those diagnosed at age 50 or younger. Most (92%) had ALS noted as a cause of death. Discussion Survival post-diagnosis may be improved compared with previous reports. Age at diagnosis continues to be the strongest predictor of prognosis; recall case reporting bias may play a role in estimates of survival time. PMID:26172548

  17. Structural insights into human angiogenin variants implicated in Parkinson’s disease and Amyotrophic Lateral Sclerosis

    PubMed Central

    Bradshaw, William J.; Rehman, Saima; Pham, Tram T. K.; Thiyagarajan, Nethaji; Lee, Rebecca L.; Subramanian, Vasanta; Acharya, K. Ravi

    2017-01-01

    Mutations in Angiogenin (ANG), a member of the Ribonuclease A superfamily (also known as RNase 5) are known to be associated with Amyotrophic Lateral Sclerosis (ALS, motor neurone disease) (sporadic and familial) and Parkinson’s Disease (PD). In our previous studies we have shown that ANG is expressed in neurons during neuro-ectodermal differentiation, and that it has both neurotrophic and neuroprotective functions. In addition, in an extensive study on selective ANG-ALS variants we correlated the structural changes to the effects on neuronal survival and the ability to induce stress granules in neuronal cell lines. Furthermore, we have established that ANG-ALS variants which affect the structure of the catalytic site and either decrease or increase the RNase activity affect neuronal survival. Neuronal cell lines expressing the ANG-ALS variants also lack the ability to form stress granules. Here, we report a detailed experimental structural study on eleven new ANG-PD/ALS variants which will have implications in understanding the molecular basis underlying their role in PD and ALS. PMID:28176817

  18. Immunomodulation in the treatment of multiple sclerosis and amyotrophic lateral sclerosis: a model for autoimmune disorders.

    PubMed Central

    Alonso, K.; Medenica, R.

    1995-01-01

    Seventeen multiple sclerosis (MS) patients progressing under conventional therapy (average treatment duration: 3 years) with performance status 3-4 (mean Disability Status Scale [DSS]: 82) who demonstrated circulating lymphokine inhibitor factors were selected for a monthly immunomodulatory protocol using plasmapheresis, followed by 3 days of human intravenous immunoglobulin, and low-dose methylprednisolone, cyclophosphamide, interferon-a, and interferon-g, as well as octreide. Twelve of the 17 patients presented with visual problems, 12 had lower extremity weakness or paraperesis/paralysis, and 6 had bladder/bowel dysfunction. Following 4 months of therapy, 4 recovered completely, 7 showed loss of paralysis/paraparesis, and 5 had improvement in lower extremity weakness. One patient progressed (mean DSS: 51). Lymphokine inhibitor factors declined in 14 patients with concomitant normalization of circulating immune complexes. Eight patients experienced rises in CD4 levels with stabilization of CD8 levels. Hypotension and hypocalcemia were observed during plasmapheresis. Twelve patients with amyotrophic lateral sclerosis with poor performance status also were studied. Four of the 12 improved with the regimen, whereas six stabilized disease. Similar alterations in laboratory parameters were described. The rationale for this approach is discussed. PMID:7674346

  19. The amyotrophic lateral sclerosis 8 protein, VAP, is required for ER protein quality control.

    PubMed

    Moustaqim-Barrette, Amina; Lin, Yong Q; Pradhan, Sreeparna; Neely, Gregory G; Bellen, Hugo J; Tsuda, Hiroshi

    2014-04-15

    A familial form of Amyotrophic lateral sclerosis (ALS8) is caused by a point mutation (P56S) in the vesicle-associated membrane protein associated protein B (VapB). Human VapB and Drosophila Vap-33-1 (Vap) are homologous type II transmembrane proteins that are localized to the ER. However, the precise consequences of the defects associated with the P56S mutation in the endoplasmic reticulum (ER) and its role in the pathology of ALS are not well understood. Here we show that Vap is required for ER protein quality control (ERQC). Loss of Vap in flies shows various ERQC associated defects, including protein accumulation, ER expansion, and ER stress. We also show that wild type Vap, but not the ALS8 mutant Vap, interacts with a lipid-binding protein, Oxysterol binding protein (Osbp), and that Vap is required for the proper localization of Osbp to the ER. Restoring the expression of Osbp in the ER suppresses the defects associated with loss of Vap and the ALS8 mutant Vap. Hence, we propose that the ALS8 mutation impairs the interaction of Vap with Osbp, resulting in hypomorphic defects that might contribute to the pathology of ALS8.

  20. Metabolic Dysfunctions in Amyotrophic Lateral Sclerosis Pathogenesis and Potential Metabolic Treatments

    PubMed Central

    Tefera, Tesfaye W.; Borges, Karin

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease primarily characterized by loss of motor neurons in brain and spinal cord. The death of motor neurons leads to denervation of muscle which in turn causes muscle weakness and paralysis, decreased respiratory function and eventually death. Growing evidence indicates disturbances in energy metabolism in patients with ALS and animal models of ALS, which are likely to contribute to disease progression. Particularly, defects in glucose metabolism and mitochondrial dysfunction limit the availability of ATP to CNS tissues and muscle. Several metabolic approaches improving mitochondrial function have been investigated in vitro and in vivo and showed varying effects in ALS. The effects of metabolic approaches in ALS models encompass delays in onset of motor symptoms, protection of motor neurons and extension of survival, which signifies an important role of metabolism in the pathogenesis of the disease. There is now an urgent need to test metabolic approaches in controlled clinical trials. In addition, more detailed studies to better characterize the abnormalities in energy metabolism in patients with ALS and ALS models are necessary to develop metabolically targeted effective therapies that can slow the progression of the disease and prolong life for patients with ALS. PMID:28119559

  1. Roots to start research in amyotrophic lateral sclerosis: molecular pathways and novel therapeutics for future.

    PubMed

    Harikrishnareddy, Dibbanti; Misra, Shubham; Upadhyay, Sujata; Modi, Manish; Medhi, Bikash

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease that rapidly progresses from mild motor symptoms to severe motor paralysis and premature death. There is currently no cure for this devastating disease; most ALS patients die of respiratory failure generally within 3-5 years from the onset of signs and symptoms. Approximately 90% of ALS cases are sporadic in nature, with no clear associated risk factors. It is reported that ALS is a complex and multifaceted neurodegenerative disease. Less is known about the key factors involved in the sporadic form of the disease. The intricate pathogenic mechanisms that target motor neurons in ALS includes oxidative stress, glutamate excitotoxicity, mitochondrial damage, protein aggregation, glia and neuroinflammation pathology, defective axonal transport, and aberrant RNA metabolism. Despite aggressive research, no therapy has been yet proven to completely reverse the core symptoms of the disease. Riluzole is the only drug approved by the Food and Drug Administration and recommended by the National Institute for Clinical Excellence so far proven to be successful against ALS and may prevent progression and extend life for a few months or so. This article provides a novel understanding in key findings of pathogenesis and interventions currently under investigation to slow disease progression in ALS.

  2. Executive dysfunction affects word list recall performance: Evidence from amyotrophic lateral sclerosis and other neurodegenerative diseases.

    PubMed

    Consonni, Monica; Rossi, Stefania; Cerami, Chiara; Marcone, Alessandra; Iannaccone, Sandro; Francesco Cappa, Stefano; Perani, Daniela

    2017-03-01

    The Rey Auditory Verbal Learning Test (RAVLT) is widely used in clinical practice to evaluate verbal episodic memory. While there is evidence that RAVLT performance can be influenced by executive dysfunction, the way executive disorders affect the serial position curve (SPC) has not been yet explored. To this aim, we analysed immediate and delayed recall performances of 13 non-demented amyotrophic lateral sclerosis (ALS) patients with a specific mild executive dysfunction (ALSci) and compared their performances to those of 48 healthy controls (HC) and 13 cognitively normal patients with ALS. Moreover, to control for the impact of a severe dysexecutive syndrome and a genuine episodic memory deficit on the SPC, we enrolled 15 patients with a diagnosis of behavioural variant of frontotemporal dementia (bvFTD) and 18 patients with probable Alzheimer's disease (AD). Results documented that, compared to cognitively normal subjects, ALSci patients had a selective mid-list impairment for immediate recall scores. The bvFTD group obtained low performances with a selectively increased forgetting rate for terminal items, whereas the AD group showed a disproportionately large memory loss on the primary and middle part of the SPC for immediate recall scores and were severely impaired in the delayed recall trial. These results suggested that subtle executive dysfunctions might influence the recall of mid-list items, possibly reflecting deficiency in control strategies at retrieval of word lists, whereas severer dysexecutive syndrome might also affect the recall of terminal items possibly due to attention deficit or retroactive interference.

  3. Abnormalities of Bell's phenomenon in amyotrophic lateral sclerosis: a clinical and electrophysiological evaluation.

    PubMed Central

    Esteban, A; De Andrés, C; Giménez-Roldán, S

    1978-01-01

    A clinical and electromyographic study of oculomotor function was carried out in a series of 24 patients with amyotrophic lateral sclerosis (ALS). In 15 cases an alteration of Bell's phenomenon was found. In addition, three patients showed some impairment of conjugate ocular motility in the form of upward gaze paly. All cases had preserved oculocephalic reflexes in the vertical and horizontal planes. On clinical and electromyographic grounds, three degrees of altered Bell's phenomenon are suggested: attenuated (short and unsustained upward displacement of the eyeballs after forced closure of the eyelids), abolished (no upward displacement), and inverted (downward instead of upward displacement of the eyes). These oculomotor alterations were not directly related to the type of ALS at onset of the illness, nor with its duration. However they were correlated with the relative degree of the clinical bilateral pyramidal tract signs at the supraspinal level. The common involvement of the corticogeniculate tract in ALS could explain the unexpectedly high incidence of alteration of Bell's phenomenon found in this disease, but is is non-specific and similar lesions from different causes may also produce it. Images PMID:681956

  4. Finding Inhibitors of Mutant Superoxide Dismutase-1 for Amyotrophic Lateral Sclerosis Therapy from Traditional Chinese Medicine

    PubMed Central

    Huang, Hung-Jin; Chang, Tung-Ti; Chen, Hsin-Yi; Chen, Calvin Yu-Chian

    2014-01-01

    Superoxide dismutase type 1 (SOD1) mutations cause protein aggregation and decrease protein stability, which are linked to amyotrophic lateral sclerosis (ALS) disease. This research utilizes the world's largest traditional Chinese medicine (TCM) database to search novel inhibitors of mutant SOD1, and molecular dynamics (MD) simulations were used to analyze the stability of protein that interacted with docked ligands. Docking results show that hesperidin and 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (THSG) have high affinity to mutant SOD1 and then dopamine. For MD simulation analysis, hesperidin and THSG displayed similar value of RMSD with dopamine, and the migration analysis reveals stable fluctuation at the end of MD simulation time. Interestingly, distance between the protein and ligand has distinct difference, and hesperidin changes the position from initial binding site to the other place. In flexibility of residues analysis, the secondary structure among all complexes does not change, indicating that the structure are not affect ligand binding. The binding poses of hesperidin and THSG are similar to dopamine after molecular simulation. Our result indicated that hesperidin and THSG might be potential lead compound to design inhibitors of mutant SOD1 for ALS therapy. PMID:24963318

  5. Is exposure to cyanobacteria an environmental risk factor for amyotrophic lateral sclerosis and other neurodegenerative diseases?

    USGS Publications Warehouse

    Bradley, Walter G.; Borenstein, Amy R.; Nelson, Lorene M.; Codd, Geoffrey A.; Rosen, Barry H.; Stommel, Elijah W.; Cox, Paul Alan

    2013-01-01

    There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS) is caused by gene-environment interactions. Mutations in genes underlying familial ALS (fALS) have been discovered in only 5–10% of the total population of ALS patients. Relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron death leading to the syndrome of ALS, although exposure to chemicals including lead and pesticides, and to agricultural environments, smoking, certain sports, and trauma have all been identified with an increased risk of ALS. There is a need for research to quantify the relative roles of each of the identified risk factors for ALS. Recent evidence has strengthened the theory that chronic environmental exposure to the neurotoxic amino acid β-N-methylamino-L-alanine (BMAA) produced by cyanobacteria may be an environmental risk factor for ALS. Here we describe methods that may be used to assess exposure to cyanobacteria, and hence potentially to BMAA, namely an epidemiologic questionnaire and direct and indirect methods for estimating the cyanobacterial load in ecosystems. Rigorous epidemiologic studies could determine the risks associated with exposure to cyanobacteria, and if combined with genetic analysis of ALS cases and controls could reveal etiologically important gene-environment interactions in genetically vulnerable individuals.

  6. Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation?

    PubMed Central

    Kanouchi, Tadashi; Ohkubo, Takuya

    2012-01-01

    Progressive accumulation of specific misfolded protein is a defining feature of amyotrophic lateral sclerosis (ALS), similarly seen in Alzheimer disease, Parkinson disease, Huntington disease and Creutzfeldt–Jakob disease. The intercellular transfer of inclusions made of tau, α-synuclein and huntingtin has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system. Evidence for such a prion-like propagation mechanism has now spread to the major misfolded proteins, superoxide dismutase 1 (SOD1) and the 43 kDa transactive response DNA binding protein (TDP-43), implicated in ALS. The focus in this review is on what is known about ALS progression in terms of clinical as well as molecular aspects. Furthermore, the concept of ‘propagation’ is dissected into contiguous and non-contiguous types, and this concept is expanded to the severity of the focal symptom as well as its regional spread which can be explained by cell to cell propagation in the local neuron pool. PMID:22544947

  7. D-Serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis

    PubMed Central

    Sasabe, Jumpei; Chiba, Tomohiro; Yamada, Marina; Okamoto, Koichi; Nishimoto, Ikuo; Matsuoka, Masaaki; Aiso, Sadakazu

    2007-01-01

    Excitotoxicity has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). More recently, glial involvement has been shown to be essential for ALS-related motoneuronal death. Here, we identified an N-methyl-D-aspartate (NMDA) receptor co-agonist, D-serine (D-Ser), as a glia-derived enhancer of glutamate (Glu) toxicity to ALS motoneurons. Cell death assay indicated that primary spinal cord neurons from ALS mice were more vulnerable to NMDA toxicity than those from control mice, in a D-Ser-dependent manner. Levels of D-Ser and its producing enzyme, serine racemase, in spinal cords of ALS mice were progressively elevated, dominantly in glia, with disease progression. In vitro, expression of serine racemase was induced not only by an extracellular pro-inflammatory factor, but also by transiently expressed G93A-superoxide dismutase1 in microglial cells. Furthermore, increases of D-Ser levels were also observed in spinal cords of both familial and sporadic ALS patients. Collectively, Glu toxicity enhanced by D-Ser overproduced in glia is proposed as a novel mechanism underlying ALS motoneuronal death, and this mechanism may be regarded as a potential therapeutic target for ALS. PMID:17762863

  8. Cognitive impairment in amyotrophic lateral sclerosis, clues from the SOD1 mouse.

    PubMed

    Spalloni, Alida; Longone, Patrizia

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is now recognized as a multisystem disorder, in which the primary pathology is the degeneration of motor neurons, with cognitive and/or behavioral dysfunctions that constitutes the non-motor manifestations of ALS. The combination of clinical, neuroimaging, and neuropathological data, and detailed genetic studies suggest that ALS and frontotemporal dementia (FTD) might form part of a disease continuum, with pure ALS and pure FTD at the two extremes. Mutations in the superoxide dismutase 1 (SOD1) gene were the first genetic mutations linked to the insurgence of ALS. Since that discovery numerous animal models carrying SOD1 mutations have been created. Despite their limitations these animal models, particularly the mice, have broaden our knowledge on the system alterations occurring in the ALS spectrum of disorders. The present review aims at providing an overview of the data obtained with the SOD1 animal models first and foremost on the cortical and subcortical regions, the cortico-striatal and hippocampal synaptic plasticity, dendritic branching and glutamate receptors function.

  9. Magnesium intake and risk of amyotrophic lateral sclerosis: results from five large cohort studies.

    PubMed

    Fondell, Elinor; O'Reilly, Eilis J; Fitzgerald, Kathryn C; Falcone, Guido J; McCullough, Marjorie L; Park, Yikyung; Kolonel, Laurence N; Ascherio, Alberto

    2013-09-01

    A low magnesium intake has been suggested to be associated with amyotrophic lateral sclerosis (ALS) in pathological and case-control studies, but prospective studies in humans are lacking. The relation between dietary intake of magnesium and ALS risk was explored in five large prospective cohort studies (the Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health - AARP Diet and Health Study), comprising over 1,050,000 males and females contributing 1093 cases of ALS during a mean of 15 years of follow-up. Cox proportional hazards models were used within each cohort, and cohort-specific estimates were subsequently pooled using a random-effects model. Results demonstrated that dietary magnesium intake was not associated with ALS risk, relative risk 1.07, 95% confidence interval 0.88 - 1.31 comparing the highest quintile of intake with the lowest. This finding does not support a protective effect of magnesium intake on ALS risk. Further analyses should explore magnesium intake in combination with heavy metal exposure and genetic variants affecting magnesium absorption.

  10. TDP-43 in the hypoglossal nucleus identifies amyotrophic lateral sclerosis in behavioral variant frontotemporal dementia.

    PubMed

    Halliday, Glenda M; Kiernan, Matthew C; Kril, Jillian J; Mito, Remika; Masuda-Suzukake, Masami; Hasegawa, Masato; McCann, Heather; Bartley, Lauren; Dobson-Stone, Carol; Kwok, John B J; Hornberger, Michael; Hodges, John R; Tan, Rachel H

    2016-07-15

    The hypoglossal nucleus was recently identified as a key brain region in which the presence of TDP-43 pathology could accurately discriminate TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis (ALS). The objective of the present study was to assess the hypoglossal nucleus in behavioral variant frontotemporal dementia (bvFTD), and determine whether TDP-43 in this region is associated with clinical ALS. Twenty-nine cases with neuropathological FTLD-TDP and clinical bvFTD that had not been previously assessed for hypoglossal TDP-43 pathology were included in this study. Of these 29 cases, 41% (n=12) had a dual diagnosis of bvFTD-ALS at presentation, all 100% (n=12) of which demonstrated hypoglossal TDP-43 pathology. Of the 59% (n=17) cohort that presented with pure bvFTD, 35% (n=6) were identified with hypoglossal TDP-43 pathology. Review of the case files of all pure bvFTD cases revealed evidence of possible or probable ALS in 5 of the 6 hypoglossal-positive cases (83%) towards the end of disease, and this was absent from all cases without such pathology. In conclusion, the present study validates grading the presence of TDP-43 in the hypoglossal nucleus for the pathological identification of bvFTD cases with clinical ALS, and extends this to include the identification of cases with possible ALS at end-stage.

  11. Efficacy of Stem Cell Therapy in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis

    PubMed Central

    Moura, Mirian Conceicao; Novaes, Maria Rita Carvalho Garbi; Zago, Yuri S. S. P.; Eduardo, Emanoel Junio; Casulari, Luiz Augusto

    2016-01-01

    Background Published studies seeking to improve survival in amyotrophic lateral sclerosis (ALS) have poor results in humans, although there are several studies in animal models with positive results. Methods We conducted a systematic review and meta-analysis of studies that were published between March 2009 and March 2015 on stem cell therapy and survival in animal models and patients with ALS. A total of 714 articles were identified, and from these, we selected preclinical in vivo studies and retrospective clinical studies. Results and conclusions A meta-analysis confirmed the efficacy of stem cell therapy in improving survival in preclinical trials, where a mean difference of 9.79 days (95% confidence interval: 4.45 - 15.14) in lifespan favored stem cell therapy. In contrast, the number of clinical studies is still insufficient to assess their effectiveness, and these studies only demonstrate the absence of serious adverse events. However, even this conclusion should be interpreted with caution because clinical studies are retrospective and heterogeneous and have an unsatisfactory quality. PMID:26985252

  12. Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis

    PubMed Central

    Riva, Nilo; Clarelli, Ferdinando; Domi, Teuta; Cerri, Federica; Gallia, Francesca; Trimarco, Amelia; Brambilla, Paola; Lunetta, Christian; Lazzerini, Alberto; Lauria, Giuseppe; Taveggia, Carla; Iannaccone, Sandro; Nobile-Orazio, Eduardo; Comi, Giancarlo; D’Antonio, Maurizio; Martinelli-Boneschi, Filippo; Quattrini, Angelo

    2016-01-01

    The aim of the present study is to investigate the molecular pathways underlying amyotrophic lateral sclerosis (ALS) pathogenesis within the peripheral nervous system. We analyzed gene expression changes in human motor nerve diagnostic biopsies obtained from eight ALS patients and seven patients affected by motor neuropathy as controls. An integrated transcriptomics and system biology approach was employed. We identified alterations in the expression of 815 genes, with 529 up-regulated and 286 down-regulated in ALS patients. Up-regulated genes clustered around biological process involving RNA processing and protein metabolisms. We observed a significant enrichment of up-regulated small nucleolar RNA transcripts (p = 2.68*10-11) and genes related to endoplasmic reticulum unfolded protein response and chaperone activity. We found a significant down-regulation in ALS of genes related to the glutamate metabolism. Interestingly, a network analysis highlighted HDAC2, belonging to the histone deacetylase family, as the most interacting node. While so far gene expression studies in human ALS have been performed in postmortem tissues, here specimens were obtained from biopsy at an early phase of the disease, making these results new in the field of ALS research and therefore appealing for gene discovery studies. PMID:27982123

  13. Amyotrophic lateral sclerosis as a paraneoplastic manifestation in the neuroendocrine tumor of stomach: a case report.

    PubMed

    Mehrpour, Masoud; Mohebi, Nafiseh; Motamed, Mohammad Reza; Zamani, Farhad

    2013-01-01

    Motor neuron diseases have been reported as a rare paraneoplastic syndrome (PNS) of a systemic neoplasm. We present a patient with amyotrophic lateral sclerosis (ALS) in association with neuroendocrine tumor (NET) of stomach, which is the first case of motor neuronopathy with underlying neuroendocrine tumor. A 79-year old woman presented with a two months history of progressive dysphagia, spastic dysarthria and marked fasciculation in her atrophic tongue. Gag reflexes were diminished bilaterally. Other cranial nerves were intact. In muscle testing there was significant atrophy in thenar and hypothenar areas of both hands compatible with diffuse motor neuronopathy with active denervation. Upper GI endoscopic study showed patchy erythematous mucosa with congestion in body of stomach, Histological biopsy of stomach confirmed the neuroendocrine tumor (NET). The importance of considering a paraneoplastic syndrome in a patient with presentation of ALS, which can leads to searching for underlying neoplasm before its apparent signs and symptoms, to initiate tumor treatment so much sooner. In addition even though paraneoplastic motor neuron disease is rare, treating the underlying neoplasm may resolve neurologic signs and symptoms.

  14. Adeno Associated Viral Vector Delivered RNAi for Gene Therapy of SOD1 Amyotrophic Lateral Sclerosis

    PubMed Central

    Stoica, Lorelei; Sena-Esteves, Miguel

    2016-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of upper and lower motor neurons. Mutations in superoxide dismutase 1 (SOD1) are a leading cause of ALS, responsible for up to 20% of familial cases. Although the exact mechanism by which mutant SOD1 causes disease remains unknown, multiple studies have shown that reduction of the mutant species leads to delayed disease onset and extension of lifespan of animal models. This makes SOD1 an ideal target for gene therapy coupling adeno associated virus vector (AAV) gene delivery with RNAi molecules. In this review we summarize the studies done thus far attempting to decrease SOD1 gene expression, using AAV vectors as delivery tools, and RNAi as therapeutic molecules. Current hurdles to be overcome, such as the need for widespread gene delivery through the entire central nervous system (CNS), are discussed. Continued efforts to improve current AAV delivery methods and capsids will accelerate the application of these therapeutics to the clinic. PMID:27531973

  15. Does dysfunction of the mirror neuron system contribute to symptoms in amyotrophic lateral sclerosis?

    PubMed

    Eisen, Andrew; Lemon, Roger; Kiernan, Matthew C; Hornberger, Michael; Turner, Martin R

    2015-07-01

    There is growing evidence that mirror neurons, initially discovered over two decades ago in the monkey, are present in the human brain. In the monkey, mirror neurons characteristically fire not only when it is performing an action, such as grasping an object, but also when observing a similar action performed by another agent (human or monkey). In this review we discuss the origin, cortical distribution and possible functions of mirror neurons as a background to exploring their potential relevance in amyotrophic lateral sclerosis (ALS). We have recently proposed that ALS (and the related condition of frontotemporal dementia) may be viewed as a failure of interlinked functional complexes having their origins in key evolutionary adaptations. This can include loss of the direct projections from the corticospinal tract, and this is at least part of the explanation for impaired motor control in ALS. Since, in the monkey, corticospinal neurons also show mirror properties, ALS in humans might also affect the mirror neuron system. We speculate that a defective mirror neuron system might contribute to other ALS deficits affecting motor imagery, gesture, language and empathy.

