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1.
J Neurol Neurosurg Psychiatry ; 86(5): 574-9, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25063584

RESUMEN

BACKGROUND: Cognitive impairment, mainly characterised by executive dysfunction, occurs in about half of cases in amyotrophic lateral sclerosis (ALS). There is evidence that gender influences some clinical features of the disease, but its influence on the cognitive spectrum is unknown. Our objective was to investigate the impact of gender on cognitive profiles of patients with ALS. METHODS: A retrospective study based on an exhaustive neuropsychological battery was performed in a group of 165 (70 females, 95 males) sporadic, non-demented patients with ALS compared with 134 healthy control participants. This assessment primarily focused on executive, memory and language functions. RESULTS: 47 (29%) patients revealed impairment in executive function and 30 (18%) patients revealed cognitive non-executive impairment. Independent from mood tone and clinical variables, a significantly greater executive impairment was determined in female patients than in male patients and control participants. The relative risk for ALS females having impairment in executive function compared with male patients was 2.6 (95% CI 1.6 to 4.4; p=0.0003). ALS females scored lower in Phonemic Fluency, Trial Making, and Wisconsin Card Sorting test. CONCLUSIONS: Results highlight a significant vulnerability of ALS female patients to develop cognitive dysfunctions peculiar to the disease, independently of bulbar onset. The explicative hypotheses of the data are focused on two interpretative lines not mutually exclusive: the role of gonadal hormones and gender-related brain asymmetry pre-existing to the disease. These findings, never reported before in the literature, can have important implications for models of ALS pathogenesis and for future clinical trial designs.


Asunto(s)
Esclerosis Amiotrófica Lateral/psicología , Trastornos del Conocimiento/psicología , Función Ejecutiva , Caracteres Sexuales , Anciano , Esclerosis Amiotrófica Lateral/complicaciones , Estudios de Casos y Controles , Trastornos del Conocimiento/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estudios Retrospectivos
2.
Acta Neuropathol ; 126(1): 109-21, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23644820

RESUMEN

Spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disease caused by expansion of a polyglutamine (polyQ) tract in the androgen receptor (AR). SBMA is triggered by the interaction between polyQ-AR and its natural ligands, testosterone and dihydrotestosterone (DHT). SBMA is characterized by the loss of lower motor neurons and skeletal muscle fasciculations, weakness, and atrophy. To test the hypothesis that the interaction between polyQ-AR and androgens exerts cell-autonomous toxicity in skeletal muscle, we characterized the process of myogenesis and polyQ-AR expression in DHT-treated satellite cells obtained from SBMA patients and age-matched healthy control subjects. Treatment with androgens increased the size and number of myonuclei in myotubes from control subjects, but not from SBMA patients. Myotubes from SBMA patients had a reduced number of nuclei, suggesting impaired myotube fusion and altered contractile structures. The lack of anabolic effects of androgens on myotubes from SBMA patients was not due to defects in myoblast proliferation, differentiation or apoptosis. DHT treatment of myotubes from SBMA patients increased nuclear accumulation of polyQ-AR and decreased the expression of interleukin-4 (IL-4) when compared to myotubes from control subjects. Following DHT treatment, exposure of myotubes from SBMA patients with IL-4 treatment rescued myonuclear number and size to control levels. This supports the hypothesis that androgens alter the fusion process in SBMA myogenesis. In conclusion, these results provide evidence of an androgen-dependent impairment of myogenesis in SBMA that could contribute to disease pathogenesis.


