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1.
Neurology ; 93(20): e1906-e1916, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31594857

RESUMO

OBJECTIVE: In the phase II, randomized, double-blind, placebo-controlled Supplementation of Vigantol Oil versus Placebo Add-on in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) Receiving Rebif Treatment (SOLAR) study (NCT01285401), we assessed the efficacy and safety of add-on vitamin D3 in patients with RRMS. METHODS: Eligible patients with RRMS treated with SC interferon-ß-1a (IFN-ß-1a) 44 µg 3 times weekly and serum 25(OH)D levels <150 nmol/L were included. From February 15, 2011, to May 11, 2015, 229 patients were included and randomized 1:1 to receive SC IFN-ß-1a plus placebo (n = 116) or SC IFN-ß-1a plus oral high-dose vitamin D3 14,007 IU/d (n = 113). The revised primary outcome was the proportion of patients with no evidence of disease activity (NEDA-3) at week 48. RESULTS: At 48 weeks, 36.3% of patients who received high-dose vitamin D3 had NEDA-3, without a statistically significant difference in NEDA-3 status between groups (placebo 35.3%; odds ratio 0.93; 95% confidence interval [CI] 0.53-1.63; p = 0.80). Compared with placebo, the high-dose vitamin D3 group had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI 0.52-0.89; p = 0.0045) and change from baseline in total volume of T2 lesions (difference in mean ranks: -0.074; p = 0.035). CONCLUSIONS: SOLAR did not establish a benefit for high-dose vitamin D3 as add-on to IFN-ß-1a, based on the primary outcome of NEDA-3, but findings from exploratory outcomes suggest protective effects on development of new MRI lesions in patients with RRMS. CLINICALTRIALSGOV IDENTIFIER: NCT01285401. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS treated with SC IFN-ß-1a, 48 weeks of cholecalciferol supplementation did not promote NEDA-3 status.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Colecalciferol/administração & dosagem , Interferon beta-1a/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Vitaminas/administração & dosagem , Adulto , Encéfalo/diagnóstico por imagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Resultado do Tratamento , Vitamina D/análogos & derivados , Vitamina D/sangue
2.
J Neuroimaging ; 29(3): 383-393, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30714241

RESUMO

BACKGROUND AND PURPOSE: While AD can be definitively confirmed by postmortem histopathologic examination, in vivo imaging may improve the clinician's ability to identify AD at the earliest stage. The aim of the study was to test the performance of amyloid PET using new processing imaging algorithm for more precise diagnosis of AD. METHODS: Amyloid PET results using a new processing imaging algorithm (MRI-Less and AAL Atlas) were correlated with clinical, cognitive status, CSF analysis, and other imaging. The regional SUVR using the white matter of cerebellum as reference region and scores from clinical and cognitive tests were used to create ROC curves. Leave-one-out cross-validation was carried out to validate the results. RESULTS: Forty-four consecutive patients with clinical evidence of dementia, were retrospectively evaluated. Amyloid PET scan was positive in 26/44 patients with dementia. After integration with 18F-FDG PET, clinical data and CSF protein levels, 22 of them were classified as AD, the remaining 4 as vascular or frontotemporal dementia. Amyloid and FDG PET, CDR 1, CSF Tau, and p-tau levels showed the best true positive and true negative rates (amyloid PET: AUC = .85, sensitivity .91, specificity .79). A SUVR value of 1.006 in the inferior frontal cortex and of 1.03 in the precuneus region was the best cutoff SUVR value and showed a good correlation with the diagnosis of AD. Thirteen of 44 amyloid PET positive patients have been enrolled in clinical trials using antiamyloid approaches. CONCLUSIONS: Amyloid PET using SPM-normalized SUVR analysis showed high predictive power for the differential diagnosis of AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Estilbenos , Idoso , Doença de Alzheimer/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade
3.
J Neurol ; 265(12): 2851-2860, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30259178

