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BACKGROUND AND PURPOSE: Heterozygous mutations in the STUB1 gene have recently been associated with an autosomal dominant form of spinocerebellar ataxia (SCA) associated with cerebellar cognitive-affective syndrome (CCAS), named SCA48. METHODS: Molecular screening was performed in a cohort of 235 unrelated patients with adult-onset, autosomal dominant (17) or sporadic (218) cerebellar ataxia, negative for pathological trinucleotide expansions in the common SCAs, FRDA and FXTAS loci, by using targeted multigene panels or whole-exome sequencing. Bioinformatics analyses, detailed neurological phenotyping and family segregation studies corroborated the pathogenicity of the novel STUB1 mutations. Clinico-diagnostic findings were reviewed to define the phenotypic spectrum. RESULTS: Eight heterozygous STUB1 mutations were identified, six of which were novel in 11 patients from eight index families, giving an estimated overall frequency of 3.4% (8/235) for SCA48 in our study cohort, rising to 23.5% (4/17) when considering only familial cases. All our SCA48 patients had cerebellar ataxia and dysarthria associated with cerebellar atrophy on brain magnetic resonance imaging; of note, many cases were also associated with parkinsonism, chorea and dystonia. CCAS also occurred frequently, whereas definite signs of pyramidal tract dysfunction and peripheral nervous system involvement were absent. One SCA48 patient presented with hypogonadism, associated with other autoimmune endocrine dysfunctions. CONCLUSIONS: Our results support SCA48 as a significant cause of adult-onset SCA. Besides CCAS, our SCA48 patients often showed movement disorders and other clinical manifestations previously described in SCAR16, linked to biallelic variants in the same gene, thus suggesting a continuous clinical spectrum and significant overlap amongst recessive and dominantly inherited mutations in STUB1.
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Ataxias Espinocerebelares/fisiopatologia , Adulto , Idade de Início , Idoso , Encéfalo/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Estudos de Coortes , Feminino , Humanos , Itália , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/etiologia , Mutação/genética , Fenótipo , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos , Ubiquitina-Proteína Ligases/genéticaRESUMO
BACKGROUND AND PURPOSE: Hereditary ataxias are heterogeneous groups of neurodegenerative disorders, characterized by cerebellar syndromes associated with dysarthria, oculomotor and corticospinal signs, neuropathy and cognitive impairment. Recent reports have suggested mutations in the SPG7 gene, causing the most common form of autosomal recessive spastic paraplegia (MIM#607259), as a main cause of ataxias. The majority of described patients were homozygotes or compound heterozygotes for the c.1529C>T (p.Ala510Val) change. We screened a cohort of 895 Italian patients with ataxia for p.Ala510Val in order to define the prevalence and genotype-phenotype correlation of this variant. METHODS: We set up a rapid assay for c.1529C>T using restriction enzyme analysis after polymerase chain reaction amplification. We confirmed the diagnosis with Sanger sequencing. RESULTS: We identified eight homozygotes and 13 compound heterozygotes, including two novel variants affecting splicing. Mutated patients showed a pure cerebellar ataxia at onset, evolving in mild spastic ataxia (alternatively) associated with dysarthria (~80% of patients), urinary urgency (~30%) and pyramidal signs (~70%). Comparing homozygotes and compound heterozygotes, we noted a difference in age at onset and Scale for the Assessment and Rating of Ataxia score between the two groups, supporting an earlier and more severe phenotype in compound heterozygotes versus homozygotes. CONCLUSIONS: The SPG7 c.1529C>T (p.Ala510Val) mutants accounted for 2.3% of cerebellar ataxia cases in Italy, suggesting that this variant should be considered as a priority test in the presence of late-onset pure ataxia. Moreover, the heterozygous/homozygous genotype appeared to predict the onset of clinical manifestation and disease progression.
