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1.
Alzheimers Dement ; 13(5): 520-530, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-27743520

RESUMEN

INTRODUCTION: Corticobasal syndrome (CBS) resulting from genetic Alzheimer's disease (AD) has been described only once. Whether familial CBS-AD is a distinct clinical entity with its own imaging signature remains unknown. METHODS: Four individuals with CBS from two families underwent detailed assessment. For two individuals, regional atrophy and hypoperfusion were compared to autopsy-confirmed typical late-onset AD and corticobasal degeneration, as well as genetically proven PSEN1 cases with an amnestic presentation. RESULTS: One family harbored a novel mutation in PSEN1:p.Phe283Leu. MRI demonstrated severe parietal, perirolandic, and temporal atrophy, with relative sparing of frontal and ipsilateral hippocampal regions. Autopsy confirmed pure AD pathology. The other family harbored a known PSEN1 mutation:p.Gly378Val. DISCUSSION: This report confirms familial CBS-AD as a distinct clinical entity, with a parietal-perirolandic-temporal atrophy signature. It illustrates the clinical heterogeneity that can occur despite a shared genetic cause and underscores the need for biomarkers such as amyloid imaging during life.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Corteza Cerebral/patología , Presenilina-1/genética , Atrofia/patología , Autopsia , Encéfalo/patología , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Mutación , Síndrome
2.
J Neurosci ; 32(39): 13568-81, 2012 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-23015446

RESUMEN

Emerging evidence implicates serotonergic descending facilitatory pathways from the brainstem to the spinal cord in the maintenance of pathologic pain. Upregulation of the serotonin receptor 2A (5-HT(2A)R) in dorsal horn neurons promotes spinal hyperexcitation and impairs spinal µ-opioid mechanisms during neuropathic pain. We investigated the involvement of spinal glutamate receptors, including metabotropic receptors (mGluRs) and NMDA, in 5-HT(2A)R-induced hyperexcitability after spinal nerve ligation (SNL) in rat. High-affinity 5-HT(2A)R agonist (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2) enhanced C-fiber-evoked dorsal horn potentials after SNL, which was prevented by mGluR1 antagonist AIDA [(RS)-1-aminoindan-1,5-dicarboxylic acid] but not by group II mGluR antagonist LY 341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid] or NMDA antagonist d-AP5 [D-(-)-2-amino-5-phosphonopentanoic acid]. 5-HT(2A)R and mGluR1 were found to be coexpressed in postsynaptic densities in dorsal horn neurons. In the absence of SNL, pharmacological stimulation of 5-HT(2A)R with TCB-2 both induced rapid bilateral upregulation of mGluR1 expression in cytoplasmic and synaptic fractions of spinal cord homogenates, which was attenuated by PKC inhibitor chelerythrine, and enhanced evoked potentials during costimulation of mGluR1 with 3,5-DHPG [(RS)-3,5-dihydroxyphenylglycine]. SNL was followed by bilateral upregulation of mGluR1 in 5-HT(2A)R-containing postsynaptic densities. Upregulation of mGluR1 in synaptic compartments was partially prevented by chronic administration of selective 5-HT(2A)R antagonist M100907 [(R)-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol], confirming 5-HT(2A)R-mediated control of mGluR1 upregulation triggered by SNL. Changes in thermal and mechanical pain thresholds following SNL were increasingly reversed over the days after injury by chronic 5-HT(2A)R blockade. These results emphasize a role for 5-HT(2A)R in hyperexcitation and pain after nerve injury and support mGluR1 upregulation as a novel feedforward activation mechanism contributing to 5-HT(2A)R-mediated facilitation.


Asunto(s)
Neuralgia/etiología , Neuralgia/patología , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Médula Espinal/metabolismo , Nervios Espinales/lesiones , Animales , Compuestos Bicíclicos con Puentes/farmacología , Línea Celular Transformada , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/fisiología , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Humanos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/patología , Masculino , Metilaminas/farmacología , Fibras Nerviosas Amielínicas/fisiología , Péptidos/farmacología , Células del Asta Posterior/efectos de los fármacos , Células del Asta Posterior/metabolismo , Ratas , Ratas Sprague-Dawley , Serotoninérgicos/farmacología , Médula Espinal/efectos de los fármacos , Fracciones Subcelulares/efectos de los fármacos , Fracciones Subcelulares/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Sinapsis/patología , Factores de Tiempo , Transfección
3.
BMC Neurol ; 13: 29, 2013 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-23514108