  16. Geographic Variation of Amyotrophic Lateral Sclerosis Incidence in New Jersey, 2009–2011

    PubMed Central

    Henry, Kevin A.; Fagliano, Jerald; Jordan, Heather M.; Rechtman, Lindsay; Kaye, Wendy E.

    2015-01-01

    Few analyses in the United States have examined geographic variation and socioeconomic disparities in amyotrophic lateral sclerosis (ALS) incidence, because of lack of population-based incidence data. In this analysis, we used population-based ALS data to identify whether ALS incidence clusters geographically and to determine whether ALS risk varies by area-based socioeconomic status (SES). This study included 493 incident ALS cases diagnosed (via El Escorial criteria) in New Jersey between 2009 and 2011. Geographic variation and clustering of ALS incidence was assessed using a spatial scan statistic and Bayesian geoadditive models. Poisson regression was used to estimate the associations between ALS risk and SES based on census-tract median income while controlling for age, sex, and race. ALS incidence varied across and within counties, but there were no statistically significant geographic clusters. SES was associated with ALS incidence. After adjustment for age, sex, and race, the relative risk of ALS was significantly higher (relative risk (RR) = 1.37, 95% confidence interval (CI): 1.02, 1.82) in the highest income quartile than in the lowest. The relative risk of ALS was significantly lower among blacks (RR = 0.57, 95% CI: 0.39, 0.83) and Asians (RR = 0.63, 95% CI: 0.41, 0.97) than among whites. Our findings suggest that ALS incidence in New Jersey appears to be associated with SES and race. PMID:26041711

  17. Functional Contribution of the Transcription Factor ATF4 to the Pathogenesis of Amyotrophic Lateral Sclerosis

    PubMed Central

    Matus, Soledad; Lopez, Estefanía; Valenzuela, Vicente; Nassif, Melissa; Hetz, Claudio

    2013-01-01

    Endoplasmic reticulum (ER) stress represents an early pathological event in amyotrophic lateral sclerosis (ALS). ATF4 is a key ER stress transcription factor that plays a role in both adaptation to stress and the activation of apoptosis. Here we investigated the contribution of ATF4 to ALS. ATF4 deficiency reduced the rate of birth of SOD1G86R transgenic mice. The fraction of ATF4−/−-SOD1G85R transgenic mice that were born are more resistant to develop ALS, leading to delayed disease onset and prolonged life span. ATF4 deficiency completely attenuated the induction of pro-apoptotic genes, including BIM and CHOP, and also led to quantitative changes in the ER protein homeostasis network. Unexpectedly, ATF4 deficiency enhanced mutant SOD1 aggregation at the end stage of the disease. Studies in the motoneuron cell line NSC34 demonstrated that knocking down ATF4 enhances mutant SOD1 aggregation possibly due to alteration in the redox status of the cell. Our results support a functional role of ATF4 in ALS, offering a novel target for disease intervention. PMID:23874395

  18. Long-term physical activity: an exogenous risk factor for sporadic amyotrophic lateral sclerosis?

    PubMed Central

    Harwood, Ceryl A.; Westgate, Kate; Gunstone, Sue; Brage, Soren; Wareham, Nicholas J.; McDermott, Christopher J.; Shaw, Pamela J.

    2016-01-01

    Abstract Objectives: To conduct a geographically defined, UK-based case-control study, to examine any association between physical activity (PA) and amyotrophic lateral sclerosis (ALS). Methods: A novel historical PA questionnaire was designed, validated, and subsequently administered in individual face-to-face interviews of 175 newly diagnosed sporadic ALS cases and 317 age- and sex-matched community controls. Historical PA energy expenditure and time spent in vigorous-intensity PA were derived from questionnaire data and compared between cases and controls. Results: Participation in an extra 10kJ/kg/day of PA (equivalent to approximately 45minutes brisk walking) was consistently associated with an increased risk of ALS, with the strongest association observed for adulthood exercise-related PA (OR 1.47, 95% CI 1.10-1.97). An extra 10mins/day of vigorous PA was also associated with the odds of ALS (OR 1.03, 95% CI 1·01-1·05). Results were slightly attenuated following adjustment for smoking and educational attainment. Conclusions: To our knowledge this is the first study to demonstrate a positive association between ALS and PA participation using a specifically designed and validated historical PA questionnaire. Despite the well-established health benefits of PA, a high activity lifestyle may also be associated with elevated risk of ALS. Large-scale prospective studies in the future may help to confirm this association. PMID:26998882

  19. Bcl11b: A New Piece to the Complex Puzzle of Amyotrophic Lateral Sclerosis Neuropathogenesis?

    PubMed

    Lennon, Matthew J; Jones, Simon P; Lovelace, Michael D; Guillemin, Gilles J; Brew, Bruce J

    2016-02-01

    Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, neurodegenerative disease of the human motor system. The pathogenesis of ALS is a topic of fascinating speculation and experimentation, with theories revolving around intracellular protein inclusions, mitochondrial structural issues, glutamate excitotoxicity and free radical formation. This review explores the rationale for the involvement of a novel protein, B-cell lymphoma/leukaemia 11b (Bcl11b) in ALS. Bcl11b is a multifunctional zinc finger protein transcription factor. It functions as both a transactivator and genetic suppressor, acting both directly, binding to promoter regions, and indirectly, binding to promoter-bound transcription factors. It has essential roles in the differentiation and growth of various cells in the central nervous system, immune system, integumentary system and cardiovascular system, to the extent that Bcl11b knockout mice are incompatible with extra-uterine life. It also has various roles in pathology including the suppression of latent retroviruses, thymic tumourigenesis and neurodegeneration. In particular its functions in neurodevelopment, viral latency and T-cell development suggest potential roles in ALS pathology.

  20. The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis.

    PubMed

    Fukunaga, Kohji; Shinoda, Yasuharu; Tagashira, Hideaki

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) patients exhibit diverse pathologies such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction in motor neurons. Five to ten percent of patients have familial ALS, a form of the disease caused by mutations in ALS-related genes, while sporadic forms of the disease occur in 90-95% of patients. Recently, it was reported that familial ALS patients exhibit a missense mutation in SIGMAR1 (c.304G > C), which encodes sigma-1 receptor (Sig-1R), substituting glutamine for glutamic acid at amino acid residue 102 (p.E102Q). Expression of that mutant Sig-1R(E102Q) protein reduces mitochondrial ATP production, inhibits proteasome activity and causes mitochondrial injury, aggravating ER stress-induced neuronal death in neuro2A cells. In this issue, we discuss mechanisms underlying mitochondrial impairment seen in ALS motor neurons and propose that therapies that protect mitochondria might improve the quality of life (QOL) of ALS patients and should be considered for clinical trials.

  1. Level of neurotoxic metals in amyotrophic lateral sclerosis: A population-based case-control study.

    PubMed

    Bocca, Beatrice; Forte, Giovanni; Oggiano, Riccardo; Clemente, Simonetta; Asara, Yolande; Peruzzu, Angela; Farace, Cristiano; Pala, Salvatore; Fois, Alessandro Giuseppe; Pirina, Pietro; Madeddu, Roberto

    2015-12-15

    The association between exposure to toxic metals and amyotrophic lateral sclerosis (ALS) was explored in a population-based case-control study in the Sardinia island (Italy), a region characterized by elevated rates of ALS cases. In 34 patients with ALS (mean age, 62 ± 10 years) and 30 controls (mean age, 65 ± 11 years), Al, Cd, Hg, Mn and Pb were determined in blood, hair and urine by sector field inductively coupled mass spectrometry. Results indicated that, in blood, concentrations of Al (p=0.045) and Pb were higher (p=0.026) in ALS patients than in control subjects. In hair, a depletion of Al (p=0.006) and Mn (p=0.032) concentrations in ALS subjects respect to controls was found. In urine, no significant differences between cases and controls were observed. Thus, some metals seemed to be associated with ALS degeneration, but a definitive conclusion is still far considering the multiple risk factors (genetic mutations, environmental toxicants and stressors) involved in the disease. Finally, the interpretation that deregulated metal concentrations can be a consequence of the degenerative process, rather than a cause, is also valid.

  2. Characterizing the complexity of spontaneous motor unit patterns of amyotrophic lateral sclerosis using approximate entropy

    NASA Astrophysics Data System (ADS)

    Zhou, Ping; Barkhaus, Paul E.; Zhang, Xu; Zev Rymer, William

    2011-10-01

    This paper presents a novel application of the approximate entropy (ApEn) measurement for characterizing spontaneous motor unit activity of amyotrophic lateral sclerosis (ALS) patients. High-density surface electromyography (EMG) was used to record spontaneous motor unit activity bilaterally from the thenar muscles of nine ALS subjects. Three distinct patterns of spontaneous motor unit activity (sporadic spikes, tonic spikes and high-frequency repetitive spikes) were observed. For each pattern, complexity was characterized by calculating the ApEn values of the representative signal segments. A sliding window over each segment was also introduced to quantify the dynamic changes in complexity for the different spontaneous motor unit patterns. We found that the ApEn values for the sporadic spikes were the highest, while those of the high-frequency repetitive spikes were the lowest. There is a significant difference in mean ApEn values between two arbitrary groups of the three spontaneous motor unit patterns (P < 0.001). The dynamic ApEn curve from the sliding window analysis is capable of tracking variations in EMG activity, thus providing a vivid, distinctive description for different patterns of spontaneous motor unit action potentials in terms of their complexity. These findings expand the existing knowledge of spontaneous motor unit activity in ALS beyond what was previously obtained using conventional linear methods such as firing rate or inter-spike interval statistics.

  3. Role of mitochondria in mutant SOD1 linked amyotrophic lateral sclerosis.

    PubMed

    Tan, Wenzhi; Pasinelli, Piera; Trotti, Davide

    2014-08-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an adult onset characterized by loss of both upper and lower motor neurons. In ~10% of cases, patients developed ALS with an apparent genetic linkage (familial ALS or fALS). Approximately 20% of fALS displays mutations in the SOD1 gene encoding superoxide dismutase 1. There are many proposed cellular and molecular mechanisms among which, mitochondrial dysfunctions occur early, prior to symptoms occurrence. In this review, we modeled the effect of mutant SOD1 protein via the formation of a toxic complex with Bcl2 on mitochondrial bioenergetics. Furthermore, we discuss that the shutdown of ATP permeation through mitochondrial outer membrane could lead to both respiration inhibition and temporary mitochondrial hyperpolarization. Moreover, we reviewed mitochondrial calcium signaling, oxidative stress, fission and fusion, autophagy and apoptosis in mutant SOD1-linked ALS. Functional defects in mitochondria appear early before symptoms are manifested in ALS. Therefore, mitochondrial dysfunction is a promising therapeutic target in ALS.

  4. Amyotrophic lateral sclerosis-like presentation in a HIV-positive patient.

    PubMed

    Anand, Kuljeet Singh; Wadhwa, Ankur; Garg, Jyoti; Mahajan, Rakesh Kumar

    2014-01-01

    There has been several reports of an MND like syndrome in HIV-1 infection, however the data is still sparse. Furthermore, HIV-associated amyotrophic lateral sclerosis (ALS) syndrome differs from the classical ALS in some key aspects.. A 44-year-old male presented with a history of insidious onset and gradually progressive asymmetric weakness of lower limbs. He also complained of thinning in both legs, the left leg more than the right since 1 year along with spontaneous twitching of muscles in both the thighs. On neurological examination, the assessment of higher mental functions was normal. There were no cranial nerve deficits. Motor power was grade 5/5 (Medical Research Council scale) in both the upper limbs and 4+ at hips and knees bilaterally, 5 at right ankle, and 4+ at left ankle. All the deep tendon reflexes were brisk with extensor planter responses. There were no cerebellar signs or sensory deficits. HIV-1 was reactive in enzyme-linked immunosorbent assay. Electrophysiological studies were conducted per the MND protocol.None of the nerves studied showed an abnormal drop in compound muscle action potential amplitude with proximal stimulation. There was evidence of diffuse spontaneous activity, which manifests as fibrillation and fasciculation potentials in most muscles tested . Overall there seems to be sufficient evidence to implicate HIV as a potential cause of an ALS-like disorder, but one must also consider the possibility of coincidental HIV infection in patients who have sporadic ALS.

  5. Clinical features of amyotrophic lateral sclerosis in south-west China.

    PubMed

    Wei, Qianqian; Chen, Xueping; Zheng, Zhenzhen; Huang, Rui; Guo, Xiaoyan; Cao, Bei; Zhao, Bi; Shang, Huifang

    2015-01-01

    Our objective was to profile clinical features of amyotrophic lateral sclerosis (ALS); we performed a large sample, cross-sectional study based on a hospital registry of ALS in south-west China. Patients were coded in our tertiary referral centre from May 2006 to September 2014. Demographic data and disease-related parameters were collected. A total of 1131 patients were included. Mean age of onset was 54.3 ± 11.6 years and the highest proportion of onset age (30.6%) was between 51 and 60 years. Male:female ratio was 1.45:1. Nearly 30% of the patients were young onset, and 20.3% of the patients were bulbar onset; only 35% received riluzole treatment. The young-onset patients had a higher educational level with a higher proportion performing manual labour and living in rural areas, and a lower proportion with bulbar onset than those who were older at onset. The bulbar-onset patients were older at age of onset, with a lower proportion of males than spinal-onset patients. In conclusion, Chinese ALS patients may be younger at age of onset than Caucasian patients. Environmental and geographical factors are related to the occurrence of ALS. The large treatment gap indicated a pressing need for medical and financial support for Chinese ALS patients.

  6. An inactivating mutation in the SOD 1 gene causes familial amyotrophic lateral sclerosis

    SciTech Connect

    Pramatarova, A.; Rouleau, G.A.; Goto, J.

    1994-09-01

    Amyotrophic lateral sclerosis (ALS) is characterized by highly selective death of large motor neurons in the cerebral cortex and spinal cord. The familial form of ALS (FALS) accounts for approximately 10% of the cases and is transmitted in an autosomal dominant manner. Recently the defective gene causing chromosome 21-linked FALS was shown to be the Cu/Zn superoxide dismutase (SOD 1). However, the precise mechanism of neurotoxicity seen in FALS with SOD 1 mutations is still unknown. Until now all SOD 1 mutations reported were single base pair substitutions (missense). We have identified a nonsense mutation in exon 5 of the SOD 1 gene in a FALS kindred. This two base pair deletion provokes a frameshift and a predicted premature truncation of the protein. The region affected has a very important structural and functional role: it contains part of the active loop and is involved in dimer contact. We would predict that the loss of these structures would impair the functioning of the enzyme.

  7. Health utility decreases with increasing clinical stage in amyotrophic lateral sclerosis.

    PubMed

    Jones, Ashley R; Jivraj, Naheed; Balendra, Rubika; Murphy, Caroline; Kelly, Joanna; Thornhill, Marie; Young, Carolyn; Shaw, Pamela J; Leigh, P Nigel; Turner, Martin R; Steen, I Nick; McCrone, Paul; Al-Chalabi, Ammar

    2014-06-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease typically causing death within three years. Understanding the impact of disease on patients using health utility at different stages of ALS would allow meaningful cost-benefit analysis of new potential therapies. A common health-related quality of life measurement, developed and validated for the UK, is the EQ-5D. Using clinical trial data from the LiCALS study, we calculated health utility using the EQ-5D for each King's ALS clinical stage from 214 patients. We analysed whether health utility, and other health-related measures, significantly changed between each of the clinical stages. Results showed that mean health utility decreased by 0.487 (the scale runs from 1 to - 0.594) between clinical stages 2A and 4. Emotional states, measured using the Hospital Anxiety and Depression Scale (HADS), showed worsening depression and anxiety scores as ALS progressed. Age of onset, disease onset, gender and treatment group were not predictors of EQ-5D, depression or anxiety. In conclusion, increasing severity of King's ALS Clinical Stage is associated with a progressive decrease in EQ-5D health utility. This is useful for cost-benefit analysis of new therapies and validates this ALS clinical staging system.

  8. Increased expression of Myosin binding protein H in the skeletal muscle of amyotrophic lateral sclerosis patients.

    PubMed

    Conti, Antonio; Riva, Nilo; Pesca, Mariasabina; Iannaccone, Sandro; Cannistraci, Carlo V; Corbo, Massimo; Previtali, Stefano C; Quattrini, Angelo; Alessio, Massimo

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is a severe and fatal neurodegenerative disease of still unknown pathogenesis. Recent findings suggest that the skeletal muscle may play an active pathogenetic role. To investigate ALS's pathogenesis and to seek diagnostic markers, we analyzed skeletal muscle biopsies with the differential expression proteomic approach. We studied skeletal muscle biopsies from healthy controls (CN), sporadic ALS (sALS), motor neuropathies (MN) and myopathies (M). Pre-eminently among several differentially expressed proteins, Myosin binding protein H (MyBP-H) expression in ALS samples was anomalously high. MyBP-H is a component of the thick filaments of the skeletal muscle and has strong affinity for myosin, but its function is still unclear. High MyBP-H expression level was associated with abnormal expression of Rho kinase 2 (ROCK2), LIM domain kinase 1 (LIMK1) and cofilin2, that might affect the actin-myosin interaction. We propose that MyBP-H expression level serves, as a putative biomarker in the skeletal muscle, to discriminate ALS from motor neuropathies, and that it signals the onset of dysregulation in actin-myosin interaction; this in turn might contribute to the pathogenesis of ALS.

  9. Association between depression and survival in Chinese amyotrophic lateral sclerosis patients.

    PubMed

    Wei, Qianqian; Zheng, Zhenzhen; Guo, Xiaoyan; Ou, Ruwei; Chen, Xueping; Huang, Rui; Yang, Jing; Shang, Huifang

    2016-04-01

    To determine the prevalence of depression, to identify correlated factors for depression, and to explore the impact on the progression or survival of amyotrophic lateral sclerosis (ALS) by depression in a Chinese population. A total of 166 ALS patients were recruited. Diagnosis of depression disorders and the severity of depression were established by using the fourth diagnostic and statistical manual of mental disorders, Hamilton Depression Rating Scale-24 items (HDRS-24) and Beck Depression Inventory (BDI). Major depression was found in 15 patients (9.6 %). The multiple regression analysis showed that a lower ALS Functional Rating Scale-Revised (ALSFRS-R) score was correlated with increasing HDRS scores and BDI scores (P = 0.018 and P = 0.012). No significant difference in the median survival time between ALS patients with and without depression was revealed by Kaplan-Meier analysis (log-rank P = 0.282). Cox hazard model showed that the presence of depression in ALS was unrelated to the survival, while the severity of depression in ALS was correlated with the survival. The presence and severity of depression in ALS did not correlate with the progression of ALS. Major depression in ALS is uncommon. Depression evaluation should be given to ALS patients, especially those with lower ALSFRS-R score. The severity of depression may be associated with the survival; however, depression does not worse the progression of ALS.

  10. Targeted assessment of lower motor neuron burden is associated with survival in amyotrophic lateral sclerosis.

    PubMed

    Devine, Matthew S; Ballard, Emma; O'Rourke, Peter; Kiernan, Matthew C; Mccombe, Pamela A; Henderson, Robert D

    2016-01-01

    Estimating survival in amyotrophic lateral sclerosis (ALS) is challenging due to heterogeneity in clinical features of disease and a lack of suitable markers that predict survival. Our aim was to determine whether scoring of upper or lower motor neuron weakness is associated with survival. With this objective, 161 ALS subjects were recruited from two tertiary referral centres. Scoring of upper (UMN) and lower motor neuron (LMN) signs was performed, in addition to a brief questionnaire. Subjects were then followed until the censorship date. Univariate analysis was performed to identify variables associated with survival to either non-invasive ventilation (NIV) or death, which were then further characterized using Cox regression. Results showed that factors associated with reduced survival included older age, bulbar and respiratory involvement and shorter diagnostic delay (all p < 0.05). Whole body LMN score was strongly associated with time to NIV or death (p ≤0.001) whereas UMN scores were poorly associated with survival. In conclusion, our results suggest that, early in disease assessment and in the context of other factors (age, bulbar, respiratory status), the burden of LMN weakness provides an accurate estimate of outcome. Such a scoring system could predict prognosis, and thereby aid in selection of patients for clinical trials.

  11. Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis

    PubMed Central

    Gaastra, Benjamin; Shatunov, Aleksey; Pulit, Sara; Jones, Ashley R.; Sproviero, William; Gillett, Alexandra; Chen, Zhongbo; Kirby, Janine; Fogh, Isabella; Powell, John F.; Leigh, P. Nigel; Morrison, Karen E.; Shaw, Pamela J.; Shaw, Christopher E.; van den Berg, Leonard H.; Veldink, Jan H.; Lewis, Cathryn M.; Al-Chalabi, Ammar

    2016-01-01

    Abstract Our objective was to identify whether rare genetic variation in amyotrophic lateral sclerosis (ALS) candidate survival genes modifies ALS survival. Candidate genes were selected based on evidence for modifying ALS survival. Each tail of the extreme 1.5% of survival was selected from the UK MND DNA Bank and all samples available underwent whole genome sequencing. A replication set from the Netherlands was used for validation. Sequences of candidate survival genes were extracted and variants passing quality control with a minor allele frequency ≤0.05 were selected for association testing. Analysis was by burden testing using SKAT. Candidate survival genes UNC13A, KIFAP3, and EPHA4 were tested for association in a UK sample comprising 25 short survivors and 25 long survivors. Results showed that only SNVs in UNC13A were associated with survival (p = 6.57 × 10−3). SNV rs10419420:G > A was found exclusively in long survivors (3/25) and rs4808092:G > A exclusively in short survivors (4/25). These findings were not replicated in a Dutch sample. In conclusion, population specific rare variants of UNC13A may modulate survival in ALS. PMID:27584932

  12. The use of integrative therapies in patients with amyotrophic lateral sclerosis in shanghai, china.

    PubMed

    Pan, Weidong; Chen, Xiangjun; Bao, Jie; Bai, Yu; Lu, Hua; Wang, Qiudong; Liu, Yi; Yuan, Canxing; Li, Wenwei; Liu, Zhenguo; Liu, Jun; Zhu, Xuying; Qin, Baofeng; Cai, Dingfang; Zhou, Hua

    2013-01-01

    Objective. To investigate the current use of integrative therapies (IT) in the treatment of patients with amyotrophic lateral sclerosis (ALS). Methods. A cross-sectional, multicenter clinical epidemiological survey was conducted in 12 hospitals in Shanghai. We investigated the type and frequency of IT use and determined whether the use of IT correlated with demographic, social, or disease-specific characteristics in our patient population. Results. A total of 231 (89.5%) of 258 patients with ALS were eligible for the study and 229 (99% of all) of 231 reported the use of at least one IT for the treatment of ALS. Vitamins and Chinese herb decoctions, Chinese herb compounds, massage therapy, and acupuncture were the 5 most commonly used therapies. There was a strong association between education level, income, and use of IT. A household income of more than 75,000 RMB ($49,995) correlated with multiple IT use, and married patients used IT more often than single individuals. The main reasons for using IT were to treat weakness and fatigue, muscle atrophy, the development of ALS, depression, insomnia, limb pain or numbness, and side effects associated with Riluzole. Conclusion. The use of IT is common in patients with ALS in Shanghai. Vitamins and TCM are the most used additional therapies and the widespread and largely unexamined use of IT for ALS requires more attention.

  13. [An Autopsy Case of Globular Glial Tauopathy Presenting with Amyotrophic Lateral Sclerosis with Dementia].

    PubMed

    Sasaki, Ryogen; Mimuro, Maya; Kokubo, Yasumasa; Imai, Hiroshi; Yoshida, Mari; Tomimoto, Hidekazu

    2016-08-01

    We report an autopsy case of globular glial tauopathy (GGT) presenting clinically with amyotrophic lateral sclerosis (ALS) with dementia. A 79-year-old female developed weakness in the right upper limb, which progressed gradually. She developed apathy and speech disorder at 80 years of age. On neurological examination, she showed signs of upper and lower motor neuron disorder and dementia, but no extrapyramidal signs. The clinical diagnosis was ALS with dementia. The autopsy revealed left predominant marked atrophy of the frontal lobe due to severe neuronal loss and Gliosis. Immunohistochemistry using anti-4-repeat tau antibody revealed numerous globular glial inclusions. Severe neurodegeneration in the primary motor cortex and corticospinal tract was observed. There were distinctive tau-positive inclusions in both Betz and anterior horn cells. TDP-43-positive inclusions in motor neurons were not detected. Sequence analysis of the tau gene revealed no mutations in exons 1-5, 7, 9-13, or the adjacent intronic sequences. GGT can cause a clinical phenotype of ALS with dementia. (Received December 28, 2015; Accepted February 23, 2016; Published August 1, 2016).