Asunto(s)
Andrógenos/farmacología , Dihidrotestosterona/farmacología , Desarrollo de Músculos/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patología , Adulto , Análisis de Varianza , Estudios de Casos y Controles , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Interacciones Farmacológicas , Femenino , Humanos , Hipertrofia/inducido químicamente , Etiquetado Corte-Fin in Situ , Interleucina-4/farmacología , Interleucina-4/fisiología , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Miosinas/metabolismo , Péptidos/genética , Factores de Tiempo , Adulto Joven
3.
Amyotroph Lateral Scler ; 13(1): 137-43, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21870999

RESUMEN

Owing to the frequent observation of poverty of movements, facial hypomimia and balance impairment, amyotrophic lateral sclerosis (ALS) variant with predominance of upper motor neuron involvement (UMN-ALS) is prone to be diagnosed with Parkinsonism. A clinical assessment, including the velocity-dependent stretch response test to differentiate between pyramidal and extrapyramidal stiffness; the Unified Parkinson's Disease Rating Scale and the Berg Balance Scale to assess degree of bradykinesia and postural instability; and (123)I-FP-CIT scintigraphy evaluation to investigate the nigrostriatal circuit involvement, were carried out to characterize Parkinson-like features in UMN-ALS patients. Sixteen UMN-ALS patients were included in the study. The velocity-dependent stretch response indicated spasticity in all the muscles tested. The degree of stiffness was found to be related to bradykinesia and postural instability. Eleven patients (70%) showed a reduction in striatal (123)I-FP-CIT uptake found to be related to disease duration and patients' ages but not to scores of the functional scales. Slowness of movements and postural instability noted in our patients could be mostly attributed to spasticity. The lack of any correlation between UPDRS or BBS scores and the degree of nigrostriatal impairment on DaTSCAN seems to disprove nigrostriatal circuit involvement in these extrapyramidal-like features.


Asunto(s)
Esclerosis Amiotrófica Lateral/fisiopatología , Neuronas Motoras/fisiología , Enfermedad de Parkinson/fisiopatología , Anciano , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Esclerosis Amiotrófica Lateral/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/patología , Cintigrafía , Estudios Retrospectivos
4.
Amyotroph Lateral Scler ; 11(5): 424-9, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19929748

RESUMEN

A new amyotrophic lateral sclerosis (ALS) category named 'UMN-dominant ALS' and defined as 'due predominantly to UMN signs but with minor electromyogram (EMG) denervation or LMN signs on examination' has been proposed. The clinical and laboratory features of 20 patients with UMN-dominant ALS are described here, their disease course is analysed longitudinally according to their disability progression, and all these parameters are compared with those of typical ALS patients. Ten women and 10 men diagnosed with UMN-dominant ALS were evaluated. Their mean age at disease onset was 58.6 years. At the most recent evaluation, after a mean disease duration of 7.7 years, all patients progressed to a tetrapyramidal syndrome with pseudobulbar features of varying degree. No patient had respiratory problems. Cognitive impairment was observed in eight patients. The differences in disease progression between the UMN-dominant ALS and typical ALS patients proved significant (p <0.02) both with regard to the total ALSFRS-R score at six months and to each single region subscore at 12 months. Our findings suggest that there is both a different pattern of disability and longer survival in UMN-dominant ALS compared to classic ALS patients.


Asunto(s)
Esclerosis Amiotrófica Lateral/fisiopatología , Progresión de la Enfermedad , Enfermedad de la Neurona Motora/fisiopatología , Neuronas Motoras/fisiología , Adulto , Anciano , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Enfermedad de la Neurona Motora/diagnóstico , Enfermedad de la Neurona Motora/patología
5.
Amyotroph Lateral Scler ; 11(1-2): 240-3, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-19306141

RESUMEN

TAR DNA binding protein (TDP-43) is the pathologic substrate of neuronal and glial aggregates in amyotrophic lateral sclerosis (ALS). Pathologic TDP-43 is hyperphosphorylated and cleaved to generate abnormal protein species that accumulate in the cytoplasm. To assess the hypothesis of TDP-43 pathology as a systemic disorder in ALS we analysed the immunohistochemical and biochemical profile of TDP-43 in muscle biopsies of 30 ALS patients and 30 controls. In all ALS muscle biopsies we observed that TDP-43 was constantly present in an intranuclear localization and TDP-43 Western blotting showed only a 43-KDa band as controls. Our results suggest that TDP-43 pathology is probably confined to the central nervous system in ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Proteínas de Unión al ADN/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Western Blotting , Encéfalo/metabolismo , Encéfalo/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad
6.
Neurol Sci ; 31(6): 735-40, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20521074