RESUMEN

BACKGROUND: Hereditary myopathy with early respiratory failure (HMERF) was described in several North European families and recently linked to a titin gene (TTN) mutation. We independently studied HMERF-like diseases with the purpose to identify the cause, refine diagnostic criteria, and estimate the frequency of this disease among myopathy patients of various ethnic origins. METHODS: Whole exome sequencing analysis was carried out in a large U.S. family that included seven members suffering from skeletal muscle weakness and respiratory failure. Subsequent mutation screening was performed in further 45 unrelated probands with similar phenotypes. Studies included muscle strength evaluation, nerve conduction studies and concentric needle EMG, respiratory function test, cardiologic examination, and muscle biopsy. RESULTS: A novel TTN p.Gly30150Asp mutation was identified in the highly conserved A-band of titin that co-segregated with the disease in the U.S. family. Screening of 45 probands initially diagnosed as myofibrillar myopathy (MFM) but excluded based on molecular screening for the known MFM genes led to the identification of a previously reported TTN p.Cys30071Arg mutation in one patient. This same mutation was also identified in a patient with suspected HMERF. The p.Gly30150Asp and p.Cys30071Arg mutations are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin. CONCLUSIONS: Missense mutations in TTN are the cause of HMERF in families of diverse origins. A comparison of phenotypic features of HMERF caused by the three known TTN mutations in various populations allowed to emphasize distinct clinical/pathological features that can serve as the basis for diagnosis. The newly identified p.Gly30150Asp and the p.Cys30071Arg mutation are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin.


Asunto(s)
Salud de la Familia , Enfermedades Genéticas Congénitas/etnología , Enfermedades Genéticas Congénitas/genética , Proteínas Musculares/genética , Enfermedades Musculares/etnología , Enfermedades Musculares/genética , Mutación/genética , Proteínas Quinasas/genética , Insuficiencia Respiratoria/etnología , Insuficiencia Respiratoria/genética , Adolescente , Adulto , Conectina , Análisis Mutacional de ADN , Evaluación de la Discapacidad , Electromiografía , Exoma/genética , Femenino , Enfermedades Genéticas Congénitas/diagnóstico , Humanos , Masculino , Proteínas Musculares/metabolismo , Fuerza Muscular/genética , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Músculo Esquelético/ultraestructura , Enfermedades Musculares/diagnóstico , Polimorfismo de Nucleótido Simple , Insuficiencia Respiratoria/diagnóstico , Tomografía Computarizada por Rayos X , Estados Unidos/etnología , Adulto Joven
4.
Brain ; 135(Pt 9): 2642-60, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22961544

RESUMEN

Mutations in FLNC cause two distinct types of myopathy. Disease associated with mutations in filamin C rod domain leading to expression of a toxic protein presents with progressive proximal muscle weakness and shows focal destructive lesions of polymorphous aggregates containing desmin, myotilin and other proteins in the affected myofibres; these features correspond to the profile of myofibrillar myopathy. The second variant associated with mutations in the actin-binding domain of filamin C is characterized by weakness of distal muscles and morphologically by non-specific myopathic features. A frameshift mutation in the filamin C rod domain causing haploinsufficiency was also found responsible for distal myopathy with some myofibrillar changes but no protein aggregation typical of myofibrillar myopathies. Controversial data accumulating in the literature require re-evaluation and comparative analysis of phenotypes associated with the position of the FLNC mutation and investigation of the underlying disease mechanisms. This is relevant and necessary for the refinement of diagnostic criteria and developing therapeutic approaches. We identified a p.W2710X mutation in families originating from ethnically diverse populations and re-evaluated a family with a p.V930_T933del mutation. Analysis of the expanded database allows us to refine clinical and myopathological characteristics of myofibrillar myopathy caused by mutations in the rod domain of filamin C. Biophysical and biochemical studies indicate that certain pathogenic mutations in FLNC cause protein misfolding, which triggers aggregation of the mutant filamin C protein and subsequently involves several other proteins. Immunofluorescence analyses using markers for the ubiquitin-proteasome system and autophagy reveal that the affected muscle fibres react to protein aggregate formation with a highly increased expression of chaperones and proteins involved in proteasomal protein degradation and autophagy. However, there is a noticeably diminished efficiency of both the ubiquitin-proteasome system and autophagy that impairs the muscle capacity to prevent the formation or mediate the degradation of aggregates. Transfection studies of cultured muscle cells imitate events observed in the patient's affected muscle and therefore provide a helpful model for testing future therapeutic strategies.


Asunto(s)
Proteínas Contráctiles/metabolismo , Proteínas de Microfilamentos/metabolismo , Músculo Esquelético/metabolismo , Distrofias Musculares/metabolismo , Mutación , Fenotipo , Actinas/metabolismo , Adulto , Proteínas Contráctiles/genética , Progresión de la Enfermedad , Femenino , Filaminas , Proteínas de Choque Térmico/metabolismo , Humanos , Masculino , Proteínas de Microfilamentos/genética , Persona de Mediana Edad , Músculo Esquelético/patología , Distrofias Musculares/genética , Distrofias Musculares/patología , Linaje , Unión Proteica , Proteolisis , Ubiquitinación
5.
Pain Med ; 14(10): 1450-60, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23915306

