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Introduction: SARS-CoV-2 infection frequently causes neurological symptoms. Cognitive alterations are among the most frequent symptoms, and may persist beyond the acute phase of infection. Methods: We conducted a narrative review of the literature. Results: Hospitalised patients, and especially critically ill patients, are at greater risk of developing cognitive symptoms. Post-COVID-19 cognitive symptoms, unlike those associated with other viral illnesses, have been observed in patients with mild infection, and present some atypical features. Cognitive symptoms may last longer in COVID-19 than in other infectious processes, and more frequently affect young people. Post-COVID-19 cognitive symptoms share common features with those described in chronic fatigue syndrome, including a similar profile with affective symptoms. Brief screening tests for cognitive impairment present suboptimal diagnostic performance, and standardised criteria are needed to ensure correct diagnosis.Post-COVID-19 cognitive impairment can have a significant impact on the patient's quality of life and functional independence, regardless of other post-COVID-19 symptoms. Currently, no specific treatments have been approved for post-COVID-19 cognitive impairment, although cognitive stimulation may be useful in some patients. Conclusions: Post-COVID-19 cognitive symptoms are common and are often associated with other systemic symptoms. Neuropsychological evaluation may be useful for diagnosis and to quantify their severity and long-term prognosis. Detailed, and individualised assessment of cognitive impairment may enable the design of treatment plans.
Introducción: La infección por SARS-Cov2 con frecuencia causa síntomas neurológicos. Los síntomas cognitivos se encuentran entre los síntomas más frecuentes y pueden persistir más allá de la fase aguda de la infección. Metodología: Revisión narrativa de la literatura. Resultados: El riesgo de padecer síntomas cognitivos es mayor en pacientes hospitalizados, especialmente en pacientes críticos. Los síntomas cognitivos post-COVID, a diferencia de los que aparecen en otros cuadros virales, se han observado en pacientes con infección leve y presentan algunos rasgos atípicos. La duración de la sintomatología cognitiva puede ser superior a otros procesos infecciosos y afectar con mayor frecuencia a personas jóvenes. Los síntomas cognitivos post-COVID comparten rasgos comunes con los descritos en el síndrome de la fatiga crónica, incluyendo un perfil similar de síntomas afectivos asociados. Los tests rápidos de cribado de deterioro cognitivo tienen un rendimiento diagnóstico subóptimo y son necesarios criterios estandarizados para un correcto diagnóstico.El deterioro cognitivo post-COVID puede ocasionar un impacto significativo en la calidad de vida y en la autonomía funcional del paciente, de forma independiente al resto de síntomas post-COVID. En la actualidad no existen tratamientos específicos aprobados para el deterioro cognitivo post-COVID, aunque la estimulación cognitiva puede ser útil en algunos pacientes. Conclusiones: Los síntomas cognitivos post-COVID son frecuentes, y con asiduidad se asocian a otros síntomas sistémicos. Una evaluación neuropsicológica puede ser de utilidad para el diagnóstico y para cuantificar su severidad y pronóstico a largo plazo. Una caracterización detallada e individualizada del deterioro cognitivo permite establecer medidas de tratamiento.
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Cerebrospinal fluid (CSF) biomarkers are useful in the diagnosis and the prediction of progression of several neurodegenerative diseases. Among them, CSF neurofilament light (NfL) protein has particular interest, as its levels reflect neuroaxonal degeneration, a common feature in various neurodegenerative diseases. In the present study, we analyzed NfL levels in the CSF of 535 participants of the SPIN (Sant Pau Initiative on Neurodegeneration) cohort including cognitively normal participants, patients with Alzheimer disease (AD), Down syndrome (DS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We evaluated the differences in CSF NfL accross groups and its association with other CSF biomarkers and with cognitive scales. All neurogenerative diseases showed increased levels of CSF NfL, with the highest levels in patients with ALS, FTD, CBS and PSP. Furthermore, we found an association of CSF NfL levels with cognitive impairment in patients within the AD and FTD spectrum and with AD pathology in DLB and DS patients. These results have implications for the use of NfL as a marker in neurodegenerative diseases.
