RESUMO
Extracellular vesicles (EVs) are mediators of cellular communication that can be released by almost all cell types in both physiological and pathological conditions and are present in most biological fluids. Such characteristics make them attractive in the research of biomarkers for age-related pathological conditions. Based on this, the aim of the present study was to examine the changes in EV concentration and size in the context of frailty, a geriatric syndrome associated with a progressive physical and cognitive decline. Specifically, total EVs and neural and microglial-derived EVs (NDVs and MDVs respectively) were investigated in plasma of frail and non-frail controls (CTRL), mild cognitive impairment (MCI) subjects, and in Alzheimer's disease (AD) patients. Results provided evidence that AD patients displayed diminished NDV concentration (3.61 × 109 ± 1.92 × 109 vs 7.16 × 109 ± 4.3 × 109 particles/ml) and showed high diagnostic performance. They are able to discriminate between AD and CTRL with an area under the curve of 0.80, a sensitivity of 78.95% and a specificity of 85.7%, considering the cut-off of 5.27 × 109 particles/ml. Importantly, we also found that MDV concentration was increased in frail MCI patients compared to CTRL (5.89 × 109 ± 3.98 × 109 vs 3.16 × 109 ± 3.04 × 109 particles/ml, P < 0.05) and showed high neurotoxic effect on neurons. MDV concentration discriminate frail MCI vs non-frail CTRL (AUC = 0.76) with a sensitivity of 80% and a specificity of 70%, considering the cut-off of 2.69 × 109 particles/ml. Altogether, these results demonstrated an alteration in NDV and MDV release during cognitive decline, providing important insight into the role of EVs in frailty status.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Vesículas Extracelulares , Fragilidade , Humanos , Idoso , Microglia , Disfunção Cognitiva/metabolismo , Doença de Alzheimer/diagnóstico , Vesículas Extracelulares/metabolismoRESUMO
BACKGROUND AND PURPOSE: Mutations in the PSEN1 gene are the most common cause of autosomal-dominant Alzheimer's disease and have been associated with the earliest disease onset. We describe an unusual presentation of the rare R377W PSEN1 mutation with a late age of onset, and we provide for the first time in vivo pathological evidence for this mutation. METHODS: A 71-year-old female patient with progressive cognitive decline in the past 3 years and positive family history for dementia underwent neurological evaluation, neuropsychological testing, lumbar puncture, conventional brain imaging, amyloid-positron emission tomography (PET) and extensive genetic screening with a next-generation sequencing technique. RESULTS: The diagnostic workup revealed mixed behavioural and amnestic disease features on neuropsychological tests, magnetic resonance imaging, and 18-fluorodeoxyglucose (FDG)-PET. Amyloid-PET detected amyloid deposition in the frontal areas, in the parietal lobes and the precunei. The genetic screening revealed the presence of the rare R377W mutation in the PSEN1 gene. CONCLUSIONS: Extensive genetic screening is also advisable for late-onset presentations of Alzheimer's disease, especially in the presence of a positive family history or atypical clinical features.
Assuntos
Doença de Alzheimer , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Mutação , Tomografia por Emissão de Pósitrons , Presenilina-1RESUMO
OBJECTIVE: To validate kappa free light chain (KFLC) and lambda free light chain (LFLC) indices as a diagnostic biomarker in multiple sclerosis (MS). METHODS: We performed a multicenter study including 745 patients from 18 centers (219 controls and 526 clinically isolated syndrome (CIS)/MS patients) with a known oligoclonal IgG band (OCB) status. KFLC and LFLC were measured in paired cerebrospinal fluid (CSF) and serum samples. Gaussian mixture modeling was used to define a cut-off for KFLC and LFLC indexes. RESULTS: The cut-off for the KFLC index was 6.6 (95% confidence interval (CI) = 5.2-138.1). The cut-off for the LFLC index was 6.9 (95% CI = 4.5-22.2). For CIS/MS patients, sensitivity of the KFLC index (0.88; 95% CI = 0.85-0.90) was higher than OCB (0.82; 95%CI = 0.79-0.85; p < 0.001), but specificity (0.83; 95% CI = 0.78-0.88) was lower (OCB = 0.92; 95% CI = 0.89-0.96; p < 0.001). Both sensitivity and specificity for the LFLC index were lower than OCB. CONCLUSION: Compared with OCB, the KFLC index is more sensitive but less specific for diagnosing CIS/MS. Lacking an elevated KFLC index is more powerful for excluding MS compared with OCB but the latter is more important for ruling in a diagnosis of CIS/MS.