RESUMO

In this retrospective, multicenter, real-world study we collected clinical and magnetic resonance imaging (MRI) data of all patients (n = 40) with relapsing-remitting multiple sclerosis (RRMS) treated with alemtuzumab according to a "free-of-charge" protocol available before the drug marketing approval in Italy. Almost all (39/40) started alemtuzumab after discontinuing multiple disease-modifying treatments (DMTs) because of either lack of response or safety concerns. We considered the proportion of alemtuzumab-treated patients who had no evidence of disease activity (NEDA-3) and disability improvement over a 36-month follow-up period. NEDA-3 was defined as absence of relapses, disability worsening, and MRI activity. Disability improvement was defined as a sustained reduction of ≥ 1-point in Expanded Disability Status Scale (EDSS) score. At follow-up, 18 (45%) patients achieved NEDA-3, 30 (75%) were relapse-free, 33 (82.5%) were EDSS worsening-free, and 25 (62.5%) were MRI activity-free. Eleven (27.5%) patients had a sustained disability improvement. We found no predictor for the NEDA-3 status, while the interaction of higher EDSS score by higher number of pre-alemtuzumab relapses was associated with a greater chance of disability improvement (odds ratio 1.10, p = 0.049). Our study provides real-world evidence that alemtuzumab can promote clinical and MRI disease remission, as well as disability improvement, in a significant proportion of patients with RRMS despite prior multiple DMT failures. The drug safety profile was consistent with data available from clinical trials.


Assuntos
Alemtuzumab/uso terapêutico , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Alemtuzumab/efeitos adversos , Feminino , Seguimentos , Humanos , Fatores Imunológicos/efeitos adversos , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Resultado do Tratamento
4.
J Neurotrauma ; 34(16): 2475-2479, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28385104

RESUMO

The mechanisms involved in secondary brain injury after the acute phase of severe traumatic brain injury (TBI) are largely unknown. Ongoing axonal degeneration, consequent to the initial trauma, may lead to secondary brain injury. To test this hypothesis, we evaluated the cerebrospinal fluid (CSF) level of neurofilament light chain (NF-L), a proposed marker of axonal degeneration, in 10 patients who developed a severe disorder of consciousness after a TBI, including 7 in a minimally conscious state and 3 with unresponsive wakefulness syndrome (time since brain injury, 309 ± 169 days). CSF NF-L level was measured with a commercially available NF-L enzyme-linked immunosorbent assay. CSF NF-L level was very high in all 10 patients, ranging from 2.4- to 60.5-fold the upper normal limit (median value, 4458 pg/mL; range, 695-23,000). Moreover, NF-L level was significantly higher after a severe TBI than in a reference group of 9 patients with probable Alzheimer's disease, a population with elevated levels of CSF NF-L attributed to neuronal degeneration (median value, 1173 pg/mL; range, 670-3643; p < 0.01). CSF NF-L level was correlated with time post-TBI (p = 0.04). These results demonstrate prolonged secondary brain injury, suggesting that patients exhibit ongoing axonal degeneration up to 19 months after a severe TBI.


Assuntos
Lesões Encefálicas Traumáticas/líquido cefalorraquidiano , Transtornos da Consciência/líquido cefalorraquidiano , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Adolescente , Adulto , Biomarcadores/líquido cefalorraquidiano , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
5.
Mult Scler ; 20(6): 705-16, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24126064

RESUMO

BACKGROUND: In previous studies, teriflunomide significantly reduced the annualised relapse rate (ARR) and disability progression. OBJECTIVE: This phase 3, rater-blinded study (NCT00883337) compared teriflunomide with interferon-beta-1a (IFNß-1a). METHODS: Patients with relapsing multiple sclerosis were randomised (1:1:1) to oral teriflunomide 7-or 14 mg, or subcutaneous IFNß-1a 44 µg. The primary composite endpoint was time to failure, defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any cause. Secondary endpoints included ARR, Fatigue Impact Scale (FIS) and Treatment Satisfaction Questionnaire for Medication (TSQM). The study was completed 48 weeks after the last patient was randomised. RESULTS: Some 324 patients were randomised (IFNß-1a: 104; teriflunomide 7 mg: 109; teriflunomide 14 mg: 111). No difference in time to failure was observed. There was no difference in ARR between teriflunomide 14 mg and IFNß-1a, but ARR was significantly higher with teriflunomide 7 mg. FIS scores indicated more frequent fatigue with IFNß-1a, though differences were only significant with teriflunomide 7 mg. TSQM scores were significantly higher with teriflunomide. There were no unexpected safety findings. CONCLUSION: Effects on time to failure were comparable between teriflunomide and IFNß-1a. There was no difference between teriflunomide 14 mg and IFNß-1a on ARR, though ARR was higher with teriflunomide 7 mg. The teriflunomide safety profile was consistent with previous studies.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Crotonatos/uso terapêutico , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Toluidinas/uso terapêutico , Adulto , Idoso , Crotonatos/administração & dosagem , Progressão da Doença , Feminino , Humanos , Interferon beta-1a , Masculino , Pessoa de Meia-Idade , Recidiva , Toluidinas/administração & dosagem , Resultado do Tratamento
6.
Mult Scler ; 18(9): 1337-9, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22389413

