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1.
Proteomics ; 24(3-4): e2300202, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37541286

RESUMEN

Parkinson's disease (PD) is a complex neurodegenerative disease with motor and non-motor symptoms. Diagnosis is complicated by lack of reliable biomarkers. To individuate peptides and/or proteins with diagnostic potential for early diagnosis, severity and discrimination from similar pathologies, the salivary proteome in 36 PD patients was investigated in comparison with 36 healthy controls (HC) and 35 Alzheimer's disease (AD) patients. A top-down platform based on HPLC-ESI-IT-MS allowed characterizing and quantifying intact peptides, small proteins and their PTMs (overall 51). The three groups showed significantly different protein profiles, PD showed the highest levels of cystatin SA and antileukoproteinase and the lowest of cystatin SN and some statherin proteoforms. HC exhibited the lowest abundance of thymosin ß4, short S100A9, cystatin A, and dimeric cystatin B. AD patients showed the highest abundance of α-defensins and short oxidized S100A9. Moreover, different proteoforms of the same protein, as S-cysteinylated and S-glutathionylated cystatin B, showed opposite trends in the two pathological groups. Statherin, cystatins SA and SN classified accurately PD from HC and AD subjects. α-defensins, histatin 1, oxidized S100A9, and P-B fragments were the best classifying factors between PD and AD patients. Interestingly statherin and thymosin ß4 correlated with defective olfactory functions in PD patients. All these outcomes highlighted implications of specific proteoforms involved in the innate-immune response and inflammation regulation at oral and systemic level, suggesting a possible panel of molecular and clinical markers suitable to recognize subjects affected by PD.


Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , alfa-Defensinas , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Cistatina B/análisis , Cistatina B/metabolismo , Proteómica/métodos , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/metabolismo , Enfermedades Neurodegenerativas/metabolismo , alfa-Defensinas/análisis , alfa-Defensinas/metabolismo , Saliva/química , Proteínas y Péptidos Salivales/metabolismo , Factores de Transcripción/metabolismo , Biomarcadores/análisis
2.
Int J Mol Sci ; 23(18)2022 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-36142123

RESUMEN

Genetic Creutzfeldt-Jakob disease (gCJD) associated with the V180I mutation in the prion protein (PrP) gene (PRNP) in phase with residue 129M is the most frequent cause of gCJD in East Asia, whereas it is quite uncommon in Caucasians. We report on a gCJD patient with the rare V180I-129V haplotype, showing an unusually long duration of the disease and a characteristic pathological PrP (PrPSc) glycotype. Family members carrying the mutation were fully asymptomatic, as commonly observed with this mutation. Neuropathological examination showed a lesion pattern corresponding to that commonly reported in Japanese V180I cases with vacuolization and gliosis of the cerebral cortexes, olfactory areas, hippocampus and amygdala. PrP was deposited with a punctate, synaptic-like pattern in the cerebral cortex, amygdala and olfactory tract. Western blot analyses of proteinase-K-resistant PrP showed the characteristic two-banding pattern of V180I gCJD, composed of mono- and un-glycosylated isoforms. In line with reports on other V180I cases in the literature, Real-Time Quaking Induced Conversion (RT-QuIC) analyses did not demonstrate the presence of seeding activity in the cerebrospinal fluid and olfactory mucosa, suggesting that this haplotype also may result in a reduced seeding efficiency of the pathological PrP. Further studies are required to understand the origin, penetrance, disease phenotype and transmissibility of 180I-129V haplotype in Caucasians.


Asunto(s)
Síndrome de Creutzfeldt-Jakob , Priones , Encéfalo/metabolismo , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patología , Endopeptidasa K/metabolismo , Haplotipos , Humanos , Proteínas Priónicas/genética , Proteínas Priónicas/metabolismo , Priones/metabolismo
3.
Neuropathology ; 37(2): 110-115, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27634418

RESUMEN

We report a case of rapidly evolving neurological disease in a patient with neuropathological lesions of Creutzfeldt-Jakob disease (CJD), Lewy body dementia (LBD), chronic subcortical vascular encephalopathy and meningothelial meningioma. The coexistence of severe multiple pathologies in a single patient strengthens the need to perform accurate clinical differential diagnoses in rapidly progressive dementias.