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ATPases Associadas a Diversas Atividades Celulares/genética , Ataxia Cerebelar/epidemiologia , Ataxia Cerebelar/genética , Metaloendopeptidases/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Estudos de Associação Genética , Heterozigoto , Homozigoto , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , PrevalênciaRESUMO
INTRODUCTION: PARK20 is a rare autosomal recessive parkinsonism related to the SYNJ1 gene and characterized by early-onset of disease and atypical signs such as supranuclear vertical gaze palsy, dementia, dystonia, and generalized tonic-clonic seizures. OBJECTIVE: Non-motor features and cardiac sympathetic innervation were assessed in two siblings affected by parkinsonism who harboured the homozygous Arg258Gln mutation in the SYNJ1 gene. METHODS: The Non-Motor Symptoms, the SCOPA-AUT, the Mayo Sleep Questionnaires and polysomnography were used to investigate non-motor signs (NMS), autonomic dysfunction and REM Behavioural Disorder (RBD). Cognitive functions were examined by an extensive battery of neuropsychological tests. In addition, motor and sensory nerve conduction studies and evoked laser potentials were performed. Cardiac sympathetic innervation was assessed in the two patients by (123)I-metaiodobenzylguanidine (MIBG) scintigraphy, computing early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates (WR). RESULTS: Among the non-motor symptoms and autonomic signs, case 1 had cold intolerance, drooling and dysphagia, while case 2 had pain and urinary dysfunction. Both cases showed mood and behavioural disorders. RBD were not found, whereas the neuropsychological assessment revealed a progressive cognitive impairment. Neurophysiological studies revealed no abnormalities. Indexes of cardiac sympathetic innervation in the two patients did not differ from those of control subjects. CONCLUSIONS: Our findings expand the phenotypic profile of SYNJ1-related parkinsonism. Preserved cardiac sympathetic function and absence of RBD suggest that PARK20 should be explained by a pathogenic mechanism different from Lewy Body pathology, or that the latter is not as widespread as idiopathic Parkinson's disease.
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Coração/inervação , Doença de Parkinson/complicações , Doença de Parkinson/genética , Monoéster Fosfórico Hidrolases/genética , Sistema Nervoso Simpático/fisiopatologia , Adulto , Coração/diagnóstico por imagem , Humanos , Masculino , Mutação , Imagem de Perfusão do Miocárdio , Doença de Parkinson/fisiopatologia , Fenótipo , IrmãosRESUMO
BACKGROUND: Autosomal recessive (AR) spastic paraplegia type 5 (SPG5) is due to mutations in the CYP7B1 gene, encoding for the cytochrome P450-7B1, responsible for oxysterols 7α-hydroxylation. Oxysterol/cholestenoic acids pool plays a role in motor neuron survival and immune response. SPG5 is characterized by white matter abnormalities at brain resonance imaging (MRI). In view of clinical presentation and MRI findings, multiple sclerosis (MS) is a possible differential diagnosis of SPG5. This study aimed to evaluate the frequency of CYP7B1 mutations in patients with MS. METHODS: One hundred and seventeen MS patients with clinical spastic paraplegia or possible AR transmission were selected for the mutational screening. RESULTS: Forty-three patients had primary progressive, 26 relapsing remitting, 26 secondary progressive, and 22 relapsing progressive MS clinical course. No CYP7B1 homozygous mutations were identified. Two novel variants and one pathogenic mutation were found at heterozygous state. CONCLUSIONS: The two novel variants cosegregated with pyramidal signs and autoimmune diseases suggesting that they might be susceptibility factors. Reduced cytochrome P450-7B1 enzymatic activity could alter the balance among neurotoxic and neuroprotective oxysterols promoting motor neuron degeneration and/or immune response.