RESUMO

The recommended natalizumab dosage is 300 mg every 4 weeks. We evaluated radiological activity at various times from the last natalizumab infusion by examining 386 magnetic resonance imaging (MRI) scans from 166 natalizumab-treated patients with relapsing-remitting MS. Of 113 scans performed >4 weeks after last natalizumab infusion, 26 were active (i.e. had ≥1 contrast-enhancing lesions). Risk of radiological activity increased by 1.34 fold for each week of delay with respect to the recommended 4-week dosing interval, compared with schedule-adherent patients (p<0.0001). Our data suggest that an increased MRI activity ≥7 weeks from the last infusion of natalizumab should be considered in cases of therapy discontinuation.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Fatores Imunológicos/administração & dosagem , Imageamento por Ressonância Magnética , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/patologia , Adolescente , Adulto , Distribuição de Qui-Quadrado , Esquema de Medicação , Feminino , Humanos , Infusões Parenterais , Modelos Lineares , Modelos Logísticos , Masculino , Adesão à Medicação , Natalizumab , Razão de Chances , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
7.
Cell Mol Neurobiol ; 32(6): 943-7, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22258649

RESUMO

Heat-shock protein 60 (Hsp60) is ubiquitous and highly conserved being present in eukaryotes and prokaryotes, including pathogens. This chaperonin, although typically a mitochondrial protein, can also be found in other intracellular sites, extracellularly, and in circulation. Thus, it can signal the immune system and participate in the development of inflammation and immune reactions. Both phenomena can be elicited by human and foreign Hsp60 (e.g., bacterial GroEL), when released into the blood by infectious agents. Consequently, all these Hsp60 proteins become part of a complex autoimmune response characterized by multiple cross reactions because of their structural similarities. In this study, we demonstrate that Hsp60 proteins from humans and two common pathogens, Chlamydia trachomatis and Chlamydia pneumoniae, share various sequence segments of potentially highly immunogenic epitopes with acetylcholine receptor α1 subunit (AChRα1). The structural data indicate that AChRα1 antibodies, implicated in the pathogenesis of myasthenia gravis, could very well be elicited and/or maintained by self- and/or bacterial Hsp60.


Assuntos
Proteínas de Bactérias/química , Chaperonina 60/química , Chaperonina 60/imunologia , Imunidade/imunologia , Miastenia Gravis/imunologia , Receptores Colinérgicos/química , Homologia de Sequência de Aminoácidos , Sequência de Aminoácidos , Proteínas de Bactérias/metabolismo , Chaperonina 60/metabolismo , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Secundária de Proteína , Receptores Colinérgicos/imunologia
8.
Qual Life Res ; 21(7): 1111-21, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21953022

RESUMO

PURPOSE: To report longitudinal changes in and explore the influence of cognition on social functioning in mildly disabled patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Italian patients (18-50 years) with RRMS and Expanded Disability Status Scale (EDSS) score ≤4.0 were assigned to interferon ß-1a, 44 or 22 µg subcutaneously three times weekly, and underwent annual assessments for social functioning (Environmental Status Scale [ESS]) over 3 years. RESULTS: Baseline total ESS score did not differ between patients with and without cognitive impairment (P = 0.505). Total ESS score remained low (<2.0) and stable over 3 years in the whole study population, but worsened slightly when assessed by assigned treatment or treatment and baseline cognitive status (both P = 0.004), driven mostly by changes in the 'transportation' and 'financial/economic status' subscales. The strongest independent predictor of worsening ESS score was baseline EDSS score. Test-retest analyses confirmed that total ESS score and most subscales changed little over 3 years. CONCLUSION: ESS scores remained low and changed minimally over 3 years, reflecting the mild physical disability and good cognitive performance in this patient population. Determining the influence of cognitive function and treatment on longitudinal changes in social functioning requires further studies.