Assuntos
Cadeias kappa de Imunoglobulina/metabolismo , Cadeias lambda de Imunoglobulina/metabolismo , Esclerose Múltipla/diagnóstico , Bandas Oligoclonais , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Cadeias kappa de Imunoglobulina/sangue , Cadeias kappa de Imunoglobulina/líquido cefalorraquidiano , Cadeias lambda de Imunoglobulina/sangue , Cadeias lambda de Imunoglobulina/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Bandas Oligoclonais/sangue , Bandas Oligoclonais/líquido cefalorraquidiano , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Homozygous mutations in Triggering Receptor Expressed on Myeloid cells 2 gene (TREM2) are one of the major causes of Nasu Hakola Disease (NHD). We analysed Peripheral Blood Mononuclear Cells (PBMC) profile of 164 inflammatory factors in patients with NHD carrying the TREM2 Q33X mutation as compared with heterozygous and wild type individuals. Several molecules related to bone formation and angiogenesis were altered in NHD compared to non-carriers: Bone Morphogenetic Protein (BMP)-1 mRNA levels were significantly increased in PBMC (2.32 fold-increase; Pâ¯=â¯0.01), as were Transforming Growth Factor Beta (TGFB)3 levels (1.51 fold-increase; Pâ¯=â¯0.02). Conversely, CXCL5 and Pro Platelet Basic Protein (PPBP) were strongly downregulated (-28.26, -9.85 fold-decrease over non-carriers, respectively, Pâ¯=â¯0.01), as well as Platelet Factor 4 Variant 1 (PF4V1; -41.44, Pâ¯=â¯0.03). Among other inflammatory factors evaluated, Interleukin (IL)-15 and Tumor Necrosis Factor Superfamily Member (TNFSF)4 mRNA levels were decreased in NHD as compared with non-carriers (-2.25 and -3.87 fold-decrease, Pâ¯=â¯0.01 and 0.001, respectively). In heterozygous individuals, no significant differences were observed, apart from IL-15 mRNA levels, that were decreased at the same extent as NHD (-2.05 fold-decrease over non-carriers, Pâ¯=â¯0.002). We identified a signature in PBMC from patients with NHD consisting of strongly decreased mRNA levels of CXCL5, PPBP, PF4V1, mildly decreased IL-15 and TNFSF4 and mildly increased BMP-1 and TGFB3.