RESUMEN

Psychopathological diagnosis has become increasingly important in amyotrophic lateral sclerosis (ALS), since the recent emphasis on the comprehensive management and end-of-life decisions. Rorschach test is the third most commonly used psychological instrument worldwide and can offer a different approach from self-reporting questionnaires, mainly providing information on issues of which individuals may be unaware or unwilling to admit to. Forty-two ALS patients underwent a psychopathological assessment with the Rorschach test. Psychopathological data were also correlated with skeletal muscle strength as measured by MRC scale and functional evaluation as ALSFRSr and FVC values. Psychopathological features, including suicidial ideation, were more frequent in the recently diagnosed ALS patients. These features were observed to be different according to the kind of functional impairment. Rorschach test may be an useful tool to assess psychopathological features in ALS. Results of our study highlight the need of an early psychopathological diagnosis and specific psychotherapeutic treatment in patients with ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/psicología , Ideación Suicida , Anciano , Esclerosis Amiotrófica Lateral/diagnóstico , Progresión de la Enfermedad , Diagnóstico Precoz , Femenino , Humanos , Masculino , Trastornos Mentales/diagnóstico , Trastornos Mentales/patología , Trastornos Mentales/psicología , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de Riesgo , Prueba de Rorschach/normas
7.
Amyotroph Lateral Scler ; 9(5): 287-93, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18608096

RESUMEN

The distinction between primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) still remains debated. Recently, PLS patients displaying lower motor neuron (LMN) signs have been defined as 'upper motor neuron (UMN)-dominant ALS', using 'clinically pure PLS' diagnosis to those with no LMN signs. To further characterize the LMN involvement in UMN-dominant ALS we investigated the presence and the extent of neurogenic abnormalities in the skeletal muscle of patients affected with a pyramidal syndrome consistent with UMN-dominant ALS. A total of nine patients affected with UMN-dominant ALS were analysed. In all cases, muscle biopsies showed the presence of scattered or clustered atrophic angulated fibres in small groups, and a mild to moderate fibre type-grouping. Target and targetoid fibres were detected in two cases only. Three patients had a second muscle biopsy which demonstrated a roughly unchanged pattern of chronic denervation with still moderate reinnervation phenomena. This study suggests that in UMN-dominant ALS muscle denervation may be characterized by an early chronic impairment of a restricted number of LMNs. The extent rather than the presence of LMN signs may allow to categorize patients with motor neuron disease involving mainly UMN into distinct entities.


Asunto(s)
Esclerosis Amiotrófica Lateral/patología , Enfermedad de la Neurona Motora/patología , Músculo Esquelético/patología , Adulto , Anciano , Esclerosis Amiotrófica Lateral/clasificación , Esclerosis Amiotrófica Lateral/fisiopatología , Biopsia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de la Neurona Motora/clasificación , Enfermedad de la Neurona Motora/fisiopatología , Neuronas Motoras/fisiología , Músculo Esquelético/citología
8.
J Neurol Sci ; 264(1-2): 100-5, 2008 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-17854832

RESUMEN

Spinal and bulbar muscular atrophy (SBMA) is an adult form of X-linked motor neuron disease caused by an expansion of a CAG repeat sequence in the first exon of the androgen receptor (AR) gene. Nuclear accumulation of mutant AR with expanded polyglutamines in motor neurons is a major pathogenic mechanism. To characterize muscle involvement in SBMA the skeletal muscle biopsies of 8 SBMA patients and 3 female carriers were studied. Six of 8 SBMA patients showed myogenic changes together with the neurogenic atrophy in their muscle biopsy. Myopathic abnormalities did not correlate with disease duration and were more prominent in the muscle of patients with an higher degree of disability. In all patients plasma CK levels were more elevated than what usually occurs in denervative diseases. Both neurogenic and myopathic changes were also observed in female carriers. Here we suggest that myopathic changes in SBMA muscle are not only related to denervation and that muscle satellite cells may have a role in the pathogenesis of muscle damage.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Heterocigoto , Músculo Esquelético/patología , Atrofia Muscular Espinal/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Creatina Quinasa/sangre , Expansión de las Repeticiones de ADN/genética , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/fisiopatología , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/fisiopatología , Degeneración Nerviosa/genética , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/fisiopatología , Péptidos/genética , Receptores Androgénicos/genética , Células Satélite del Músculo Esquelético/metabolismo , Células Satélite del Músculo Esquelético/patología , Índice de Severidad de la Enfermedad , Caracteres Sexuales
9.
Neurobiol Aging ; 35(5): 1212.e7-1212.e10, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24325798