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Família 7 do Citocromo P450/genética , Esclerose Múltipla/genética , Paraplegia Espástica Hereditária/genética , Esteroide Hidroxilases/genética , Adolescente , Adulto , Encéfalo/patologia , Criança , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico , Mutação , Paraplegia Espástica Hereditária/complicações , Paraplegia Espástica Hereditária/diagnósticoRESUMO
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease due to mutations in SACS, which encodes sacsin, a protein localized on the mitochondrial surface and possibly involved in mitochondrial dynamics. In view of the possible mitochondrial involvement of sacsin, we investigated mitochondrial activity at functional and molecular level in skin fibroblasts obtained from ARSACS patients. We observed remarkable bioenergetic damage in ARSACS cells, as indicated by reduced basal, adenosine triphosphate (ATP)-linked and maximal mitochondrial respiration rate, and by reduced respiratory chain activities and mitochondrial ATP synthesis. These phenomena were associated with increased reactive oxygen species production and oxidative nuclear DNA damage. Our results suggest that loss of sacsin is associated with oxidative stress and mitochondrial dysfunction, and thus highlight a novel mechanism in the pathogenesis of ARSACS. The involvement of mitochondria and oxidative stress in disease pathogenesis has been described in a number of other neurodegenerative diseases. Therefore, on the basis of our findings, which suggest a potential therapeutic role for antioxidant agents, ARSACS seems to fall within a larger group of disorders.
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Fibroblastos/metabolismo , Doenças Mitocondriais/metabolismo , Espasticidade Muscular/metabolismo , Estresse Oxidativo/fisiologia , Pele/metabolismo , Ataxias Espinocerebelares/congênito , Adulto , Feminino , Proteínas de Choque Térmico/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/etiologia , Espasticidade Muscular/complicações , Espasticidade Muscular/genética , Pele/citologia , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismoRESUMO
BACKGROUND AND PURPOSE: Apathy may be either a symptom of major depression or a behavioral disturbance occurring in concomitance with depression or alone in Parkinson's disease (PD). The aim of the present study was to determine the progression of cognitive impairment in drug-naïve untreated PD patients with or without clinically significant apathy. METHODS: Sixty-two PD patients with a disease duration <2 years and without history of present or past therapy with pro-dopaminergic agents were included and underwent the Apathy Evaluation Scale (S-AES), a clinical interview based on diagnostic criteria for apathy and a comprehensive neuropsychological battery to assess memory, frontal functions and visuospatial functions. Two years after the first assessment, all patients were re-evaluated on the S-AES, a clinical interview and neuropsychological tests. RESULTS: According to the cut-off value of the S-AES and diagnostic criteria for apathy, eight patients experienced apathy at both baseline and follow-up (A+A+), nine patients had apathy only at follow-up (A-A+), 37 patients never experienced apathy (A-A-) and eight patients showed apathy at the baseline only (A+A-). Cognitive performance significantly declined in all four groups. At both baseline and follow-up A+A+ performed worse than A-A- on visuospatial and frontal tests; A-A+ had lower scores than A-A- on the interference task of the Stroop test (IT-ST). Regression analysis showed that poor performance on the IT-ST at baseline was the only independent predictor of onset of apathy at follow-up. CONCLUSIONS: The results indicated a relationship between apathy and dysexecutive syndrome in early PD. Reduced scores on the IT-ST may predict development of apathy in PD patients.
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Apatia/fisiologia , Transtornos Cognitivos/etiologia , Função Executiva/fisiologia , Doença de Parkinson/complicações , Idoso , Transtornos Cognitivos/fisiopatologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologiaRESUMO
Metabolic ataxias are rare. They usually start in the childhood and often have autosomal recessive inheritance. They may also present in adulthood. The diagnosis is important since some patients may be successfully managed with diet and treatments.
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BACKGROUND AND PURPOSE: Cognitive impairment is common in Parkinson's disease (PD), even in the early stages. We aimed to assess the relationship between insulin-like growth factor-1 (IGF-1) and cognitive functions in early, drug-naïve patients with PD. METHODS: Serum IGF-1 was measured in 65 early, drug-naïve patients with PD that underwent a complete neuropsychological battery at baseline and after 2â years. Linear regression analysis was used to evaluate the relationships between neuropsychological scores and IGF-1. Repeated-measures anova was applied to assess changes in neuropsychological variables over time. RESULTS: At baseline, IGF-1 levels were related to phonological fluency. At follow-up, IGF-1 levels were associated with the Rey auditory verbal learning test (RAVLT) - immediate and delayed recall, Frontal Assessment Battery, verbal span and Benton judgement of the line orientation test. Patients with low IGF-1 levels at baseline showed a significantly faster decline of performances than patients with high IGF-1 levels on immediate and delayed recall of the RAVLT and interference task of the Stroop test. CONCLUSIONS: Low serum IGF-1 levels are related to poor performance on executive tasks in early, drug-naïve patients with PD, and may predict poor performance on attention/executive and verbal memory tasks after a 2-year follow-up.