Assuntos
Citocinas/sangue , Leucócitos Mononucleares/imunologia , Lipodistrofia/genética , Osteocondrodisplasias/genética , RNA Mensageiro/análise , Panencefalite Esclerosante Subaguda/genética , Proteína Morfogenética Óssea 1/genética , Quimiocina CXCL5/genética , Citocinas/genética , Feminino , Humanos , Inflamação , Leucócitos Mononucleares/patologia , Lipodistrofia/sangue , Lipodistrofia/patologia , Masculino , Glicoproteínas de Membrana/genética , Ligante OX40/genética , Osteocondrodisplasias/sangue , Osteocondrodisplasias/patologia , Fator Plaquetário 4/genética , RNA Mensageiro/genética , Receptores Imunológicos/genética , Panencefalite Esclerosante Subaguda/sangue , Panencefalite Esclerosante Subaguda/patologia , Fator de Crescimento Transformador beta3/genética , beta-Tromboglobulina/genéticaRESUMO
BACKGROUND: Multiple sclerosis (MS) is a complex disorder of the central nervous system whose cause is currently unknown. Evidence is increasing that DNA methylation alterations could be involved in inflammatory and neurodegenerative diseases and could contribute to MS pathogenesis. Repetitive elements Alu, LINE-1 and SAT-α, are widely known as estimators of global DNA methylation. We investigated Alu, LINE-1 and SAT-α methylation levels to evaluate their difference in a case-control setup and their role as a marker of disability. RESULTS: We obtained blood samples from 51 MS patients and 137 healthy volunteers matched by gender, age and smoking. Methylation was assessed using bisulfite-PCR-pyrosequencing. For all participants, medical history, physical and neurological examinations and screening laboratory tests were collected. All repetitive elements were hypermethylated in MS patients compared to healthy controls. A lower Expanded Disability Status Scale (EDSS) score was associated with a lower levels of LINE-1 methylation for 'EDSS = 1.0' and '1.5 ≤ EDSS ≤ 2.5' compared to an EDSS higher than 3, while Alu was associated with a higher level of methylation in these groups: 'EDSS = 1.0' and '1.5 ≤ EDSS ≤ 2.5'. CONCLUSIONS: MS patients exhibit an hypermethylation in repetitive elements compared to healthy controls. Alu and LINE-1 were associated with degree of EDSS score. Forthcoming studies focusing on epigenetics and the multifactorial pathogenetic mechanism of MS could elucidate these links further.
Assuntos
Metilação de DNA , Esclerose Múltipla/genética , Sequências Repetitivas de Ácido Nucleico , Adulto , Elementos Alu , Feminino , Humanos , Elementos Nucleotídeos Longos e Dispersos , MasculinoRESUMO
Mutations in progranulin gene (GRN) are one of the major causes of autosomal dominant Frontotemporal Lobar Degeneration (FTLD). Progranulin displays anti-inflammatory properties and is likely a ligand of Tumor Necrosis Factor (TNF) receptor 2, expressed on microglia. A few cytokines and chemokines are altered in cerebrospinal fluid (CSF) from patients with sporadic FTLD, whereas no information is available in familial cases. We evaluated, through BioPlex, levels of 27 inflammatory molecules, including cytokines, chemokines, and related receptors, in CSF and matched serum, from FTLD patients carrying GRN mutations as compared with sporadic FTLD with no GRN mutations and controls. Mean±SD Monocyte Chemoattractant Protein-1 (MCP-1) levels were significantly increased in CSF from sporadic FTLD patients as compared with controls (334.27±151.5 versus 159.7±49pg/ml; P⩽0.05). In GRN mutation carriers versus controls, CSF levels of MCP-1 were unchanged, whereas Interferon-γ-inducible protein-10 (IP-10) levels were increased (809.17±240.0 versus 436.61±202.5pg/ml; P=0.012). In the same group, TNFα and Interleukin (IL)-15 levels were decreased (3.18±1.41 versus 35.68±30.5pg/ml; P=0.013 and 9.34±5.54 versus 19.15±10.03pg/ml; P=0.023, respectively). Conversely, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) levels were decreased in patients, with or without mutations, as compared with controls (4.63±3.30 and 2.58±20 versus 87.57±70pg/ml, respectively; P<0.05). Moreover, IP-10, IL-15 and RANTES CSF levels were not influenced by age, whereas MCP-1 levels increased with age (ρ=0.48; P=0.007). In conclusion, inflammatory de-regulation was observed in both sporadic FTLD and GRN carriers compared to controls, with a specific inflammatory profile for the latter group.
Assuntos
Demência Frontotemporal/líquido cefalorraquidiano , Demência Frontotemporal/genética , Mediadores da Inflamação/líquido cefalorraquidiano , Inflamação/líquido cefalorraquidiano , Inflamação/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Idoso , Quimiocina CCL2/sangue , Quimiocina CCL2/líquido cefalorraquidiano , Quimiocina CXCL10/sangue , Quimiocina CXCL10/líquido cefalorraquidiano , Feminino , Demência Frontotemporal/complicações , Humanos , Inflamação/complicações , Mediadores da Inflamação/sangue , Interleucina-15/sangue , Interleucina-15/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Mutação , Progranulinas , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/líquido cefalorraquidianoRESUMO
BACKGROUND AND OBJECTIVE: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. METHODS: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. RESULTS: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. CONCLUSIONS: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.