Assuntos
Fatores Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Relações Interpessoais , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Qualidade de Vida , Adolescente , Adulto , Ensaios Clínicos como Assunto , Cognição , Pessoas com Deficiência/psicologia , Feminino , Humanos , Interferon beta-1a , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Resultado do Tratamento , Adulto Jovem
9.
J Neurol Sci ; 311(1-2): 44-9, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21620416

RESUMO

Recent studies have demonstrated the immunomodulatory properties of vitamin D, and vitamin D deficiency may be a risk factor for the development of MS. The risk of developing MS has, in fact, been associated with rising latitudes, past exposure to sun and serum vitamin D status. Serum 25-hydroxyvitamin D [25(OH)D] levels have also been associated with relapses and disability progression. The identification of risk factors, such as vitamin D deficiency, in MS may provide an opportunity to improve current treatment strategies, through combination therapy with established MS treatments. Accordingly, vitamin D may play a role in MS therapy. Small clinical studies of vitamin D supplementation in patients with MS have reported positive immunomodulatory effects, reduced relapse rates and a reduction in the number of gadolinium-enhancing lesions. However, large randomized clinical trials of vitamin D supplementation in patients with MS are lacking. SOLAR (Supplementation of VigantOL(®) oil versus placebo as Add-on in patients with relapsing-remitting multiple sclerosis receiving Rebif(®) treatment) is a 96-week, three-arm, multicenter, double-blind, randomized, placebo-controlled, Phase II trial (NCT01285401). SOLAR will evaluate the efficacy of vitamin D(3) as add-on therapy to subcutaneous interferon beta-1a in patients with RRMS. Recruitment began in February 2011 and is aimed to take place over 1 calendar year due to the potential influence of seasonal differences in 25(OH)D levels.


Assuntos
Colecalciferol/administração & dosagem , Interferon beta/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adolescente , Adulto , Colecalciferol/uso terapêutico , Suplementos Nutricionais/normas , Método Duplo-Cego , Sinergismo Farmacológico , Feminino , Humanos , Interferon beta-1a , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/tratamento farmacológico , Adulto Jovem
10.
PLoS One ; 5(2): e9287, 2010 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-20174631

RESUMO

BACKGROUND: Albeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cells involvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in the production of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation and regulation of autoreactive CD8+ T cells in Multiple Sclerosis. METHODOLOGY/PRINCIPAL FINDINGS: Immunoproteasomes and PA28-alphabeta regulator are present in MS affected brain area and accumulated in plaques. They are expressed in cell types supposed to be involved in MS development such as neurons, endothelial cells, oligodendrocytes, macrophages/macroglia and lymphocytes. Furthermore, in a genetic study on 1262 Italian MS cases and 845 controls we observed that HLA-A*02+ female subjects carrying the immunoproteasome LMP2 codon 60HH variant have a reduced risk to develop MS. Accordingly, immunoproteasomes carrying the LMP2 60H allele produce in vitro a lower amount of the HLA-A*0201 restricted immunodominant epitope MBP(111-119). CONCLUSION/SIGNIFICANCE: The immunoproteasome LMP2 60HH variant reduces the risk to develop MS amongst Italian HLA-A*02+ females. We propose that such an effect is mediated by the altered proteasome-dependent production of a specific MBP epitope presented on the MHC class I. Our observations thereby support the hypothesis of an involvement of immunoproteasome in the MS pathogenesis.