Asunto(s)
Encefalopatías/diagnóstico , Encefalopatías/patología , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/patología , Enfermedad por Cuerpos de Lewy/diagnóstico , Enfermedad por Cuerpos de Lewy/patología , Meningioma/diagnóstico , Meningioma/patología , Anciano , Encéfalo/patología , Encéfalo/fisiopatología , Encefalopatías/complicaciones , Encefalopatías/fisiopatología , Síndrome de Creutzfeldt-Jakob/complicaciones , Síndrome de Creutzfeldt-Jakob/fisiopatología , Progresión de la Enfermedad , Electroencefalografía , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/complicaciones , Enfermedad por Cuerpos de Lewy/fisiopatología , Meningioma/complicaciones , Meningioma/fisiopatología , Examen Neurológico
4.
Radiol Med ; 122(5): 369-385, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28110369

RESUMEN

Human transmissible spongiform encephalopathies (TSEs), or prion diseases, are invariably fatal conditions associated with a range of clinical presentations. TSEs are classified as sporadic [e.g. sporadic Creutzfeldt-Jakob disease (sCJD), which is the most frequent form], genetic (e.g. Gerstmann-Straussler-Scheinker disease, fatal familial insomnia, and inherited CJD), and acquired or infectious (e.g. Kuru, iatrogenic CJD, and variant CJD). In the past, brain imaging played a supporting role in the diagnosis of TSEs, whereas nowadays magnetic resonance imaging (MRI) plays such a prominent role that MRI findings have been included in the diagnostic criteria for sCJD. Currently, MRI is required for all patients with a clinical suspicion of TSEs. Thus, MRI semeiotics of TSEs should become part of the cultural baggage of any radiologist. The purposes of this update on the neuroradiology of CJD are to (i) review the pathophysiology and clinical presentation of TSEs, (ii) describe both typical and atypical MRI findings of CJD, and (iii) illustrate diseases mimicking CJD, underlining the MRI key findings useful in the differential diagnosis.


Asunto(s)
Imagen por Resonancia Magnética , Enfermedades por Prión/diagnóstico por imagen , Diagnóstico Diferencial , Humanos , Neurorradiografía/métodos
5.
Dement Geriatr Cogn Disord ; 39(3-4): 194-206, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25572669

RESUMEN

AIMS: To investigate the relationship between psychotic symptoms and cognitive impairment in Alzheimer's disease (AD). METHODS: A total of 108 subjects affected by AD were subdivided into subjects without delusions (ND), subjects with paranoid delusions (PD), subjects with delusional misidentifications (DM), subjects with both DM and PD (DM+PD), subjects with visual hallucinations (v-HALL), and subjects without visual hallucinations (N-HALL). RESULTS: PD and ND subjects performed similarly on neuropsychological tests, while DM patients performed significantly worse than PD and ND patients. v-HALL patients performed worse than N-HALL patients on memory, visuospatial, and executive functions. As for behavioral features, DM and v-HALL subjects reported higher scores on the abnormal motor behavior subscale of the neuropsychiatric inventory (NPI); PD subjects reported higher scores on the disinhibition subscale of the NPI. The severity of PD was predicted by the severity of disinhibition (B = 0.514; p = 0.016) but not by neuropsychological performances. The severity of DM was predicted by age (B = 0.099; p = 0.048) and MMSE (B = -0.233; p = 0.001). The severity of v-HALL was predicted by age (B = 0.052; p = 0.037) and scores on an immediate visual memory task (B = -0.135; p = 0.007). CONCLUSIONS: The occurrence of PD may require the relative sparing of cognitive functions and be favored by frontal lobe dysfunction, while DM is associated with the overall level of cognitive impairment. Finally, v-HALL are associated with the impairment of visuospatial abilities.