  14. A gene-environment study of the paraoxonase 1 gene and pesticides in amyotrophic lateral sclerosis.

    PubMed

    Morahan, Julia M; Yu, Bing; Trent, Ronald J; Pamphlett, Roger

    2007-05-01

    Sporadic amyotrophic lateral sclerosis (SALS) causes progressive muscle weakness because of the loss of motor neurons. SALS has been associated with exposure to environmental toxins, including pesticides and chemical warfare agents, many of which are organophosphates. The enzyme paraoxonase 1 (PON1) detoxifies organophosphates and the efficacy of this enzyme varies with polymorphisms in the PON1 gene. To determine if an impaired ability to break down organophosphates underlies some cases of SALS, we compared the frequencies of PON1 polymorphisms in SALS patients and controls and investigated gene-environment interactions with self-reported pesticide/herbicide exposure. The PON1 coding polymorphisms L55M, Q192R and I102V, and the promoter polymorphisms -909c>g, -832g>a, -162g>a and -108c>t, were genotyped in 143 SALS patients and 143 matched controls. Statistical comparisons were carried out at allele, genotype and haplotype levels. The PON1 promoter allele -108t, which reduces PON1 expression, was strongly associated with SALS. Overall, promoter haplotypes that decrease PON1 expression were associated with SALS, whereas haplotypes that increase expression were associated with controls. Coding polymorphisms did not correlate with SALS. Gene-environment interactions were identified at the allele level for some promoter SNPs and pesticide/herbicide exposure, but not at the genotype or haplotype level. In conclusion, some PON1 promoter polymorphisms may predispose to SALS, possibly by making motor neurons more susceptible to organophosphate-containing toxins.

  15. EEG functional network topology is associated with disability in patients with amyotrophic lateral sclerosis

    NASA Astrophysics Data System (ADS)

    Fraschini, Matteo; Demuru, Matteo; Hillebrand, Arjan; Cuccu, Lorenza; Porcu, Silvia; di Stefano, Francesca; Puligheddu, Monica; Floris, Gianluca; Borghero, Giuseppe; Marrosu, Francesco

    2016-12-01

    Amyotrophic Lateral Sclerosis (ALS) is one of the most severe neurodegenerative diseases, which is known to affect upper and lower motor neurons. In contrast to the classical tenet that ALS represents the outcome of extensive and progressive impairment of a fixed set of motor connections, recent neuroimaging findings suggest that the disease spreads along vast non-motor connections. Here, we hypothesised that functional network topology is perturbed in ALS, and that this reorganization is associated with disability. We tested this hypothesis in 21 patients affected by ALS at several stages of impairment using resting-state electroencephalography (EEG) and compared the results to 16 age-matched healthy controls. We estimated functional connectivity using the Phase Lag Index (PLI), and characterized the network topology using the minimum spanning tree (MST). We found a significant difference between groups in terms of MST dissimilarity and MST leaf fraction in the beta band. Moreover, some MST parameters (leaf, hierarchy and kappa) significantly correlated with disability. These findings suggest that the topology of resting-state functional networks in ALS is affected by the disease in relation to disability. EEG network analysis may be of help in monitoring and evaluating the clinical status of ALS patients.

  16. Unusual association of amyotrophic lateral sclerosis and myasthenia gravis: A dysregulation of the adaptive immune system?

    PubMed

    Del Mar Amador, Maria; Vandenberghe, Nadia; Berhoune, Nawel; Camdessanché, Jean-Philippe; Gronier, Sophie; Delmont, Emilien; Desnuelle, Claude; Cintas, Pascal; Pittion, Sophie; Louis, Sarah; Demeret, Sophie; Lenglet, Timothée; Meininger, Vincent; Salachas, François; Pradat, Pierre-François; Bruneteau, Gaëlle

    2016-06-01

    Myasthenia gravis is an autoimmune disorder affecting neuromuscular junctions that has been associated with a small increased risk of amyotrophic lateral sclerosis (ALS). Here, we describe a retrospective series of seven cases with a concomitant diagnosis of ALS and myasthenia gravis, collected among the 18 French reference centers for ALS in a twelve year period. After careful review, only six patients strictly met the diagnostic criteria for both ALS and myasthenia gravis. In these patients, limb onset of ALS was reported in five (83%) cases. Localization of myasthenia gravis initial symptoms was ocular in three (50%) cases, generalized in two (33%) and bulbar in one (17%). Median delay between onset of the two conditions was 19 months (6-319 months). Anti-acetylcholine receptor antibodies testing was positive in all cases. All patients were treated with riluzole and one had an associated immune-mediated disease. In the one last ALS case, the final diagnosis was false-positivity for anti-acetylcholine receptor antibodies. The co-occurrence of ALS and myasthenia gravis is rare and requires strict diagnostic criteria. Its demonstration needs thoughtful interpretation of electrophysiological results and exclusion of false positivity for myasthenia gravis antibody testing in some ALS cases. This association may be triggered by a dysfunction of adaptive immunity.

  17. Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis

    PubMed Central

    Leroy, Félix; Lamotte d'Incamps, Boris; Imhoff-Manuel, Rebecca D; Zytnicki, Daniel

    2014-01-01

    In amyotrophic lateral sclerosis (ALS) the large motoneurons that innervate the fast-contracting muscle fibers (F-type motoneurons) are vulnerable and degenerate in adulthood. In contrast, the small motoneurons that innervate the slow-contracting fibers (S-type motoneurons) are resistant and do not degenerate. Intrinsic hyperexcitability of F-type motoneurons during early postnatal development has long been hypothesized to contribute to neural degeneration in the adult. Here, we performed a critical test of this hypothesis by recording from identified F- and S-type motoneurons in the superoxide dismutase-1 mutant G93A (mSOD1), a mouse model of ALS at a neonatal age when early pathophysiological changes are observed. Contrary to the standard hypothesis, excitability of F-type motoneurons was unchanged in the mutant mice. Surprisingly, the S-type motoneurons of mSDO1 mice did display intrinsic hyperexcitability (lower rheobase, hyperpolarized spiking threshold). As S-type motoneurons are resistant in ALS, we conclude that early intrinsic hyperexcitability does not contribute to motoneuron degeneration. DOI: http://dx.doi.org/10.7554/eLife.04046.001 PMID:25313866

  18. Monitoring systemic oxidative stress in an animal model of amyotrophic lateral sclerosis.

    PubMed

    Miana-Mena, Francisco Javier; González-Mingot, Cristina; Larrodé, Pilar; Muñoz, María Jesús; Oliván, Sara; Fuentes-Broto, Lorena; Martínez-Ballarín, Enrique; Reiter, Russel J; Osta, Rosario; García, Joaquín José

    2011-05-01

    A mutant form of the ubiquitous copper/zinc superoxide dismutase (SOD1) protein has been found in some patients with amyotrophic lateral sclerosis (ALS). We monitored oxidative stress in an animal model of ALS, the SOD(G93A) mouse, which develops a disease similar to ALS with an accelerated course. The aim of this work was to show that ALS damages several organs and tissues, from an oxidative stress point of view. We measured lipid and protein oxidative damage in different tissue homogenates of SOD(G93A) mice. The biomarkers that we analyzed were malondialdehyde + 4-hydroxyalkenal (MDA + 4-HDA) and carbonyls, respectively. The spinal cord and brain of SOD(G93A) mice showed increased lipid peroxidation after 100 or 130 days compared to age-matched littermate controls. The CNS was most affected, but lipid peroxidation was also detected in the skeletal muscle and liver on day 130. No changes were observed in protein carbonylation in the homogenates. Our results are consistent with a multisystem etiology of ALS and suggest that oxidative stress may play a primary role in ALS pathogenesis. Thus, oxidative stress represents a potential biomarker that might be useful in developing new therapeutic strategies for ALS.

  19. Fingolimod: A Disease-Modifier Drug in a Mouse Model of Amyotrophic Lateral Sclerosis.

    PubMed

    Potenza, Rosa Luisa; De Simone, Roberta; Armida, Monica; Mazziotti, Valentina; Pèzzola, Antonella; Popoli, Patrizia; Minghetti, Luisa

    2016-10-01

    Fingolimod phosphate (FTY720), the first approved oral therapy for multiple sclerosis, primarily acts as an immunomodulator. Its concomitant effects in the central nervous system, however, indicate a potentially broader spectrum of activity in neurodegenerative diseases. In the present study, we investigated the possible effects of fingolimod in a mouse model of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by a strong neuroinflammatory component. Fingolimod (0.1 and 1 mg/kg i.p.) was administered to mSOD1(G93A) mice, a well-characterized mouse model of ALS, starting from the onset of motor symptoms to the end stage of the disease. The drug was able to improve the neurological phenotype (p < 0.05) and to extend the survival (p < 0.01) of ALS mice. The beneficial effect of fingolimod administration was associated with a significant modulation of neuroinflammatory and protective genes (CD11b, Foxp3, iNOS, Il1β, Il10, Arg1, and Bdnf) in motor cortex and spinal cord of animals. Our data show, for the first time, that fingolimod is protective in ALS mice and that its beneficial effects are accompanied by a modulation of microglial activation and innate immunity. Considering that the treatment was started in already symptomatic mice, our data strongly support fingolimod as a potential new therapeutic approach to ALS.

  20. MHC class I protects motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis (ALS)

    PubMed Central

    Braun, Lyndsey; Meyer, Kathrin; Frakes, Ashley E.; Ferraiuolo, Laura; Likhite, Shibi; Bevan, Adam K.; Foust, Kevin D.; McConnell, Michael J.; Walker, Christopher M.; Kaspar, Brian K.

    2016-01-01

    Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic towards motor neurons (MNs) and play a non-cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of motor neurons to cell death remains unclear. Here, we report that astrocytes derived from mice bearing ALS mutations and from individuals with ALS reduce expression of major histocompatibility complex class I (MHCI) on MNs. Reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MN against astrocyte toxicity. A single MHCI molecule, HLA-F, protects MNs from ALS astrocyte-mediated toxicity, while knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, an inhibitory receptor that recognizes MHCI, on astrocytes results in enhanced MN death. These data indicate that in ALS upon loss of MHCI expression MNs become vulnerable to astrocyte-mediated toxicity. PMID:26928464

  1. Validation of qPCR reference genes in lymphocytes from patients with amyotrophic lateral sclerosis

    PubMed Central

    Usarek, Ewa; Barańczyk-Kuźma, Anna; Kaźmierczak, Beata; Gajewska, Beata; Kuźma-Kozakiewicz, Magdalena

    2017-01-01

    Quantitative polymerase chain reaction (qPCR) is the most specific and reliable method for determination of mRNA gene expression. Crucial point for its accurate normalization is the choice of appropriate internal control genes (ICGs). In the present work we determined and compare the expression of eight commonly used ICGs in lymphocytes from 26 patients with amyotrophic lateral sclerosis (ALS) and 30 control subjects. Peripheral blood mononuclear cells (PBMCs) before and after immortalization by EBV transfection (lymphoblast cell lines—LCLs) were used for qPCR analysis. LCLs were studied before and after liquid nitrogen cryopreservation and culturing (groups LCL1 and LCL2, respectively). qPCR data of 8 ICGs expression was analyzed by BestKeeper, NormFinder and geNorm methods. All studied genes (18SRNA, ACTB, B2M, GUSB,GAPDH, HPRT1, MT-ATP6 and RPS17) were expressed in PBMCs, whereas only first four in LCLs. LCLs cryopreservation had no effect on ICGs expression. Comprehensive ranking indicated RPS17 with MT-ATP6 as the best ICGs for qPCR in PBMCs of control and ALS subjects, and RPS17 with 18RNA or MT-ATP6 in LCLs from ALS. In PBMCs 18RNA shouldn’t be used as ICG. PMID:28328930

  2. Balancing between autonomy and support: coping strategies by patients with amyotrophic lateral sclerosis.

    PubMed

    Tramonti, Francesco; Bongioanni, Paolo; Fanciullacci, Chiara; Rossi, Bruno

    2012-09-15

    Amyotrophic lateral sclerosis (ALS) makes a strong psychological impact, and the study of efforts by patients to cope with the course of the disease could be an important first step in the optimisation of care treatment. With this aim, in our study we assessed the coping strategies by a population of ALS patients, according to some clinical parameters and the worsening of the disease. We have administered the MND coping scale to 62 patients, firstly at the admission to our neurorehabilitation unit and secondly after 1year. Each factor score has been related to age and progression of the disease, and comparisons between males and females have also been made. The increasing relevance of seeking support from families and technological devices is probably the most interesting finding: such a result stimulates remarkable considerations about the proper balance between such support and patients' autonomy. As a whole, data confirm the importance of a proper and well-timed psychological intervention for patients and their families. In detail, improving adaptive coping strategies, together with sustaining those which tend to weaken along the progression of the disease, could be an important goal in psychological counselling for both patients and family members.

  3. Functional contribution of the transcription factor ATF4 to the pathogenesis of amyotrophic lateral sclerosis.

    PubMed

    Matus, Soledad; Lopez, Estefanía; Valenzuela, Vicente; Nassif, Melissa; Hetz, Claudio

    2013-01-01

    Endoplasmic reticulum (ER) stress represents an early pathological event in amyotrophic lateral sclerosis (ALS). ATF4 is a key ER stress transcription factor that plays a role in both adaptation to stress and the activation of apoptosis. Here we investigated the contribution of ATF4 to ALS. ATF4 deficiency reduced the rate of birth of SOD1(G86R) transgenic mice. The fraction of ATF4(-/-)-SOD1(G85R) transgenic mice that were born are more resistant to develop ALS, leading to delayed disease onset and prolonged life span. ATF4 deficiency completely attenuated the induction of pro-apoptotic genes, including BIM and CHOP, and also led to quantitative changes in the ER protein homeostasis network. Unexpectedly, ATF4 deficiency enhanced mutant SOD1 aggregation at the end stage of the disease. Studies in the motoneuron cell line NSC34 demonstrated that knocking down ATF4 enhances mutant SOD1 aggregation possibly due to alteration in the redox status of the cell. Our results support a functional role of ATF4 in ALS, offering a novel target for disease intervention.

  4. New links between SOD1 and metabolic dysfunction from a yeast model of amyotrophic lateral sclerosis

    PubMed Central

    Bastow, Emma L.; Peswani, Amber R.; Tarrant, Daniel S. J.; Pentland, Daniel R.; Chen, Xi; Staniforth, Gemma L.; Rowe, Michelle L.; Howard, Mark J.

    2016-01-01

    ABSTRACT A number of genes have been linked to familial forms of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS). Over 150 mutations within the gene encoding superoxide dismutase 1 (SOD1) have been implicated in ALS, but why such mutations lead to ALS-associated cellular dysfunction is unclear. In this study, we identify how ALS-linked SOD1 mutations lead to changes in the cellular health of the yeast Saccharomyces cerevisiae. We find that it is not the accumulation of aggregates but the loss of Sod1 protein stability that drives cellular dysfunction. The toxic effect of Sod1 instability does not correlate with a loss of mitochondrial function or increased production of reactive oxygen species, but instead prevents acidification of the vacuole, perturbs metabolic regulation and promotes senescence. Central to the toxic gain-of-function seen with the SOD1 mutants examined was an inability to regulate amino acid biosynthesis. We also report that leucine supplementation results in an improvement in motor function in a Caenorhabditis elegans model of ALS. Our data suggest that metabolic dysfunction plays an important role in Sod1-mediated toxicity in both the yeast and worm models of ALS. PMID:27656112

  5. Increased prevalence of bladder and intestinal dysfunction in amyotrophic lateral sclerosis.

    PubMed

    Nübling, Georg S; Mie, Eva; Bauer, Ricarda M; Hensler, Mira; Lorenzl, Stefan; Hapfelmeier, Alexander; Irwin, Debra E; Borasio, Gian Domenico; Winkler, Andrea S

    2014-06-01

    Amyotrophic lateral sclerosis (ALS) is predominantly characterized by a progressive loss of motor function. While autonomic dysfunction has been described in ALS, little is known about the prevalence of lower urinary tract symptoms (LUTS) and intestinal dysfunction. We investigated disease severity, LUTS and intestinal dysfunction in 43 patients with ALS attending our outpatient department applying the ALS functional rating scale, the International Consultation on Incontinence Modular Questionnaire, the Urinary Distress Inventory and the Cleveland Clinic Incontinence Score. Results were compared to the German population of a cross-sectional study assessing LUTS in the healthy population, the EPIC study. Results showed that urinary incontinence was increased in patients with ALS aged ≥ 60 years compared to the EPIC cohort (female: 50%/19% (ALS/EPIC), p = 0.026; male: 36%/11% (ALS/EPIC), p = 0.002). No difference was seen at 40-59 years of age. Urge incontinence was the predominant presentation (73% of symptoms). A high symptom burden was stated (ICIQ-SF quality of life subscore 5.5/10). Intake of muscle relaxants and anticholinergics was associated with both urinary incontinence and severity of symptoms. Furthermore, a high prevalence of constipation (46%), but not stool incontinence (9%), was noted. In conclusion, the increased prevalence of urge incontinence and high symptom burden imply that in patients with ALS, LUTS should be increasingly investigated for.

  6. Breaking bad news in amyotrophic lateral sclerosis: the need for medical education.

    PubMed

    Schellenberg, Kerri L; Schofield, Susie J; Fang, Shoufan; Johnston, Wendy S W

    2014-03-01

    The manner in which physicians deliver difficult diagnoses is an area of discontent for patients with amyotrophic lateral sclerosis (ALS). The American Academy of Neurology's Practice Parameter for care of the ALS Patient recommended teaching and evaluating strategies for disclosing the diagnosis (10). Our objective was to examine residents' ability in and perceptions of communicating the diagnosis of ALS. Twenty-two resident physicians were videotaped and rated by two ALS neurologists as they delivered an ALS diagnosis to a standardized patient (SP) during an objective structured clinical examination (OSCE). Residents self-rated immediately after the OSCE, again after viewing their videotape, and completed a survey regarding the OSCE and delivering difficult diagnoses. OSCE performance was suboptimal, particularly for communication skills and empathy. The two examiners' scores correlated except for the empathy subscore. Residents' self-assessments did not align with the examiners' scores either before or after watching their videotape. The survey uncovered residents' apprehension and dissatisfaction with their training in diagnosis delivery. The results highlight a need for resident education in delivering an ALS diagnosis. The lack of correlation between residents' and examiners' scoring requires further study. Evaluation of empathy is particularly challenging. Residents agreed that OSCE participation was worthwhile.

  7. A Novel Missense Mutation of the DDHD1 Gene Associated with Juvenile Amyotrophic Lateral Sclerosis

    PubMed Central

    Wu, Chujun; Fan, Dongsheng

    2016-01-01

    Background: Juvenile amyotrophic lateral sclerosis (jALS) is a rare form of ALS with an onset age of less than 25 years and is frequently thought to be genetic in origin. DDHD1 gene mutations have been reported to be associated with the SPG28 subtype of autosomal recessive HSP but have never been reported in jALS patients. Methods: Gene screens for the causative genes of ALS, HSP and CMT using next-generation sequencing (NGS) technologies were performed on a jALS patient. Sanger sequencing was used to validate identified variants and perform segregation analysis. Results: We identified a novel c.1483A>G (p.Met495Val) homozygous missense mutation of the DDHD1 gene in the jALS patient. All of his parents and young bother were heterozygous for this mutation. The mutation was not found in 800 Chinese control subjects or the database of dbSNP, ExAC and 1000G. Conclusion: The novel c.1483A>G (p.Met495Val) missense mutation of the DDHD1 gene could be a causative mutation of autosomal recessive jALS. PMID:27999540

  8. The Cognitive and Behavioural Profile of Amyotrophic Lateral Sclerosis: Application of the Consensus Criteria

    PubMed Central

    Consonni, Monica; Iannaccone, Sandro; Cerami, Chiara; Frasson, Paola; Lacerenza, Marco; Lunetta, Christian; Corbo, Massimo; Cappa, Stefano F.

    2013-01-01

    Objective: The study aims to assess the spectrum of cognitive and behavioural disorders in patients affected by Amyotrophic Lateral Sclerosis (ALS) according to the recent consensus criteria [9]. The study also intends to assess the impact of physical disability on cognitive and behavioural abnormalities. Methods: Detailed neurological, neuropsychological and neurobehavioral evaluations were administered to 23 ALS patients, 11 Lower Motor Neuron Disease (LMND) patients and 39 healthy controls. Strong et al.’s criteria [9] were applied to diagnose the presence of cognitive/behavioural impairment. Clinical and neuropsychological scores were used for group comparisons and correlation analyses. Results: In comparison with LMND and controls, a subgroup of ALS patients (∼30%) manifested executive dysfunction, which was severe enough to classify them as cognitively impaired. Action naming difficulties and short-term memory deficits were also observed. Aspontaneity, disorganization and mental rigidity reached clinical relevance in 20% of ALS patients. A small percentage of ALS patients (13%) also had comorbid dementia. The cognitive or behavioural status was not related to the clinical features of ALS. Conclusion: The use of consensus criteria for cognitive and behavioural impairment and the comparison with the LMND group proved useful in defining the spectrum of non-motor manifestations of ALS. PMID:23001631

  9. Diffusion tensor imaging detects corticospinal tract involvement at multiple levels in amyotrophic lateral sclerosis

    PubMed Central

    Toosy, A; Werring, D; Orrell, R; Howard, R; King, M; Barker, G; Miller, D; Thompson, A

    2003-01-01

    Background: Histopathological studies of amyotrophic lateral sclerosis (ALS) are of end stage disease. Diffusion tensor imaging (DTI) provides the opportunity to investigate indirectly corticospinal tract pathology of ALS in vivo. Methods: DTI was used to study the water diffusion characteristics of the corticospinal tracts in 21 patients with ALS and 14 normal controls. The authors measured the fractional anisotropy (FA) and mean diffusivity (MD) along the pyramidal tracts from the internal capsules down to the pyramids. A mixed model regression analysis was used to compare FA and MD between the ALS and control groups. Results: FA showed a downward linear trend from the cerebral peduncles to the pyramids and was lower in the ALS group than controls at multiple levels of the corticospinal tract. At the internal capsules, FA was higher on the right. MD showed an upward trend, progressing caudally from the internal capsules to the pyramids. MD was higher at the level of the internal capsule in the ALS group, but caudally this difference was not maintained. No correlations were found between clinical markers of disability and water diffusion indices. Conclusions: These findings provide insights into the pathological processes of ALS. Differences in diffusion characteristics at different anatomical levels may relate to underlying tract architecture or the distribution of pathological damage in ALS. Further development may permit monitoring of progression and treatment of disease. PMID:12933929

  10. Functional studies of the parotid and pancreas glands in amyotrophic lateral sclerosis.

    PubMed

    Charchaflie, R J; Bustos Fernandez, L; Perec, C J; Gonzalez, E; Marzi, A

    1974-07-01

    Functional studies of the pancreas and parotid glands are reported in 17 patients with amyotrophic lateral sclerosis (ALS). The exocrine function of the pancreas was studied by measuring amylase concentration after stimulation with the endogenous secretin-pancreozymine test (ESP). Under these conditions, the pancreatic amylase concentration in ALS patients was found to be markedly decreased by about 45% when compared with those of healthy control subjects. Different conclusions in the literature about a possible impairment of the exocrine pancreas in ALS patients induced us to study the function of the parotid gland, which has close structural, functional, and physiopathological relationship with the pancreas. Flow rate and bicarbonate concentration of parotid saliva were measured after indirect stimulation (intraoral citric acid) and direct stimulation (pilocarpine). After indirect stimulation, both parotid flow rate and bicarbonate concentration from ALS patients were found to be decreased by about 66% and 70% respectively, when compared with controls. On the other hand, direct stimulation with pilocarpine in ALS patients elicited normal responses in both flow rate and bicarbonate concentration of saliva. It is concluded that the pancreatic and parotid deficiencies observed in ALS patients do not indicate primary disease of these exocrine glands. This interpretation is further emphasized by the results obtained by a sweat test, plasma osmolarity, and sialographic studies. The possibility that the gland impairments observed might be due to modifications of the neuroendocrine mechanisms regulating their secretory activity is suggested.

  11. Changes in tongue pressure, pulmonary function, and salivary flow in patients with amyotrophic lateral sclerosis.

    PubMed

    Easterling, Caryn; Antinoja, Jodi; Cashin, Susan; Barkhaus, Paul E

    2013-06-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving nerve cells that control voluntary muscle movement (Rowland LP, Shneider NA, N Engl J Med 344(22):1688-1700, 2001). The aim of this study were to determine the pattern of neurodegenerative change in (1) isometric tongue strength (ITS) and spontaneous saliva swallow (SSS) pressure, (2) saliva weight, and (3) forced vital capacity (FVC) in patients with ALS who present with primary spinal versus primary bulbar symptoms. Twenty-three consecutive patients (age = 48-80 years, mean = 59.5 years) were enrolled. Data were collected over three visits (12-week interval) for each group: 9 patients with bulbar symptoms and 14 with spinal symptoms. A significant difference was noted in SSS and ITS in the group with bulbar symptoms from Trial 1 to II and from Trial II to III. SSS and ITS showed a significant difference when comparing Trial I to III but not when comparing Trial I to II for the spinal symptom group, indicating that this group experienced a slower decline in SSS. Saliva production did not show a significant change in the bulbar symptom group but did in the spinal group. FVC was significantly different when comparing Trial I to III and Trial II to III for both groups. FVC, SSS, and ITS may be complimentary measures used as a gauge of an ALS patient's ability to efficiently take oral nutrition and to support required alterations in diet consistency.