RESUMEN

OBJECTIVE: The objective of this study was to evaluate the ability of artificial neural networks (ANNs) to predict, on the basis of clinical variables, the response of persons with fibromyalgia syndrome (FMS) to a standard, 4-week interdisciplinary pain program. DESIGN: The design of this study is retrospective longitudinal. SETTING: Fibromyalgia outpatient clinic in a tertiary-care general hospital. SUBJECTS: The subjects of this study include outpatients with FMS. INTERVENTION: Multidisciplinary pain program including pain pharmacotherapy, cognitive-behavioral therapy, physical therapy, and occupational therapy. OUTCOME MEASURES: Reliable change (RC) of scores on the Stanford Health Assessment Questionnaire (HAQ), and accuracy of ANNs in predicting RC at discharge or at 6-month follow-up as compared to Logistic Regression. RESULTS: ANN-based models using the sensory-discriminative and affective-motivational subscales of the McGill Pain Questionnaire, the HAQ disability index, and the anxiety subscale of Hospital Anxiety and Depression Scale at baseline as input variables correctly classified 81.81% of responders at discharge and 83.33% of responders at 6-month follow-up, as well as 100% of nonresponders at either evaluation time-point. Logistic regression analysis, which was used for comparison, could predict treatment outcome with accuracies of 86.11% and 61.11% at discharge and follow-up, respectively, based on baseline scores on the HAQ and the mental summary component of the Medical Outcomes Study-Short Form 36. CONCLUSIONS: Properly trained ANNs can be a useful tool for optimal treatment selection at an early stage after diagnosis, thus contributing to minimize the lag until symptom amelioration and improving tertiary prevention in patients with FMS.


Asunto(s)
Fibromialgia/psicología , Fibromialgia/terapia , Redes Neurales de la Computación , Recuperación de la Función , Resultado del Tratamiento , Adulto , Terapia Cognitivo-Conductual , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Ocupacional , Dolor/tratamiento farmacológico , Modalidades de Fisioterapia , Adulto Joven
6.
Clin Neuropathol ; 32(4): 291-7, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23320997

RESUMEN

IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory condition which often shows a dramatic response to steroid therapy. IgG4-RD can present either as a single lesion or as a systemic multi-organ disorder. Common histological findings include a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and phlebitis. Although diagnostic criteria for IgG4-RD have been proposed in many organs/sites, they are not well established in the central nervous system. Published data on IgG4-RD in meninges is also limited. To our knowledge, only 15 potential cases of meningeal IgG4-RD have been reported. We add a case of probable IgG4-related pachymeningitis in a 42-year-old woman who presented with headache and left transverse sinus obstruction. Follow-up after 2-months of high dose steroids shows dramatic clinical and imaging improvement. The differential diagnosis for IgG4-related pachymeningitis, including lymphoplasmacyte-rich meningioma, idiopathic hypertrophic pachymeningitis, and lymphoproliferative disease is discussed.


Asunto(s)
Inmunoglobulina G/inmunología , Meningitis/inmunología , Meningitis/patología , Senos Transversos/patología , Adulto , Antiinflamatorios/uso terapéutico , Femenino , Humanos , Meningitis/tratamiento farmacológico
7.
Clin Neuropathol ; 32(6): 461-70, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24131748

RESUMEN

AIMS: Pathologists are under increasing pressure to accurately subclassify sarcomas, yet neuropathologists have limited collective experience with rare sarcoma types such as synovial sarcoma. We reviewed 9 synovial sarcomas affecting peripheral nerve diagnosed by neuropathologists and explored the morphologic and immunohistochemical differences between these and MPNST. Our goal was to make practical recommendations for neuropathologists regarding which spindle cell tumors affecting nerve should be sent for SYT-SSX testing. METHODS: Clinical records and genetics were reviewed retrospectively and central pathology review of 9 synovial sarcomas and 6 MPNST included immunohistochemistry for SOX10, S100, BAF47, CK (lmw, pan, CK7, CK19), EMA, CD34, bcl2, CD99, and neurofilament. RESULTS: Common synovial sarcoma sites were brachial plexus, spinal and femoral nerve, none were "intra-neural", all had the SYTSSX1 translocation, and 6/9 were monophasic with myxoid stroma and distinct collagen. Half of the monophasic synovial sarcomas expressed CK7, CK19 or panCK in a "rare positive cells pattern", 8/9 (89%) expressed EMA, and all were SOX10 immunonegative with reduced but variable BAF47 expression. CONCLUSIONS: We recommend that upon encountering a cellular spindle cell tumor affecting nerve neuropathologists consider the following: 1) SYT-SSX testing should be performed on any case with morphology suspicious for monophasic synovial sarcoma including wiry or thick bands of collagen and relatively monomorphous nuclei; 2) neuropathologists should employ a screening immunohistochemical panel including one of CK7, panCK or CK19, plus EMA, S100 and SOX10, and 3) SYT-SSX testing should be performed on any spindle cell tumor with CK and/or EMA immunopositivity if SOX10 immunostaining is negative or only labels entrapped nerve elements.