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Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Fator de Crescimento Insulin-Like I/metabolismo , Doença de Parkinson/sangue , Doença de Parkinson/complicações , Estimulação Acústica , Análise de Variância , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Análise de Regressão , Aprendizagem Verbal/fisiologiaRESUMO
OBJECTIVE: To characterize brain metabolic changes associated with mild cognitive impairment (MCI) in drug-naive patients with Parkinson disease (PD) using (18)F-fluorodeoxyglucose (FDG) and PET (FDG-PET). METHODS: This cross-sectional study included newly diagnosed patients with PD with MCI in single or multiple domain (PD-MCI; n =12) and without MCI (PD-nMCI; n =12), and healthy controls (n =12). The groups were matched for age. Moreover, the patient groups were matched for motor disability. All subjects underwent a FDG-PET study. Cerebral regional relative metabolic maps were compared in PD-MCI, PD-nMCI, and controls using regions of interest analysis (ROIs) and voxel-based analysis with statistical parametric mapping. RESULTS: ROIs and voxel-based analyses revealed significant relative hypometabolism in the prefrontal, superior/inferior parietal, and associative occipital cortices as well as in the striatum in patients with PD-MCI relative to controls (p < 0.05) and to a lesser extent in patients with PD-nMCI. In contrast, patients with PD-nMCI did not show significant metabolic changes as compared to controls. CONCLUSION: MCI in patients with PD is associated with cortical hypometabolism since the earliest stage, independent of therapy or motor disability. The early involvement of posterior cortical region, a pattern shared by advanced stages of PD-MCI and PD with dementia, could represent an early marker of dementia. The relevance of this pattern in predicting prodromal dementia has to be evaluated in longitudinal studies.
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Mapeamento Encefálico , Córtex Cerebral/metabolismo , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Doença de Parkinson/complicações , Idoso , Análise de Variância , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Distribuição de Qui-Quadrado , Transtornos Cognitivos/diagnóstico por imagem , Feminino , Fluordesoxiglucose F18 , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de PósitronsRESUMO
Different lines of evidence suggest that higher intake of fiber may somehow protect against metabolic syndrome. The prebiotic inulin has widely been studied in relation to its putative beneficial effects on lipid and glucose metabolism. Therefore, adding inulin to diet may be a suitable strategy to prevent metabolic syndrome. Aim of the present study was to evaluate the effects of the daily consumption of inulin-enriched pasta on lipid and glucose metabolism as well as on gastrointestinal motility in young healthy subjects. Methods. Twenty-two healthy young male volunteers entered a randomized double blind cross-over study consisting of a 2-weeks a run-in period, two 5-weeks study periods (11% inulin-enriched or control pasta), and an 8-weeks wash-out period in between. Serum lipid and glucose concentrations were evaluated by routine biochemical analyses. Gastric emptying time and electrical activity were non-invasively evaluated by ultrasound and electrogastrography. Data were analyzed by Friedman Repeated Measures ANOVA test. Results. Significant differences among baseline and the treatment group were found for HDL-cholesterol (p=0.004), total cholesterol/HDL-cholesterol ratio (p=0.006), triglycerides (p=0.04), fasting glucose level (p=0.044), fructosamine (p=0.0478), HbA1c (p=0.04), and homeostatic model assessment (HOMA-IR) (p=0.045). The gastric emptying, expressed as final emptying time, was found significantly delayed in the group that assumed inulin-enriched pasta (p=0.008). Conclusions. Inulin-enriched pasta improved lipidic and glicidic metabolism as well as the insulin resistance in healthy young subjects. In addition, it delayed the gastric emptying time which may represent the physiological counterpart of its metabolic effects.