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Enfermedades Neurodegenerativas/diagnóstico , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Anciano , Biomarcadores/líquido cefalorraquídeo , Estudios de Cohortes , Progresión de la Enfermedad , Diagnóstico Precoz , Femenino , Estudios de Seguimiento , Humanos , Masculino , Distrofias Neuroaxonales/diagnóstico , Distrofias Neuroaxonales/patología , Enfermedades Neurodegenerativas/patologíaRESUMEN
BACKGROUND: The efficacy of direct-acting anti-viral (DAA) therapy in patients with a history of hepatocellular carcinoma (HCC) is unknown. AIM: We prospectively evaluated whether previously treated HCC affects DAA efficacy in a large real-life cohort of cirrhotic patients. METHODS: From January to December 2015 all consecutive HCV mono-infected patients with cirrhosis and/or history of HCC attending 10 Italian tertiary liver centres were enrolled. Baseline characteristics and response to therapy were recorded. 1927 patients were enrolled (mean age: 62.1 ± 10.9 years; 1.205 males). Genotype 1 was the most frequent (67.9%) followed by genotypes 3 (12.4%), 2 (11.2%) and 4 (8.6%). 88.4% and 10.9% of cases were classified Child A and B, respectively, and 14 (<1%) cases were classified Child C. Ascites and hepatic encephalopathy occurred in 10.7% and 3.2% of patients, respectively. Varices were detected in 39.3% of patients. Suboptimal and optimal treatment was prescribed: 15.9% of patients received sofosbuvir/simeprevir, 33.4% sofosbuvir/ledipasvir, 20.2% a Viekirax + Exviera regimen, 15.7% sofosbuvir/ribavirin, 9.9% sofosbuvir/daclatasvir and 3.4% Viekirax; 1.3% of patients received an interferon-based regimen. RESULTS: The sustained virologic response (SVR) rate at intention-to-treat analysis was 95.1%. It differed significantly across Child classes, that is, 96.3%, 86.1% and 71.4% Child A, B and C, respectively (P < 0.0001) and across genotypes (P = 0.002). The SVR rate did not differ between patients with (95.0%) and those without previous HCC (95.1%). At multivariable analysis, SVR was significantly associated with HCV genotype, Child class. CONCLUSION: This large real-life study proves that the efficacy of DAA in cirrhotic patients is not impaired by successfully treated HCC.
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Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Anciano , Bencimidazoles/administración & dosificación , Carbamatos , Carcinoma Hepatocelular/etiología , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Fluorenos/administración & dosificación , Genotipo , Hepacivirus/genética , Encefalopatía Hepática/epidemiología , Humanos , Imidazoles/administración & dosificación , Interferones/uso terapéutico , Italia , Neoplasias Hepáticas/etiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pirrolidinas , Ribavirina/uso terapéutico , Simeprevir/administración & dosificación , Sofosbuvir/uso terapéutico , Respuesta Virológica Sostenida , Uridina Monofosfato/administración & dosificación , Uridina Monofosfato/análogos & derivados , Valina/análogos & derivadosRESUMEN
BACKGROUND: Niemann-Pick type C (NPC) disease is characterized by lysosomal accumulation of cholesterol. Interestingly, NPC patients' brains also show increased levels of amyloid-ß (Aß) peptide, a key protein in Alzheimer's disease pathogenesis. We previously reported that the c-Abl tyrosine kinase is active in NPC neurons and in AD animal models and that Imatinib, a specific c-Abl inhibitor, decreased the amyloid burden in brains of the AD mouse model. Active c-Abl was shown to interact with the APP cytosolic domain, but the relevance of this interaction to APP processing has yet to be defined. RESULTS: In this work we show that c-Abl inhibition reduces APP amyloidogenic cleavage in NPC cells overexpressing APP. Indeed, we found that levels of the Aß oligomers and the carboxy-terminal fragment ßCTF were decreased when the cells were treated with Imatinib and upon shRNA-mediated c-Abl knockdown. Moreover, Imatinib decreased APP amyloidogenic processing in the brain of an NPC mouse model. In addition, we found decreased levels of ßCTF in neuronal cultures from c-Abl null mice. We demonstrate that c-Abl directly interacts with APP, that c-Abl inhibition prevents this interaction, and that Tyr682 in the APP cytoplasmic tail is essential for this interaction. More importantly, we found that c-Abl inhibition by Imatinib significantly inhibits the interaction between APP and BACE1. CONCLUSION: We conclude that c-Abl activity facilitates the APP-BACE1 interaction, thereby promoting amyloidogenic processing of APP. Thus, inhibition of c-Abl could be a pharmacological target for preventing the injurious effects of increased Aß levels in NPC disease.