RESUMEN

Amyotrophic lateral sclerosis (ALS) is as an adult-onset neurodegenerative disorder involving both upper and lower motor neurons. About 5% of all cases exhibit signs of frontotemporal degeneration (FTD). We established the mutation frequency of C9ORF72, SOD1, TARDBP, and FUS genes in 307 patients with sporadic ALS, 46 patients with familial ALS (FALS), and 73 patients affected with FTD, all originating from the northeastern part of Italy. C9ORF72 pathogenic expansion was found on 22% of familial ALS, 5% of sporadic ALS, and 14% of FTD patients, resulting the most frequently genetic determinant in our cohort. Sequence analysis of ALS cohort identified 2 novel variants on SOD1 (p.Glu41Gly) and FUS (p.Gly496Glyfs*31). Interestingly, the single base deletion on FUS was observed in an homozygous state, suggesting a recessive pattern of inheritance. No point mutations were identified on FTD cohort. Although useful to direct genetic testing, this study results expand the current knowledge of ALS genetics.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Tasa de Mutación , Mutación , Proteína FUS de Unión a ARN/genética , Superóxido Dismutasa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Proteína C9orf72 , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Femenino , Degeneración Lobar Frontotemporal/genética , Eliminación de Gen , Homocigoto , Humanos , Italia , Masculino , Persona de Mediana Edad , Proteínas/genética , Superóxido Dismutasa-1 , Adulto Joven
10.
Artículo en Inglés | MEDLINE | ID: mdl-22953735

RESUMEN

The present study investigated for the first time numerical processing in sporadic amyotrophic lateral sclerosis (ALS) patients. Twenty-four non-demented patients affected by probable or definite ALS and 27 healthy controls underwent cognitive assessment. Numerical abilities (Number Comprehension, Number Transcoding, Arithmetic Fact retrieval, Calculation Skills and Arithmetic Principles) and neuropsychological functions were evaluated in accordance with Strong's consensus criteria. Clear group differences between the patients and controls were found in Multiplication Facts (Tables), Multiplication Approximation, and Multiplication Principles. These deficits were not statistically related to impairments of more general cognitive functioning. In conclusion, specific, previously unreported arithmetical deficits have been found in ALS patients. This particular impairment pattern could be indicative of damage to the cortico-subcortical circuits involved in some specific aspects of multiplication. Our findings could contribute to further delineate the profile of cognitive impairment in ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/fisiopatología , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/fisiopatología , Función Ejecutiva , Solución de Problemas , Comprensión , Femenino , Humanos , Masculino , Matemática , Persona de Mediana Edad
11.
Neurology ; 80(23): 2095-8, 2013 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-23645595

RESUMEN

OBJECTIVE: To test the efficacy and tolerability of clenbuterol in patients with spinal and bulbar muscular atrophy (SBMA). METHODS: Twenty patients with a diagnosis of SBMA were given oral clenbuterol (0.04 mg/d) for 12 months. The primary efficacy end point was the change from baseline of the walking distance covered in 6 minutes at 12 months. Secondary end points included the change over time in muscle strength assessed with the Medical Research Council scale, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and forced vital capacity values. Safety was assessed by a series of laboratory and instrumental tests, as well as reporting of adverse events. RESULTS: Sixteen patients completed the study. There was a significant and sustained increase in walking distance covered in 6 minutes and forced vital capacity between the baseline and the 12-month assessments (p < 0.001). No differences were recorded in Medical Research Council or ALSFRS-R scores between baseline and follow-up assessments. Serious side effects, including those on heart function, were absent. A significant increase in serum creatine kinase levels was observed. CONCLUSIONS: Our findings suggest a positive effect of clenbuterol on SBMA disease progression. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that clenbuterol is effective in improving motor function in SBMA.


Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Atrofia Bulboespinal Ligada al X/tratamiento farmacológico , Clenbuterol/farmacología , Actividades Cotidianas , Agonistas Adrenérgicos beta/administración & dosificación , Agonistas Adrenérgicos beta/efectos adversos , Adulto , Anciano , Clenbuterol/administración & dosificación , Clenbuterol/efectos adversos , Prueba de Esfuerzo/métodos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Fuerza Muscular , Proyectos Piloto , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Caminata/fisiología
12.
Neurobiol Aging ; 33(3): 630.e1-2, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22137929

RESUMEN

Mutations in valosin-containing protein (VCP) gene, already known to be associated with the multisystemic disorder, inclusion body myopathy with Paget's disease and frontotemporal dementia (IBMPFD), have been recently found also in familial cases of amyotrophic lateral sclerosis (ALS). To further define the frequency of VCP mutations in ALS Italian population, we screened a cohort of 166 familial ALS and 14 ALS-frontotemporal dementia (FTD) individuals. We identified a previously reported synonymous mutation (c.2093A>C; p.Q568Q), 2 intronic variants (c.1749-14C>T; c.2085-3C>T), and 1 nucleotide change (c.2814G>T) in the 3' untranslated region (UTR). Bioinformatical analyses predicted no changes in splicing process or microRNA binding sites. Our results do not confirm a main contribution of VCP gene to familial ALS in the Italian population.


Asunto(s)
Adenosina Trifosfatasas/genética , Esclerosis Amiotrófica Lateral/genética , Proteínas de Ciclo Celular/genética , Mutación Puntual/genética , Adenosina Trifosfatasas/metabolismo , Empalme Alternativo/genética , Proteínas de Ciclo Celular/metabolismo , Estudios de Cohortes , Biología Computacional/métodos , Análisis Mutacional de ADN/métodos , Genotipo , Humanos , Italia/epidemiología , MicroARNs/metabolismo , Valor Predictivo de las Pruebas , Unión Proteica/genética , Proteína que Contiene Valosina
13.
Neurobiol Aging ; 33(10): 2528.e7-14, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22766072

RESUMEN

A hexanucleotide repeat expansion (RE) in C9ORF72 gene was recently reported as the main cause of amyotrophic lateral sclerosis (ALS) and cases with frontotemporal dementia. We screened C9ORF72 in a large cohort of 259 familial ALS, 1275 sporadic ALS, and 862 control individuals of Italian descent. We found RE in 23.9% familial ALS, 5.1% sporadic ALS, and 0.2% controls. Two cases carried the RE together with mutations in other ALS-associated genes. The phenotype of RE carriers was characterized by bulbar-onset, shorter survival, and association with cognitive and behavioral impairment. Extrapyramidal and cerebellar signs were also observed in few patients. Genotype data revealed that 95% of RE carriers shared a restricted 10-single nucleotide polymorphism haplotype within the previously reported 20-single nucleotide polymorphism risk haplotype, detectable in only 27% of nonexpanded ALS cases and in 28% of controls, suggesting a common founder with cohorts of North European ancestry. Although C9ORF72 RE segregates with disease, the identification of RE both in controls and in patients carrying additional pathogenic mutations suggests that penetrance and phenotypic expression of C9ORF72 RE may depend on additional genetic risk factors.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Expansión de las Repeticiones de ADN/genética , Efecto Fundador , Proteínas/genética , Adulto , Edad de Inicio , Anciano , Enfermedades de los Ganglios Basales/genética , Proteína C9orf72 , Enfermedades Cerebelosas/genética , Disfunción Cognitiva/genética , Estudios de Cohortes , Femenino , Pruebas Genéticas , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Riesgo , Factores Sexuales
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