Assuntos
Esclerose Múltipla/patologia , Adulto , Estudos de Coortes , Progressão da Doença , Endonucleases , Feminino , Seguimentos , Humanos , Imunoglobulina G/análise , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla/líquido cefalorraquidiano , Proteínas Nucleares/análise , Bandas Oligoclonais/genética , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Análise de Sobrevida , Vitamina D/sangueRESUMO
In the prospect of improved disease management and future clinical trials in Frontotemporal Dementia, it is desirable to share common diagnostic procedures. To this aim, the Italian FTD Network, under the aegis of the Italian Neurological Society for Dementia, has been established. Currently, 85 Italian Centers involved in dementia care are part of the network. Each Center completed a questionnaire on the local clinical procedures, focused on (1) clinical assessment, (2) use of neuroimaging and genetics; (3) support for patients and caregivers; (4) an opinion about the prevalence of FTD. The analyses of the results documented a comprehensive clinical and instrumental approach to FTD patients and their caregivers in Italy, with about 1,000 newly diagnosed cases per year and 2,500 patients currently followed by the participating Centers. In analogy to other European FTD consortia, future aims will be devoted to collect data on epidemiology of FTD and its subtypes and to provide harmonization of procedures among Centers.
Assuntos
Redes Comunitárias , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/epidemiologia , Disseminação de Informação , Idoso , Idoso de 80 Anos ou mais , Cuidadores/psicologia , Feminino , Humanos , Itália , Masculino , PrevalênciaRESUMO
An expanded hexanucleotide (GGGGCC) repeat in a non-coding promoter region of open reading frame 72 of chromosome 9 (C9ORF72) has been recently identified as a major cause of familial and sporadic frontotemporal lobar degeneration. We describe the clinical picture of a 64-year-old woman carrying the hexanucleotide repeat expansion, who developed a sporadic early-onset form of behavioral variant frontotemporal dementia characterized by the occurrence of uncommon behavioral manifestations such as binge eating disturbance and by a rapid worsening of cognitive abilities. Our report confirms previous studies asserting that C9ORF72 repeats may sustain heterogeneous clinical syndromes.
Assuntos
Bulimia/complicações , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Proteínas/genética , Encéfalo/patologia , Bulimia/genética , Proteína C9orf72 , Cognição , Expansão das Repetições de DNA , Feminino , Demência Frontotemporal/complicações , Demência Frontotemporal/psicologia , Humanos , Pessoa de Meia-Idade , Regiões Promotoras GenéticasRESUMO
As neuroinflammation is an early event in the pathogenesis of Alzheimer's disease, new selective anti-inflammatory drugs could lead to promising preventive strategies. We evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of CHF5074, a new microglial modulator, in a 12-week, double-blind, placebo-controlled, parallel groups, ascending dose study involving 96 MCI patients. Subjects were allocated into three successive study cohorts to receive ascending, titrated doses of CHF5074 (200, 400 or 600 mg/day) or placebo. Vital signs, cardiac safety, neuropsychological performance and safety clinical laboratory parameters were assessed on all subjects. Plasma samples were collected throughout the study for measuring drug concentrations, soluble CD40 ligand (sCD40L) and TNF-α. At the end of treatment, cerebrospinal fluid (CSF) samples were optionally collected after the last dose to measure drug levels, ß-amyloid1-42 (Aß42), tau, phospho-tau181, sCD40L and TNF-α. Ten patients did not complete the study: one in the placebo group (consent withdrawn), two in the 200-mg/day treatment group (consent withdrawn and unable to comply) and seven in the 400-mg/day treatment group (five AEs, one consent withdrawn and one unable to comply). The most frequent treatment-emergent adverse events were diarrhea, dizziness and back pain. There were no clinically significant treatment-related clinical laboratory, vital sign or ECG abnormalities. CHF5074 total body clearance depended by gender, age and glomerular filtration rate. CHF5074 CSF concentrations increased in a dose-dependent manner. At the end of treatment, mean sCD40L and TNF-α levels in CSF were found to be inversely related to the CHF5074 dose (p=0.037 and p=0.001, respectively). Plasma levels of sCD40L in the 600-mg/day group were significantly lower than those measured in the placebo group (p=0.010). No significant differences between treatment groups were found in neuropsychological tests but a positive dose-response trend was found on executive function in APOE4 carriers. This study shows that CHF5074 is well tolerated in MCI patients after a 12-week titrated treatment up to 600 mg/day and dose-dependently affects central nervous system biomarkers of neuroinflammation.