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The diagnosis of primary sclerosing cholangitis (PSC) is difficult due to the lack of sensitive and specific biomarkers, as is the early diagnosis of cholangiocarcinoma (CC), a complication of PSC. The aim of this study was to identify specific serum miRNAs as diagnostic biomarkers for PSC and CC. The levels of 667 miRNAs were evaluated in 90 human serum samples (30 PSC, 30 CC and 30 control subjects) to identify disease-associated candidate miRNAs (discovery phase). The deregulated miRNAs were validated in an independent cohort of 140 samples [40 PSC, 40 CC, 20 primary biliary cirrhosis (PBC) and 40 controls]. Receiver operating characteristic (ROC) curves were established and only miRNAs with an area under the curve (AUC) > 0·70 were considered useful as biomarkers. In the discovery phase we identified the following: 21 miRNAs expressed differentially in PSC, 33 in CC and 26 in both in comparison to control subjects as well as 24 miRNAs expressed differentially between PSC and CC. After the validation phase, miR-200c was found to be expressed differentially in PSC versus controls, whereas miR-483-5p and miR-194 showed deregulated expression in CC compared with controls. We also demonstrate a difference in the expression of miR-222 and miR-483-5p in CC versus PSC. Combination of these specific miRNAs further improved the specificity and accuracy of diagnosis. This study provides a basis for the use of miRNAs as biomarkers for the diagnosis of PSC and CC.
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Biomarcadores de Tumor/genética , Colangiocarcinoma/diagnóstico , Colangitis Esclerosante/diagnóstico , Regulación Neoplásica de la Expresión Génica , Cirrosis Hepática Biliar/diagnóstico , Adulto , Anciano , Área Bajo la Curva , Biomarcadores de Tumor/sangre , Estudios de Casos y Controles , Colangiocarcinoma/sangre , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Colangitis Esclerosante/sangre , Colangitis Esclerosante/genética , Colangitis Esclerosante/patología , Diagnóstico Diferencial , Femenino , Perfilación de la Expresión Génica , Humanos , Cirrosis Hepática Biliar/sangre , Cirrosis Hepática Biliar/genética , Cirrosis Hepática Biliar/patología , Masculino , MicroARNs/sangre , MicroARNs/genética , Persona de Mediana Edad , Curva ROCRESUMEN
Circulating insulin-like growth factor I (IGF-I) enters the brain and promotes clearance of amyloid peptides known to accumulate in Alzheimer's disease (AD) brains. Both patients and mouse models of AD show decreased level of circulating IGF-I enter the brain as evidenced by a lower ratio of cerebrospinal fluid/plasma IGF-I. Importantly, in presymptomatic AD mice this reduction is already manifested as a decreased brain input of serum IGF-I in response to environmental enrichment. To explore a potential diagnostic use of this early loss of IGF-I input, we monitored electrocorticogram (ECG) responses to systemic IGF-I in mice. Whereas control mice showed enhanced ECG activity after IGF-I, presymptomatic AD mice showed blunted ECG responses. Because nonhuman primates showed identically enhanced electroencephalogram (EEG) activity in response to systemic IGF-I, loss of the EEG signature of serum IGF-I may be exploited as a disease biomarker in AD patients.
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Enfermedad de Alzheimer/diagnóstico , Encéfalo/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/farmacología , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Animales , Encéfalo/metabolismo , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Diagnóstico Precoz , Humanos , Factor I del Crecimiento Similar a la Insulina/líquido cefalorraquídeo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Macaca , RatonesRESUMEN
OBJECTIVES: Gait and movement abnormalities are traditionally considered infrequent in patients with mild/moderate Alzheimer's disease (AD). However, an increased risk of falls and gait abnormalities has been detected, even in early stages of the disease. Whether these abnormalities are associated with cerebrovascular disease, which has a high prevalence in AD, remains unclear. DESIGN: Cross-sectional study. SETTING: Dementia outpatient clinics. PARTICIPANTS: 24 mild/moderate AD patients with (AD+CVD) and 20 without (AD-CVD) cerebrovascular disease without a history of stroke and antipsychotic medications. MEASUREMENTS: Physical performance, measured with the short physical performance battery [SPPB], a summary measure combining 4-meter gait speed, balance and muscle strength, and with 8-meter gait speed with a turn was compared between the two groups. RESULTS: AD+CVD patients showed a significant higher prevalence of 4-meter gait speed slower than 0.8 m/s (37.5% vs. 5%, p-value=0.01) and balance impairment (37.5% vs. 10%, p-value=0.038), as well as a slower 8-meter gait speed with a turn (mean+SD=0.6±0.2 vs. 0.8±0.2, p-value=0.024). These associations were confirmed in multivariable models. No differences were observed for muscle strength. CONCLUSION: In our sample, AD with cerebrovascular disease had worse gait and balance than AD without cerebrovascular disease. If confirmed, these results may have clinical implications, since cerebrovascular disease can be potentially prevented.