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Glicemia/metabolismo , Carboidratos da Dieta/administração & dosagem , Inulina/administração & dosagem , Lipídeos/sangue , Adolescente , Colesterol/sangue , Estudos Cross-Over , Dieta , Fibras na Dieta , Método Duplo-Cego , Esvaziamento Gástrico , Humanos , Resistência à Insulina , Masculino , Prebióticos , Triglicerídeos/sangueRESUMO
Left ventricular hypertrophy (LVH) is a frequent finding in Friedreich's ataxia (FRDA). In previous studies treatment with idebenone, a synthetic analogue of coenzyme Q10, has been associated with a substantial decrease in myocardial hypertrophy, despite great variability in cardiac responsiveness among patients. Here we present the results of a retrospective analysis of a cohort of 35 patients (20 with LVH, 15 without LVH) with confirmed molecular diagnosis of FRDA, treated with idebenone 5 mg/kg/day for up to five years. At the end of the study, we found an increase of interventricular septum and posterior wall thickness in the group without LVH before treatment and no change in the group with LVH before treatment. The neurological picture of the disease significantly deteriorated with time in both groups.
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Antioxidantes/uso terapêutico , Ataxia de Friedreich/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Ubiquinona/análogos & derivados , Adulto , Análise de Variância , Estudos de Coortes , Ecocardiografia , Feminino , Seguimentos , Ataxia de Friedreich/complicações , Ataxia de Friedreich/patologia , Coração/efeitos dos fármacos , Septos Cardíacos/diagnóstico por imagem , Septos Cardíacos/efeitos dos fármacos , Septos Cardíacos/patologia , Humanos , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/patologia , Masculino , Miocárdio/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Ubiquinona/uso terapêuticoRESUMO
Autonomic nervous system dysfunction is part of the spinocerebellar ataxia (SCA) clinical picture, but few data are available on this topic. The present study is aimed to report a detailed investigation of autonomic nervous system in patients with molecular diagnosis of SCA type 2, one of the most frequent forms and the commonest in Italy. Nine patients with a mild to moderate form of SCA2 underwent a questionnaire about dysautonomic symptoms and a complete cardiovascular neurophysiologic evaluation of both sympathetic and parasympathetic system, comprising head-up tilt, standing, isometric hand grip, cold pressure, mental arithmetic, Valsalva manoeuvre, deep breathing, and hyperventilation tests. An echocardiographic study and Holter-ECG recording were also performed. All patients complained dysautonomic problems regarding urinary tract, cardiovascular system, or gastrointestinal dysfunction. The neurophysiologic study showed both sympathetic and parasympathetic involvement, with highly variable degree and pattern of dysautonomia. The present study results show that the autonomic dysfunction is common in SCA2 representing a significant component of the complex picture of the disease. We found a wide spectrum of cardiovascular autonomic abnormalities, without a typical pattern of dysfunction and without correlation with clinical variables.