RESUMO
Although it is still debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients underwent endovascular treatment (ET) of CCSVI. The objective of the study is to evaluate the outcome and safety of ET in Italian MS patients. Italian MS centers that are part of the Italian MS Study Group were all invited to participate to this retrospective study. A structured questionnaire was used to collect detailed clinical data before and after the ET. Data from 462 patients were collected in 33 centers. ET consisted of balloon dilatation (93 % of cases) or stent application. The mean follow-up duration after ET was 31 weeks. Mean EDSS remained unchanged after ET (5.2 vs. 4.9), 144 relapses occurred in 98/462 cases (21 %), mainly in RR-MS patients. Fifteen severe adverse events were recorded in 3.2 % of cases. Given the risk of severe adverse events and the lack of objective beneficial effects, our findings confirm that at present ET should not be recommended to patients with MS.
Assuntos
Encéfalo/irrigação sanguínea , Procedimentos Endovasculares/efeitos adversos , Esclerose Múltipla/cirurgia , Medula Espinal/irrigação sanguínea , Insuficiência Venosa/cirurgia , Adulto , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Inquéritos e Questionários , Resultado do Tratamento , Insuficiência Venosa/complicaçõesRESUMO
BACKGROUND: The abrupt fall in estrogens levels during the menopausal transition may connote an hormonal state predisposing to neurodegenerative disorders, e.g. Alzheimer's disease (AD). Reportedly, the neurotrophic activity of estrogen involves an interaction with IGF-I. AIM: To evaluate the leukocyte gene expression of progesterone receptor (PR-A/B) and interleukin 6 (IL-6), two parameters under the control of estrogens and involved in the pathogenesis of AD. SUBJECTS: The study was conducted in non-demented women divided into two groups according to their pre- or post-menopausal state; each group being further divided into two subgroups based on their circulating levels of IGF-I (normal or low). An additional sample of AD-affected women served as a comparison group. RESULTS: Estrogens maintained their full activity only when IGF-I levels were in the range of normalcy. On the contrary, if the concentrations of one or both hormones were reduced, estrogens were not anymore capable to control the gene expression of PR-A/B or IL-6. CONCLUSIONS: Before administering hormone-based replacement therapy, characterization of the somatotropic function should be performed in the early phase of the menopause.