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Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/fisiopatología , Trastornos Cerebrovasculares/complicaciones , Trastornos Cerebrovasculares/fisiopatología , Marcha/fisiología , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Masculino , Actividad Motora/fisiología , Equilibrio Postural , PrevalenciaRESUMEN
Aside from APOE, the genetic factors that influence the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) remain largely unknown. We assessed whether a genetic risk score (GRS), based on eight non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD. Among 288 subjects with MCI, follow-up (mean 26.3 months) identified 118 MCI-converters to AD and 170 MCI-nonconverters. We genotyped ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179. For each subject we calculated a cumulative GRS, defined as the number of risk alleles (range 0-16) with each allele weighted by the AD risk odds ratio. GRS was not associated with risk of conversion from MCI to AD. However, MCI-converters to AD harboring six or more risk alleles (second and third GRS tertiles) progressed twofold more rapidly to AD when compared with those with less than six risk alleles (first GRS tertile). Our GRS is a first step toward development of prediction models for conversion from MCI to AD that incorporate aggregate genetic factors.
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Enfermedad de Alzheimer/genética , Disfunción Cognitiva/genética , Predisposición Genética a la Enfermedad , Transportadoras de Casetes de Unión a ATP/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Apolipoproteínas E/genética , Clusterina/genética , Disfunción Cognitiva/complicaciones , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Estudios de Asociación Genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Proteínas de Ensamble de Clatrina Monoméricas/genética , Receptores de Complemento 3b/genética , RiesgoRESUMEN
UNLABELLED: The importance of accurate and early diagnosis of dementia with Lewy bodies (DLB) lies in its pharmacological management. Delayed imaging of cardiac (123)I-MIBG scintigraphy allows differentiation between DLB and other neurodegenerative diseases with cognitive impairment. The aim of this study was to assess the utility of early imaging of cardiac (123)I-MIBG scintigraphy for differentiating DLB from others neurodegenerative disease with cognitive impairment. MATERIAL AND METHODS: We assess retrospectively 106 patients (51 men, mean age 78 years) with cognitive impairment that underwent a cardiac (123)I-MIBG study. Planar images were acquired in anterior view of the thorax 15min (early) and 4h (delayed) after tracer administration. The heart-to-mediastinum ratios (HMR) at 15m (HMR15m) and at 4h (HMR4h) were obtained. RESULTS: After four years, 52 patients were diagnosed of DLB.HMR15m and HMR4h were significantly inferior in DLB respect to the others neurodegenerative diseases (1,27±0,15 vs 1,76±0,15,p<0,05) and (1,14±0,13 vs 1,68±0,19,p<0.01), respectively. The ROC analysis showed a HMR15m cut off point of 1.56 to differentiated DLB from the other dementias with a sensitivity and a specificity of 98%. CONCLUSIONS: Early imaging of cardiac (123)I-MIBG scintigraphy can help to differentiate DLB from other neurodegenerative diseases with cognitive impairment.