Asunto(s)
Neoplasias del Sistema Nervioso Periférico/diagnóstico , Sarcoma Sinovial/diagnóstico , Adulto , Anciano , Biomarcadores de Tumor/análisis , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias del Sistema Nervioso Periférico/clasificación , Guías de Práctica Clínica como Asunto , Sarcoma Sinovial/clasificación
8.
Acta Neuropathol ; 124(5): 705-16, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22842875

RESUMEN

Accumulation of the DNA/RNA binding protein fused in sarcoma (FUS) as inclusions in neurons and glia is the pathological hallmark of amyotrophic lateral sclerosis patients with mutations in FUS (ALS-FUS) as well as in several subtypes of frontotemporal lobar degeneration (FTLD-FUS), which are not associated with FUS mutations. Despite some overlap in the phenotype and neuropathology of FTLD-FUS and ALS-FUS, significant differences of potential pathomechanistic relevance were recently identified in the protein composition of inclusions in these conditions. While ALS-FUS showed only accumulation of FUS, inclusions in FTLD-FUS revealed co-accumulation of all members of the FET protein family, that include FUS, Ewing's sarcoma (EWS) and TATA-binding protein-associated factor 15 (TAF15) suggesting a more complex disturbance of transportin-mediated nuclear import of proteins in FTLD-FUS compared to ALS-FUS. To gain more insight into the mechanisms of inclusion body formation, we investigated the role of Transportin 1 (Trn1) as well as 13 additional cargo proteins of Transportin in the spectrum of FUS-opathies by immunohistochemistry and biochemically. FUS-positive inclusions in six ALS-FUS cases including four different mutations did not label for Trn1. In sharp contrast, the FET-positive pathology in all FTLD-FUS subtypes was also strongly labeled for Trn1 and often associated with a reduction in the normal nuclear staining of Trn1 in inclusion bearing cells, while no biochemical changes of Trn1 were detectable in FTLD-FUS. Notably, despite the dramatic changes in the subcellular distribution of Trn1 in FTLD-FUS, alterations of its cargo proteins were restricted to FET proteins and no changes in the normal physiological staining of 13 additional Trn1 targets, such as hnRNPA1, PAPBN1 and Sam68, were observed in FTLD-FUS. These data imply a specific dysfunction in the interaction between Trn1 and FET proteins in the inclusion body formation in FTLD-FUS. Moreover, the absence of Trn1 in ALS-FUS provides further evidence that ALS-FUS and FTLD-FUS have different underlying pathomechanisms.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Encéfalo/metabolismo , Degeneración Lobar Frontotemporal/metabolismo , Factores Asociados con la Proteína de Unión a TATA/metabolismo , beta Carioferinas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Esclerosis Amiotrófica Lateral/genética , Encéfalo/patología , Proteínas de Unión al ADN/metabolismo , Femenino , Degeneración Lobar Frontotemporal/genética , Regulación de la Expresión Génica/genética , Ribonucleoproteína Nuclear Heterogénea A1 , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Humanos , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/patología , Masculino , Mutación/genética , Proteína I de Unión a Poli(A)/metabolismo , Proteína EWS de Unión a ARN/metabolismo , Proteína FUS de Unión a ARN/genética , Proteína FUS de Unión a ARN/metabolismo , Proteínas de Unión al ARN/metabolismo
9.
Brain ; 134(Pt 9): 2595-609, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21856723

RESUMEN

Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in FUS as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with FUS mutations. The mechanisms leading to inclusion formation and fused in sarcoma-associated neurodegeneration are only poorly understood. Because fused in sarcoma belongs to a family of proteins known as FET, which also includes Ewing's sarcoma and TATA-binding protein-associated factor 15, we investigated the potential involvement of these other FET protein family members in the pathogenesis of fused in sarcoma proteinopathies. Immunohistochemical analysis of FET proteins revealed a striking difference among the various conditions, with pathology in amyotrophic lateral sclerosis with FUS mutations being labelled exclusively for fused in sarcoma, whereas fused in sarcoma-positive inclusions in subtypes of frontotemporal lobar degeneration also consistently immunostained for TATA-binding protein-associated factor 15 and variably for Ewing's sarcoma. Immunoblot analysis of proteins extracted from post-mortem tissue of frontotemporal lobar degeneration with fused in sarcoma pathology demonstrated a relative shift of all FET proteins towards insoluble protein fractions, while genetic analysis of the TATA-binding protein-associated factor 15 and Ewing's sarcoma gene did not identify any pathogenic variants. Cell culture experiments replicated the findings of amyotrophic lateral sclerosis with FUS mutations by confirming the absence of TATA-binding protein-associated factor 15 and Ewing's sarcoma alterations upon expression of mutant fused in sarcoma. In contrast, all endogenous FET proteins were recruited into cytoplasmic stress granules upon general inhibition of Transportin-mediated nuclear import, mimicking the findings in frontotemporal lobar degeneration with fused in sarcoma pathology. These results allow a separation of fused in sarcoma proteinopathies caused by FUS mutations from those without a known genetic cause based on neuropathological features. More importantly, our data imply different pathological processes underlying inclusion formation and cell death between both conditions; the pathogenesis in amyotrophic lateral sclerosis with FUS mutations appears to be more restricted to dysfunction of fused in sarcoma, while a more global and complex dysregulation of all FET proteins is involved in the subtypes of frontotemporal lobar degeneration with fused in sarcoma pathology.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Biomarcadores/metabolismo , Degeneración Lobar Frontotemporal/patología , Proteína EWS de Unión a ARN/metabolismo , Proteína FUS de Unión a ARN/metabolismo , Factores Asociados con la Proteína de Unión a TATA/metabolismo , Esclerosis Amiotrófica Lateral/fisiopatología , Animales , Degeneración Lobar Frontotemporal/genética , Degeneración Lobar Frontotemporal/fisiopatología , Células HeLa , Humanos , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/patología , Mutación , Proteína EWS de Unión a ARN/genética , Proteína FUS de Unión a ARN/genética , Factores Asociados con la Proteína de Unión a TATA/genética
10.
Compr Psychiatry ; 53(4): 396-402, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-21741039