Asunto(s)
Enfermedad de Alzheimer/psicología , Deluciones/etiología , Alucinaciones/etiología , Trastornos Psicóticos/etiología , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/fisiopatología , Trastornos del Conocimiento/psicología , Estudios Transversales , Femenino , Lóbulo Frontal/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Actividad Motora , Pruebas Neuropsicológicas , Índice de Severidad de la Enfermedad
6.
Am J Geriatr Psychiatry ; 21(1): 67-77, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23290204

RESUMEN

OBJECTIVE: Polymorphism C in the solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4) gene has been variously associated with major depressive disorder (MDD). To the best of our knowledge, no data were reported regarding a role of SLC6A4 in late-life MDD. The aim of this study was to explore the possible involvement of the SLC6A4 locus in patients with late-life MDD by means of a haplotype-tagged approach. DESIGN: Case-control study. SETTING: Older patients attending a geriatric unit. PARTICIPANTS: A total of 218 patients with late-life MDD (61 men and 157 women) age 65 to 92 years (76.29 ± 6.53 years) and 363 depression-free healthy subjects (156 men and 207 women) age 41 to 65 years (48.33 ± 5.94 years). MEASUREMENTS: Genotyping and haplotype estimation of the three markers rs4795541, rs140701, and rs3813034 spanning a 39-kb block the SLC6A4 locus. Diagnoses of late-life MDD, mild cognitive impairment, Alzheimer disease, vascular dementia, and other dementing diseases were made using current clinical criteria. RESULTS: No significant differences were observed in allele or genotype distribution for the three SLC6A4 markers across the study groups. Because the comparison group could not be matched for age, a sensitivity analysis for the misclassification of controls was performed according to different scenarios. For each simulated scenario, the same nonsignificant result was observed. However, the results are limited to late-life MDD that is specifically not associated with cognitive impairment, and there was limited power for detecting very small effect sizes. CONCLUSIONS: Our findings suggested that the SLC6A4 locus play a minor role, if any, in the pathogenesis of late-life MDD. Also, tempering our conclusions, we were unable to account for population stratification, recurrence or chronicity of depression, nor the influence of coexisting medical, cognitive, and psychosocial stressors.


Asunto(s)
Trastorno Depresivo Mayor/genética , Predisposición Genética a la Enfermedad/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Alelos , Enfermedad de Alzheimer/genética , Estudios de Casos y Controles , Disfunción Cognitiva/genética , Demencia/genética , Demencia Vascular , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético/genética
7.
Life (Basel) ; 13(3)2023 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-36983903

RESUMEN

Cystatin B is a small, multifunctional protein involved in the regulation of inflammation, innate immune response, and neuronal protection and found highly abundant in the brains of patients with Alzheimer's disease (AD). Recently, our study demonstrated a significant association between the level of salivary cystatin B and AD. Since the protein is able to establish protein-protein interaction (PPI) in different contexts and aggregation-prone proteins and the PPI networks are relevant for AD pathogenesis, and due to the relevance of finding new AD markers in peripheral biofluids, we thought it was interesting to study the possible involvement of cystatin B in PPIs in saliva and to evaluate differences and similarities between AD and age-matched elderly healthy controls (HC). For this purpose, we applied a co-immunoprecipitation procedure and a bottom-up proteomics analysis to purify, identify, and quantify cystatin B interactors. Results demonstrated for the first time the existence of a salivary cystatin B-linked multi-protein complex composed by 82 interactors and largely expressed in the body. Interactors are involved in neutrophil activation, antimicrobial activity, modulation of the cytoskeleton and extra-cellular matrix (ECM), and glucose metabolism. Preliminary quantitative data showed significantly lower levels of triosophosphate isomerase 1 and higher levels of mucin 7, BPI, and matrix Gla protein in AD with respect to HC, suggesting implications associated with AD of altered glucose metabolism, antibacterial activities, and calcification-associated processes. Data are available via ProteomeXchange with identifiers PXD039286 and PXD030679.