  12. Role of the Sigma-1 receptor in Amyotrophic Lateral Sclerosis (ALS).

    PubMed

    Mavlyutov, Timur A; Guo, Lian-Wang; Epstein, Miles L; Ruoho, Arnold E

    2015-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease affecting spinal cord motoneurons (MN) with an associative connection to Frontotemporal Lobar Dementia (FTLD). The endoplasmic reticulum (ER) bound Sigma-1 Receptor (S1R) chaperone protein localizes to specialized ER cisternae within 10 nm of the plasma membrane in spinal cord ventral horn cholinergic post synaptic C-terminals. Removal of the S1R gene in the Superoxide Dismutase-1 (SOD-1) mouse model of ALS exacerbated the neurodegenerative condition and resulted in a significantly reduced longevity when compared to the SOD-1/S1R wild type (WT) mouse. The proposed amelioration of the ALS phenotype by the S1R is likely due to a "brake" on excitation of the MN as evidenced by a reduction in action potential generation in the MN of the WT when compared to the S1R KO mouse MN. Although the precise signal transduction pathway(s) regulated by the S1R in the MN has/have not been elucidated at present, it is likely that direct or indirect functional interactions occur between the S1R in the ER cisternae with voltage gated potassium channels and/or with muscarinic M2 receptor signaling in the post synaptic plasma membrane. Possible mechanisms for regulation of MN excitability by S1R are discussed.

  13. Cortical synaptic and dendritic spine abnormalities in a presymptomatic TDP-43 model of amyotrophic lateral sclerosis

    PubMed Central

    Fogarty, Matthew J.; Klenowski, Paul M.; Lee, John D.; Drieberg-Thompson, Joy R.; Bartlett, Selena E.; Ngo, Shyuan T.; Hilliard, Massimo A.; Bellingham, Mark C.; Noakes, Peter G.

    2016-01-01

    Layer V pyramidal neurons (LVPNs) within the motor cortex integrate sensory cues and co-ordinate voluntary control of motor output. In amyotrophic lateral sclerosis (ALS) LVPNs and spinal motor neurons degenerate. The pathogenesis of neural degeneration is unknown in ALS; 10% of cases have a genetic cause, whereas 90% are sporadic, with most of the latter showing TDP-43 inclusions. Clinical and experimental evidence implicate excitotoxicity as a prime aetiological candidate. Using patch clamp and dye-filling techniques in brain slices, combined with high-resolution confocal microscopy, we report increased excitatory synaptic inputs and dendritic spine densities in early presymptomatic mice carrying a TDP-43Q331K mutation. These findings demonstrate substantive alterations in the motor cortex neural network, long before an overt degenerative phenotype has been reported. We conclude that increased excitatory neurotransmission is a common pathophysiology amongst differing genetic cases of ALS and may be of relevance to the 95% of sporadic ALS cases that exhibit TDP-43 inclusions. PMID:27897242

  14. Physiologic deficits in the orofacial system underlying dysarthria in amyotrophic lateral sclerosis.

    PubMed

    Langmore, S E; Lehman, M E

    1994-02-01

    The purpose of this study was to delineate some of the physiological deficits in the orofacial musculature of patients with dysarthria associated with amyotrophic lateral sclerosis (ALS) and to relate the physiologic deficits to perceived severity of dysarthria. Strain gauge force transducers placed on the lower lip, jaw, and tongue tip were used to measure maximum strength and maximum rate of repeated contractions. Diadochokinetic rates for repeated /pe/ and and /te/ were also determined. Fourteen ALS patients and 15 normal subjects were tested. It was found that the ALS patients with dysarthria were impaired in all tasks compared to the normal subjects, and that some measures revealed impairment even in those ALS patients who were not yet dysarthric. Bulbar ALS patients were generally more severely affected than the corticobulbar or spinal ALS patients, and the tongue was generally the most affected structure in all ALS groups. Perceived severity of dysarthria was more highly correlated with the measures of repeated contraction rate than with the measures of strength, suggesting that more severe dysarthria may be largely due to slower movement of the orofacial structures until substantial muscle strength has been lost.

  15. Macular sub-layer thinning and association with pulmonary function tests in Amyotrophic Lateral Sclerosis

    PubMed Central

    Simonett, Joseph M.; Huang, Russell; Siddique, Nailah; Farsiu, Sina; Siddique, Teepu; Volpe, Nicholas J.; Fawzi, Amani A.

    2016-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder that may have anterior visual pathway involvement. In this study, we compare the macular structure of patients with ALS to healthy controls, and examine correlations between macular sub-layer thickness measurements and pulmonary function tests and disease duration. ALS patients underwent optical coherence tomography (OCT) imaging to obtain macular cube scans of the right eye. Macular cube OCT data from age-matched healthy subjects were provided by the OCT reading center. Semi-automated retinal segmentation software was used to quantify macular sub-layers. Pulmonary function tests and time since symptom onset were collected retrospectively from the electronic medical records of ALS patients. Macular retinal nerve fiber layer was significantly thinner in ALS patients compared to healthy controls (P < 0.05). Total macular and other sub-layer thicknesses were not reduced in the ALS cohort. Macular retinal nerve fiber layer thickness positively correlated with forced vital capacity % predicted and forced expiratory volume in 1 second % predicted (P < 0.05). In conclusion, analysis of OCT measurements supports the involvement of the anterior visual pathway in ALS. Subtle structural thinning in the macular retinal nerve fiber layer correlates with pulmonary function tests. PMID:27383525

  16. Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1

    PubMed Central

    Barmada, Sami J.; Ju, Shulin; Arjun, Arpana; Batarse, Anthony; Archbold, Hilary C.; Peisach, Daniel; Li, Xingli; Zhang, Yuxi; Tank, Elizabeth M. H.; Qiu, Haiyan; Huang, Eric J.; Ringe, Dagmar; Petsko, Gregory A.; Finkbeiner, Steven

    2015-01-01

    Over 30% of patients with amyotrophic lateral sclerosis (ALS) exhibit cognitive deficits indicative of frontotemporal dementia (FTD), suggesting a common pathogenesis for both diseases. Consistent with this hypothesis, neuronal and glial inclusions rich in TDP43, an essential RNA-binding protein, are found in the majority of those with ALS and FTD, and mutations in TDP43 and a related RNA-binding protein, FUS, cause familial ALS and FTD. TDP43 and FUS affect the splicing of thousands of transcripts, in some cases triggering nonsense-mediated mRNA decay (NMD), a highly conserved RNA degradation pathway. Here, we take advantage of a faithful primary neuronal model of ALS and FTD to investigate and characterize the role of human up-frameshift protein 1 (hUPF1), an RNA helicase and master regulator of NMD, in these disorders. We show that hUPF1 significantly protects mammalian neurons from both TDP43- and FUS-related toxicity. Expression of hUPF2, another essential component of NMD, also improves survival, whereas inhibiting NMD prevents rescue by hUPF1, suggesting that hUPF1 acts through NMD to enhance survival. These studies emphasize the importance of RNA metabolism in ALS and FTD, and identify a uniquely effective therapeutic strategy for these disorders. PMID:26056265

  17. Oral Solubilized Ursodeoxycholic Acid Therapy in Amyotrophic Lateral Sclerosis: A Randomized Cross-Over Trial

    PubMed Central

    Min, Ju-Hong; Hong, Yoon-Ho; Sung, Jung-Joon; Kim, Sung-Min; Lee, Jung Bok

    2012-01-01

    To evaluate the efficacy and safety of ursodeoxycholic acid (UDCA) with oral solubilized formula in amyotrophic lateral sclerosis (ALS) patients, patients with probable or definite ALS were randomized to receive oral solubilized UDCA (3.5 g/140 mL/day) or placebo for 3 months after a run-in period of 1 month and switched to receive the other treatment for 3 months after a wash-out period of 1 month. The primary outcome was the rate of progression, assessed by the Appel ALS rating scale (AALSRS), and the secondary outcomes were the revised ALS functional rating scale (ALSFRS-R) and forced vital capacity (FVC). Fifty-three patients completed either the first or second period of study with only 16 of 63 enrolled patients given both treatments sequentially. The slope of AALSRS was 1.17 points/month lower while the patients were treated with UDCA than with placebo (95% CI for difference 0.08-2.26, P = 0.037), whereas the slopes of ALSFRS-R and FVC did not show significant differences between treatments. Gastrointestinal adverse events were more common with UDCA (P < 0.05). Oral solubilized UDCA seems to be tolerable in ALS patients, but we could not make firm conclusion regarding its efficacy, particularly due to the high attrition rate in this cross-over trial. PMID:22323869

  18. The Use of Integrative Therapies in Patients with Amyotrophic Lateral Sclerosis in Shanghai, China

    PubMed Central

    Chen, Xiangjun; Bao, Jie; Bai, Yu; Lu, Hua; Wang, Qiudong; Liu, Yi; Yuan, Canxing; Li, Wenwei; Liu, Zhenguo; Liu, Jun; Zhu, Xuying; Qin, Baofeng; Cai, Dingfang; Zhou, Hua

    2013-01-01

    Objective. To investigate the current use of integrative therapies (IT) in the treatment of patients with amyotrophic lateral sclerosis (ALS). Methods. A cross-sectional, multicenter clinical epidemiological survey was conducted in 12 hospitals in Shanghai. We investigated the type and frequency of IT use and determined whether the use of IT correlated with demographic, social, or disease-specific characteristics in our patient population. Results. A total of 231 (89.5%) of 258 patients with ALS were eligible for the study and 229 (99% of all) of 231 reported the use of at least one IT for the treatment of ALS. Vitamins and Chinese herb decoctions, Chinese herb compounds, massage therapy, and acupuncture were the 5 most commonly used therapies. There was a strong association between education level, income, and use of IT. A household income of more than 75,000 RMB ($49,995) correlated with multiple IT use, and married patients used IT more often than single individuals. The main reasons for using IT were to treat weakness and fatigue, muscle atrophy, the development of ALS, depression, insomnia, limb pain or numbness, and side effects associated with Riluzole. Conclusion. The use of IT is common in patients with ALS in Shanghai. Vitamins and TCM are the most used additional therapies and the widespread and largely unexamined use of IT for ALS requires more attention. PMID:24363770

  19. Altered Intracellular Milieu of ADAR2-Deficient Motor Neurons in Amyotrophic Lateral Sclerosis.

    PubMed

    Yamashita, Takenari; Akamatsu, Megumi; Kwak, Shin

    2017-02-08

    Transactive response DNA-binding protein (TDP-43) pathology, and failure of A-to-I conversion (RNA editing) at the glutamine/arginine (Q/R) site of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of most patients with amyotrophic lateral sclerosis (ALS). Adenosine deaminase acting on RNA 2 (ADAR2) specifically catalyzes GluA2 Q/R site-RNA editing. Furthermore, conditional ADAR2 knockout mice (AR2) exhibit a progressive ALS phenotype with TDP-43 pathology in the motor neurons, which is the most reliable pathological marker of ALS. Therefore, the evidence indicates that ADAR2 downregulation is a causative factor in ALS, and AR2 mice exhibit causative molecular changes that occur in ALS. We discuss the contributors to ADAR2 downregulation and TDP-43 pathology in AR2 mouse motor neurons. We describe mechanisms of exaggerated Ca(2+) influx amelioration via AMPA receptors, which is neuroprotective in ADAR2-deficient motor neurons with normalization of TDP-43 pathology in AR2 mice. Development of drugs to treat diseases requires appropriate animal models and a sensitive method of evaluating efficacy. Therefore, normalization of disrupted intracellular environments resulting from ADAR2 downregulation may be a therapeutic target for ALS. We discuss the development of targeted therapy for ALS using the AR2 mouse model.

  20. Characterization of Intercostal Muscle Pathology in Canine Degenerative Myelopathy: A Disease Model for Amyotrophic Lateral Sclerosis

    PubMed Central

    Morgan, Brandie R.; Coates, Joan R.; Johnson, Gayle C.; Bujnak, Alyssa C.; Katz, Martin L.

    2014-01-01

    Dogs homozygous for missense mutations in the SOD1 gene develop a late-onset neuromuscular disorder called degenerative myelopathy (DM) that has many similarities to amyotrophic lateral sclerosis (ALS). Both disorders are characterized by widespread progressive declines in motor functions accompanied by atrophic changes in the descending spinal cord tracts , and some forms of ALS are also associated with SOD1 mutations. In end-stage ALS, death usually occurs as a result of respiratory failure due to severe functional impairment of respiratory muscles. The mechanisms that lead to this loss of function are not known. Dogs with DM are euthanized at all stages of disease progression providing an opportunity to characterize the onset and progression of any pathological changes in the respiratory muscles that may precede respiratory failure. To characterize such potential disease-related pathology we evaluated intercostal muscles from Boxer and Pembroke Welsh Corgi dogs that were euthanized at various stages of DM disease progression. DM was found to result in intercostal muscle atrophy, fibrosis, increased variability in muscle fiber size and shape, and an alteration in muscle fiber type composition. This pathology was not accompanied by retraction of the motor neuron terminals from the muscle acetylcholine receptor complexes, suggesting that the muscle atrophy did not result from physical denervation. These findings provide a better understanding of the mechanisms that likely lead to respiratory failure in at least some forms of ALS and will be useful in the development and evaluation of potential therapeutic interventions using the DM model. PMID:24043596

  1. De Novo Truncating FUS Gene Mutation as a Cause of Sporadic Amyotrophic Lateral Sclerosis

    PubMed Central

    DeJesus-Hernandez, Mariely; Kocerha, Jannet; Finch, NiCole; Crook, Richard; Baker, Matt; Desaro, Pamela; Johnston, Amelia; Rutherford, Nicola; Wojtas, Aleksandra; Kennelly, Kathleen; Wszolek, Zbigniew K.; Graff-Radford, Neill; Boylan, Kevin; Rademakers, Rosa

    2010-01-01

    Mutations in the gene encoding fused in sarcoma (FUS) were recently identified as a novel cause of amyotrophic lateral sclerosis (ALS), emphasizing the genetic heterogeneity of ALS. We sequenced the genes encoding superoxide dismutase (SOD1), TAR DNA-binding protein 43 (TARDBP) and FUS in 99 sporadic and 17 familial ALS patients ascertained at Mayo Clinic. We identified two novel mutations in FUS in two out of 99 (2.0%) sporadic ALS patients and established the de novo occurrence of one FUS mutation. In familial patients, we identified three (17.6%) SOD1 mutations, while FUS and TARDBP mutations were excluded. The de novo FUS mutation (g.10747A>G; IVS13-2A>G) affects the splice-acceptor site of FUS intron 13 and was shown to induce skipping of FUS exon 14 leading to the C-terminal truncation of FUS (p.G466VfsX14). Subcellular localization studies showed a dramatic increase in the cytoplasmic localization of FUS and a reduction of normal nuclear expression in cells transfected with truncated compared to wild-type FUS. We further identified a novel in-frame insertion/deletion mutation in FUS exon 12 (p.S402 P411delinsGGGG) which is predicted to expand a conserved poly-glycine motif. Our findings extend the mutation spectrum in FUS leading to ALS and describe the first de novo mutation in FUS. PMID:20232451

  2. Season and weather patterns at time of birth in amyotrophic lateral sclerosis.

    PubMed

    Pamphlett, Roger; Fang, Fang

    2012-09-01

    Studies in the northern hemisphere suggest that the numbers of amyotrophic lateral sclerosis (ALS) births vary depending on the season of the year. We wished to determine if a southern hemisphere study would show the same seasonal changes, and whether particular weather conditions were associated with the numbers of ALS births. Birth data from a case-control study of Australian residents were used to relate monthly birth rates of ALS to the seasons and weather conditions. The results were compared with previous studies in Japan, Sweden and Switzerland. Four hundred and ninety-one Australian sporadic ALS patients and 629 controls (partners, friends, and community volunteers) completed a self-reported questionnaire that included dates of birth. Australian ALS birth rates increased between late summer and early winter, and decreased between mid-winter and early summer. Similar patterns were seen in Japan and Sweden. Monthly average humidity correlated positively with the numbers of ALS births in Australia, Sweden, and Japan. In conclusion, seasonal differences in ALS birth rates in the southern hemisphere are similar to those in two out of three northern hemisphere countries. Early life factors related to weather conditions, such as increased humidity leading to more infectious diseases and allergens, need to be further investigated in ALS.

  3. Skeletal Muscle Remodelling as a Function of Disease Progression in Amyotrophic Lateral Sclerosis

    PubMed Central

    Jensen, L.; Jørgensen, L. H.; Bech, R. D.; Frandsen, U.; Schrøder, H. D.

    2016-01-01

    Muscle weakness is considered the pivotal sign of amyotrophic lateral sclerosis (ALS). Knowledge about the skeletal muscle degeneration/regeneration process and the myogenic potential is limited in ALS patients. Therefore, we investigate these processes in a time course perspective by analysing skeletal muscle biopsies from ALS patients collected before and after a 12-week period of normal daily activities and compare these with healthy age-matched control tissue. We do this by evaluating mRNA and protein (immunohistochemical) markers of regeneration, neurodegeneration, myogenesis, cell cycle regulation, and inflammation. Our results show morphological changes indicative of active denervation and reinnervation and an increase in small atrophic fibres. We demonstrate differences between ALS and controls in pathways controlling skeletal muscle homeostasis, cytoskeletal and regenerative markers, neurodegenerative factors, myogenic factors, cell cycle determinants, and inflammatory markers. Our results on Pax7 and MyoD protein expression suggest that proliferation and differentiation of skeletal muscle stem cells are affected in ALS patients, and the myogenic processes cannot overcome the denervation-induced wasting. PMID:27195289

  4. Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis.

    PubMed

    Rajan, Thangavelu Soundara; Scionti, Domenico; Diomede, Francesca; Grassi, Gianpaolo; Pollastro, Federica; Piattelli, Adriano; Cocco, Lucio; Bramanti, Placido; Mazzon, Emanuela; Trubiani, Oriana

    2017-04-01

    Research in recent years has extensively investigated the therapeutic efficacy of mesenchymal stromal cells in regenerative medicine for many neurodegenerative diseases at preclinical and clinical stages. However, the success rate of stem cell therapy remains less at translational phase. Lack of relevant animal models that potentially simulate the molecular etiology of human pathological symptoms might be a reason behind such poor clinical outcomes associated with stem cell therapy. Apparently, self-renewal and differentiation ability of mesenchymal stem cells may help to study the early developmental signaling pathways connected with the diseases, such as Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), etc., at in vitro level. Cannabidiol, a non-psychotrophic cannabinoid, has been demonstrated as a potent anti-inflammatory and neuroprotective agent in neurological preclinical models. In the present study, we investigated the modulatory role of cannabidiol on genes associated with ALS using human gingiva-derived mesenchymal stromal cells (hGMSCs) as an in vitro model system. Next generation transcriptomic sequencing analysis demonstrated considerable modifications in the expression of genes connected with ALS pathology, oxidative stress, mitochondrial dysfunction, and excitotoxicity in hGMSCs treated with cannabidiol. Our results suggest the efficacy of cannabidiol to delineate the unknown molecular pathways, which may underlie ALS pathology at an early stage using hGMSCs as a compelling in vitro system. J. Cell. Biochem. 118: 819-828, 2017. © 2016 Wiley Periodicals, Inc.

  5. Eye-Tracking Control to Assess Cognitive Functions in Patients with Amyotrophic Lateral Sclerosis.

    PubMed

    Keller, Jürgen; Gorges, Martin; Aho-Özhan, Helena E A; Uttner, Ingo; Schneider, Erich; Kassubek, Jan; Pinkhardt, Elmar H; Ludolph, Albert C; Lulé, Dorothée

    2016-10-13

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with pathological involvement of upper and lower motoneurons, subsequently leading to progressive loss of motor and speech abilities. In addition, cognitive functions are impaired in a subset of patients. To evaluate these potential deficits in severely physically impaired ALS patients, eye-tracking is a promising means to conduct cognitive tests. The present article focuses on how eye movements, an indirect means of communication for physically disabled patients, can be utilized to allow for detailed neuropsychological assessment. The requirements, in terms of oculomotor parameters that have to be met for sufficient eye-tracking in ALS patients are presented. The properties of stimuli, including type of neuropsychological tests and style of presentation, best suited to successfully assess cognitive functioning, are also described. Furthermore, recommendations regarding procedural requirements are provided. Overall, this methodology provides a reliable, easy to administer and fast approach for assessing cognitive deficits in patients who are unable to speak or write such as patients with severe ALS. The only confounding factor might be deficits in voluntary eye movement control in a subset of ALS patients.

  6. Exploring sarcasm detection in amyotrophic lateral sclerosis using ecologically valid measures.

    PubMed

    Staios, Mathew; Fisher, Fiona; Lindell, Annukka K; Ong, Ben; Howe, Jim; Reardon, Katrina

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a rapidly progressive condition involving degeneration of both upper and lower motor neurons. Recent research suggests that a proportion of persons with ALS show a profile similar to that of frontotemporal dementia (FTD), with this group of ALS patients exhibiting social cognitive deficits. Although social cognitive deficits have been partially explored in ALS, research has yet to investigate such changes using ecologically valid measures. Therefore, this study aimed to further characterize the scope of social cognitive and emotion recognition deficits in non-demented ALS patients using an ecologically valid measure of social cognition. A sample of 35 ALS patients and 30 age-and-education matched controls were assessed using the Addenbrooke's Cognitive Examination, the Brixton Spatial Anticipation Test, and The Awareness of Social Inference Test, where participants were required to discriminate between various emotions and decipher socially challenging scenarios enacted in video vignettes. Participants with ALS showed significant difficulties in recognizing both sarcastic and paradoxical sarcastic statements, but not sincere statements, when compared to controls. After controlling for executive difficulties, ALS patients still displayed significant difficulties on tasks that assessed their comprehension of both sarcastic and paradoxical sarcastic statements. The inability to read social cues and make social inferences has the potential to place significant strain on familial/interpersonal relationships in ALS. The findings of this study highlight the importance of employing a broader range of neuropsychological assessment tools to aid in early detection of frontal lobe impairment in non-demented ALS patients.

  7. Functional studies of the parotid and pancreas glands in amyotrophic lateral sclerosis

    PubMed Central

    Charchaflie, R. J.; Fernandez, L. Bustos; Perec, C. J.; Gonzalez, E.; Marzi, A.

    1974-01-01

    Functional studies of the pancreas and parotid glands are reported in 17 patients with amyotrophic lateral sclerosis (ALS). The exocrine function of the pancreas was studied by measuring amylase concentration after stimulation with the endogenous secretin-pancreozymine test (ESP). Under these conditions, the pancreatic amylase concentration in ALS patients was found to be markedly decreased by about 45% when compared with those of healthy control subjects. Different conclusions in the literature about a possible impairment of the exocrine pancreas in ALS patients induced us to study the function of the parotid gland, which has close structural, functional, and physiopathological relationship with the pancreas. Flow rate and bicarbonate concentration of parotid saliva were measured after indirect stimulation (intraoral citric acid) and direct stimulation (pilocarpine). After indirect stimulation, both parotid flow rate and bicarbonate concentration from ALS patients were found to be decreased by about 66% and 70% respectively, when compared with controls. On the other hand, direct stimulation with pilocarpine in ALS patients elicited normal responses in both flow rate and bicarbonate concentration of saliva. It is concluded that the pancreatic and parotid deficiencies observed in ALS patients do not indicate primary disease of these exocrine glands. This interpretation is further emphasized by the results obtained by a sweat test, plasma osmolarity, and sialographic studies. The possibility that the gland impairments observed might be due to modifications of the neuroendocrine mechanisms regulating their secretory activity is suggested. PMID:4852110

  8. Neurodegenerative Models in Drosophila: Polyglutamine Disorders, Parkinson Disease, and Amyotrophic Lateral Sclerosis

    PubMed Central

    Ambegaokar, Surendra S.; Roy, Bidisha; Jackson, George R.