Assuntos
Cisteína Endopeptidases/imunologia , Epitopos/imunologia , Antígenos HLA-A/imunologia , Esclerose Múltipla/imunologia , Adulto , Sequência de Aminoácidos , Encéfalo/metabolismo , Encéfalo/patologia , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Epitopos/metabolismo , Feminino , Frequência do Gene , Genótipo , Antígenos HLA-A/genética , Antígenos HLA-A/metabolismo , Antígeno HLA-A2 , Humanos , Imuno-Histoquímica , Itália , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Microglia/metabolismo , Microglia/patologia , Pessoa de Meia-Idade , Dados de Sequência Molecular , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Proteínas Musculares/metabolismo , Proteína Básica da Mielina/imunologia , Proteína Básica da Mielina/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Fatores de Risco , Fatores Sexuais
11.
Neurol Sci ; 30 Suppl 2: S163-5, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19882367

RESUMO

At the end of 2006 a country-based surveillance program on natalizumab therapy in multiple sclerosis was settled in Italy by a collaborative effort of the Italian Drug Agency (AIFA) and a group of experts and neurologists appointed by the National Society of Neurology (SIN). After 2 years, 1,818 patients are registered in the database. The majority of cases (88.6%) failed the therapy with beta interferon or glatiramer acetate and had relapses or accumulated disability during immunomodulating treatment, while 11.4% of patients enrolled in the surveillance study were not previously treated with immunomodulating therapies and had a rapidly evolving clinical course. Almost 10% of the patients treated with natalizumab interrupted, for various different reasons, the therapy. Treatment was well tolerated and side effects were similar to those reported in the registrative studies. The majority of treated cases are stable or ameliorated.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Vigilância de Produtos Comercializados , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Bases de Dados Factuais , Feminino , Seguimentos , Humanos , Itália , Imageamento por Ressonância Magnética , Masculino , Natalizumab , Pacientes Desistentes do Tratamento
12.
Neuroepidemiology ; 28(1): 28-32, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17164567

RESUMO

BACKGROUND: Epidemiological studies conducted in Sicily and Sardinia, the two major Mediterranean islands, showed elevated incidence and prevalence of multiple sclerosis (MS)and a recent increase in disease frequency. OBJECTIVE: To confirm the central highlands of Sicily as areas of increasing MS prevalence and elevated incidence, we performed a follow-up study based on the town of Caltanissetta (Sicily), southern Italy. METHODS: We made a formal diagnostic reappraisal of all living patients found in the previous study performed in 1981. All possible information sources were used to search for patients affected by MS diagnosed according to the Poser criteria. We calculated prevalence ratios, for patients affected by MS who were living and resident in the study area on December 31, 2002. Crude and age- and sex-specific incidence ratios were computed for the period from January 1, 1993, to December 31, 2002. RESULTS: The prevalence of definite MS rose in 20 years from 69.2 (retrospective prevalence rate) to 165.8/100,000 population. We calculated the incidence of definite MS for the period 1970-2000. These rates calculated for 5-year periods increased from 2.3 to 9.2/100,000/year. CONCLUSION: This survey shows the highest prevalence and incidence figures of MS in the Mediterranean area and confirms central Sicily as a very-high-risk area for MS.


Assuntos
Esclerose Múltipla/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Feminino , Seguimentos , Inquéritos Epidemiológicos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Distribuição por Sexo , Sicília/epidemiologia , Saúde da População Urbana
13.
J Neuroimmunol ; 179(1-2): 108-16, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16934875

RESUMO

By combining all the data available from the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) project, we have been able to identify 17 microsatellite markers showing consistent evidence for apparent association. As might be expected five of these markers map within the Major Histocompatibility Complex (MHC) and are in LD with HLA-DRB1. Individual genotyping of the 12 non-MHC markers confirmed association for three of them--D11S1986, D19S552 and D20S894. Association mapping across the candidate genes implicated by these markers in 937 UK trio families revealed modestly associated haplotypes in JAG1 (p=0.019) on chromosome 20p12.2 and POU2AF1 (p=0.003) on chromosome 11q23.1.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Predisposição Genética para Doença , Testes Genéticos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Desequilíbrio de Ligação/genética , Proteínas de Membrana/genética , Esclerose Múltipla/genética , Transativadores/genética , Europa (Continente)/epidemiologia , Feminino , Genótipo , Humanos , Proteína Jagged-1 , Masculino , Repetições de Microssatélites , Esclerose Múltipla/epidemiologia , Proteínas Serrate-Jagged
14.
Neurobiol Aging ; 26(4): 449-53, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15653173