8.
Brain Cogn ; 80(1): 155-9, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22771855

RESUMEN

Semantic memory was investigated in a patient (MR) affected by a severe apperceptive visual agnosia, due to an ischemic cerebral lesion, bilaterally affecting the infero-mesial parts of the temporo-occipital cortices. The study was made by means of a Semantic Knowledge Questionnaire (Laiacona, Barbarotto, Trivelli, & Capitani, 1993), which takes separately into account four categories of living beings (animals, fruits, vegetables and body parts) and of artefacts (furniture, tools, vehicles and musical instruments), does not require a visual analysis and allows to distinguish errors concerning super-ordinate categorization, perceptual features and functional/encyclopedic knowledge. When the total number of errors obtained on all the categories of living and non-living beings was considered, a non-significant trend toward a higher number of errors in living stimuli was observed. This difference, however, became significant when body parts and musical instruments were excluded from the analysis. Furthermore, the number of errors obtained on the musical instruments was similar to that obtained on the living categories of animals, fruits and vegetables and significantly higher of that obtained in the other artefact categories. This difference was still significant when familiarity, frequency of use and prototypicality of each stimulus entered into a logistic regression analysis. On the other hand, a separate analysis of errors obtained on questions exploring super-ordinate categorization, perceptual features and functional/encyclopedic attributes showed that the differences between living and non-living stimuli and between musical instruments and other artefact categories were mainly due to errors obtained on questions exploring perceptual features. All these data are at variance with the 'domains of knowledge' hypothesis', which assumes that the breakdown of different categories of living and non-living things respects the distinction between biological entities and artefacts and support the models assuming that 'category-specific semantic disorders' are the by-product of the differential weighting that visual-perceptual and functional (or action-related) attributes have in the construction of different biological and artefacts categories.


Asunto(s)
Agnosia/psicología , Isquemia Encefálica/psicología , Recuerdo Mental/fisiología , Accidente Cerebrovascular/psicología , Anciano , Agnosia/etiología , Agnosia/fisiopatología , Isquemia Encefálica/complicaciones , Isquemia Encefálica/fisiopatología , Humanos , Conocimiento , Masculino , Pruebas Neuropsicológicas , Reconocimiento en Psicología/fisiología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/fisiopatología
9.
J Alzheimers Dis ; 89(2): 605-622, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35912740

RESUMEN

BACKGROUND: Aging is a risk factor for several pathologies as Alzheimer's disease (AD). Great interest exists, therefore, in discovering diagnostic biomarkers and indicators discriminating biological aging and health status. To this aim, omic investigations of biological matrices, as saliva, whose sampling is easy and non-invasive, offer great potential. OBJECTIVE: Investigate the salivary proteome through a statistical comparison of the proteomic data by several approaches to highlight quali-/quantitative variations associated specifically either to aging or to AD occurrence, and, thus, able to classify the subjects. METHODS: Salivary proteomic data of healthy controls under-70 (adults) and over-70 (elderly) years old, and over-70 AD patients, obtained by liquid chromatography/mass spectrometry, were analyzed by multiple Mann-Whitney test, Kendall correlation, and Random-Forest (RF) analysis. RESULTS: Almost all the investigated proteins/peptides significantly decreased in relation to aging in elderly subjects, with or without AD, in comparison with adults. AD subjects exhibited the highest levels of α-defensins, thymosin ß4, cystatin B, S100A8 and A9. Correlation tests also highlighted age/disease associated differences. RF analysis individuated quali-/quantitative variations in 20 components, as oxidized S100A8 and S100A9, α-defensin 3, P-B peptide, able to classify with great accuracy the subjects into the three groups. CONCLUSION: The findings demonstrated a strong change of the salivary protein profile in relation to the aging. Potential biomarkers candidates of AD were individuated in peptides/proteins involved in antimicrobial defense, innate immune system, inflammation, and in oxidative stress. RF analysis revealed the feasibility of the salivary proteome to discriminate groups of subjects based on age and health status.


Asunto(s)
Enfermedad de Alzheimer , alfa-Defensinas , Anciano , Envejecimiento , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/metabolismo , Calgranulina A , Cistatina B/metabolismo , Humanos , Proteoma/metabolismo , Proteómica/métodos , Proteínas y Péptidos Salivales/metabolismo , alfa-Defensinas/metabolismo
10.
Front Aging Neurosci ; 14: 932354, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36204549