    2010-01-01

    Neurodegenerative diseases encompass a large group of neurological disorders. Clinical symptoms can include memory loss, cognitive impairment, loss of movement or loss of control of movement, and loss of sensation. Symptoms are typically adult onset (although severe cases can occur in adolescents) and are reflective of neuronal and glial cell loss in the central nervous system. Neurodegenerative diseases also are considered progressive, with increased severity of symptoms over time, also reflective of increased neuronal cell death. However, various neurodegenerative diseases differentially affect certain brain regions or neuronal or glial cell types. As an example, Alzheimer disease (AD) primarily affects the temporal lobe, whereas neuronal loss in Parkinson disease (PD) is largely (although not exclusively) confined to the nigrostriatal system. Neuronal loss is almost invariably accompanied by abnormal insoluble aggregates, either intra- or extracellular. Thus, neurodegenerative diseases are categorized by (a) the composite of clinical symptoms, (b) the brain regions or types of brain cells primarily affected, and (c) the types of protein aggregates found in the brain. Here we review the methods by which Drosophila melanogaster has been used to model aspects of polyglutamine diseases, Parkinson disease, and amyotrophic lateral sclerosis and key insights into that have been gained from these models; Alzheimer disease and the tauopathies are covered elsewhere in this special issue. PMID:20561920

  9. Roles of vitamin D in amyotrophic lateral sclerosis: possible genetic and cellular signaling mechanisms

    PubMed Central

    2013-01-01

    Evidence suggests that there are aberrations in the vitamin D-endocrine system in subjects with amyotrophic lateral sclerosis (ALS). Here, we review the relationship between vitamin D and ALS. Vitamin D deficiency was reported in patients with ALS. Dietary vitamin D3 supplementation improves functional capacity in the G93A transgenic mouse model of ALS. Genetic studies have provided an opportunity to identify the proteins that link vitamin D to ALS pathology, including major histocompatibility complex (MHC) class II molecules, toll-like receptors, poly(ADP-ribose) polymerase-1, heme oxygenase-1, and calcium-binding proteins, as well as the reduced form of nicotinamide adenine dinucleotide phosphate. Vitamin D also exerts its effect on ALS through cell-signaling mechanisms, including glutamate, matrix metalloproteinases, mitogen-activated protein kinase pathways, the Wnt/β-catenin signaling pathway, prostaglandins, reactive oxygen species, and nitric oxide synthase. In conclusion, vitamin D may have a role in ALS. Further investigation of vitamin D in ALS patients is needed. PMID:23570271

  10. Adducin at the Neuromuscular Junction in Amyotrophic Lateral Sclerosis: Hanging on for Dear Life

    PubMed Central

    Krieger, Charles; Wang, Simon Ji Hau; Yoo, Soo Hyun; Harden, Nicholas

    2016-01-01

    The neurological dysfunction in amyotrophic lateral sclerosis (ALS)/motor neurone disease (MND) is associated with defective nerve-muscle contacts early in the disease suggesting that perturbations of cell adhesion molecules (CAMs) linking the pre- and post-synaptic components of the neuromuscular junction (NMJ) are involved. To search for candidate proteins implicated in this degenerative process, researchers have studied the Drosophila larval NMJ and find that the cytoskeleton-associated protein, adducin, is ideally placed to regulate synaptic contacts. By controlling the levels of synaptic proteins, adducin can de-stabilize synaptic contacts. Interestingly, elevated levels of phosphorylated adducin have been reported in ALS patients and in a mouse model of the disease. Adducin is regulated by phosphorylation through protein kinase C (PKC), some isoforms of which exhibit Ca2+-dependence, raising the possibility that changes in intracellular Ca2+ might alter PKC activation and secondarily influence adducin phosphorylation. Furthermore, adducin has interactions with the alpha subunit of the Na+/K+-ATPase. Thus, the phosphorylation of adducin may secondarily influence synaptic stability at the NMJ and so influence pre- and post-synaptic integrity at the NMJ in ALS. PMID:26858605

  11. Amyotrophic lateral sclerosis mortality rates in Chile: A population based study (1994-2010).

    PubMed

    Valenzuela, Daniel; Zitko, Pedro; Lillo, Patricia

    2015-01-01

    Our objective was to describe amyotrophic lateral sclerosis (ALS) mortality rates in the Chilean population over a 17-year period. Chilean death records (1994-2010) were reviewed for the ICD-10 diagnosis G.12.2 (including motor neuron disease and similar conditions), and weighted with population data. Crude and standardized mortality rates by ALS were calculated at the nationwide level and by geographic zone. A risk analysis was performed in successive cohorts from 1910-1919 to 1960-1969, comparing mortality slopes. One thousand six hundred and seventy-one deaths were recorded during 1994-2010, with an average of 1.13 per 100,000, a 1.2:1 male/female ratio, and a statistically significant increase in mortality rate. According to geographical distribution, the Austral area, with a larger population of European origin, showed higher mortality rates compared to the national average. The cohort analysis showed an increasing risk of dying from ALS for all cohorts, and highest above 64 years of age, becoming a competitive cause of death in older ages. In conclusion, as expected, the mortality rate in Chile by ALS is higher than that reported previously in our country, and similar to other Latin American countries. ALS mortality rate has increased over time probably due to the aging of the population and decline in rates for competing causes of death.

  12. Genetic analysis of SS18L1 in French amyotrophic lateral sclerosis.

    PubMed

    Teyssou, Elisa; Vandenberghe, Nadia; Moigneu, Carine; Boillée, Séverine; Couratier, Philippe; Meininger, Vincent; Pradat, Pierre-François; Salachas, François; Leguern, Eric; Millecamps, Stéphanie

    2014-05-01

    Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease including about 15% of genetically determined forms. A de novo mutation in the SS18L1 (also known as CREST or KIAA0693) gene encoding the calcium-responsive transactivator and/or neuronal chromatin remodeling complex subunit has recently been identified by exome sequencing of 47 sporadic ALS trios. This Q388stop mutation deleting the last 9 amino acids was shown to impair activity-dependent dendritic outgrowth. A missense mutation (c.369T>G, p.Ileu123Met) was also found in 1 of 62 ALS families previously screened for other ALS-related genes and not carrying any mutation. To confirm the contribution of SS18L1 to ALS, we sequenced the 11 coding exons and exon-intron boundaries in 87 familial ALS (FALS). We identified 2 variants: the c.660_668del, p.Gln222_Ser224del in a patient devoid of mutation in any ALS related genes and the c.790G>A, p.Ala264Thr in a patient carrying a p.Arg96Leu variant in the OPTN gene. As these variants were not found in Single Nucleotide Polymorphism databases and were absent from 180 controls they could be new SS18L1 mutations causing ALS.

  13. Performance predictors of brain-computer interfaces in patients with amyotrophic lateral sclerosis

    NASA Astrophysics Data System (ADS)

    Geronimo, A.; Simmons, Z.; Schiff, S. J.

    2016-04-01

    Objective. Patients with amyotrophic lateral sclerosis (ALS) may benefit from brain-computer interfaces (BCI), but the utility of such devices likely will have to account for the functional, cognitive, and behavioral heterogeneity of this neurodegenerative disorder. Approach. In this study, a heterogeneous group of patients with ALS participated in a study on BCI based on the P300 event related potential and motor-imagery. Results. The presence of cognitive impairment in these patients significantly reduced the quality of the control signals required to use these communication systems, subsequently impairing performance, regardless of progression of physical symptoms. Loss in performance among the cognitively impaired was accompanied by a decrease in the signal-to-noise ratio of task-relevant EEG band power. There was also evidence that behavioral dysfunction negatively affects P300 speller performance. Finally, older participants achieved better performance on the P300 system than the motor-imagery system, indicating a preference of BCI paradigm with age. Significance. These findings highlight the importance of considering the heterogeneity of disease when designing BCI augmentative and alternative communication devices for clinical applications.

  14. Neuromuscular Junction Impairment in Amyotrophic Lateral Sclerosis: Reassessing the Role of Acetylcholinesterase

    PubMed Central

    Campanari, Maria-Letizia; García-Ayllón, María-Salud; Ciura, Sorana; Sáez-Valero, Javier; Kabashi, Edor

    2016-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a highly debilitating disease caused by progressive degeneration of motorneurons (MNs). Due to the wide variety of genes and mutations identified in ALS, a highly varied etiology could ultimately converge to produce similar clinical symptoms. A major hypothesis in ALS research is the “distal axonopathy” with pathological changes occurring at the neuromuscular junction (NMJ), at very early stages of the disease, prior to MNs degeneration and onset of clinical symptoms. The NMJ is a highly specialized cholinergic synapse, allowing signaling between muscle and nerve necessary for skeletal muscle function. This nerve-muscle contact is characterized by the clustering of the collagen-tailed form of acetylcholinesterase (ColQ-AChE), together with other components of the extracellular matrix (ECM) and specific key molecules in the NMJ formation. Interestingly, in addition to their cholinergic role AChE is thought to play several “non-classical” roles that do not require catalytic function, most prominent among these is the facilitation of neurite growth, NMJ formation and survival. In all this context, abnormalities of AChE content have been found in plasma of ALS patients, in which AChE changes may reflect the neuromuscular disruption. We review these findings and particularly the evidences of changes of AChE at neuromuscular synapse in the pre-symptomatic stages of ALS. PMID:28082868

  15. Amyotrophic lateral sclerosis in a patient with a family history of huntington disease: genetic counseling challenges.

    PubMed

    Smith, Andrea L; Teener, James W; Callaghan, Brian C; Harrington, Jack; Uhlmann, Wendy R

    2014-10-01

    Amyotrophic lateral sclerosis (ALS) and Huntington disease (HD) are generally considered to be distinct and easily differentiated neurologic conditions. However, there are case reports of the co-occurrence of ALS with HD. We present a 57-year-old male with a clinical diagnosis of sporadic ALS in the context of a family history of HD. This case adds to the limited literature regarding individuals with a family history of HD who present with features of ALS. There were several genetic counseling challenges in counseling this patient including the diagnostic consideration of two fatal conditions, complex risk information, the personal and familial implications, and the patient's inability to communicate verbally or through writing due to disease progression. DNA banking effectively preserved the right of our patient and his wife not to learn his HD genetic status during a stressful time of disease progression while providing the option for family members to learn this information in the future if desired. We present lessons learned and considerations for other clinical genetics professionals who are presented with similar challenging issues.

  16. A Novel F45S SOD1 Mutation in Amyotrophic Lateral Sclerosis Coexisting with Bullous Pemphigoid

    PubMed Central

    Oh, Seong-il; Hong, Jeong Ho; Choi, Byung Woo; Oh, Ki-Wook; Park, Chan Kum; Kwon, Min-Jung; Ki, Chang-Seok

    2015-01-01

    Background The coexistence of an autoimmune disease and amyotrophic lateral sclerosis (ALS) has led to the hypothesis that immune-mediated pathological mechanisms are overlapping in the two diseases. We report herein a rare coexistence of bullous pemphigoid (BP) in a novel mutation (F45S) of the gene encoding Cu/Zn superoxide dismutase (SOD1) in an ALS patient, and discuss a role for the SOD1 mutation in this unusual overlap. Case Report A 57-year-old male with familial ALS, including vesicles and tense bullae on erythematous bases, was diagnosed with BP. Direct immunofluorescence revealed deposits of C3 and immunoglobulin G in the basement membrane zone. Direct sequencing of SOD1 in the patient revealed a novel mutation (c.137T>C; F45S). Conclusions We report a novel SOD1 mutation in ALS, which was combined with BP. This novel SOD1 mutation could affect the phenotype of a combined autoimmune disease and matrix metalloproteinase-9. There may therefore be common factors linking BP and ALS with the SOD1 mutation. PMID:25749822

  17. The use of upper extremity anthropometrics in the clinical assessment of patients with amyotrophic lateral sclerosis.

    PubMed

    Kasarskis, E J; Berryman, S; English, T; Nyland, J; Vanderleest, J G; Schneider, A; Berger, R; McClain, C

    1997-03-01

    We evaluated the feasibility of using upper extremity anthropometrics to monitor the clinical status of 18 patients with amyotrophic lateral sclerosis (ALS). The bone-free arm muscle area (AMA) was computed using measurement of triceps skinfold thickness and the mid-upper arm circumference according to published formulae. The AMA correlated significantly with body mass, isokinetic muscle force generation, cross-sectional muscle area on computerized tomography scanning, and pulmonary functions including forced vital capacity and maximal voluntary ventilation. Serial determinations of AMA demonstrated a decline in 10 of 13 patients over 6 months. We pilot tested the use of AMA in a clinical trial of ciliary neurotrophic factor (CNTF) in the treatment of ALS. The AMA progressively decreased by 13%, 15%, and 30% in ALS patients treated with 0 microg CNTF/kg, 15 microg CNTF/kg, and 30/microg CNTF/kg, respectively, over a 9-month treatment period. We conclude that measurement of AMA provides a simple, inexpensive method to monitor the progression of muscle atrophy in ALS patients. The technique does not require effort on the part of the patient and as such, appears to have potential utility as an outcome measure in clinical drug trials.

  18. Epidemiology and surveillance of amyotrophic lateral sclerosis in two large metropolitan areas in California.

    PubMed

    Valle, Jhaqueline; Roberts, Eric; Paulukonis, Susan; Collins, Natalie; English, Paul; Kaye, Wendy

    2015-06-01

    Our objective was to provide demographic profiles and incidence estimates of amyotrophic lateral sclerosis (ALS) in two diverse California metropolitan areas: Los Angeles County (LA) and the San Francisco Bay Area (SFBA). Data were retrospectively collected from multiple sources. Case eligibility criteria included residency in SFBA or LA, and treatment for or diagnosis of ALS between 1 January 2009 and 31 December 2011. Overall incidence rates as well as age-, gender-, race- and ethnicity-specific rates were calculated. We identified 539 ALS cases in SFBA and 545 in LA; 618 were incident cases. Cases were more likely to be male and white. There were considerably more cases (p < 0.05) in LA who were foreign-born (LA, 22%; SFBA, 15%), black (LA, 10%; SFBA, 6%) or Hispanic (LA, 19%; SFBA, 10%). Conversely, the age adjusted incidence rates (per 100,000) were higher in SFBA for whites (LA, 1.40; SFBA, 2.49) and Hispanics (LA, 0.66; SFBA, 1.57) compared with LA. General case demographics and incidence rates in these two areas were similar to published studies. However, the differences between the two areas raise questions about how factors such as geography, access to care, and referral patterns may affect case ascertainment and diagnosis.

  19. Pharmacological properties of microneurotrophin drugs developed for treatment of amyotrophic lateral sclerosis.

    PubMed

    Bennett, James P; O'Brien, Laura C; Brohawn, David G

    2016-10-01

    Microneurotrophins (MNT's) are small molecule derivatives of dehydroepiandrosterone (DHEA) and do not have significant interactions with sex steroid receptors. MNT's retain high-affinity binding to protein tyrosine kinase (Trk) receptors and can mimic many pleiotropic actions of neurotrophin (NT) proteins on neurons. MNT's offer therapeutic potential for diseases such as amyotrophic lateral sclerosis (ALS) where motor neurons (MN) degenerate. MNT's cross artificial membranes mimicking the blood-brain barrier, are not major substrates for ABC (ATP-binding cassette) transporters and are metabolized rapidly by mouse but more slowly by human hepatocytes. A lead MNT (BNN27) and its mono-oxidation metabolites enter mouse brain rapidly. RNA-sequencing measured gene expression profiles of human H9eSC-(embryonic stem cell)-derived or CTL (control) subject iPSC-(induced pluripotential stem cell)-derived MN's exposed to NT proteins or MNT molecules. Expression ratios (relative to DMSO (dimethylsulfoxide) vehicle) were calculated, and the resulting top 500 gene lists were analyzed for Gene Ontology (GO) grouping using DAVID (Database for Annotation, Visualization and Integrated Discovery). The MNT's BNN20, BNN23, and BNN27 showed overlap of GO terms with NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor) in the H9eSC-derived MN's. In the iPSC-derived MN's two (BNN20, BNN27) showed overlap of GO terms with NGF or BDNF. Each NT protein had GO terms that did not overlap with any MNT in the MN cell lines.

  20. Differentiation of CD133+ Stem Cells From Amyotrophic Lateral Sclerosis Patients Into Preneuron Cells

    PubMed Central

    Martínez, Héctor R.; Caro-Osorio, Enrique; Cruz-Vega, Delia E.; Hernández-Torre, Martin; Moreno-Cuevas, Jorge E.

    2013-01-01

    Improvements in quality of life and life expectancy have been observed in amyotrophic lateral sclerosis (ALS) patients transplanted with CD133+ stem cells into their frontal motor cortices. However, questions have emerged about the capacity of cells from these patients to engraft and differentiate into neurons. The objective of this work was to evaluate the in vitro capacity of CD133+ stem cells from 13 ALS patients to differentiate into neuron lineage. Stem cells were obtained through leukapheresis and cultured in a control medium or a neuroinduction medium for 2–48 hours. Expression of neuronal genes was analyzed by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical techniques. Fluorescence microscopy demonstrated that CD133+ stem cells from ALS patients incubated for 48 hours in a neuroinduction medium increased the detection of neuronal proteins such as nestin, β-tubulin III, neuronal-specific enolase, and glial fibrillary acidic protein. RT-PCR assays demonstrated an increase in the expression of β-tubulin III, nestin, Olig2, Islet-1, Hb9, and Nkx6.1. No correlation was found between age, sex, or ALS functional scale and the CD133+ stem cell response to the neuroinduction medium. We conclude that CD133+ stem cells from ALS patients, like the stem cells of healthy subjects, are capable of differentiating into preneuron cells. PMID:23341441

  1. Imbalance of mitochondrial dynamics in Drosophila models of amyotrophic lateral sclerosis.

    PubMed

    Altanbyek, Volodya; Cha, Sun-Joo; Kang, Ga-Un; Im, Dai Sig; Lee, Seongsoo; Kim, Hyung-Jun; Kim, Kiyoung

    2016-12-09

    Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease, characterized by progressive and selective loss of motor neurons in the brain and spinal cord. DNA/RNA-binding proteins such as TDP-43, FUS, and TAF15 have been linked with the sporadic and familial forms of ALS. However, the exact pathogenic mechanism of ALS is still unknown. Recently, we found that ALS-causing genes such as TDP-43, FUS, and TAF15 genetically interact with mitochondrial dynamics regulatory genes. In this study, we show that mitochondrial fission was highly enhanced in muscles and motor neurons of TDP-43, FUS, and TAF15-induced fly models of ALS. Furthermore, the mitochondrial fission defects were rescued by co-expression of mitochondrial dynamics regulatory genes such as Marf, Opa1, and the dominant negative mutant form of Drp1. Moreover, we found that the expression level of Marf was decreased in ALS-induced flies. These results indicate that the imbalance of mitochondrial dynamics caused by instability of Marf is linked to the pathogenesis of TDP-43, FUS, and TAF15-associated ALS.

  2. Evidence for fungal infection in cerebrospinal fluid and brain tissue from patients with amyotrophic lateral sclerosis.

    PubMed

    Alonso, Ruth; Pisa, Diana; Marina, Ana Isabel; Morato, Esperanza; Rábano, Alberto; Rodal, Izaskun; Carrasco, Luis

    2015-01-01

    Among neurogenerative diseases, amyotrophic lateral sclerosis (ALS) is a fatal illness characterized by a progressive motor neuron dysfunction in the motor cortex, brainstem and spinal cord. ALS is the most common form of motor neuron disease; yet, to date, the exact etiology of ALS remains unknown. In the present work, we have explored the possibility of fungal infection in cerebrospinal fluid (CSF) and in brain tissue from ALS patients. Fungal antigens, as well as DNA from several fungi, were detected in CSF from ALS patients. Additionally, examination of brain sections from the frontal cortex of ALS patients revealed the existence of immunopositive fungal antigens comprising punctate bodies in the cytoplasm of some neurons. Fungal DNA was also detected in brain tissue using PCR analysis, uncovering the presence of several fungal species. Finally, proteomic analyses of brain tissue demonstrated the occurrence of several fungal peptides. Collectively, our observations provide compelling evidence of fungal infection in the ALS patients analyzed, suggesting that this infection may play a part in the etiology of the disease or may constitute a risk factor for these patients.

  3. Early-onset alopecia and amyotrophic lateral sclerosis: a cohort study.

    PubMed

    Fondell, Elinor; Fitzgerald, Kathryn C; Falcone, Guido J; O'Reilly, Eilis J; Ascherio, Alberto

    2013-10-01

    A recent meta-analysis of 7 genome-wide association studies on early balding (alopecia) revealed single nucleotide polymorphism variants in the region of the amyotrophic lateral sclerosis (ALS) gene TAR DNA-binding protein 43 (TARDBP/TDP-43). We therefore explored the association of early-onset alopecia and ALS in the Health Professionals Follow-up Study, a large cohort of 51,529 US men. In 1992, the participants (then aged 46-81 years) were asked to report their hair line pattern at age 45 years. During the follow-up period (1992-2008), 42 men were diagnosed with ALS. Of those, 13 had reported no alopecia, 18 had reported moderate alopecia, and 11 had reported extensive alopecia at age 45 years. Those who reported extensive alopecia had an almost 3-fold increased risk of ALS compared with those who reported no alopecia (relative risk = 2.74, 95% confidence interval: 1.23, 6.13). Furthermore, we observed a linear trend of increased risk of ALS with increasing level of balding at age 45 years (Ptrend = 0.02). In conclusion, men with early-onset alopecia seem to have a higher risk of ALS. The mechanisms underlying this association deserve further investigation.

  4. Metabolic Dysfunctions in Amyotrophic Lateral Sclerosis Pathogenesis and Potential Metabolic Treatments.

    PubMed

    Tefera, Tesfaye W; Borges, Karin

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease primarily characterized by loss of motor neurons in brain and spinal cord. The death of motor neurons leads to denervation of muscle which in turn causes muscle weakness and paralysis, decreased respiratory function and eventually death. Growing evidence indicates disturbances in energy metabolism in patients with ALS and animal models of ALS, which are likely to contribute to disease progression. Particularly, defects in glucose metabolism and mitochondrial dysfunction limit the availability of ATP to CNS tissues and muscle. Several metabolic approaches improving mitochondrial function have been investigated in vitro and in vivo and showed varying effects in ALS. The effects of metabolic approaches in ALS models encompass delays in onset of motor symptoms, protection of motor neurons and extension of survival, which signifies an important role of metabolism in the pathogenesis of the disease. There is now an urgent need to test metabolic approaches in controlled clinical trials. In addition, more detailed studies to better characterize the abnormalities in energy metabolism in patients with ALS and ALS models are necessary to develop metabolically targeted effective therapies that can slow the progression of the disease and prolong life for patients with ALS.

  5. Voxel-Wise Meta-Analysis of Gray Matter Changes in Amyotrophic Lateral Sclerosis

    PubMed Central

    Shen, Dongchao; Cui, Liying; Fang, Jia; Cui, Bo; Li, Dawei; Tai, Hongfei

    2016-01-01

    Background: Increasing neuroimaging studies have revealed gray matter (GM) anomalies of several brain regions by voxel-based morphometry (VBM) studies in patients with amyotrophic lateral sclerosis (ALS). A voxel-wise meta-analysis was conducted to integrate the reported studies to determine the consistent GM alterations in ALS based on VBM methods. Methods: Ovid Medline, Pubmed, Emabase, and BrainMap database were searched for relevant studies.Data were extracted by two independent researchers. Voxel-wise meta-analysis was performed using the effect-size signed differential mapping (ES-SDM) software. Results: Twenty-nine VBM studies comprising 638 subjects with ALS and 622 healthy controls (HCs) met inclusion criteria.The global GM volumes of ALS patients were significantly decreased compared with those of HCs. GM reductions in patients were mainly located in the right precentral gyrus, the left Rolandic operculum, the left lenticular nucleus and the right anterior cingulate/paracingulate gyri. The right precentral gyrus and the left inferior frontal gyrus might be potential anatomical biomarkers to evaluate the severity of the disease, and longer disease duration was associated with more GM atrophy in the left frontal aslant tract and the right precentral gyrus in ALS patients. Conclusion: The results support that ALS is a complex degenerative disease involving multisystems besides the motor system.The mechanism of asymmetric atrophy of the motor cortex and the implication of Rolandic operculum involvement in ALS need to be further elucidated in future studies. PMID:27065078

  6. Well-being in amyotrophic lateral sclerosis: a pilot experience sampling study

    PubMed Central

    Real, Ruben G. L.; Dickhaus, Thorsten; Ludolph, Albert; Hautzinger, Martin; Kübler, Andrea

    2014-01-01

    Objective: The aim of this longitudinal study was to identify predictors of instantaneous well-being in patients with amyotrophic lateral sclerosis (ALS). Based on flow theory well-being was expected to be highest when perceived demands and perceived control were in balance, and that thinking about the past would be a risk factor for rumination which would in turn reduce well-being. Methods: Using the experience sampling method, data on current activities, associated aspects of perceived demands, control, and well-being were collected from 10 patients with ALS three times a day for two weeks. Results: Results show that perceived control was uniformly and positively associated with well-being, but that demands were only positively associated with well-being when they were perceived as controllable. Mediation analysis confirmed thinking about the past, but not thinking about the future, to be a risk factor for rumination and reduced well-being. Discussion: Findings extend our knowledge of factors contributing to well-being in ALS as not only perceived control but also perceived demands can contribute to well-being. They further show that a focus on present experiences might contribute to increased well-being. PMID:25071670

  7. Osteopathic Manual Treatment for Amyotrophic Lateral Sclerosis: A Feasibility Pilot Study

    PubMed Central

    Maggiani, Alberto; Tremolizzo, Lucio; Valentina, Andrea Della; Mapelli, Laurent; Sosio, Silvia; Milano, Valeria; Bianchi, Manuel; Badi, Francesco; Lavazza, Carolina; Grandini, Marco; Corna, Giovanni; Prometti, Paola; Lunetta, Christian; Riva, Nilo; Ferri, Alessandra; Lanfranconi, Francesca

    2016-01-01

    Background: Current interventions in amyotrophic lateral sclerosis (ALS) are focused on supporting quality of life (QoL) and easing pain with a multidisciplinary approach. Objective: Primary aim of this pilot work assessed feasibility, safety, tolerability and satisfaction of osteopathic manual treatment (OMT) in 14 ALS outpatients. Methods: Patients were randomized according to an initial single-blind design (12 weeks, T0-T1), in order to receive OMT (weekly for 4 weeks, and fortnightly for the following 8 weeks) versus usual-care (n=7 each group), followed by an OMT open period (T1-T2, once a week for 8 weeks, n=10). Secondary aims included blind osteopathic assessment of somatic dysfunctions (SD) for goal attainment scale (GAS) calculation, Brief Pain Inventory-short form and McGill QoL-16 items. Results: OMT was demonstrated feasible and safe and patients displayed high satisfaction (T1-VAS=8.34 ± 0.46; T2-VAS=8.52 ± 0.60). Considering secondary aims no significant differences emerged. Finally, at study entry (T0), a cervico-dorsal SD was found in 78% of ALS patients versus 28% of healthy matched controls (p<0.01). Conclusion: OMT was found feasible, safe and satisfactory in ALS. The lack of secondary aim differences can be due to the limited sample size. OMT could be an interesting option to explore in ALS. PMID:27651843

  8. Immunohistochemical studies of angiogenin in the skin of patients with amyotrophic lateral sclerosis.

    PubMed

    Higashida, Kazuhiro; Tsukie, Tomomi; Fukazawa, Hiroyuki; Fujikura, Mikio; Ono, Seiitsu

    2013-03-15

    Angiogenin (ANG) is a member of the ribonuclease superfamily which is implicated in angiogenesis. ANG maintains normal vasculature and thereby protects motor neurons from various stress conditions. It is suggested that ANG may play a role in pathomechanism of amyotrophic lateral sclerosis (ALS). However, there have been no studies of ANG in ALS skin. We made a quantitative immunohistochemical study of the expression of ANG in the skin from 20 patients with sporadic ALS, 20 patients with other neurologic or muscular disorders (control group A), and 20 patients without neurologic or muscular disorders (control group B). The nuclei of the epidermal cells showed a weak ANG immunoreactivity in ALS patients. These findings became more marked as ALS progressed. The optical density for ANG immunoreactivity of the nucleus in the epidermal cells in ALS patients was significantly lower (p<0.001) than in control groups A and B. There was a significant negative relationship (r=-0.82, p<0.001) between the optical density for ANG immunoreactivity of the nucleus and duration of illness in ALS patients. These data suggest that changes of ANG in ALS skin are related to the disease process and that metabolic alterations of ANG may take place in the skin of ALS patients.