RESUMEN

BACKGROUND: Most patients having eating disorders (EDs) experience depressive symptoms. To date, there have been few reports about the different depressive dimensions in EDs. OBJECTIVE: The aim of this study was to investigate the dimensions of depressive symptoms and highlight the distribution of the symptoms. The psychometric properties of these measures were tested using item response theory methods. METHODS: A total of 103 consecutively admitted inpatients and outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, Revised Fourth Edition, criteria for anorexia nervosa, bulimia nervosa, and EDs not otherwise specified were rated with the Hamilton Depression Rating Scale (HDRS-17). A factor analysis of the HDRS-17 was carried out with the Cf-varimax rotation. RESULTS: Factor analysis showed 2 independent and clinically interpretable factors corresponding to "anxious depression" and "somatic complaints" that constituted the core of depression. For the HDRS-17, item response theory analyses revealed that most of the items were maximally related to the core concept of depression and provided a good functioning. The 17 items were distributed in almost the same way as in the factor analyses found by other authors with different clinical groups. We conclude therefore that for the sample of EDs, 2 factors constitute the core symptoms of depression and most of the items provided a good functioning.


Asunto(s)
Depresión/diagnóstico , Trastornos de Alimentación y de la Ingestión de Alimentos/psicología , Adolescente , Adulto , Niño , Depresión/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Psicometría , Índice de Severidad de la Enfermedad
11.
Rheumatol Int ; 32(11): 3463-9, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22065070

RESUMEN

Clinical presentation of fibromyalgia syndrome (FMS) is heterogeneous and often involves psychological comorbidities. Clinical subgrouping of FMS patients has been proposed as a strategy to improve patients' long-term outcomes by helping identify specific treatment needs. Using the 90 Symptom Checklist Revised (SCL-90-R), we have assessed emotional distress in two FMS patient subpopulations discriminated on the basis of their differences in scores on specific items of the Fibromyalgia Impact Questionnaire (FIQ). Subjects classed as type II exhibited high emotional distress on all ten dimensions studied, which included somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, psychoticism, and additional items subscales, as well as on the global severity index (GSI), positive symptom total (PST), and positive symptom distress index (PDSI). T-scores in these patients were above diagnostic cutoff level of 60 on somatization, obsessive-compulsive, and depression subscales. In contrast, the profile exhibited by type I subjects fell entirely within normal values for nonpsychiatric population. Emotional status was significantly inversely correlated with present clinical pain in type I-, but not in type II-fibromyalgia patients. Regression analysis revealed a model based on phobic anxiety, paranoid ideation, and depression subscales as best contributing to classification. The present data suggest that associated psychological distress and maladaptive emotional responses that are commonly attributed to the general FMS population may be largely a distinguishing feature of one subset of patients.


Asunto(s)
Fibromialgia/psicología , Dolor/psicología , Calidad de Vida/psicología , Estrés Psicológico/psicología , Actividades Cotidianas/psicología , Adulto , Anciano , Anciano de 80 o más Años , Ansiedad/psicología , Estudios Transversales , Depresión/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios
12.
Neuropathology ; 32(3): 280-4, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21981108

RESUMEN

JC virus (JCV) granular neuronopathy remains an under-appreciated phenomenon whereby JCV inhabits neurons in the granular layer of the cerebellum causing neuronal loss, gliosis and a clinical cerebellar syndrome. The following case describes a man with sarcoidosis and idiopathic leukopenia who developed a clinical cerebellar syndrome due to JCV granular neuronopathy, followed by neurological decline due to rhombencephalic progressive multifocal leukoencephalopathy. This case reminds us of the ability of JCV to produce dual neuropathology which includes JCV granular neuronopathy, and the pathogenesis and clinical implications for this phenomenon are discussed.