Assuntos
Estrogênios/uso terapêutico , Terapia de Reposição Hormonal/métodos , Fator de Crescimento Insulin-Like I/fisiologia , Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Pós-Menopausa/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Estrogênios/metabolismo , Estrogênios/fisiologia , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Pessoa de Meia-Idade , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/metabolismo , Pós-Menopausa/efeitos dos fármacos , Pós-Menopausa/metabolismo , Adulto JovemRESUMO
The human ZC3HAV1 gene encodes an antiviral protein. The longest splicing isoform of ZC3HAV1 contains a C-terminal PARP-like domain, which has evolved under positive selection in primates. We analyzed the evolutionary history of this same domain in humans and in Pan troglodytes. We identified two variants that segregate in both humans and chimpanzees; one of them (rs3735007) does not occur at a hypermutable site and accounts for a nonsynonymous substitution (Thr851Ile). The probability that the two trans-specific polymorphisms have occurred independently in the two lineages was estimated to be low (P = 0.0054), suggesting that at least one of them has arisen before speciation and has been maintained by selection. Population genetic analyses in humans indicated that the region surrounding the shared variants displays strong evidences of long-standing balancing selection. Selection signatures were also observed in a chimpanzee population sample. Inspection of 1000 Genomes data confirmed these findings but indicated that search for selection signatures using low-coverage whole-genome data may need masking of repetitive sequences. A case-control study of more than 1,000 individuals from mainland Italy indicated that the Thr851Ile SNP is significantly associated with susceptibility to multiple sclerosis (MS) (odds ratio [OR] = 1.47, 95% confidence intervals [CI]: 1.08-1.99, P = 0.011). This finding was confirmed in a larger sample of 4,416 Sardinians cases/controls (OR = 1.18, 95% CI: 1.037-1.344, P = 0.011), but not in a population from Belgium. We provide one of the first instances of human/chimpanzee trans-specific coding variant located outside the major histocompatibility complex region. The selective pressure is likely to be virus driven; in modern populations, this variant associates with susceptibility to MS, possibly via the interaction with environmental factors.
Assuntos
Predisposição Genética para Doença , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Proteínas de Ligação a RNA/genética , Seleção Genética , Acebutolol , Animais , Estudos de Casos e Controles , Interação Gene-Ambiente , Estudos de Associação Genética , Genoma Humano , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Razão de Chances , Pan troglodytes/genética , Filogenia , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Estrutura Terciária de Proteína , Proteínas de Ligação a RNA/química , Análise de Sequência de DNARESUMO
BACKGROUND: Neurofibrillary tangles and senile plaques are hallmarks of Alzheimer's disease (AD) although the molecular basis of their coexistence remains elusive. The peptidyl-prolyl cis/trans isomerase Pin1 acts on both tau and amyloid precursor protein to regulate their functions by influencing tau phosphorylation and amyloid precursor protein processing. OBJECTIVE: In order to identify potential biomarkers for AD in easily accessible cells and to gain insight into the relationship between the brain and peripheral compartments in AD pathology, we investigated Pin1 expression and activity in the peripheral blood mononuclear cells of subjects with late-onset AD (LOAD) and age-matched controls (CT). METHODS: Gene and protein expression, promoter methylation, Ser(16) phosphorylation and activity of Pin1 were evaluated in 32 samples from subjects with LOAD and in 28 samples from CT. RESULTS: In LOAD subjects, there was a statistically significant reduction in Ser(16) phosphorylation (-30%; p = 0.041) and promoter methylation (-8%; p = 0.001), whereas Pin1 expression was significantly increased (+74%; p = 0.018). CONCLUSION: The modifications of Pin1 found in LOAD subjects support its involvement in the pathogenesis of the disease with an important role being played by epigenetic mechanisms.