  9. Predicting Speech Intelligibility Decline in Amyotrophic Lateral Sclerosis Based on the Deterioration of Individual Speech Subsystems

    PubMed Central

    Yunusova, Yana; Wang, Jun; Zinman, Lorne; Pattee, Gary L.; Berry, James D.; Perry, Bridget; Green, Jordan R.

    2016-01-01

    Purpose To determine the mechanisms of speech intelligibility impairment due to neurologic impairments, intelligibility decline was modeled as a function of co-occurring changes in the articulatory, resonatory, phonatory, and respiratory subsystems. Method Sixty-six individuals diagnosed with amyotrophic lateral sclerosis (ALS) were studied longitudinally. The disease-related changes in articulatory, resonatory, phonatory, and respiratory subsystems were quantified using multiple instrumental measures, which were subjected to a principal component analysis and mixed effects models to derive a set of speech subsystem predictors. A stepwise approach was used to select the best set of subsystem predictors to model the overall decline in intelligibility. Results Intelligibility was modeled as a function of five predictors that corresponded to velocities of lip and jaw movements (articulatory), number of syllable repetitions in the alternating motion rate task (articulatory), nasal airflow (resonatory), maximum fundamental frequency (phonatory), and speech pauses (respiratory). The model accounted for 95.6% of the variance in intelligibility, among which the articulatory predictors showed the most substantial independent contribution (57.7%). Conclusion Articulatory impairments characterized by reduced velocities of lip and jaw movements and resonatory impairments characterized by increased nasal airflow served as the subsystem predictors of the longitudinal decline of speech intelligibility in ALS. Declines in maximum performance tasks such as the alternating motion rate preceded declines in intelligibility, thus serving as early predictors of bulbar dysfunction. Following the rapid decline in speech intelligibility, a precipitous decline in maximum performance tasks subsequently occurred. PMID:27148967

  10. Predicting Early Bulbar Decline in Amyotrophic Lateral Sclerosis: A Speech Subsystem Approach

    PubMed Central

    2015-01-01

    Purpose. To develop a predictive model of speech loss in persons with amyotrophic lateral sclerosis (ALS) based on measures of respiratory, phonatory, articulatory, and resonatory functions that were selected using a data-mining approach. Method. Physiologic speech subsystem (respiratory, phonatory, articulatory, and resonatory) functions were evaluated longitudinally in 66 individuals with ALS using multiple instrumentation approaches including acoustic, aerodynamic, nasometeric, and kinematic. The instrumental measures of the subsystem functions were subjected to a principal component analysis and linear mixed effects models to derive a set of comprehensive predictors of bulbar dysfunction. These subsystem predictors were subjected to a Kaplan-Meier analysis to estimate the time until speech loss. Results. For a majority of participants, speech subsystem decline was detectible prior to declines in speech intelligibility and speaking rate. Among all subsystems, the articulatory and phonatory predictors were most responsive to early bulbar deterioration; and the resonatory and respiratory predictors were as responsive to bulbar decline as was speaking rate. Conclusions. The articulatory and phonatory predictors are sensitive indicators of early bulbar decline due to ALS, which has implications for predicting disease onset and progression and clinical management of ALS. PMID:26136624

  11. Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.

    PubMed

    Ditsworth, Dara; Maldonado, Marcus; McAlonis-Downes, Melissa; Sun, Shuying; Seelman, Amanda; Drenner, Kevin; Arnold, Eveline; Ling, Shuo-Chien; Pizzo, Donald; Ravits, John; Cleveland, Don W; Da Cruz, Sandrine

    2017-03-29

    Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43(Q331K) mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43(Q331K) gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types.

  12. Characterization of intercostal muscle pathology in canine degenerative myelopathy: a disease model for amyotrophic lateral sclerosis.

    PubMed

    Morgan, Brandie R; Coates, Joan R; Johnson, Gayle C; Bujnak, Alyssa C; Katz, Martin L

    2013-12-01

    Dogs homozygous for missense mutations in the SOD1 gene develop a late-onset neuromuscular disorder called degenerative myelopathy (DM) that has many similarities to amyotrophic lateral sclerosis (ALS). Both disorders are characterized by widespread progressive declines in motor functions, accompanied by atrophic changes in the descending spinal cord tracts. Some forms of ALS are also associated with SOD1 mutations. In end-stage ALS, death usually occurs as a result of respiratory failure from severe functional impairment of respiratory muscles. The mechanisms that lead to this loss of function are not known. Dogs with DM are euthanized at all stages of disease progression, providing an opportunity to characterize the onset and progression of any pathological changes in the respiratory muscles that may precede respiratory failure. To characterize such potential disease-related pathology, we evaluated intercostal muscles from Boxer and Pembroke Welsh Corgi dogs that were euthanized at various stages of DM disease progression. DM was found to result in intercostal muscle atrophy, fibrosis, increased variability in muscle fiber size and shape, and alteration in muscle fiber type composition. This pathology was not accompanied by retraction of the motor neuron terminals from the muscle acetylcholine receptor complexes, suggesting that the muscle atrophy did not result from physical denervation. These findings provide a better understanding of the mechanisms that likely lead to respiratory failure in at least some forms of ALS and will be useful in the development and evaluation of potential therapeutic interventions using the DM model.

  13. [Dissociated Small Hand Muscle Atrophy Occurs in Amyotrophic Lateral Sclerosis: Split Hand].

    PubMed

    Shibuya, Kazumoto

    2016-05-01

    Split hand is a peculiar atrophy of hand muscle and was named by Willbourn in 1992. In this phenomenon, the hypothenar muscle is relatively preserved, but the thenar and the first dorsal interossei (FDI) muscles are preferentially involved. Some studies have measured compound muscle action potential (CMAP) amplitudes of intrinsic hand muscles in various neurological diseases and have revealed that this phenomenon is a specific feature of amyotrophic lateral sclerosis (ALS). The measurements of CMAP amplitude in intrinsic hand muscles may be useful for diagnosis of ALS. FDI and thenar muscles are innervated by the same ulnar nerve and same spinal segments (C8 and Th1), although atrophies of these muscles are dissociated. Anatomical innervations are not enough to explain this phenomenon. Motor neuronal hyperexcitability potentially contributes to motor neuron death in ALS, and in several articles, it is reported to be the possible mechanism of this phenomenon. In healthy controls and ALS patients, cortical and peripheral motor nerves, which project to the thenar and FDI muscles, may be more excitable than those of the hypothenar muscle. This article reviews the findings of previous articles about the utility of this phenomenon as a diagnostic marker, and its potential mechanisms.

  14. Voluntary contraction direction dependence of motor unit number index in patients with amyotrophic lateral sclerosis.

    PubMed

    Zhou, Ping; Nandedkar, Sanjeev D; Barkhaus, Paul E

    2014-09-01

    We investigated the voluntary contraction direction dependence of motor unit number index (MUNIX) for multifunctional muscles in patients with amyotrophic lateral sclerosis (ALS). The MUNIX technique was applied in nine first dorsal interosseous muscles of eight ALS subjects, using surface electromyography (EMG) signals from index finger abduction and flexion, respectively. In seven examined muscles, the MUNIX derived from the index finger abduction mode was smaller than that from the flexion mode. For the remaining two muscles, one had the same MUNIX; the other showed an abduction mode MUNIX much higher than the flexion mode MNUIX. Across all muscles, the median MUNIX was 96 for the index finger abduction mode and 161 for the flexion mode. The findings reveal the dependence of multifunctional muscle MUNIX on voluntary contraction directions in ALS patients. Based on this analysis, we further explored the concept of "multidimensional MUNIX" for an appropriate performance or interpretation of MUNIX in multifunctional muscles of ALS patients. An effort towards such a development was presented using both abduction and flexion mode surface EMG for MUNIX calculation.

  15. Evidence for Fungal Infection in Cerebrospinal Fluid and Brain Tissue from Patients with Amyotrophic Lateral Sclerosis

    PubMed Central

    Alonso, Ruth; Pisa, Diana; Marina, Ana Isabel; Morato, Esperanza; Rábano, Alberto; Rodal, Izaskun; Carrasco, Luis

    2015-01-01

    Among neurogenerative diseases, amyotrophic lateral sclerosis (ALS) is a fatal illness characterized by a progressive motor neuron dysfunction in the motor cortex, brainstem and spinal cord. ALS is the most common form of motor neuron disease; yet, to date, the exact etiology of ALS remains unknown. In the present work, we have explored the possibility of fungal infection in cerebrospinal fluid (CSF) and in brain tissue from ALS patients. Fungal antigens, as well as DNA from several fungi, were detected in CSF from ALS patients. Additionally, examination of brain sections from the frontal cortex of ALS patients revealed the existence of immunopositive fungal antigens comprising punctate bodies in the cytoplasm of some neurons. Fungal DNA was also detected in brain tissue using PCR analysis, uncovering the presence of several fungal species. Finally, proteomic analyses of brain tissue demonstrated the occurrence of several fungal peptides. Collectively, our observations provide compelling evidence of fungal infection in the ALS patients analyzed, suggesting that this infection may play a part in the etiology of the disease or may constitute a risk factor for these patients. PMID:25892962

  16. Altered Intracellular Milieu of ADAR2-Deficient Motor Neurons in Amyotrophic Lateral Sclerosis

    PubMed Central

    Yamashita, Takenari; Akamatsu, Megumi; Kwak, Shin

    2017-01-01

    Transactive response DNA-binding protein (TDP-43) pathology, and failure of A-to-I conversion (RNA editing) at the glutamine/arginine (Q/R) site of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of most patients with amyotrophic lateral sclerosis (ALS). Adenosine deaminase acting on RNA 2 (ADAR2) specifically catalyzes GluA2 Q/R site-RNA editing. Furthermore, conditional ADAR2 knockout mice (AR2) exhibit a progressive ALS phenotype with TDP-43 pathology in the motor neurons, which is the most reliable pathological marker of ALS. Therefore, the evidence indicates that ADAR2 downregulation is a causative factor in ALS, and AR2 mice exhibit causative molecular changes that occur in ALS. We discuss the contributors to ADAR2 downregulation and TDP-43 pathology in AR2 mouse motor neurons. We describe mechanisms of exaggerated Ca2+ influx amelioration via AMPA receptors, which is neuroprotective in ADAR2-deficient motor neurons with normalization of TDP-43 pathology in AR2 mice. Development of drugs to treat diseases requires appropriate animal models and a sensitive method of evaluating efficacy. Therefore, normalization of disrupted intracellular environments resulting from ADAR2 downregulation may be a therapeutic target for ALS. We discuss the development of targeted therapy for ALS using the AR2 mouse model. PMID:28208729

  17. [Muro disease: amyotrophic lateral sclerosis/parkinsonism-dementia complex in Kii peninsula of Japan].

    PubMed

    Kuzuhara, Shigeki

    2011-02-01

    Muro disease refers to the endemic amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) in the high incidence ALS focus in the Muro district of the Kii peninsula. Kii paralysis was first described in the 1680s in a folk literature, and as ALS in the medical literature by Kin-no-suke Miura in 1911. Two high-incidence ALS foci were discovered in 1960s by Kimura and Yase, and retro- and anterospective epidemiological surveys were started. Kii ALS was neuropathologically characterized by classical ALS pathology together with many neurofibrillary tangles (NFTs) in the brain, similar to Guamanian ALS. The incidence rates of ALS dramatically declined during the 1950s and 1980s, resulting in the disappearance of the high-incidence foci. In the early 1990s, however, Kuzuhara found existence of high-incidence of ALS in the region, and, in addition, of a high-incidence of PDC with abundant NFTs, similar to Guamanian PDC. The incidence rates of PDC dramatically rose during the 1980s and 1990s, and PDC replaced ALS. Unsuccessful attempts were made to identify cause and pathogenesis of the disease in minerals and environmental factors. More than 70% of patients in the endemic region had a family history of ALS or PDC; therefore, genetic factors were suspected as the cause. The authors analyzed the causative and risk candidate genes in the affected and unaffected family members, but failed to find genes related to ALS/PDC. The changing pattern of Muro disease from ALS with a younger onset and rapid progression to PDC with a later onset and longer survival suggests that some unknown environmental factor(s) might modulate the disease process, which basically might be programmed in the gene(s).

  18. A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis

    PubMed Central

    Zhao, Zhong; Lange, Dale J; Voustianiouk, Andrei; MacGrogan, Donal; Ho, Lap; Suh, Jason; Humala, Nelson; Thiyagarajan, Meenakshisundaram; Wang, Jun; Pasinetti, Giulio M

    2006-01-01

    Background The cause of neuronal death in amyotrophic lateral sclerosis (ALS) is uncertain but mitochondrial dysfunction may play an important role. Ketones promote mitochondrial energy production and membrane stabilization. Results SOD1-G93A transgenic ALS mice were fed a ketogenic diet (KD) based on known formulations for humans. Motor performance, longevity, and motor neuron counts were measured in treated and disease controls. Because mitochondrial dysfunction plays a central role in neuronal cell death in ALS, we also studied the effect that the principal ketone body, D-β-3 hydroxybutyrate (DBH), has on mitochondrial ATP generation and neuroprotection. Blood ketones were > 3.5 times higher in KD fed animals compared to controls. KD fed mice lost 50% of baseline motor performance 25 days later than disease controls. KD animals weighed 4.6 g more than disease control animals at study endpoint; the interaction between diet and change in weight was significant (p = 0.047). In spinal cord sections obtained at the study endpoint, there were more motor neurons in KD fed animals (p = 0.030). DBH prevented rotenone mediated inhibition of mitochondrial complex I but not malonate inhibition of complex II. Rotenone neurotoxicity in SMI-32 immunopositive motor neurons was also inhibited by DBH. Conclusion This is the first study showing that diet, specifically a KD, alters the progression of the clinical and biological manifestations of the G93A SOD1 transgenic mouse model of ALS. These effects may be due to the ability of ketone bodies to promote ATP synthesis and bypass inhibition of complex I in the mitochondrial respiratory chain. PMID:16584562

  19. DiPALS: Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis - a randomised controlled trial.

    PubMed Central

    McDermott, Christopher J; Bradburn, Mike J; Maguire, Chin; Cooper, Cindy L; Baird, Wendy O; Baxter, Susan K; Cohen, Judith; Cantrill, Hannah; Dixon, Simon; Ackroyd, Roger; Baudouin, Simon; Bentley, Andrew; Berrisford, Richard; Bianchi, Stephen; Bourke, Stephen C; Darlison, Roy; Ealing, John; Elliott, Mark; Fitzgerald, Patrick; Galloway, Simon; Hamdalla, Hisham; Hanemann, C Oliver; Hughes, Philip; Imam, Ibrahim; Karat, Dayalan; Leek, Roger; Maynard, Nick; Orrell, Richard W; Sarela, Abeezar; Stradling, John; Talbot, Kevin; Taylor, Lyn; Turner, Martin; Simonds, Anita K; Williams, Tim; Wedzicha, Wisia; Young, Carolyn; Shaw, Pamela J

    2016-01-01

    BACKGROUND Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in death, usually from respiratory failure, within 2-3 years of symptom onset. Non-invasive ventilation (NIV) is a treatment that when given to patients in respiratory failure leads to improved survival and quality of life. Diaphragm pacing (DP), using the NeuRx/4(®) diaphragm pacing system (DPS)™ (Synapse Biomedical, Oberlin, OH, USA), is a new technique that may offer additional or alternative benefits to patients with ALS who are in respiratory failure. OBJECTIVE The Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis (DiPALS) trial evaluated the effect of DP on survival over the study duration in patients with ALS with respiratory failure. DESIGN The DiPALS trial was a multicentre, parallel-group, open-label, randomised controlled trial incorporating health economic analyses and a qualitative longitudinal substudy. PARTICIPANTS Eligible participants had a diagnosis of ALS (ALS laboratory-supported probable, clinically probable or clinically definite according to the World Federation of Neurology revised El Escorial criteria), had been stabilised on riluzole for 30 days, were aged ≥ 18 years and were in respiratory failure. We planned to recruit 108 patients from seven UK-based specialist ALS or respiratory centres. Allocation was performed using 1 : 1 non-deterministic minimisation. INTERVENTIONS Participants were randomised to either standard care (NIV alone) or standard care (NIV) plus DP using the NeuRX/4 DPS. MAIN OUTCOME MEASURES The primary outcome was overall survival, defined as the time from randomisation to death from any cause. Secondary outcomes were patient quality of life [assessed by European Quality of Life-5 Dimensions, three levels (EQ-5D-3L), Short Form questionnaire-36 items and Sleep Apnoea Quality of Life Index questionnaire]; carer quality of life (EQ-5D-3L and Caregiver Burden Inventory); cost-utility analysis and health

  20. White matter structural network abnormalities underlie executive dysfunction in amyotrophic lateral sclerosis.

    PubMed

    Dimond, Dennis; Ishaque, Abdullah; Chenji, Sneha; Mah, Dennell; Chen, Zhang; Seres, Peter; Beaulieu, Christian; Kalra, Sanjay

    2017-03-01

    Research in amyotrophic lateral sclerosis (ALS) suggests that executive dysfunction, a prevalent cognitive feature of the disease, is associated with abnormal structural connectivity and white matter integrity. In this exploratory study, we investigated the white matter constructs of executive dysfunction, and attempted to detect structural abnormalities specific to cognitively impaired ALS patients. Eighteen ALS patients and 22 age and education matched healthy controls underwent magnetic resonance imaging on a 4.7 Tesla scanner and completed neuropsychometric testing. ALS patients were categorized into ALS cognitively impaired (ALSci, n = 9) and ALS cognitively competent (ALScc, n = 5) groups. Tract-based spatial statistics and connectomics were used to compare white matter integrity and structural connectivity of ALSci and ALScc patients. Executive function performance was correlated with white matter FA and network metrics within the ALS group. Executive function performance in the ALS group correlated with global and local network properties, as well as FA, in regions throughout the brain, with a high predilection for the frontal lobe. ALSci patients displayed altered local connectivity and structural integrity in these same frontal regions that correlated with executive dysfunction. Our results suggest that executive dysfunction in ALS is related to frontal network disconnectivity, which potentially mediates domain-specific, or generalized cognitive impairment, depending on the degree of global network disruption. Furthermore, reported co-localization of decreased network connectivity and diminished white matter integrity suggests white matter pathology underlies this topological disruption. We conclude that executive dysfunction in ALSci is associated with frontal and global network disconnectivity, underlined by diminished white matter integrity. Hum Brain Mapp 38:1249-1268, 2017. © 2016 Wiley Periodicals, Inc.

  1. Different occupations associated with amyotrophic lateral sclerosis: is diesel exhaust the link?

    PubMed

    Pamphlett, Roger; Rikard-Bell, Anna

    2013-01-01

    The cause of sporadic amyotrophic lateral sclerosis (SALS) remains unknown. We attempted to find out if occupational exposure to toxicants plays a part in the pathogenesis of this disease. In an Australia-wide case-control study we compared the lifetime occupations of 611 SALS and 775 control individuals. Occupations were coded using country-specific as well as international classifications. The risk of SALS for each occupation was calculated with odds ratios using logistic regression. In addition, the literature was searched for possible toxicant links between our findings and previously-reported occupational associations with SALS. Male occupations in our study that required lower skills and tasks tended to have increased risks of SALS, and conversely, those occupations that required higher skills and tasks had decreased risks of SALS. Of all the occupations, only truck drivers, where exposure to diesel exhaust is common, maintained an increased risk of SALS throughout all occupational groups. Another large case-control study has also found truck drivers to be at risk of SALS, and almost two-thirds of occupations, as well as military duties, that have previously been associated with SALS have potential exposure to diesel exhaust. In conclusion, two of the largest case-control studies of SALS have now found that truck drivers have an increased risk of SALS. Since exposure to diesel exhaust is common in truck drivers, as well as in other occupations that have been linked to SALS, exposure to this toxicant may underlie some of the occupations that are associated with SALS.