RESUMEN

Red blood cells (RBCs) are characterized by a remarkable elasticity, which allows them to undergo very large deformation when passing through small vessels and capillaries. This extreme deformability is altered in various clinical conditions, suggesting that the analysis of red blood cell (RBC) mechanics has potential applications in the search for non-invasive and cost-effective blood biomarkers. Here, we provide a comparative study of the mechanical response of RBCs in patients with Alzheimer's disease (AD) and healthy subjects. For this purpose, RBC viscoelastic response was investigated using atomic force microscopy (AFM) in the force spectroscopy mode. Two types of analyses were performed: (i) a conventional analysis of AFM force-distance (FD) curves, which allowed us to retrieve the apparent Young's modulus, E; and (ii) a more in-depth analysis of time-dependent relaxation curves in the framework of the standard linear solid (SLS) model, which allowed us to estimate cell viscosity and elasticity, independently. Our data demonstrate that, while conventional analysis of AFM FD curves fails in distinguishing the two groups, the mechanical parameters obtained with the SLS model show a very good classification ability. The diagnostic performance of mechanical parameters was assessed using receiving operator characteristic (ROC) curves, showing very large areas under the curves (AUC) for selected biomarkers (AUC > 0.9). Taken all together, the data presented here demonstrate that RBC mechanics are significantly altered in AD, also highlighting the key role played by viscous forces. These RBC abnormalities in AD, which include both a modified elasticity and viscosity, could be considered a potential source of plasmatic biomarkers in the field of liquid biopsy to be used in combination with more established indicators of the pathology.

11.
Pharmacogenet Genomics ; 21(4): 225-30, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20859244

RESUMEN

OBJECTIVE: Cytochrome P450 (CYP) 2D6 enzyme is the major responsible for the metabolism of donepezil, an inhibitor of acetyl cholinesterase currently used for the symptomatic treatment of mild-to-moderate Alzheimer's disease (AD). Functional polymorphisms in the CYP2D6 gene may affect enzyme activity and thus, the metabolism of donepezil. The aim of this study was to evaluate the effect of 16 functional polymorphisms in the CYP2D6 gene on the clinical response to donepezil treatment in patients with mild-to-moderate AD. METHODS: In this multicenter prospective cohort study we evaluated 57 unrelated Caucasians clinically diagnosed as AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association Work Group criteria. Patients were treated with donepezil (5-10 mg/daily) for 6 months. The response to donepezil treatment was evaluated at 6-month follow-up according to the National Institute for Health and Clinical Excellence requirements. The identification of 16 clinically relevant CYP2D6 gene variants was performed by a high-throughput genetic analysis. RESULTS: Thirty-eight of 57 patients (67%) were responders and 19 patients (33%) were nonresponders to donepezil treatment. A significantly higher frequency of gene variants conferring decreased or absent enzyme activity was observed in responder than in nonresponder patients (73.68% vs. 36.84%; P=0.005). The presence of gene variants conferring decreased or absent activity of the CYP2D6 enzyme was significantly associated with a clinical response to donepezil treatment (odds ratio=6.286; 95% confidence interval=1.828-21.667). CONCLUSIONS: Functional polymorphisms in the CYP2D6 gene can influence the clinical efficacy of donepezil. The analysis of CYP2D6 genotypes may be useful in identifying subgroups of AD patients with different clinical response to donepezil treatment.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Citocromo P-450 CYP2D6/genética , Indanos/uso terapéutico , Nootrópicos/uso terapéutico , Piperidinas/uso terapéutico , Polimorfismo Genético/genética , Enfermedad de Alzheimer/genética , Estudios de Cohortes , Donepezilo , Femenino , Variación Genética , Humanos , Masculino
12.
Clin Lab ; 57(11-12): 887-93, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22239018

RESUMEN

BACKGROUND: Recent studies investigating the single cytochrome P450 (CYP) 2D6 allele *2A reported an association with the response to drug treatments. More genetic data can be obtained, however, by high-throughput based-technologies. Aim of this study is the high-throughput analysis of the CYP2D6 polymorphisms to evaluate its effectiveness in the identification of patient responders/non-responders to CYP2D6-metabolized drugs. METHODS: An attempt to compare our results with those previously obtained with the standard analysis of CYP2D6 allele *2A was also made. Sixty blood samples from patients treated with CYP2D6-metabolized drugs previously genotyped for the allele CYP2D6*2A, were analyzed for the CYP2D6 polymorphisms with the AutoGenomics INFINITI CYP4502D6-I assay on the AutoGenomics INFINITI analyzer. RESULTS: A higher frequency of mutated alleles in responder than in non-responder patients (75.38 % vs 43.48 %; p = 0.015) was observed. Thus, the presence of a mutated allele of CYP2D6 was associated with a response to CYP2D6-metabolized drugs (OR = 4.044 (1.348 - 12.154). No difference was observed in the distribution of allele *2A (p = 0.320). CONCLUSIONS: The high-throughput genetic analysis of the CYP2D6 polymorphisms better discriminate responders/non-responders with respect to the standard analysis of the CYP2D6 allele *2A. A high-throughput genetic assay of the CYP2D6 may be useful to identify patients with different clinical responses to CYP2D6-metabolized drugs.