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Doenças do Sistema Nervoso Autônomo/etiologia , Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Ataxias Espinocerebelares/complicações , Adulto , Ecocardiografia/métodos , Eletroencefalografia , Feminino , Força da Mão/fisiologia , Humanos , Hiperventilação/etiologia , Magnetoterapia/métodos , Masculino , Pessoa de Meia-Idade , Postura , Índice de Gravidade de Doença , Ataxias Espinocerebelares/patologia , Inquéritos e Questionários , Manobra de Valsalva/fisiologia , Adulto JovemRESUMO
AIMS AND BACKGROUND: Various genes have been identified for monogenic disorders resembling Parkinson's disease. The products of some of these genes are associated with mitochondria and have been implicated in cellular protection against oxidative damage. In the present study we analysed fibroblasts from a patient carrying the homozygous mutation p.W437X in the PTEN-induced kinase 1 (PINK1), which manifested a very early onset parkinsonism. RESULTS: Patient's fibroblasts did not show variation in the mtDNA copy number or in the expression of the oxidative phosphorylation complexes. Sequence analysis of the patient's mtDNA presented two new missense mutations in the ND5 (m.12397A>G, p.T21A) and ND6 (m. 14319T>C, p.N119D) genes coding for two subunits of complex I. The two mutations were homoplasmic in both the patient and the patient's mother. Patient's fibroblasts resulted in enhanced constitutive production of the superoxide anion radical that was abrogated by inhibitor of the complex I. Moreover enzyme kinetic analysis of the NADH:ubiquinone oxidoreductase showed changes in the substrates affinity. CONCLUSION: To our knowledge, this is the first report showing co-segregation of a Parkinson's disease related nuclear gene mutation with mtDNA mutation(s). Our observation might shed light on the clinical heterogeneity of the hereditary cases of Parkinson's disease, highlighting the hitherto unappreciated impact of coexisting mtDNA mutations in determining the development and the clinical course of the disease.
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DNA Mitocondrial/química , Complexo I de Transporte de Elétrons/genética , Mutação de Sentido Incorreto , Transtornos Parkinsonianos/genética , Proteínas Quinases/genética , Adulto , Células Cultivadas , Análise Mutacional de DNA , DNA Mitocondrial/análise , Complexo I de Transporte de Elétrons/metabolismo , Feminino , Fibroblastos/enzimologia , Fibroblastos/metabolismo , Genótipo , Humanos , Fosforilação Oxidativa , Transtornos Parkinsonianos/enzimologia , Transtornos Parkinsonianos/metabolismo , Fenótipo , Superóxidos/metabolismoRESUMO
OBJECTIVE: Neuropathological descriptions of the brain in Friedreich's ataxia (FRDA) were obtained before availability of the current molecular genetic tests for this disease. Voxel-based morphometry (VBM) enables an unbiased whole-brain quantitative analysis of differences in gray matter (GM) and white matter (WM) volume. METHODS: Using VBM, we assessed the brain structural damage in 22 patients with genetically confirmed FRDA and 25 healthy controls. The results were correlated with the disease duration and the severity of the patients' clinical deficits--evaluated using the International Cerebellar Ataxia Rating Scale and Inherited Ataxia Clinical Rating Scale. RESULTS: In patients with FRDA, VBM showed a symmetrical volume loss in dorsal medulla, infero-medial portions of the cerebellar hemispheres, the rostral vermis and in the dentate region. No volume loss in cerebral hemispheres was observed. The atrophy of the cerebellum and medulla correlated with the severity of the clinical deficit and disease duration. CONCLUSIONS: In patients with FRDA, significant GM and WM loss was observed only in the cerebellum and dorsal medulla. These structural changes correlate with the severity of the clinical deficit and disease duration.
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Encéfalo/anatomia & histologia , Encéfalo/fisiopatologia , Ataxia de Friedreich/diagnóstico , Ataxia de Friedreich/fisiopatologia , Adolescente , Adulto , Idoso , Alelos , Atrofia/patologia , Atrofia/fisiopatologia , Cerebelo/patologia , Cerebelo/fisiopatologia , Giro Denteado/patologia , Giro Denteado/fisiopatologia , Avaliação da Deficiência , Progressão da Doença , Feminino , Ataxia de Friedreich/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de TempoAssuntos
Ataxia/epidemiologia , Ataxia/genética , DNA Polimerase Dirigida por DNA/genética , Adolescente , Adulto , Idade de Início , Substituição de Aminoácidos , Criança , Pré-Escolar , DNA Polimerase gama , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação/genéticaRESUMO
The study of the role of glycemia in the causation of cardiovascular disease has been limited by several factors, above all by its measurement over time. Non enzymatic glycated proteins in the blood, the product of the non enzymatic reaction of a reducing sugar with the reactive amino acid of a target protein, are an integrated measure of blood glucose over days to weeks. They have been used in the management of clinical diabetes mellitus, but are still infrequently used in epidemiological studies in non diabetic subjects. There are few epidemiological studies that show that glycated hemoglobin, fructosamine, an index of total non enzymatic glycated proteins in the blood, and glycated apolipoprotein B and other non enzymatic glycated proteins in the blood in non diabetic subjects are associated with cardiovascular diseases. In this paper we review: 1) the overall mechanisms of non enzymatic glycation of proteins; 2) the measurement of glycated hemoglobin, fructosamine, and glycated apolipoprotein B and their relationship with blood glucose levels in non diabetic subjects; 3) the association of glycated hemoglobin, fructosamine and glycated apolipoprotein B with cardiovascular disease. We conclude that non enzymatic glycation of protein in the blood is associated with cardiovascular disease also in non diabetic subjects, and could be used to define dietary risk factors of cardiovascular disease.