RESUMO

Increased levels of alpha-1-antichymotrypsin (ACT), a protease inhibitor and an acute phase protein, have been found in the brain and peripheral blood of patients with Alzheimer's disease (AD). Patients from northern Italy with a clinical diagnosis of probable AD, and patients with early onset AD (EOAD) from UK with AD neuropathological diagnosis were genotyped for a new polymorphism in the promoter region of the ACT gene which has been shown to affect ACT expression. A subset of patients with clinical AD from northern Italy was also followed up for 2 years and monitored for cognitive decline. The ACT TT promoter genotype was associated with an increased risk of EOAD independently from the presence of the apolipoprotein E (APOE) epsilon 4 allele. After manifestation of the disease the ACT TT genotype was also associated with faster cognitive decline in patients with the APOE allele epsilon 4. The ACT gene appears to influence the early clinical development of the disease, and the interaction of the ACT and APOE genes affects clinical progression of AD.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Polimorfismo Genético , Regiões Promotoras Genéticas , alfa 1-Antiquimotripsina/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/complicações , Doença de Alzheimer/fisiopatologia , Apolipoproteína E4 , Apolipoproteínas E/genética , Distribuição de Qui-Quadrado , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/genética , Intervalos de Confiança , Feminino , Seguimentos , Frequência do Gene , Humanos , Itália/etnologia , Masculino , Entrevista Psiquiátrica Padronizada , Testes Neuropsicológicos , Razão de Chances
15.
Neurodegener Dis ; 2(5): 233-41, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16909003

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia. It is characterized by beta-amyloid (A beta) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5' region of CH25H revealed three common haplotypes, CH25Hchi2, CH25Hchi3 and CH25Hchi4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25Hchi4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain A beta deposits in carriers of CH25Hchi4 and CH25Hchi3 haplotypes, whereas no A beta deposits were present in CH25Hchi2 carriers. Together, these results are compatible with a role of CH25Hchi4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain A beta deposition.


Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 10/genética , Esteroide Hidroxilases/genética , Regiões 5' não Traduzidas/genética , Idoso , Alelos , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Encéfalo/patologia , Colesterol/sangue , Feminino , Regulação Enzimológica da Expressão Gênica , Marcadores Genéticos , Genótipo , Haplótipos , Humanos , Masculino , Placa Amiloide/genética , Placa Amiloide/patologia , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Risco
16.
Hum Mol Genet ; 13(1): 47-52, 2004 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-14583441

RESUMO

Because glucocorticoid excess increases neuronal vulnerability, genetic variations in the glucocorticoid system may be related to the risk for Alzheimer's disease (AD). We analyzed single-nucleotide polymorphisms in 10 glucocorticoid-related genes in a population of 814 AD patients and unrelated control subjects. Set-association analysis revealed that a rare haplotype in the 5' regulatory region of the gene encoding 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) was associated with a 6-fold increased risk for sporadic AD. Results of a reporter-gene assay indicated that the rare risk-associated haplotype altered HSD11B1 transcription. HSD11B1 controls tissue levels of biologically active glucocorticoids and thereby influences neuronal vulnerability. Our results indicate that a functional variation in the glucocorticoid system increases the risk for AD, which may have important implications for the diagnosis and treatment of this disease.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Doença de Alzheimer/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença/genética , Glucocorticoides/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/análogos & derivados , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Idoso , Células Cultivadas , Europa (Continente) , Componentes do Gene , Vetores Genéticos , Genótipo , Haplótipos/genética , Humanos , Luciferases , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Transfecção
17.
J Neuroimmunol ; 143(1-2): 97-100, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14575923

RESUMO

We have systematically screened the genome for evidence of linkage disequilibrium (LD) with multiple sclerosis (MS) by typing 6000 microsatellite markers in case-control and family based (AFBAC) cohorts from the Italian population. DNA pooling was used to reduce the genotyping effort involved. Four DNA pools were considered: cases (224 Italian MS patients), controls (231 healthy Italians), index (185 index cases from trio families) and parents (the 370 parents of the patient included in the Index pool), respectively. After refining analysis of the most promising 14 markers to emerge from this screening process, only marker D2S367 retained evidence for association.