Asunto(s)
Virus JC , Leucoencefalopatía Multifocal Progresiva/patología , Rombencéfalo/patología , Anciano , Encéfalo/patología , Enfermedades Cerebelosas , Cerebelo/patología , ADN Viral/sangre , Resultado Fatal , Humanos , Hibridación in Situ , Virus JC/genética , Leucopenia/etiología , Leucopenia/patología , Imagen por Resonancia Magnética , Masculino , Reacción en Cadena de la Polimerasa , Sarcoidosis/etiología , Sarcoidosis/patología
13.
Mol Cell Neurosci ; 47(3): 167-80, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21421050

RESUMEN

TDP-43 is a predominantly nuclear DNA/RNA binding protein involved in transcriptional regulation and RNA processing. TDP-43 is also a component of the cytoplasmic inclusion bodies characteristic of amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). We have investigated the premise that abnormalities of TDP-43 in disease would be reflected by changes in processing of its target RNAs. To this end, we have firstly identified RNA targets of TDP-43 using UV-Cross-Linking and Immunoprecipitation (UV-CLIP) of SHSY5Y cells, a human neuroblastoma cell line. We used conventional cloning strategies to identify, after quality control steps, 127 targets. Results show that TDP-43 binds mainly to introns at UG/TG repeat motifs (49%) and polypyrimidine rich sequences (17.65%). To determine if the identified RNA targets of TDP-43 were abnormally processed in ALS versus control lumbar spinal cord RNA, we performed RT-PCR using primers designed according to the location of TDP-43 binding within the gene, and prior evidence of alternative splicing of exons adjacent to this site. Of eight genes meeting these criteria, five were differentially spliced in ALS versus control. This supports the premise that abnormalities of TDP-43 in ALS are reflected in changes of RNA processing.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Proteínas de Unión al ADN/metabolismo , ARN/metabolismo , Médula Espinal/metabolismo , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/genética , Línea Celular Tumoral , Clonación de Organismos , Proteínas de Unión al ADN/genética , Femenino , Humanos , Inmunoprecipitación/métodos , Masculino , Persona de Mediana Edad , ARN/genética , Empalme del ARN , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo
14.
Mov Disord Clin Pract ; 9(4): 501-507, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35586540

RESUMEN

Background: Progressive supranuclear palsy (PSP)-pallido-nigro-luysian atrophy (PNLA) is a neuropathological entity thought to be a variant of classic PSP. Clinical features and pathologic hallmarks are the same in both conditions; however, age and order of symptom onset, disease duration and prognosis, and distribution and density of pathology differentiate the 2 entities. Objectives: This study presents a PSP-PNLA case confirmed pathologically with a clinical presentation of hemichorea/ballism, spasticity, progressive hemiparesis, and a frontal behavioral syndrome with relative cognitive sparing early in the disease course. Methods: We describe the clinical progression in this unique case supplemented with video and imaging findings in the form of magnetic resonance imaging and brain single photon emission computed tomography. Final diagnosis is via pathological analysis at autopsy. Results: We present an elderly gentleman who manifested a clinical syndrome consisting of subacute onset of chorea that at presentation was distinctly unilateral and a frontal behavioral syndrome in the setting of mild thrombocytopenia and elevated anticardiolipin antibodies. Positive antiphospholipid antibodies resulted in an initial antemortem diagnosis of primary antiphospholipid syndrome as a cause of his chorea. Longitudinal follow-up over 5 years demonstrated a progression of clinical features with hemi-motor impersistence/chorea, disinhibition and impulsivity, and eventually corticospinal distribution weakness on the initially affected side. He required nursing home care and falls necessitated wheelchair use. Postmortem neuropathological study revealed a diagnosis of frontotemporal lobar degeneration-tau, PSP-PNLA. Conclusions: This case broadens the phenotype of PSP-PNLA and to our knowledge is the only case presenting with unilateral chorea.

15.
Acta Neuropathol ; 122(1): 87-98, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21604077

RESUMEN

Mutations in the gene encoding the fused in sarcoma (FUS) protein are responsible for ~3% of familial amyotrophic lateral sclerosis (ALS) and <1% of sporadic ALS (ALS-FUS). Descriptions of the associated neuropathology are few and largely restricted to individual case reports. To better define the neuropathology associated with FUS mutations, we have undertaken a detailed comparative analysis of six cases of ALS-FUS that include sporadic and familial cases, with both juvenile and adult onset, and with four different FUS mutations. We found significant pathological heterogeneity among our cases, with two distinct patterns that correlated with the disease severity and the specific mutation. Frequent basophilic inclusions and round FUS-immunoreactive (FUS-ir) neuronal cytoplasmic inclusions (NCI) were a consistent feature of our early-onset cases, including two with the p.P525L mutation. In contrast, our late-onset cases that included two with the p.R521C mutation had tangle-like NCI and numerous FUS-ir glial cytoplasmic inclusions. Double-labeling experiments demonstrated that many of the glial inclusions were in oligodendrocytes. Comparison with the neuropathology of cases of frontotemporal lobar degeneration with FUS-ir pathology showed significant differences and suggests that FUS mutations are associated with a distinct pathobiology.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Mutación/genética , Proteína FUS de Unión a ARN/genética , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Femenino , Humanos , Cuerpos de Inclusión/patología , Masculino , Bulbo Raquídeo/metabolismo , Bulbo Raquídeo/patología , Persona de Mediana Edad , Corteza Motora/metabolismo , Corteza Motora/patología , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Neuroglía/metabolismo , Neuroglía/patología , Proteína FUS de Unión a ARN/metabolismo , Médula Espinal/metabolismo , Médula Espinal/patología , Adulto Joven
16.
Ann Neurol ; 66(1): 75-80, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19670443