Asunto(s)
Citocromo P-450 CYP2D6/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Polimorfismo Genético , Alelos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Biotransformación/genética , Citocromo P-450 CYP2D6/deficiencia , Citocromo P-450 CYP2D6/metabolismo , Donepezilo , Resistencia a Medicamentos/genética , Eliminación de Gen , Duplicación de Gen , Frecuencia de los Genes , Genotipo , Humanos , Indanos/farmacocinética , Indanos/uso terapéutico , Nootrópicos/farmacocinética , Nootrópicos/uso terapéutico , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Polimorfismo de Nucleótido Simple , Muestreo , Método Simple Ciego
13.
J Neuroimmunol ; 361: 577726, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34628135

RESUMEN

We describe a case of a 28-year-old man who developed a cervical myelitis while exposed to ixekizumab (IL-17 inhibitor) for psoriatic arthritis. Spinal MRI showed a T2 hyperintense lesion at the C4-C5 level while brain MRI was unspecific. Oligoclonal bands were absent and extensive screening for autoimmunity was negative. Rechallenge with ixekizumab was positive corroborating a relation between drug exposure and the neurological event. To the best of our knowledge, this is the first case of CNS inflammatory adverse event associated with ixekizumab. We also provide a review of case reports of demyelinating disorders associated with the use of biologic drugs for the treatment of psoriasis and psoriatic arthritis.


Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Factores Inmunológicos/efectos adversos , Mielitis/inducido químicamente , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/efectos adversos , Artritis Psoriásica/tratamiento farmacológico , Mapeo Encefálico , Sustitución de Medicamentos , Femenino , Humanos , Hipoestesia/inducido químicamente , Factores Inmunológicos/uso terapéutico , Interleucina-17/antagonistas & inhibidores , Pierna/inervación , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mielitis/diagnóstico por imagen , Mielitis/tratamiento farmacológico , Paresia/inducido químicamente , Médula Espinal/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto Joven
14.
Front Neurosci ; 15: 668852, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34121996

RESUMEN

Alzheimer disease (AD) is the most prevalent neurodegenerative disease in the elderly, characterized by accumulation in the brain of misfolded proteins, inflammation, and oxidative damage leading to neuronal cell death. By considering the viewpoint that AD onset and worsening may be influenced by environmental factors causing infection, oxidative stress, and inflammatory reaction, we investigated the changes of the salivary proteome in a population of patients with respect to that in healthy controls (HCs). Indeed, the possible use of saliva as a diagnostic tool has been explored in several oral and systemic diseases. Moreover, the oral cavity continuously established adaptative and protective processes toward exogenous stimuli. In the present study, qualitative/quantitative variations of 56 salivary proteoforms, including post-translationally modified derivatives, have been analyzed by RP-HPLC-ESI-IT-MS and MS/MS analyses, and immunological methods were applied to validate MS results. The salivary protein profile of AD patients was characterized by significantly higher levels of some multifaceted proteins and peptides that were either specific to the oral cavity or also expressed in other body districts: (i) peptides involved in the homeostasis of the oral cavity; (ii) proteins acting as ROS/RNS scavengers and with a neuroprotective role, such as S100A8, S100A9, and their glutathionylated and nitrosylated proteoforms; cystatin B and glutathionylated and dimeric derivatives; (iii) proteins with antimicrobial activity, such as α-defensins, cystatins A and B, histatin 1, statherin, and thymosin ß4, this last with a neuroprotective role at the level of microglia. These results suggested that, in response to injured conditions, Alzheimer patients established defensive mechanisms detectable at the oral level. Data are available via ProteomeXchange with identifier PXD021538.