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Glicemia/metabolismo , Doenças Cardiovasculares/sangue , Frutosamina/sangue , Hemoglobinas Glicadas/metabolismo , Produtos Finais de Glicação Avançada/sangue , Lipoproteínas LDL/sangue , Animais , Biomarcadores/sangue , Análise Química do Sangue/métodos , Doenças Cardiovasculares/etiologia , Glicosilação , Humanos , Fatores de RiscoRESUMO
AIMS: To evaluate the association of serum concentrations of glycated apolipoprotein B (ApoBg) with the incidence of myocardial infarction (MI) in subjects with and without diabetes. METHODS: The design is a nested case-control study. The cohort included 5632 subjects over 50 years of age attending the clinical laboratories of a small geographic area in southern Italy. After five years, 4563 subjects were traced and 103 had developed MI. We sampled from the cohort two controls for each incident case of MI, frequency matched for sex and diabetes. ApoBg was measured using a monoclonal antibody. Logistic regression was used for statistical analysis of the data. RESULTS: ApoBg at baseline was higher in subjects who developed myocardial infarction than in controls in both non-diabetic and diabetic subjects (t test, P=0.009 and P=0.05 respectively). MI odds ratio in the third tertile of ApoBg was 2.01 (95% CI 0.93-4.33) in non-diabetic and 2.88 (0.85-9.68) in diabetic subjects (chi-square test for trend; non-diabetics P=0.03, diabetics P=0.06). Serum triglycerides, cholesterol, HDL and LDL cholesterol, glucose and insulin were not associated with MI (P>0.10). CONCLUSION: ApoBg at baseline is directly associated with the development of MI in the following five years in both diabetic and non-diabetic individuals.
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Lipoproteínas LDL/sangue , Infarto do Miocárdio/etiologia , Idoso , Aterosclerose/sangue , Aterosclerose/etiologia , Estudos de Casos e Controles , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos de Coortes , Eletrocardiografia , Feminino , Produtos Finais de Glicação Avançada , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/mortalidade , Razão de ChancesRESUMO
Post-marketing surveillance studies are needed to assess the long-term safety, compliance and clinical efficacy of interferon beta-1a (IFNbeta-1a) therapy in multiple sclerosis (MS) patients. The goals of this study were to (i) assess the safety, compliance and clinical efficacy of long-term intramuscular (i.m.) IFNbeta-1a therapy in a large cohort of patients, and (ii) suggest possible predictors of therapeutic response. A total of 255 patients were included in the study. Mean time on therapy was 31.7 +/- 19.3 months. Within 3 years, 31% of patients discontinued treatment, mainly for disease activity. No significant sustained blood analysis alteration was observed over time, apart from a decrease of cholesterol levels. After 3 years of treatment, mean Expanded Disability Status Scale (EDSS) scores increased by 0.4 points compared with baseline. The mean annual relapse rate was reduced compared with baseline. Patients with < or = 2 relapses in the previous 2 years and with baseline EDSS scores of < or = 2 had a longer estimated time to first relapse and to progression and first relapse, respectively. These results confirm the safety and suggest a sustained effectiveness of i.m. IFNbeta-1a, extending the reported follow-up period to 6.3 years, and hypothesize the presence of possible predictors of clinical outcome.