Assuntos
Doença de Alzheimer/genética , Epigênese Genética/genética , Predisposição Genética para Doença/genética , Peptidilprolil Isomerase/genética , Peptidilprolil Isomerase/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Análise de Variância , Apolipoproteína E4/genética , Estudos de Casos e Controles , Feminino , Humanos , Itália , Leucócitos Mononucleares/metabolismo , Masculino , Metilação , Peptidilprolil Isomerase de Interação com NIMA , Fosforilação/genética , Regiões Promotoras Genéticas/genética , Serina/metabolismoRESUMO
Spastic paraplegia type 10 (SPG10) is an autosomal dominant form of hereditary spastic paraplegia (HSP) due to mutations in KIF5A, a gene encoding the neuronal kinesin heavy chain implicated in anterograde axonal transport. KIF5A mutations were found in both pure and complicated forms of the disease; a single KIF5A mutation was also detected in a CMT2 patient belonging to an SPG10 mutant family. To confirm the involvement of the KIF5A gene in both CMT2 and SPG10 phenotypes and to define the frequency of KIF5A mutations in an Italian HSP patient population, we performed a genetic screening of this gene in a series of 139 HSP and 36 CMT2 affected subjects. We identified five missense changes, four in five HSP patients and one in a CMT2 subject. All mutations, including the one segregating in the CMT2 patient, are localized in the kinesin motor domain except for one, falling within the stalk domain and predicted to generate protein structure destabilization. The results obtained indicate a KIF5A mutation frequency of 8.8% in the Italian HSP population and identify a region of the kinesin protein, the stalk domain, as a novel target for mutation. In addition, the mutation found in the CMT2 patient strengthens the hypothesis that CMT2 and SPG10 are the extreme phenotypes resulting from mutations in the same gene.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Cinesinas/genética , Mutação , Domínios e Motivos de Interação entre Proteínas/genética , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Éxons , Humanos , Pessoa de Meia-Idade , Linhagem , Adulto JovemRESUMO
BACKGROUND: Over recent years numerous patients with severe forms of multiple sclerosis (MS) refractory to conventional therapies have been treated with intense immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT). The clinical outcome and the toxicity of AHSCT can be diverse, depending on the various types of conditioning protocols and on the disease phase. OBJECTIVES: To report the Italian experience on all the consecutive patients with MS treated with AHSCT with an intermediate intensity conditioning regimen, named BEAM/ATG, in the period from 1996 to 2008. METHODS: Clinical and magnetic resonance imaging outcomes of 74 patients were collected after a median follow-up period of 48.3 (range = 0.8-126) months. RESULTS: Two patients (2.7%) died from transplant-related causes. After 5 years, 66% of patients remained stable or improved. Among patients with a follow-up longer than 1 year, eight out of 25 subjects with a relapsing-remitting course (31%) had a 6-12 months confirmed Expanded Disability Status Scale improvement > 1 point after AHSCT as compared with one out of 36 (3%) patients with a secondary progressive disease course (p = 0.009). Among the 18 cases with a follow-up longer than 7 years, eight (44%) remained stable or had a sustained improvement while 10 (56%), after an initial period of stabilization or improvement with median duration of 3.5 years, showed a slow disability progression. CONCLUSIONS: This study shows that AHSCT with a BEAM/ATG conditioning regimen has a sustained effect in suppressing disease progression in aggressive MS cases unresponsive to conventional therapies. It can also cause a sustained clinical improvement, especially if treated subjects are still in the relapsing-remitting phase of the disease.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Esclerose Múltipla Crônica Progressiva/cirurgia , Esclerose Múltipla Recidivante-Remitente/cirurgia , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Distribuição de Qui-Quadrado , Avaliação da Deficiência , Progressão da Doença , Intervalo Livre de Doença , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Itália , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Crônica Progressiva/mortalidade , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/mortalidade , Valor Preditivo dos Testes , Sistema de Registros , Índice de Gravidade de Doença , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/mortalidade , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.
Assuntos
Doença de Alzheimer/genética , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Predisposição Genética para Doença/genética , Hereditariedade/genética , Fatores Etários , Idoso , Alelos , Doença de Alzheimer/epidemiologia , Estudos de Casos e Controles , Feminino , França/epidemiologia , Genótipo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estados Unidos/epidemiologiaRESUMO
Epigenetics is believed to play a role in Alzheimer's disease (AD). DNA methylation, the most investigated epigenetic hallmark, is a reversible mechanism that modifies genome function and chromosomal stability through the addition of methyl groups to cytosine located in CpG dinucleotides to form 5 methylcytosine (5mC). Methylation status of repetitive elements (i.e. Alu, LINE-1 and SAT-α) is a major contributor of global DNA methylation patterns and has been investigated in relation to a variety of human diseases. However, the role of methylation of repetitive elements in blood of AD patients has never been investigated so far. In the present study, a quantitative bisulfite-PCR pyrosequencing method was used to evaluate methylation of Alu, LINE-1 and SAT-α sequences in 43 AD patients and 38 healthy donors. In multivariate analysis adjusting for age and gender, LINE-1 was increased in AD patients compared with healthy volunteers (ADs: 83.6%5mC, volunteers: 83.1%5mC, p-value: 0.05). The group with best performances in mini mental state examination (MMSE) showed higher levels of LINE-1 methylation compared to the group with worst performances (MMSE>22: 83.9%5mC; MMSE≤22: 83.2%5mC; p=0.05). Our data suggest that LINE-1 methylation may lead to a better understanding of AD pathogenesis and course, and may contribute to identify novel markers useful to assess risk stratification. Further prospective investigations are warranted to evaluate the dynamics of DNA methylation from early-stage AD to advanced phases of the disease.