RESUMEN

OBJECTIVE: In familial amyotrophic lateral sclerosis (fALS) harboring superoxide dismutase (SOD1) mutations (fALS1), SOD1 toxicity has been linked to its propensity to misfold and aggregate. It has recently been proposed that misfolded SOD1 may be causative of all types of ALS, including sporadic cases (sALS). In the present study, we have used a specific antibody to test for the presence of monomer/misfolded SOD1 in sALS. METHODS: Sections from lumbar spinal cords of 5 fALS1 cases, 13 sALS cases, and 1 non-SOD1 fALS case were labeled immunocytochemically using SOD1-exposed-dimer-interface (SEDI) antibody, which we have previously validated as being specific for pathological monomer/misfolded forms of SOD1. RESULTS: Monomer/misfolded SOD1 was detected with SEDI antibody in all 5 of the fALS1 cases, localizing predominantly to hyaline conglomerate inclusions, a specific pathological feature of fALS1. In contrast, monomer/misfolded SOD1 was not detected in any of the 13 sALS cases or in the non-SOD1 fALS cases. These results were confirmed by immunoprecipitation. INTERPRETATION: Although SEDI antibody does not necessarily label all misfolded forms of SOD1, these findings show a distinct difference between fALS1 and sALS, and do not support that monomer/misfolded SOD1 is a common disease entity linking all types of ALS. This is important to our understanding of ALS disease pathogenesis and to considerations of the applicability of using therapeutics that target misfolded SOD1 to non-SOD1-related cases. Ann Neurol 2009;66:75-80.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Superóxido Dismutasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Pliegue de Proteína , Superóxido Dismutasa/genética , Superóxido Dismutasa-1
17.
Acta Neuropathol ; 119(3): 335-44, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20111867

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a conformational disease in which misfolding and aggregation of proteins such as SOD1 (familial ALS) and TDP-43 (sporadic ALS) are central features. The conformations adopted by such proteins within motor neurons in affected patients are not well known. We have developed a novel conformation-specific antibody (USOD) targeted against SOD1 residues 42-48 that specifically recognizes SOD1 in which the beta barrel is unfolded. Use of this antibody, in conjunction with the previously described SEDI antibody that recognizes the SOD1 dimer interface, allows a detailed investigation of the in vivo conformation of SOD1 at the residue-specific level. USOD and SEDI immunohistochemistry of spinal cord sections from ALS cases resulting from SOD1 mutations (A4V and DeltaG27/P28) shows that inclusions within remaining motor neurons contain SOD1 with both an unfolded beta barrel and a disrupted dimer interface. Misfolded SOD1 can also be immunoprecipitated from spinal cord extracts of these cases using USOD. However, in ten cases of sporadic ALS, misfolded SOD1 is not detected by either immunohistochemistry or immunoprecipitation. Using the amyloid-specific dyes, Congo Red and Thioflavin S, we find that SOD1-positive inclusions in familial ALS, as well as TDP-43- and ubiquitin-positive inclusions in sporadic ALS, contain non-amyloid protein deposits. We conclude that SOD1 misfolding is not a feature of sporadic ALS, and that both SOD1-ALS and sporadic ALS, rather than being amyloid diseases, are conformational diseases that involve amorphous aggregation of misfolded protein. This knowledge will provide new insights into subcellular events that cause misfolding, aggregation and toxicity.


Asunto(s)
Amiloide/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Deficiencias en la Proteostasis/genética , Deficiencias en la Proteostasis/patología , Superóxido Dismutasa/genética , Esclerosis Amiotrófica Lateral/metabolismo , Anticuerpos/química , Especificidad de Anticuerpos , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunohistoquímica , Inmunoprecipitación , Cuerpos de Inclusión/patología , Modelos Moleculares , Neuronas/patología , Conformación Proteica , Deficiencias en la Proteostasis/metabolismo , Superóxido Dismutasa/química , Superóxido Dismutasa/inmunología , Superóxido Dismutasa-1 , Proteinopatías TDP-43/patología , Ubiquitina/metabolismo
18.
Stroke ; 40(3 Suppl): S48-52, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19064767

RESUMEN

Most strokes are covert and observed incidentally on brain scans, but their presence increases risk of overt stroke and dementia. Amyloid angiopathy, associated with Alzheimer Disease (AD) causes stroke, and when even small strokes coexist with AD, they lower the threshold for dementia. Diffuse ischemic white matter disease impairs executive functioning, information processing speed, and gait. Neuroimaging techniques, such as tissue segmentation, Diffusion Tensor Imaging, MR Spectroscopy, functional MRI and amyloid PET, probe microstructural integrity, molecular biology, and activation patterns, providing new insights into brain-behavior relationships. MR-pathological studies of periventricular hyperintensity (leukoaraiosis) in aging and dementia reveal arteriolar tortuosity, reduced vessel density, and occlusive venous collagenosis which causes venous insufficiency and vasogenic edema. Activated microglia, oligodendroglial apoptosis, clasmatodendritic astrocytosis, and upregulated hypoxia-markers are seen on immunohistochemistry. Further research is needed to understand and treat this chronic subcortical vascular disease, which is epidemic in our aging population.