  2. Estimating daily energy expenditure in individuals with amyotrophic lateral sclerosis123

    PubMed Central

    Kasarskis, Edward J; Mendiondo, Marta S; Matthews, Dwight E; Mitsumoto, Hiroshi; Tandan, Rup; Simmons, Zachary; Bromberg, Mark B; Kryscio, Richard J

    2014-01-01

    Background: Patients with amyotrophic lateral sclerosis (ALS) experience progressive limb weakness, muscle atrophy, and dysphagia, making them vulnerable to insufficient energy intake. Methods to estimate energy requirements have not been devised for this patient group. Objective: The goal was to develop equations to estimate energy requirements of ALS patients. Design: We enrolled 80 ALS participants at varying stages of their illness and studied them every 16 wk over 48 wk. At each time, we determined total daily energy expenditure (TDEE) in the home setting over a 10-d period by using the doubly labeled water method. We then developed statistical models to estimate TDEE by using factors easily obtained during a routine clinical visit. Results: The most practical TDEE models used the Harris-Benedict, Mifflin-St Jeor, or Owen equations to estimate resting metabolic rate (RMR) and 6 questions from the revised ALS Functional Rating Scale (ALSFRS-R) that relate to physical activity. We developed a Web-based calculator to facilitate its use. In the research setting, measuring body composition with bioelectrical impedance spectroscopy enabled the estimation of RMR with the Rosenbaum equation and the same 6 questions from the ALSFRS-R to estimate TDEE. By using these models, the estimate of TDEE for nutritional maintenance was ±500 kcal/d across the spectrum of ALS progression. Conclusions: Our results emphasize the importance of physical function and body composition in estimating TDEE. Our predictive equations can serve as a basis for recommending placement of a feeding gastrostomy in ALS patients who fail to meet their energy requirements by oral intake. This trial was registered at clinicaltrials.gov as NCT00116558. PMID:24522445

  3. Neuropsychological study of amyotrophic lateral sclerosis and parkinsonism-dementia complex in Kii peninsula, Japan

    PubMed Central

    2014-01-01

    Background The Kii peninsula of Japan is one of the foci of amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS/PDC) in the world. The purpose of this study is to clarify the neuropsychological features of the patients with ALS/PDC of the Kii peninsula (Kii ALS/PDC). Methods The medical interview was done on 13 patients with Kii ALS/PDC, 12 patients with Alzheimer’s disease, 10 patients with progressive supranuclear palsy, 10 patients with frontotemporal lobar degeneration and 10 patients with dementia with Lewy bodies. These patients and their carer/spouse were asked to report any history of abulia-apathy, hallucination, personality change and other variety of symptoms. Patients also underwent brain magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and neuropsychological tests comprising the Mini Mental State Examination, Raven’s Colored Progressive Matrices, verbal fluency, and Paired-Associate Word Learning Test and some of them were assessed with the Frontal Assessment Battery (FAB). Results All patients with Kii ALS/PDC had cognitive dysfunction including abulia-apathy, bradyphrenia, hallucination, decrease of extraversion, disorientation, and delayed reaction time. Brain MRI showed atrophy of the frontal and/or temporal lobes, and SPECT revealed a decrease in cerebral blood flow of the frontal and/or temporal lobes in all patients with Kii ALS/PDC. Disorientation, difficulty in word recall, delayed reaction time, and low FAB score were recognized in Kii ALS/PDC patients with cognitive dysfunction. Conclusions The core neuropsychological features of the patients with Kii ALS/PDC were characterized by marked abulia-apathy, bradyphrenia, and hallucination. PMID:25041813

  4. Novel Mutations in TARDBP (TDP-43) in Patients with Familial Amyotrophic Lateral Sclerosis

    PubMed Central

    Rutherford, Nicola J.; Zhang, Yong-Jie; Baker, Matt; Gass, Jennifer M.; Finch, NiCole A.; Xu, Ya-Fei; Stewart, Heather; Kelley, Brendan J.; Kuntz, Karen; Crook, Richard J. P.; Sreedharan, Jemeen; Vance, Caroline; Sorenson, Eric; Lippa, Carol; Bigio, Eileen H.; Geschwind, Daniel H.; Knopman, David S.; Mitsumoto, Hiroshi; Petersen, Ronald C.; Cashman, Neil R.; Hutton, Mike; Shaw, Christopher E.; Boylan, Kevin B.; Boeve, Bradley; Graff-Radford, Neill R.; Wszolek, Zbigniew K.; Caselli, Richard J.; Dickson, Dennis W.; Mackenzie, Ian R.; Petrucelli, Leonard; Rademakers, Rosa

    2008-01-01

    The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43–positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the ∼25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis. PMID:18802454

  5. The Edinburgh Cognitive and Behavioural ALS Screen in a Chinese Amyotrophic Lateral Sclerosis Population

    PubMed Central

    Ye, Shan; Ji, Ying; Li, Chengyu; He, Ji; Liu, Xiaolu; Fan, Dongsheng

    2016-01-01

    Objective The existing screening batteries assessing multiple neuropsychological functions are not specific to amyotrophic lateral sclerosis (ALS) patients and are limited to their physical dysfunctions, whereas category cognitive tests are too time-consuming to assess all the domains. The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was recently developed as a fast and easy cognitive screening tool specifically designed for patients. The purpose of the study was to validate the effectiveness of the Chinese version in Chinese ALS populations. Methods Eighty-four ALS patients and 84 age-, gender- and education-matched healthy controls were included in this cross-sectional study. All the participants took the ECAS, Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB). Primary caregivers of patients were interviewed for behavioural and psychiatric changes. Results Significant differences were noted in language (p = 0.01), fluency, executive function, ALS-specific functions, and ECAS total score (p<0.01) between ALS patients and controls. The cut-off value of the total ECAS score was 81.92. Cognitive impairment was observed in 35.71% of patients, and 27.38% exhibited behavioural abnormalities. The ECAS total score had a medium correlation with education year. Memory was more easily impaired in the lower education group, whereas verbal fluency and language function tended to be preserved in the higher education group. The average time of ECAS was only 18 minutes. Conclusion The Chinese version of the ECAS is the first screening battery assessing multiple neuropsychological functions specially designed for the ALS population in China, which provides an effective and rapid tool to screen cognitive and behavioural impairments. PMID:27195772

  6. Gacyclidine improves the survival and reduces motor deficits in a mouse model of amyotrophic lateral sclerosis

    PubMed Central

    Gerber, Yannick N.; Privat, Alain; Perrin, Florence E.

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder typified by a massive loss of motor neurons with few therapeutic options. The exact cause of neuronal degeneration is unknown but it is now admitted that ALS is a multifactorial disease with several mechanisms involved including glutamate excitotoxicity. More specifically, N-methyl-D-aspartate (NMDA)-mediated cell death and impairment of the glutamate-transport has been suggested to play a key role in ALS pathophysiology. Thus, evaluating NMDAR antagonists is of high therapeutic interest. Gacyclidine, also named GK11, is a high affinity non-competitive NMDAR antagonist that may protect against motor neuron death in an ALS context. Moreover, GK11 presents a low intrinsic neurotoxicity and has already been used in two clinical trials for CNS lesions. In the present study, we investigated the influence of chronic administration of two doses of GK11 (0.1 and 1 mg/kg) on the survival and the functional motor activity of hSOD1G93A mice, an animal model of ALS. Treatment started at early symptomatic age (60 days) and was applied bi-weekly until the end stage of the disease. We first confirmed that functional alteration of locomotor activity was evident in the hSOD1G93A transgenic female mice by 60 days of age. A low dose of GK11 improved the survival of the mice by 4.3% and partially preserved body weight. Improved life span was associated with a delay in locomotor function impairment. Conversely, the high dose treatment worsened motor functions. These findings suggest that chronic administration of GK11 beginning at early symptomatic stage may be beneficial for patients with ALS. PMID:24409117

  7. Terminal latency abnormality in amyotrophic lateral sclerosis without split hand syndrome.

    PubMed

    Park, Donghwi; Park, Jin-Sung

    2017-02-10

    Amyotrophic lateral sclerosis (ALS) has a peculiar involvement pattern; clinically it is known as split hand syndrome and electrophysiologically shows abnormalities in the abductor pollicis brevis (APB)/abductor digiti minimi (ADM) ratio. The aim of this study was to find a significant electrophysiological parameter in upper limb onset ALS patients with normal APB/ADM ratio when compared to cervical spondylotic amyotrophy (CSA) and healthy controls. We retrospectively reviewed the electrophysiological results of 47 upper limb onset ALS and 42 CSA cases; 20 healthy individuals were included as controls. We included ALS and CSA patients with normal ADM/APB ratio (≥0.6, and ≤1.7), and the parameters of electrophysiological study were compared. The electrophysiological parameters of statistical significance among ALS, CSA and normal controls were: amplitude of median and ulnar nerves, the terminal latency of median nerve, F-wave latency of median and ulnar nerves, terminal latency ratio of ulnar/median nerves, and F-wave latency ratio of ulnar/median nerves (p < 0.05). Among these parameters, the terminal latency ratio of ulnar/median nerve and terminal latency of median nerve in ALS were significantly different with both of CSA and normal control (p < 0.006). The abnormality in the terminal latency of the median nerve can be partly explained by the distal motor axonal dysfunction due to sodium and potassium channel abnormalities. The hypothesis of distal axonopathy is known to play an important role in the pathogenesis of ALS causing a significant prolongation of the terminal latency in the median nerve and the ulnar/median nerve ratio.

  8. Patient-ventilator asynchrony, leaks and sleep in patients with amyotrophic lateral sclerosis.

    PubMed

    Vrijsen, Bart; Testelmans, Dries; Belge, Catharina; Vanpee, Goele; Van Damme, Philip; Buyse, Bertien

    2016-01-01

    Sleeping with non-invasive ventilation (NIV) in amyotrophic lateral sclerosis appears to be accompanied by a high patient-ventilator asynchrony (PVA) index. This prospective observational cohort study quantifies PVA and leaks, and searches for effects of these events on sleep after polysomnographic NIV titration. Full-video polysomnography, with incorporation of transcutaneous carbon dioxide and ventilator software, was used to analyse sleep epoch-by-epoch and respiratory events and PVA breath-by-breath in 35 patients (17 non-bulbar). After diagnostic polysomnography, NIV was titrated during three consecutive nights. Sleep, PVA and leaks were evaluated at discharge and after one month. Results showed that non-bulbar patients improved in sleep architecture and oxygen and carbon dioxide levels while bulbar patients only improved oxygen saturation. PVA remained present at discharge (non-bulbar 54 (21-101) and bulbar 31 (9-39)/h sleep) and one month (non-bulbar 31 (9-39) and bulbar 32 (17-55)/h sleep), with ineffective effort as most prominent asynchrony. Leaks also persisted after titration (non-bulbar 16.6 (3.1-44.6) and bulbar 5.1 (0.0-19.5)% of total sleep time (TST)) and one month (non-bulbar 7.7 (1.4-29.3) and bulbar 12.7 (0.0-35.2)% TST). PVA and leaks have none to minor effect on sleep architecture. In conclusion, although PVA and leaks remain present after meticulous NIV titration, these events seem not to interfere with sleep.

  9. Elucidation of Relevant Neuroinflammation Mechanisms Using Gene Expression Profiling in Patients with Amyotrophic Lateral Sclerosis

    PubMed Central

    Choi, Young-Chul; Ha, Yoon; Kim, Hyongbum; Kim, Do-Young; Kim, Myung-Sun; Yu, Ji Hea; Seo, Jung Hwa; Kim, MinGi; Cho, Sung-Rae; Kang, Seong-Woong

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by damage of motor neurons. Recent reports indicate that inflammatory responses occurring within the central nervous system contribute to the pathogenesis of ALS. We aimed to investigate disease-specific gene expression associated with neuroinflammation by conducting transcriptome analysis on fibroblasts from three patients with sporadic ALS and three normal controls. Several pathways were found to be upregulated in patients with ALS, among which the toll-like receptor (TLR) and NOD-like receptor (NLR) signaling pathways are related to the immune response. Genes—toll-interacting protein (TOLLIP), mitogen-activated protein kinase 9 (MAPK9), interleukin-1β (IL-1β), interleukin-8 (IL-8), and chemokine (C-X-C motif) ligand 1 (CXCL1)—related to these two pathways were validated using western blotting. This study validated the genes that are associated with TLR and NLR signaling pathways from different types of patient-derived cells. Not only fibroblasts but also induced pluripotent stem cells (iPSCs) and neural rosettes from the same origins showed similar expression patterns. Furthermore, expression of TOLLIP, a regulator of TLR signaling pathway, decreased with cellular aging as judged by changes in its expression through multiple passages. TOLLIP expression was downregulated in ALS cells under conditions of inflammation induced by lipopolysaccharide. Our data suggest that the TLR and NLR signaling pathways are involved in pathological innate immunity and neuroinflammation associated with ALS and that TOLLIP, MAPK9, IL-1β, IL-8, and CXCL1 play a role in ALS-specific immune responses. Moreover, changes of TOLLIP expression might be associated with progression of ALS. PMID:27812125

  10. Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis

    PubMed Central

    Casas, Caty; Herrando-Grabulosa, Mireia; Manzano, Raquel; Mancuso, Renzo; Osta, Rosario; Navarro, Xavier

    2013-01-01

    Sporadic and familiar amyotrophic lateral sclerosis (ALS) cases presented lower cholinergic activity than in healthy individuals in their still preserved spinal motoneurons (MNs) suggesting that cholinergic reduction might occur before MN death. To unravel how and when cholinergic function is compromised, we have analyzed the spatiotemporal expression of choline acetyltransferase (ChAT) from early presymptomatic stages of the SOD1G93A ALS mouse model by confocal immunohistochemistry. The analysis showed an early reduction in ChAT content in soma and presynaptic boutons apposed onto MNs (to 76%) as well as in cholinergic interneurons in the lumbar spinal cord of the 30-day-old SOD1G93A mice. Cholinergic synaptic stripping occurred simultaneously to the presence of abundant surrounding major histocompatibility complex II (MHC-II)-positive microglia and the accumulation of nuclear Tdp-43 and the appearance of mild oxidative stress within MNs. Besides, there was a loss of neuronal MHC-I expression, which is necessary for balanced synaptic stripping after axotomy. These events occurred before the selective raise of markers of denervation such as ATF3. By the same time, alterations in postsynaptic cholinergic-related structures were also revealed with a loss of the presence of sigma-1 receptor, a Ca2+ buffering chaperone in the postsynaptic cisternae. By 2 months of age, ChAT seemed to accumulate in the soma of MNs, and thus efferences toward Renshaw interneurons were drastically diminished. In conclusion, cholinergic dysfunction in the local circuitry of the spinal cord may be one of the earliest events in ALS etiopathogenesis. PMID:23531559

  11. Early Pathogenesis in the Adult-Onset Neurodegenerative Disease Amyotrophic Lateral Sclerosis

    PubMed Central

    van Zundert, Brigitte; Izaurieta, Pamela; Fritz, Elsa; Alvarez, Francisco J.

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by dysfunction and degeneration of motor neurons starting in adulthood. Most of our knowledge about the pathophysiological mechanisms of ALS comes from transgenic mice models that emulate a subgroup of familial ALS cases (FALS), with mutations in the gene encoding superoxide dismutase (SOD1). In the more than 15 years since these mice were generated, a large number of abnormal cellular mechanisms underlying motor neuron degeneration have been identified, but to date this effort has led to few improvements in therapy, and no cure. Here, we consider that this surfeit of mechanisms is best interpreted by current insights that suggest a very early initiation of pathology in motor neurons, followed by a diversity of secondary cascades and compensatory mechanisms that mask symptoms for decades, until trauma and/or aging overloads their protective function. This view thus posits that adultonset ALS is the consequence of processes initiated during early development. In fact, motor neurons in neonatal mutant SOD mice display important alterations in their intrinsic electrical properties, synaptic inputs and morphology that are accompanied by subtle behavioral abnormalities. We consider evidence that human mutant SOD1 protein in neonatal hSOD1G93A mice instigates motor neuron degeneration by increasing persistent sodium currents and excitability, in turn altering synaptic circuits that control excessive motor neuron firing and leads to excitotoxicity. We also discuss how therapies that are aimed at suppressing abnormal neuronal activity might effectively mitigate or prevent the onset of irreversible neuronal damage in adulthood. PMID:22740507

  12. Is Innate Immunity and Inflammasomes Involved in Pathogenesis of Amyotrophic Lateral Sclerosis (ALS)?

    PubMed

    Volpe, Caroline M O; Nogueira-Machado, Jose A

    2015-01-01

    Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's disease is an axonopathy with adultonset, progressive and irreversible degeneration of upper and lower motor neurons. Around 90% of ALS is considered as sporadic ALS (sALS) without apparent genetic cause while in the familial type of ALS (fALS) at least one affected blood relative needs to be identified. Both sALS and fALS show similar progression and pathological profile. Biochemical and immunological roles have been reported for both types of ALS. It has been suggested that mutation in SOD1 gene would be responsible for the oxidative stress and neurotoxicity. Besides, oxidative stress, protein aggregation, altered cholinergic synapse, neuro-inflammation and production of pro-inflammatory cytokines have also been reported. Thus, the focus of the present review was on biochemical and immunological biomarkers and pathogenic mechanism. Regulatory T cells, pro-inflammatory cytokines and activation of pro-inflammatory signaling pathway are discussed. The activation of NRL inflammasomes in ALS and the involvement of IL-18, IL-1β and caspases-1 are also suggested. The presence and importance of HMGB-1 (DAMP) and activation of Tolllike receptors and/or RAGE also are envisaged. The patents US20140212508, WO2014145776, WO2014145118, US20140255371, US20140194427, US20140243400, WO2014128254, WO2014076702, WO2014071449, WO2014043696, WO2014001742, and WO2013082299 are summarized. This review intends to evaluate the biochemical and immunological responses and the involvement of inflammasomes in the pathogenesis of ALS. In the present review, we suggest hypothetical model for ALS pathogenesis and we discuss some patents that suggest new treatment and/or therapeutic targets. Due to a large number of patents covering therapy and control of neurodegenerative diseases, our focus was restricted only to discuss the latest registered patents in 2014.

  13. SQSTM1 Mutations in French Patients With Frontotemporal Dementia or Frontotemporal Dementia With Amyotrophic Lateral Sclerosis

    PubMed Central

    Le Ber, Isabelle; Camuzat, Agnès; Guerreiro, Rita; Bouya-Ahmed, Kawtar; Bras, Jose; Nicolas, Gael; Gabelle, Audrey; Didic, Mira; De Septenville, Anne; Millecamps, Stéphanie; Lenglet, Timothée; Latouche, Morwena; Kabashi, Edor; Campion, Dominique; Hannequin, Didier; Hardy, John; Brice, Alexis

    2014-01-01

    IMPORTANCE Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD. OBJECTIVE To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients. DESIGN A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes. SETTING Primary care or referral center. PARTICIPANTS An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS. MAIN OUTCOMES AND MEASURES Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes. RESULTS We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations. CONCLUSIONS AND RELEVANCE Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD. PMID:24042580

  14. Analysis of the neurofilament heavy subunit (NFH) gene in familial amyotrophic lateral sclerosis

    SciTech Connect

    Rooke, K.; Rouleau, G.A.; Figlewicz, D.A.

    1994-09-01

    Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, degenerative disorder of the motor neurons in the cortex, brainstem and spinal cord. Approximately 10% of ALS cases are familial (FALS) and are inherited as an age-dependent autosomal dominant trait. Mutations in the Cu/Zn superoxide dismutase (SOD-1) gene on chromosome 21 have been found in a subset of cases. However, for the remaining FALS cases, the etiology is unknown. The abnormal accumulation of neurofilaments in the cell body and proximal axon of motor neurons is a characteristic pathological finding in ALS. Furthermore, aberrant neuronal swellings that closely resemble those found in ALS have been reported in transgenic mice overexpressing NFH. The C-terminal region of NFH contains a unique functional domain with multiple repeats of the amino acids (Lys-Ser-Pro) (KSP) and forms the side-arms which appear, at the level of electron microscopy, to cross-link neurofilaments. Recently, deletions in the DSP repeat domain have been identified in five ALS patients diagnosed as sporadic cases of the disease. Based on these findings, we propose to analyze all 4 exons of the NFH gene for variation in FALS. DNA from 110 FALS cases has been amplified by the polymerase chain reaction (PCR) and analyzed by single strand conformation polymorphism (SSCP) analysis. Exon 2, exon 3 and the KSP repeat domain (part of exon 4) appear normal in all our FALS individuals under several different SSCP conditions. The analysis of exon 1 and the remainder of exon 4 has yet to be completed.

  15. Different Occupations Associated with Amyotrophic Lateral Sclerosis: Is Diesel Exhaust the Link?

    PubMed Central

    Pamphlett, Roger; Rikard-Bell, Anna

    2013-01-01

    The cause of sporadic amyotrophic lateral sclerosis (SALS) remains unknown. We attempted to find out if occupational exposure to toxicants plays a part in the pathogenesis of this disease. In an Australia-wide case-control study we compared the lifetime occupations of 611 SALS and 775 control individuals. Occupations were coded using country-specific as well as international classifications. The risk of SALS for each occupation was calculated with odds ratios using logistic regression. In addition, the literature was searched for possible toxicant links between our findings and previously-reported occupational associations with SALS. Male occupations in our study that required lower skills and tasks tended to have increased risks of SALS, and conversely, those occupations that required higher skills and tasks had decreased risks of SALS. Of all the occupations, only truck drivers, where exposure to diesel exhaust is common, maintained an increased risk of SALS throughout all occupational groups. Another large case-control study has also found truck drivers to be at risk of SALS, and almost two-thirds of occupations, as well as military duties, that have previously been associated with SALS have potential exposure to diesel exhaust. In conclusion, two of the largest case-control studies of SALS have now found that truck drivers have an increased risk of SALS. Since exposure to diesel exhaust is common in truck drivers, as well as in other occupations that have been linked to SALS, exposure to this toxicant may underlie some of the occupations that are associated with SALS. PMID:24244728

  16. Exendin-4 Ameliorates Motor Neuron Degeneration in Cellular and Animal Models of Amyotrophic Lateral Sclerosis

    PubMed Central

    Li, Yazhou; Chigurupati, Srinivasulu; Holloway, Harold W.; Mughal, Mohamed; Tweedie, David; Bruestle, Daniel A.; Mattson, Mark P.; Wang, Yun; Harvey, Brandon K.; Ray, Balmiki; Lahiri, Debomoy K.; Greig, Nigel H.

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by a progressive loss of lower motor neurons in the spinal cord. The incretin hormone, glucagon-like peptide-1 (GLP-1), facilitates insulin signaling, and the long acting GLP-1 receptor agonist exendin-4 (Ex-4) is currently used as an anti-diabetic drug. GLP-1 receptors are widely expressed in the brain and spinal cord, and our prior studies have shown that Ex-4 is neuroprotective in several neurodegenerative disease rodent models, including stroke, Parkinson's disease and Alzheimer's disease. Here we hypothesized that Ex-4 may provide neuroprotective activity in ALS, and hence characterized Ex-4 actions in both cell culture (NSC-19 neuroblastoma cells) and in vivo (SOD1 G93A mutant mice) models of ALS. Ex-4 proved to be neurotrophic in NSC-19 cells, elevating choline acetyltransferase (ChAT) activity, as well as neuroprotective, protecting cells from hydrogen peroxide-induced oxidative stress and staurosporine-induced apoptosis. Additionally, in both wild-type SOD1 and mutant SOD1 (G37R) stably transfected NSC-19 cell lines, Ex-4 protected against trophic factor withdrawal-induced toxicity. To assess in vivo translation, SOD1 mutant mice were administered vehicle or Ex-4 at 6-weeks of age onwards to end-stage disease via subcutaneous osmotic pump to provide steady-state infusion. ALS mice treated with Ex-4 showed improved glucose tolerance and normalization of behavior, as assessed by running wheel, compared to control ALS mice. Furthermore, Ex-4 treatment attenuated neuronal cell death in the lumbar spinal cord; immunohistochemical analysis demonstrated the rescue of neuronal markers, such as ChAT, associated with motor neurons. Together, our results suggest that GLP-1 receptor agonists warrant further evaluation to assess whether their neuroprotective potential is of therapeutic relevance in ALS. PMID:22384126

  17. Ophthalmic Manifestations of Amyotrophic Lateral Sclerosis (An American Ophthalmological Society Thesis)

    PubMed Central

    Volpe, Nicholas J.; Simonett, Joseph; Fawzi, Amani A.; Siddique, Teepu

    2015-01-01

    Purpose: To determine if clinical and histopathologic findings were present in the eyes of patients with amyotrophic lateral sclerosis (ALS) and explore correlations to an animal model of ALS. Methods: Two patients with ALS were studied histopathologically as well as the retinas of ALS/dementia transgenic mice with dysfunctional ubiquilin2, UBQLN2P497H. Clinical study 1, an observational, cross-sectional study, was performed using optical coherence tomography (OCT) to obtain and compare mean total macular thickness and average and quadrant specific peripapillary retinal nerve fiber layer (pRNFL) scans from 16 patients with ALS to controls. Correlation analysis was performed to evaluate the association with disease duration. Clinical study 2 consisted of measuring visual acuity, color vision, contrast sensitivity, and quality of life in 12 patients. Results: Histopathologic studies demonstrated intraretinal inclusions in one patient and loss of ganglion cell axons in another. Mouse eyes had intraretinal inclusions in the inner plexiform layers. Total macular volume was thinner in patients compared to controls (P<.05), and 37.5% of patients with ALS had an average pRNFL below the 1st percentile. Total macular and pRNFL thickness correlated inversely with disease duration. Conclusions: Histopathologic analysis of ALS eyes and mice with the UBQLN2P497H mutation, as well as OCT measurements, supports involvement of the anterior visual pathway. We identified pathologies, including intraretinal deposits and axonal loss. pRNFL and total macular thinning found on OCT correlated with disease duration. A pattern of vision loss specific for ALS was not identified. This study confirms ocular involvement in patients and transgenic animals with ALS/dementia. PMID:26877563

  18. Military Service and Amyotrophic Lateral Sclerosis in a Population-based Cohort

    PubMed Central

    Cudkowicz, Merit E.; Johnson, Norman

    2015-01-01

    Background: Military service has been suggested to be associated with an increased risk of amyotrophic lateral sclerosis (ALS), but only one prospective study—of a volunteer cohort—has examined this question. Methods: We prospectively assessed the relation between service in the military and ALS mortality among participants in the National Longitudinal Mortality Study, a population-representative cohort of U.S. men and women surveyed from 1973 through 2002. Participant follow-up was conducted from 1979 through 2002 for ALS mortality. There were 696,743 men and 392,571 women who were 25 years old or more with military service data. In this group, there were 375 male ALS deaths and 96 female ALS deaths. Adjusted hazard ratios (HRs) were calculated using Cox proportional hazards. Results: Men who served in the military had an increased adjusted ALS death rate [HR: 1.23; 95% confidence interval (CI): 0.98, 1.53] compared with those who did not serve. An increase in ALS mortality was found among those who served during World War II (HR: 1.47; 95% CI: 1.13, 1.91) but not during other time periods. This pattern of results was similar for women, but with larger confidence intervals (HR for military service: 1.26; 95% CI: 0.29, 5.59; HR for service during World War II: 2.03; 95% CI: 0.45, 9.05). Conclusions: Military personnel have an increased risk of ALS, which may be specific to certain service periods although there was no data on actual deployment. Because of the longer follow-up time for World War II veterans, we cannot rule out that increased risk for those who served during other periods would be seen with further follow-up. PMID:26414854

  19. Genetic linkage analysis of familial amyotrophic lateral sclerosis using human chromosome 21 microsatellite DNA markers

    SciTech Connect

    Rosen, D.R.; Sapp, P.; O`Regan, J.; McKenna-Yasek, D.; Schlumpf, K.S.; Haines, J.L.; Gusella, J.F.; Horvitz, H.R.; Brown, R.H. Jr.