Assuntos
Testes Genéticos , Genoma Humano , Desequilíbrio de Ligação/genética , Esclerose Múltipla/genética , Alelos , Estudos de Casos e Controles , Grupos de Populações Continentais/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Genótipo , Humanos , Cooperação Internacional , Itália/epidemiologia , Masculino , Repetições de Microssatélites , Esclerose Múltipla/epidemiologia
18.
Neurosci Lett ; 343(3): 155-8, 2003 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-12770686

RESUMO

To assess the role of interleukin-6 (IL-6) in migraine, we analyzed the -174 G/C IL-6 gene polymorphism in 268 patients with migraine and 305 controls. No significant difference in the distribution of IL-6 genotypes (chi(2)=0.601, P=0.74) and allelic frequencies (chi(2)=0.024, P=0.876) was found. When patients were subdivided into subgroups (migraine with aura, migraine without aura and mixed headaches), IL-6 alleles were similarly distributed. Comparison of the clinical features of the disease with the -174 G/C IL-6 genotypes showed no significant difference. In conclusion, we found no significant association between the -174 G/C IL-6 polymorphism and the occurrence or the clinical features of migraine.


Assuntos
Interleucina-6/genética , Transtornos de Enxaqueca/genética , Polimorfismo Genético/genética , Adulto , Alelos , Estudos de Coortes , DNA/genética , Feminino , Ligação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Enxaqueca com Aura/genética , Enxaqueca sem Aura/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
Psychiatr Genet ; 12(3): 155-60, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12218659

RESUMO

Tissue inhibitor of metalloproteinases 1 (TIMP-1) inhibits several proteinases including a disintegrin and metalloproteinase 10 (ADAM10), a major alpha-secretase that cleaves the beta-amyloid precursor protein within its amyloidogenic Abeta domain. The gene encoding TIMP-1 (TIMP 1) maps to the short arm of the X chromosome, in a region previously suggested as conferring genetic susceptibility for Alzheimer's disease (AD). To determine whether genetic variability of TIMP 1 contributes to the pathogenesis of AD, we analysed one single nucleotide polymorphism within TIMP 1 and one single nucleotide polymorphism in the 5'-untranslated region of TIMP 1 in patients with AD and control subjects from two independent and ethnically different populations. We did not observe any association between TIMP 1 genotypes and the diagnosis of AD in men or women. We also measured TIMP-1 protein levels in the cerebrospinal fluid of patients with AD, healthy control subjects, and patients with other neurological disorders. TIMP-1 levels were similar in all groups. In addition, no significant differences were observed after stratification for TIMP 1 genotypes. Our data show that neither genetic variability nor protein levels of TIMP-1 are associated with AD.


Assuntos
Doença de Alzheimer/genética , Polimorfismo Genético , Inibidor Tecidual de Metaloproteinase-1/líquido cefalorraquidiano , Inibidor Tecidual de Metaloproteinase-1/genética , Regiões 5' não Traduzidas/genética , Doença de Alzheimer/líquido cefalorraquidiano , Mapeamento Cromossômico , Cromossomos Humanos X , DNA/sangue , DNA/genética , Feminino , Frequência do Gene , Variação Genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Valores de Referência
20.
Headache ; 42(5): 337-40, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12047332

RESUMO

OBJECTIVE: To evaluate whether a particular genotype of the interleukin-1alpha (IL1A) gene affects the clinical features of migraine. BACKGROUND: Proinflammatory mediators have been reported to play a role in the pathophysiology of migraine. Recent studies suggest that polymorphisms in the interleukin-1 genes influence the age at onset and subsequent course of several chronic inflammatory diseases. METHODS: In a group of 269 patients with migraine, we tested the association of the -889 C/T biallelic polymorphism of the IL1A gene with several clinical features of the disease. RESULTS: Patients with migraine carrying the T/T genotype show an age at onset of the disease that is significantly (P <.01) lower than IL1A C/C or C/T carriers. In addition, the same genotype was significantly (P <.05) more frequent in patients with migraine with aura than in patients with migraine without aura. CONCLUSIONS: The results of our study suggest a role for the IL1A gene in modifying the clinical features of migraine.


Assuntos
Interleucina-1/genética , Enxaqueca com Aura/genética , Enxaqueca sem Aura/genética , Adolescente , Adulto , Idade de Início , Criança , Estudos de Coortes , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Polimorfismo Genético/genética
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