Asunto(s)
Envejecimiento/patología , Trastornos del Conocimiento/patología , Demencia Vascular/patología , Enfermedad de Alzheimer/patología , Humanos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Tomografía de Emisión de Positrones
19.
Neuropharmacology ; 55(8): 1376-82, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18775732

RESUMEN

The depression rate of C fibre-evoked spinal field potentials by spinally applied morphine is increased in two states of spinal hyperexcitation, namely the spinal ligation model (SNL) of neuropathic pain and long-term potentiation (LTP) of C fibre-evoked spinal field potentials. This present work sought to determine opioid receptor subtypes involved in such increase in the SNL model. We recorded spinal field potentials during spinal superfusion with increasing, cumulative concentrations of selective subtype-specific agonists in rats subjected to SNL, as well as in non-ligated animals. The mu opioid receptor (MOR) agonist DAMGO significantly depressed field potentials evoked by C (100 nM) or Adelta fibres (1 microM) both in neuropathic and non-ligated rats, whereas the kappa receptor opioid (KOR) agonist +/-U-50488 was ineffective. The delta opioid receptor (DOR) (D-Ala2)-Deltorphin II was more effective in reducing C fibre-evoked spinal field potentials in rats subjected to SNL (100 nM) than in non-ligated rats (100 microM). Subclinical MOR activation (10 nM DAMGO) produced a leftward shift in (D-Ala2)-Deltorphin II dose-response curve in non-ligated rats (IC50 16.59 +/- 0.99 microM vs 120.3 +/- 1.0 microM in the absence of DAMGO), and isobolar analysis revealed synergistic interaction (interaction index 0.25). MOR blockade (100 microM CTOP) disinhibited C fibre-evoked potentials in neuropathic, but not in basal animals, and partially impeded DOR depression in both groups. DOR blockade (1 mM naltrindole) was ineffective in either group. We show that DOR-mediated depression of spinal responses to peripheral unmyelinated fibre-input is increased in the SNL model, an increase that is contributed to by positive interaction with the spinal MOR.


Asunto(s)
Potenciales Evocados/fisiología , Fibras Nerviosas Amielínicas/fisiología , Neuralgia/patología , Neuralgia/fisiopatología , Receptores Opioides mu/metabolismo , Médula Espinal/fisiopatología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Analgésicos no Narcóticos/farmacología , Analgésicos no Narcóticos/uso terapéutico , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Animales , Conducta Animal , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Encefalina Ala(2)-MeFe(4)-Gli(5)/uso terapéutico , Potenciales Evocados/efectos de los fármacos , Masculino , Antagonistas de Narcóticos/farmacología , Fibras Nerviosas Amielínicas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Somatostatina/análogos & derivados , Somatostatina/farmacología
20.
Virchows Arch ; 452(2): 221-7, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18188596

RESUMEN

Erdheim-Chester disease is a rare xanthomatosis that may present with characteristic radiologic and histologic features. There have been conflicting reports regarding the nature of this process, including whether it represents a reactive or neoplastic lesion. We present the clinical histories, pathologic findings, and an analysis of clonality using the HUMARA assay in two patients diagnosed with Erdheim-Chester disease. One case has previously been documented in the literature. Histologically, both cases demonstrated sheets of foamy xanthomatous histiocytes with widespread infiltration of the viscera. These regions were punctuated by variable amounts of inflammation, including lymphocytes, plasma cells, and occasional Touton-type giant cells. The histiocytes were immunoreactive for CD68 and CD163; they did not stain with S100 or CD1a. One case was found to be monoclonal; however, the second case had extensive DNA degradation; thus, clonality could not be assessed. In addition to contributing an additional report of this rare disease to the literature, we demonstrate the histiocytes to express CD163, thereby further supporting a monocyte/macrophage basis. Moreover, in confirming clonality, our observations lend additional evidence to the view that Erdheim-Chester disease represents a neoplastic process.


Asunto(s)
Células Clonales/patología , Enfermedad de Erdheim-Chester/patología , Histiocitos/patología , Xantomatosis/patología , Adulto , Anciano , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Biomarcadores/metabolismo , Cromosomas Humanos X , Células Clonales/metabolismo , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/metabolismo , Resultado Fatal , Femenino , Histiocitos/metabolismo , Humanos , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Receptores de Superficie Celular/metabolismo , Xantomatosis/genética , Xantomatosis/metabolismo
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