    1994-05-15

    Amyotrophic lateral sclerosis (ALS; Lou Gehrig`s Disease) is a lethal neurodegenerative disease of upper and lower motorneurons in the brain and spinal cord. We previously reported linkage of a gene for familial ALS (FALS) to human chromosome 21 using 4 restriction fragment length polymorphism DNA markers and identified disease-associated mutations in the superoxide dismutase (SOD)-1 gene in some ALS families. We report here the genetic linkage data that led us to examine the SOD-1 gene for mutations. We also report a new microsatellite DNA marker for D21S63, derived from the cosmid PW517. Ten microsatellite DNA markers, including the new marker D21S63, were used to reinvestigate linkage of FALS to chromosome 21. Genetic linkage analysis performed with 13 ALS familes for these 10 DNA markers confirmed the presence of a FALS gene on chromosome 21. The highest total 2-point LOD score for all families was 4.33, obtained at a distance of 10 cM from the marker D21S223. For 5 ALS families linked to chromosome 21, a peak 2-point LOD score of 5.94 was obtained at the DNA marker D21S223. A multipoint score of 6.50 was obtained with the markers D21S213, D21S223, D21S167, and FALS for 5 chromosome 21-linked ALS families. The haplotypes of these families for the 10 DNA markers reveal recombination events that further refined the location of the FALS gene to a segment of approximately 5 megabases (Mb) between D21S213 and D21S219. The only characterized gene within this segment was SOD-1, the structural gene for Cu, Zn SOD. 30 refs., 4 figs., 4 tabs.

  20. Neuroprotective Effect of Human Adipose Stem Cell-Derived Extract in Amyotrophic Lateral Sclerosis.

    PubMed

    Jeon, Gye Sun; Im, Wooseok; Shim, Yu-Mi; Lee, Mijung; Kim, Myung-Jin; Hong, Yoon-Ho; Seong, Seung-Yong; Kim, Manho; Sung, Jung-Joon

    2016-04-01

    Amyotrophic lateral sclerosis (ALS) is a devastating human neurodegenerative disease. The precise pathogenic mechanisms of the disease remain uncertain, and as of yet, there is no effective cure. Human adipose stem cells (hASC) can be easily obtained during operative procedures. hASC have a clinically feasible potential to treat neurodegenerative disorders, since cytosolic extract of hASC contain a number of essential neurotrophic factors. In this study, we investigated effects of hASC extract on the SOD1 G93A mouse model of ALS and in vitro test. Administration of hASC extract improved motor function and prolonged the time until symptom onset, rotarod failure, and death in ALS mice. In the hASC extracts group, choline acetyltransferase immunostaining in the ventral horn of the lumbar spinal cord showed a large number of motor neurons, suggesting normal morphology. The neuroprotective effect of hASC extract in ALS mice was also suggested by western blot analysis of spinal cord extract from ALS mice and in vitro test. hASC extract treatment significantly increased expression of p-Akt, p-CREB, and PGC-1α in SOD1 G93A mouse model and in vitro test. Our results indicated that hASC extract reduced apoptotic cell death and recovered mutant SOD1-induced mitochondrial dysfunction. Moreover, hASC extract reduced mitochondrial membrane potential. In conclusion, we have demonstrated, for the first time, that hASC extract exert a potential therapeutic action in the SOD1 G93A mouse model of ALS and in vitro test. These findings suggest that hASC hold promise as a novel therapeutic strategy for treating ALS.

  1. Amyotrophic lateral sclerosis and parkinsonism in Papua, Indonesia: 2001–2012 survey results

    PubMed Central

    Okumiya, Kiyohito; Wada, Taizo; Fujisawa, Michiko; Ishine, Masayuki; Garcia del Saz, Eva; Hirata, Yutaka; Kuzuhara, Shigeki; Kokubo, Yasumasa; Seguchi, Harumichi; Sakamoto, Ryota; Manuaba, Indrajaya; Watofa, Paulina; Rantetampang, Andreas L; Matsubayashi, Kozo

    2014-01-01

    Objective Only one previous follow-up study of amyotrophic lateral sclerosis (ALS) and parkinsonism in Papua, Indonesia has been carried out since a survey undertaken in 1962–1981 by Gajdusek and colleagues. Therefore, to clarify the clinical epidemiology of ALS and parkinsonism in the southern coastal region of Papua, the clinical characteristics and prevalence of the diseases in this region were examined and assessed. Methods Cases of ALS and parkinsonism were clinically examined during a 2001–2012 survey in Bade and other villages along the Ia, Edera, Dumut and Obaa rivers in Papua, Indonesia. Possible, probable and definite ALS was diagnosed clinically by certified neurologists based on El Escorial criteria. The criteria for a diagnosis of parkinsonism were the presence of at least two of the four following signs: tremor, rigidity, bradykinesia and postural impairment with a progressive course. Results During the survey, 46 cases of ALS and/or parkinsonism were diagnosed within a population range of 7000 (2001–2002) to 13 900 (2007–2012). The 46 cases consisted of 17 probable-definite cases of ALS, including three with cognitive impairment (CI), 13 cases of overlapping possible, probable or definite ALS and parkinsonism, including five with CI, and 16 cases of parkinsonism, including one with CI. The crude point prevalence rate of pure ALS was estimated to be at least 73 (95% CI 0 to 156) to 133 (27 to 240)/100 000 people and that of overlapping ALS and parkinsonism at least 53 (0 to 126) to 98 (2 to 193)/100 000 in 2007, or 2010 in some regions. Conclusions While the prevalence of ALS in Papua has decreased over the past ∼30–35 years, it remains higher than the global average. There was a high prevalence of overlapping ALS, parkinsonism and CI, which has also been previously reported in Guam and Kii. PMID:24740977

  2. Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials

    PubMed Central

    Gordon, Paul H.

    2013-01-01

    Amyotrophic lateral sclerosis (ALS), first described by Jean-Martin Charcot in the 1870s, is an age-related disorder that leads to degeneration of motor neurons. The disease begins focally in the central nervous system and then spreads relentlessly. The clinical diagnosis, defined by progressive signs and symptoms of upper and lower motor neuron dysfunction, is confirmed by electromyography. Additional testing excludes other conditions. The disease is heterogeneous, but most patients die of respiratory muscle weakness less than 3 years from symptom-onset. Like other age-related neurodegenerative diseases, ALS has genetic and environmental triggers. Of the five to 10% of cases that are inherited, mutations have been discovered for a high proportion. In addition to genetic factors, age, tobacco use, and athleticism may contribute to sporadic ALS, but important etiologies are unidentified for most patients. Complex pathophysiological processes, including mitochondrial dysfunction, aggregation of misfolded protein, oxidative stress, excitotoxicity, inflammation and apoptosis, involve both motor neurons and surrounding glial cells. There is clinical and pathological overlap with other neurodegenerative diseases, particularly frontotemporal dementia. The mechanisms leading to disease propagation in the brain are a current focus of research. To date, one medication, riluzole, licensed in 1996, has been proved to prolong survival in ALS. Numerous clinical trials have so far been unable to identify another neuroprotective agent. Researchers now aim to slow disease progression by targeting known pathophysiological pathways or genetic defects. Current approaches are directed at muscle proteins such as Nogo, energetic balance, cell replacement, and abnormal gene products resulting from mutations. Until better understanding of the causes and mechanisms underlying progression lead to more robust neuroprotective agents, symptomatic therapies can extend life and improve quality of

  3. Aspirin Use Associated With Amyotrophic Lateral Sclerosis: a Total Population-Based Case-Control Study

    PubMed Central

    Tsai, Ching-Piao; Lin, Feng-Cheng; Lee, Johnny Kuang-Wu; Lee, Charles Tzu-Chi

    2015-01-01

    Background The association of aspirin use and nonsteroid anti-inflammatory drug (NSAID) use with amyotrophic lateral sclerosis (ALS) risk is unclear. This study determined whether use of any individual compound is associated with ALS risk by conducting a total population-based case-control study in Taiwan. Methods A total of 729 patients with newly diagnosed ALS who had a severely disabling disease certificate between January 1, 2002, and December 1, 2008, comprised the case group. These cases were compared with 7290 sex-, age-, residence-, and insurance premium-matched controls. Drug use by each Anatomical Therapeutic Chemical code was analyzed using conditional logistic regression models. False discovery rate (FDR)-adjusted P values were reported in order to avoid inflating false positives. Results Of the 1336 compounds, only the 266 with use cases exceeding 30 in our database were included in the screening analysis. Without controlling for steroid use, the analysis failed to reveal any compound that was inversely associated with ALS risk according to FDR criteria. After controlling for steroid use, we found use of the following compounds to be associated with ALS risk: aspirin, diphenhydramine (one of the antihistamines), and mefenamic acid (one of the NSAIDs). A multivariate analysis revealed that aspirin was independently inversely associated with ALS risk after controlling for diphenhydramine, mefenamic acid, and steroid use. The inverse association between aspirin and ALS was present predominately in patients older than 55 years. Conclusions The results of this study suggested that aspirin use might reduce the risk of ALS, and the benefit might be more prominent for older people. PMID:25721071

  4. Pattern Differences of Small Hand Muscle Atrophy in Amyotrophic Lateral Sclerosis and Mimic Disorders

    PubMed Central

    Fang, Jia; Liu, Ming-Sheng; Guan, Yu-Zhou; Du, Hua; Li, Ben-Hong; Cui, Bo; Ding, Qing-Yun; Cui, Li-Ying

    2016-01-01

    Background: Amyotrophic lateral sclerosis (ALS) and some mimic disorders, such as distal-type cervical spondylotic amyotrophy (CSA), Hirayama disease (HD), and spinobulbar muscular atrophy (SBMA) may present with intrinsic hand muscle atrophy. This study aimed to investigate different patterns of small hand muscle involvement in ALS and some mimic disorders. Methods: We compared the abductor digiti minimi/abductor pollicis brevis (ADM/APB) compound muscle action potential (CMAP) ratios between 200 ALS patients, 95 patients with distal-type CSA, 88 HD patients, 43 SBMA patients, and 150 normal controls. Results: The ADM/APB CMAP amplitude ratio was significantly higher in the ALS patients (P < 0.001) than that in the normal controls. The ADM/APB CMAP amplitude ratio was significantly reduced in the patients with distal-type CSA (P < 0.001) and the HD patients (P < 0.001) compared with that in the normal controls. The patients with distal-type CSA had significantly lower APB CMAP amplitude than the HD patients (P = 0.004). The ADM/APB CMAP amplitude ratio was significantly lower in the HD patients (P < 0.001) than that in the patients with distal-type CSA. The ADM/APB CMAP amplitude ratio of the SBMA patients was similar to that of the normal controls (P = 0.862). An absent APB CMAP and an abnormally high ADM/APB CMAP amplitude ratio (≥4.5) were observed exclusively in the ALS patients. Conclusions: The different patterns of small hand muscle atrophy between the ALS patients and the patients with mimic disorders presumably reflect distinct pathophysiological mechanisms underlying different disorders, and may aid in distinguishing between ALS and mimic disorders. PMID:26996473

  5. Neurofilaments as Biomarkers for Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis

    PubMed Central

    Henderson, Robert David; David, Michael; McCombe, Pamela Ann

    2016-01-01

    Background To allow early diagnosis and monitoring of disease progression, there is a need for biomarkers in amyotrophic lateral sclerosis (ALS). Neurofilaments (NF) are emerging protein biomarkers in other neurological diseases, and are of possible use in ALS. Objective The aim of this study is to evaluate the utility of NF levels as blood or cerebrospinal fluid (CSF) biomarker in patients with ALS. Methods A systematic search of Pubmed, Embase and Scopus was performed. Methodological quality assessment was applied to refine the final search results. Meta-analysis of the data was performed. Results Level of NF heavy chain and light chains were significantly elevated in the CSF of ALS patients compared to healthy controls/controls without parenchymal central nervous system (CNS) involvement and ALS mimic disease patients. NF light chain level in CSF was higher in ALS patients than in neurological patients with CNS involvement (SMD = 1.352, P = 0.01). NF light chain concentration in blood was higher in ALS patients than healthy controls/controls without CNS involvement (SMD = 1.448, P<0.0001). NF heavy chain levels in CSF were negatively correlated disease duration and ALSFRS-R ((r = -0.447, P<0.0001; r = -0.486, P<0.0001). NF light chain levels in CSF were negatively correlated with disease duration (r = -0.273, P = 0.011). Conclusion NF heavy and light chain levels have potential use as a marker of neural degeneration in ALS, but are not specific for the disease, and are more likely to be used as measures of disease progression. PMID:27732645

  6. Functional Connectivity Changes in Resting-State EEG as Potential Biomarker for Amyotrophic Lateral Sclerosis

    PubMed Central

    Iyer, Parameswaran Mahadeva; Egan, Catriona; Pinto-Grau, Marta; Burke, Tom; Elamin, Marwa; Nasseroleslami, Bahman; Pender, Niall; Lalor, Edmund C.; Hardiman, Orla

    2015-01-01

    Background Amyotrophic Lateral Sclerosis (ALS) is heterogeneous and overlaps with frontotemporal dementia. Spectral EEG can predict damage in structural and functional networks in frontotemporal dementia but has never been applied to ALS. Methods 18 incident ALS patients with normal cognition and 17 age matched controls underwent 128 channel EEG and neuropsychology assessment. The EEG data was analyzed using FieldTrip software in MATLAB to calculate simple connectivity measures and scalp network measures. sLORETA was used in nodal analysis for source localization and same methods were applied as above to calculate nodal network measures. Graph theory measures were used to assess network integrity. Results Cross spectral density in alpha band was higher in patients. In ALS patients, increased degree values of the network nodes was noted in the central and frontal regions in the theta band across seven of the different connectivity maps (p<0.0005). Among patients, clustering coefficient in alpha and gamma bands was increased in all regions of the scalp and connectivity were significantly increased (p=0.02). Nodal network showed increased assortativity in alpha band in the patients group. The Clustering Coefficient in Partial Directed Connectivity (PDC) showed significantly higher values for patients in alpha, beta, gamma, theta and delta frequencies (p=0.05). Discussion There is increased connectivity in the fronto-central regions of the scalp and areas corresponding to Salience and Default Mode network in ALS, suggesting a pathologic disruption of neuronal networking in early disease states. Spectral EEG has potential utility as a biomarker in ALS. PMID:26091258

  7. Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials.

    PubMed

    Gordon, Paul H

    2013-10-01

    Amyotrophic lateral sclerosis (ALS), first described by Jean-Martin Charcot in the 1870s, is an age-related disorder that leads to degeneration of motor neurons. The disease begins focally in the central nervous system and then spreads relentlessly. The clinical diagnosis, defined by progressive signs and symptoms of upper and lower motor neuron dysfunction, is confirmed by electromyography. Additional testing excludes other conditions. The disease is heterogeneous, but most patients die of respiratory muscle weakness less than 3 years from symptom-onset. Like other age-related neurodegenerative diseases, ALS has genetic and environmental triggers. Of the five to 10% of cases that are inherited, mutations have been discovered for a high proportion. In addition to genetic factors, age, tobacco use, and athleticism may contribute to sporadic ALS, but important etiologies are unidentified for most patients. Complex pathophysiological processes, including mitochondrial dysfunction, aggregation of misfolded protein, oxidative stress, excitotoxicity, inflammation and apoptosis, involve both motor neurons and surrounding glial cells. There is clinical and pathological overlap with other neurodegenerative diseases, particularly frontotemporal dementia. The mechanisms leading to disease propagation in the brain are a current focus of research. To date, one medication, riluzole, licensed in 1996, has been proved to prolong survival in ALS. Numerous clinical trials have so far been unable to identify another neuroprotective agent. Researchers now aim to slow disease progression by targeting known pathophysiological pathways or genetic defects. Current approaches are directed at muscle proteins such as Nogo, energetic balance, cell replacement, and abnormal gene products resulting from mutations. Until better understanding of the causes and mechanisms underlying progression lead to more robust neuroprotective agents, symptomatic therapies can extend life and improve quality of

  8. Riluzole 5 mg/mL oral suspension: for optimized drug delivery in amyotrophic lateral sclerosis

    PubMed Central

    Dyer, Ann Margaret; Smith, Alan

    2017-01-01

    The aim of the present work is to extensively evaluate the pharmaceutical attributes of currently available riluzole presentations. The article describes the limitations and risks associated with the administration of crushed tablets, including the potential for inaccurate dosing and reduced rate of absorption when riluzole is administered with high-fat foods, and the advantages that a recently approved innovative oral liquid form of riluzole confers on amyotrophic lateral sclerosis (ALS) patients. The article further evaluates the patented and innovative controlled flocculation technology used in the pseudoplastic suspension formulation to reduce the oral anesthesia seen with crushed tablets, resulting in optimized drug delivery for riluzole. Riluzole is the only drug licensed for treating ALS, which is the most common form of motor neurone disease and a highly devastating neurodegenerative condition. The licensed indication is to extend life or the time to mechanical ventilation. Until recently, riluzole was only available as an oral tablet dosage form in the UK; however, an innovative oral liquid form, Teglutik® 5 mg/mL oral suspension, is now available. An oral liquid formulation provides an important therapeutic option for patients with ALS, >80% of who may become unable to swallow solid oral dosage forms due to disease-related dysphagia. Prior to the launch of riluzole oral suspension, the only way for many patients to continue to take riluzole as their disease progressed was through crushed tablets. A novel suspension formulation enables more accurate dosing and consistent ongoing administration of riluzole. There are clear and important advantages such as enhanced patient compliance compared with crushed tablets administered with food or via an enteral feeding tube and the potential for an improved therapeutic outcome and enhanced quality of life for ALS patients. PMID:28053507

  9. Dysphagia in Amyotrophic Lateral Sclerosis: Impact on Patient Behavior, Diet Adaptation, and Riluzole Management

    PubMed Central

    Onesti, Emanuela; Schettino, Ilenia; Gori, Maria Cristina; Frasca, Vittorio; Ceccanti, Marco; Cambieri, Chiara; Ruoppolo, Giovanni; Inghilleri, Maurizio

    2017-01-01

    This retrospective study aimed to investigate the clinical features associated with deteriorated swallow in amyotrophic lateral sclerosis (ALS) patients with spinal and bulbar onset, describe the modification of diet and liquid intake, and assess the impact of dysphagia on the use of riluzole. One hundred forty-five patients were observed periodically every 3–6 months. They underwent routinely fiberoptic endoscopic evaluation of swallowing (FEES) and spirometry; dysphagia severity was classified according to the Penetration Aspiration Scale and the Pooling score (P-score) integrated with other parameters such as sensation, collaboration, and age (P-SCA score). During a mean follow-up period of about 2 years, the percentage of ALS patients suffering from dysphagia increased to 85 (rising from 35 to 73% in patients with spinal onset and from 95 to 98% in those with bulbar onset). Also, 8% of patients with dysphagia by FEES did not perceive the disorder. The frequency of normal and semi-solid diets decreased over time, while that of pureed diets and percutaneous endoscopic gastrostomy (PEG) prescription increased. Forty-four percent of dysphagic patients refused thickeners or PEG. A significant difference was observed in the mortality rate between patients untreated with riluzole and patients treated with riluzole oral suspension (p < 0.05). Disease duration mainly impacted on the frequency of dysphagia in spinal onset patients, appearing very early in those with bulbar onset. Riluzole oral suspension would allow the safe administration in dysphagic ALS patients to avoid tablet crushing and consequent dispersion in food, common practices that are inconsistent with the safe and effective use of the drug. PMID:28377742

  10. Perception of Emotional Facial Expressions in Amyotrophic Lateral Sclerosis (ALS) at Behavioural and Brain Metabolic Level

    PubMed Central

    Aho-Özhan, Helena E. A.; Keller, Jürgen; Heimrath, Johanna; Uttner, Ingo; Kassubek, Jan; Birbaumer, Niels; Ludolph, Albert C.; Lulé, Dorothée

    2016-01-01

    Introduction Amyotrophic lateral sclerosis (ALS) primarily impairs motor abilities but also affects cognition and emotional processing. We hypothesise that subjective ratings of emotional stimuli depicting social interactions and facial expressions is changed in ALS. It was found that recognition of negative emotions and ability to mentalize other’s intentions is reduced. Methods Processing of emotions in faces was investigated. A behavioural test of Ekman faces expressing six basic emotions was presented to 30 ALS patients and 29 age-, gender and education matched healthy controls. Additionally, a subgroup of 15 ALS patients that were able to lie supine in the scanner and 14 matched healthy controls viewed the Ekman faces during functional magnetic resonance imaging (fMRI). Affective state and a number of daily social contacts were measured. Results ALS patients recognized disgust and fear less accurately than healthy controls. In fMRI, reduced brain activity was seen in areas involved in processing of negative emotions replicating our previous results. During processing of sad faces, increased brain activity was seen in areas associated with social emotions in right inferior frontal gyrus and reduced activity in hippocampus bilaterally. No differences in brain activity were seen for any of the other emotional expressions. Inferior frontal gyrus activity for sad faces was associated with increased amount of social contacts of ALS patients. Conclusion ALS patients showed decreased brain and behavioural responses in processing of disgust and fear and an altered brain response pattern for sadness. The negative consequences of neurodegenerative processes in the course of ALS might be counteracted by positive emotional activity and positive social interactions. PMID:27741285

  11. The Potential for Transition Metal-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis

    PubMed Central

    Lovejoy, David B.; Guillemin, Gilles J.

    2014-01-01

    Modulations of the potentially toxic transition metals iron (Fe) and copper (Cu) are implicated in the neurodegenerative process in a variety of human disease states including amyotrophic lateral sclerosis (ALS). However, the precise role played by these metals is still very much unclear, despite considerable clinical and experimental data suggestive of a role for these elements in the neurodegenerative process. The discovery of mutations in the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD-1) in ALS patients established the first known cause of ALS. Recent data suggest that various mutations in SOD-1 affect metal-binding of Cu and Zn, in turn promoting toxic protein aggregation. Copper homeostasis is also disturbed in ALS, and may be relevant to ALS pathogenesis. Another set of interesting observations in ALS patients involves the key nutrient Fe. In ALS patients, Fe loading can be inferred by studies showing increased expression of serum ferritin, an Fe-storage protein, with high serum ferritin levels correlating to poor prognosis. Magnetic resonance imaging of ALS patients shows a characteristic T2 shortening that is attributed to the presence of Fe in the motor cortex. In mutant SOD-1 mouse models, increased Fe is also detected in the spinal cord and treatment with Fe-chelating drugs lowers spinal cord Fe, preserves motor neurons, and extends lifespan. Inflammation may play a key causative role in Fe accumulation, but this is not yet conclusive. Excess transition metals may enhance induction of endoplasmic reticulum (ER) stress, a system that is already under strain in ALS. Taken together, the evidence suggests a role for transition metals in ALS progression and the potential use of metal-chelating drugs as a component of future ALS therapy. PMID:25100994

  12. Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model.

    PubMed

    Wu, Shaoping; Yi, Jianxun; Zhang, Yong-Guo; Zhou, Jingsong; Sun, Jun

    2015-04-01

    Emerging evidence has demonstrated that intestinal homeostasis and the microbiome play essential roles in neurological diseases, such as Parkinson's disease. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and muscle atrophy. Currently, there is no effective treatment. Most patients die within 3-5 years due to respiratory paralysis. Although the death of motor neurons is a hallmark of ALS, other organs may also contribute to the disease progression. We examined the gut of an ALS mouse model, G93A, which expresses mutant superoxide dismutase (SOD1(G93A)), and discovered a damaged tight junction structure and increased permeability with a significant reduction in the expression levels of tight junction protein ZO-1 and the adherens junction protein E-cadherin. Furthermore, our data demonstrated increased numbers of abnormal Paneth cells in the intestine of G93A mice. Paneth cells are specialized intestinal epithelial cells that can sense microbes and secrete antimicrobial peptides, thus playing key roles in host innate immune responses and shaping the gut microbiome. A decreased level of the antimicrobial peptides defensin 5 alpha was indeed found in the ALS intestine. These changes were associated with a shifted profile of the intestinal microbiome, including reduced levels of Butyrivibrio Fibrisolvens, Escherichia coli, and Fermicus, in G93A mice. The relative abundance of bacteria was shifted in G93A mice compared to wild-type mice. Principal coordinate analysis indicated a difference in fecal microbial communities between ALS and wild-type mice. Taken together, our study suggests a potential novel role of the intestinal epithelium and microbiome in the progression of ALS.