Assuntos
Elementos Alu/genética , Doença de Alzheimer/genética , Metilação de DNA , DNA Satélite/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação , Processamento de Proteína Pós-Traducional , Testes Psicológicos , Proteínas tau/líquido cefalorraquidianoRESUMO
OBJECTIVES: To assess the frequency of clinical features of Sjogren's syndrome (SS) in patients with multiple sclerosis (MS) receiving treatment with disease-modifying drugs (DMDs) or naïve to treatment and the possible association with clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) parameters. METHODS: A multicentre cross-sectional observational study was designed, based on a structured neurologist-administered questionnaire to 440 patients. RESULTS: Twenty-eight of 230 (12%) patients receiving treatment with DMDs (DMDs(+)) and 14 of 210 (6.6%) treatment-naïve patients (DMDs(-) ) showed clinical features of SS. Four primary SS were diagnosed, two of which were DMDs(+) and two were DMDs(-) . Sicca symptoms were significantly associated with higher EDSS scores (P = 0.018), a low frequency of gadolinium-enhanced MRI-positive lesions (P = 0.018) and cerebral disturbances (P = 0.001). CONCLUSIONS: Screening for the clinical features of SS should be performed in patients with MS both receiving treatment with immunomodulatory drugs and without therapy.
Assuntos
Antirreumáticos/uso terapêutico , Interferon beta/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Síndrome de Sjogren/tratamento farmacológico , Adulto , Estudos Transversais , Avaliação da Deficiência , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico , Observação , Estudos Retrospectivos , Índice de Gravidade de Doença , Síndrome de Sjogren/líquido cefalorraquidiano , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico , Inquéritos e QuestionáriosRESUMO
Progranulin (GRN) gene variability has been analyzed in a sample of 354 patients with multiple sclerosis (MS) compared with 343 controls. No significant differences were observed, but by stratifying according to MS subtypes, a significant increased frequency of the rs2879096 TT genotype was found in primary progressive MS (PPMS) patients versus controls (16.0 vs 3.5%, P=0.023, odds ratio (OR) 5.2, 95% confidence interval (CI) 1.2-21.4). In addition, in PPMS, an association with the C allele of rs4792938 was observed (55.3 vs 33.5%, P=0.011, OR 2.4, 95% CI 1.2-4.7). An independent population was studied as replication, failing to confirm results previously obtained. Stratifying according to gender, an association with rs4792938 C allele was found in male PPMS patients compared with controls (40.7 vs 26.9%, P=0.002, OR 1.87, 95% CI 1.2-2.8). An association with the rs2879096T allele was observed (29.2 in patients compared with 18.9% in controls, P=0.012, OR 1.77, 95% CI 1.1-2.8). Haplotype analysis showed that TC haplotype frequency is increased in PPMS male patients compared with male controls (25.7 vs 16.6%; P=0.02, OR 1.69, 95% CI 1.1-2.7), whereas the respective GC haplotype seems to exert a protective effect, as its frequency is decreased in patients compared with controls (55.8% vs 70.9%; P=0.001, OR 0.52, 95% CI 0.4-0.8). Therefore, GRN haplotypes likely influence the risk of developing PPMS in males.