16.
Dement Geriatr Cogn Disord ; 29(5): 424-31, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20502016

RESUMEN

BACKGROUND: Genotypes of the solute carrier family 6 (neurotransmitter transporter, serotonin) member 4 (SLC6A4) have been variously associated with depression, obsessive-compulsive disorder, memory impairment, and anxiety. Less clear are data regarding their association with severe dementia, in particular with vascular dementia (VaD). AIMS: To evaluate the possible involvement of different SLC6A4 genotypes/haplotypes in VaD. METHODS: The analysis of the 3 markers rs3813034, rs140701 and rs4795541 spanning the SLC6A4 locus was made in 541 consecutive patients clinically diagnosed as having VaD (n = 372) or no cognitive impairment (n = 169) attending a geriatric ward. A community-dwelling sample of 353 healthy subjects, as a reference for the genetic frequencies in the recruitment area, was also included in the study. All patients and subjects were free from any symptoms of depression, obsessive-compulsive disorder and anxiety. A complete neuroimaging documentation was available for all patients. RESULTS: No important differences were observed in genotype distribution across the study groups. Similarly, no important differences were observed in haplotype distribution when a 3-point analysis was made. CONCLUSION: Our findings suggest that polymorphism C in the promoter region of the SLC6A4 gene plays a minor role, if any, in the pathogenesis of VaD.


Asunto(s)
Demencia Vascular/genética , Depresión/genética , Polimorfismo Genético/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adulto , Anciano , Anciano de 80 o más Años , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/psicología , ADN/genética , Demencia Vascular/diagnóstico , Demencia Vascular/psicología , Depresión/psicología , Femenino , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Polimorfismo de Nucleótido Simple , Escalas de Valoración Psiquiátrica
17.
Neurol Sci ; 31(6): 837-9, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20730466

RESUMEN

E200K mutation of the prion protein gene (PRNP) presented with a variety of phenotypes. A 55-year-old woman complaining of slowly progressive walking difficulties came to our observation. She showed a severe progressive ataxo-spastic syndrome but a mild cognitive impairment only. Repeated EEGs showed a diffuse slowing of the rhythm without specificity. Brain MRI revealed by FLAIR showed widespread multiple hyperintensities in the whole cerebral cortex, caudate and putamen nuclei, and in the pulvinar and medial thalamus bilaterally. These signal abnormalities were best detected by DWI with restricted diffusion on ADC map. The clinical diagnosis of possible genetic Creutzfeldt-Jakob disease (CJD) has been confirmed by PRNP gene analysis which revealed the presence of a E200K mutation. This report confirms the heterogeneity of phenotypes in E200K mutated familial CJD with the occurrence of a new phenotype not previously described.


Asunto(s)
Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patología , Mutación Puntual/genética , Priones/genética , Sustitución de Aminoácidos/genética , Femenino , Heterogeneidad Genética , Ácido Glutámico/genética , Humanos , Lisina/genética , Persona de Mediana Edad , Fenotipo , Proteínas Priónicas
18.
J Alzheimers Dis ; 16(1): 173-80, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19158433

RESUMEN

The occurrence of psychotic symptoms is common in Alzheimer's disease (AD), configuring a possibly distinguished clinical entity defined "Psychosis in Alzheimer's Disease" (AD-P). In order to investigate demographic clinical and biological variables potentially associated to the occurrence of AD-P, 148 AD patients were selected. Mini-Mental State Examination (MMSE), Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL) scores, socio-economic status and 5-HTTLPR and APOE gene polymorphisms were determined for each subject. AD-P patients were significantly more frequent carriers of the long (L) allele of 5-HTTLPR. The percentage of AD-P increased with the number of copies of the L-allele: 13% among S homozygote; 36% among heterozygotes; 51% among L-homozygotes. No difference resulted between AD-P and non-psychotic AD (AD-NP) in the distribution of the epsilon4 allele of APOE. The risk of AD-P was increased in L/L homozygous (OR = 7.25, p = 0.003) and, to a lesser extent, in heterozygous (OR = 3.91; p = 0.018). Backward logistic regression analysis showed that the risk for AD-P was increased in older subjects (OR = 1.07; p = 0.018) while an increase of MMSE score was protective (OR = 0.90; p = 0.004). The occurrence of AD-P resulted significantly related to age at examination, cognitive status, and to the presence of the 5-HTTLPR L-allele.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Trastornos Psicóticos/genética , Trastornos Psicóticos/psicología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Actividades Cotidianas , Anciano , Alelos , Enfermedad de Alzheimer/epidemiología , Apolipoproteínas E/genética , Cognición/fisiología , Educación , Femenino , Genotipo , Humanos , Italia/epidemiología , Masculino , Estado Civil , Pruebas Neuropsicológicas , Ocupaciones , Polimorfismo Genético/genética , Trastornos Psicóticos/epidemiología
19.
J Alzheimers Dis ; 14(3): 335-44, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18599960

RESUMEN

Reelin, a serine protease encoded by the RELN gene, is part of the apolipoprotein E (apoE) biochemical pathway that is involved in the pathogenesis of Alzheimer's disease (AD). Sex-related differences in the epidemiology, pathology and clinical characteristics of AD have been reported. To explore the potential contribution of RELN gene variants in the pathogenesis of AD, we investigated three polymorphisms spanning the RELN locus, i.e., a triplet tandem repeat in the 5'UTR and two single-nucleotide polymorphisms (SNPs) rs607755 and rs2229874, located in the splice-junction of exon 6 and in the coding region of exon 50. The analysis was made in 223 sporadic AD patients and 181 age-matched controls of Caucasian ethnicity. Significant differences between AD patients and controls were found in distribution of 5'UTR and rs607755 genotypes, whereas no differences were found in the distribution of rs2229874 genotypes. When patients and controls were divided according to sex, significant differences in genotype distribution were found in females and not in males, also after adjustment for APOE genotypes. These findings suggest that RELN gene variants may play a role in the pathogenesis of AD, particularly in females.


Asunto(s)
Enfermedad de Alzheimer/genética , Moléculas de Adhesión Celular Neuronal/genética , Proteínas de la Matriz Extracelular/genética , Proteínas del Tejido Nervioso/genética , Serina Endopeptidasas/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Apolipoproteínas E/metabolismo , ADN Recombinante/genética , Exones/genética , Femenino , Genotipo , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Proteína Reelina
20.
Dement Geriatr Cogn Disord ; 25(3): 287-92, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18303265

RESUMEN

BACKGROUND: The glutamatergic neurotransmitter systems play a crucial role in memory formation and information processing. Alterations in this system contribute to the manifestation of symptoms in Alzheimer's disease (AD). Glutamate transmits signals via the N-methyl-D-aspartate receptors (NMDARs). AIMS: The potential involvement of polymorphisms in the GRIN2B gene, encoding subunit 2B of the NMDA receptor, in the risk for AD was evaluated. METHODS: We investigated the 3 single-nucleotide polymorphisms (SNPs) rs1019385, rs1806201 and rs890, i.e. the G(-200)-->T transversion in the 5'UTR, the A(2664)-->G transition in exon 13 and the G(5072)-->T transition in the 3'UTR of the GRIN2B gene, in 222 Caucasian AD patients and 170 healthy Caucasian age-matched controls. RESULTS: No differences were found in the overall distribution of the single-nucleotide polymorphism genotypes between AD patients and healthy controls, even when the analysis was adjusted for sex, age and APOE. As expected from genotype frequencies, no differences were found in the distribution of the estimated allele and haplotype frequencies between AD patients and healthy controls. CONCLUSION: In this study no significant association between polymorphisms in the GRIN2B gene and AD was observed. Further investigations of polymorphisms in the gene encoding the NMDA receptor 2B subunit in AD patients with different genetic setting are needed to clarify their role in the pathogenesis of AD.


Asunto(s)
Enfermedad de Alzheimer/genética , Receptores de N-Metil-D-Aspartato/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Encéfalo/patología , Estudios de Casos y Controles , Estudios Transversales , Cartilla de ADN/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Índice de Severidad de la Enfermedad
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