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3-Yodobencilguanidina , Trastornos del Conocimiento/diagnóstico por imagen , Corazón/diagnóstico por imagen , Corazón/inervación , Radioisótopos de Yodo , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Enfermedades Neurodegenerativas/diagnóstico por imagen , Radiofármacos , Anciano , Técnicas de Imagen Cardíaca/métodos , Trastornos del Conocimiento/complicaciones , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Enfermedades Neurodegenerativas/complicaciones , Cintigrafía , Estudios Retrospectivos , Factores de TiempoRESUMEN
Scleroderma (SSc) is a rare connective tissue disease characterized by fibrosis, microvasculopathy and autoimmune features. The role of genetics is limited in SSc, as suggested by similar concordance rates in monozygotic and dizygotic twin pairs, while environmental factors may act through epigenetic changes, as demonstrated for specific genes. Further, sex chromosome changes have been reported in SSc and may explain the female preponderance. In the present study we compared the methylation profile of all X chromosome genes in peripheral blood mononuclear cells from monozygotic twins discordant (n=7) and concordant (n=1) for SSc. Methylated DNA immunoprecipitations from each discordant twin pair were hybridized to a custom-designed array included 998 sites encompassing promoters of all X chromosome genes and randomly chosen autosomal genes. Biostatistical tools identified sites with an elevated probability to be consistently hypermethylated (n=18) or hypomethylated (n=25) in affected twins. Identified genes include transcription factors (ARX, HSFX1, ZBED1, ZNF41) and surface antigens (IL1RAPL2, PGRMC1), and pathway analysis suggests their involvement in cell proliferation (PGK1, SMS, UTP14A, SSR4), apoptosis (MTM1), inflammation (ARAF) and oxidative stress (ENOX2). In conclusion, we propose that X chromosome genes with different methylation profiles in monozygotic twin pairs may constitute candidates for SSc susceptibility.
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Cromosomas Humanos X/química , Metilación de ADN , Enfermedades en Gemelos/genética , Genes Ligados a X/genética , Linfocitos/química , Esclerodermia Sistémica/genética , Gemelos Monocigóticos/genética , Adulto , Mapeo Cromosómico , Cromosomas Humanos X/genética , Islas de CpG , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas/genéticaRESUMEN
Susceptibility to primary biliary cirrhosis (PBC) is strongly associated with human leukocyte antigen (HLA)-region polymorphisms. To determine if associations can be explained by classical HLA determinants, we studied Italian, 676 cases and 1440 controls, genotyped with dense single-nucleotide polymorphisms (SNPs) for which classical HLA alleles and amino acids were imputed. Although previous genome-wide association studies and our results show stronger SNP associations near DQB1, we demonstrate that the HLA signals can be attributed to classical DRB1 and DPB1 genes. Strong support for the predominant role of DRB1 is provided by our conditional analyses. We also demonstrate an independent association of DPB1. Specific HLA-DRB1 genes (*08, *11 and *14) account for most of the DRB1 association signal. Consistent with previous studies, DRB1*08 (P=1.59 × 10(-11)) was the strongest predisposing allele, whereas DRB1*11 (P=1.42 × 10(-10)) was protective. Additionally, DRB1*14 and the DPB1 association (DPB1*03:01; P=9.18 × 10(-7)) were predisposing risk alleles. No signal was observed in the HLA class 1 or class 3 regions. These findings better define the association of PBC with HLA and specifically support the role of classical HLA-DRB1 and DPB1 genes and alleles in susceptibility to PBC.
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Cadenas beta de HLA-DP/genética , Cadenas HLA-DRB1/genética , Cirrosis Hepática Biliar/genética , Cirrosis Hepática Biliar/inmunología , Estudios de Casos y Controles , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Italia , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Población Blanca/genéticaRESUMEN
Dysfunction of T cells is a common feature in chronic persistent viral infections, including hepatitis C virus (HCV), and although hepatic and peripheral T cells have been studied extensively in chronic HCV hepatitis, the role of splenic T cell responses in such patients is poorly defined. This is an important issue, as thrombocytopenia is a complication of HCV-related liver cirrhosis (LC), due to splenic platelet sequestration and bone marrow suppression; splenectomy has been proposed to treat such patients. Herein, we studied peripheral blood mononuclear cells (PBMC) and splenic lymphoid subpopulations from a total of 22 patients, including 15 with HCV-related LC with marked thrombocytopenia treated with splenectomy, and seven controls. CD4(+) T cells from peripheral blood and spleen were isolated and phenotype and function evaluated. Splenic CD4(+) T cells in patients with LC expressed molecules associated with inhibitory signalling, including increased frequency of negative markers such as cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed death 1 (PD-1) and decreased production of cytokines. Patients with LC manifest higher levels of splenic CD4(+) regulatory T cells and PD-L1- and PD-L2-expressing cells than controls. Blocking of PD-1/PD-1 ligand interaction reconstituted proliferative and cytokine responses of splenic mononuclear cells (SMC) from patients with LC. Splenectomy was followed by an increase in the ratio of interferon (IFN)-γ to interleukin (IL)-10 and a reduction of PD-1-expressing CD4(+) T cells in peripheral blood. Our data suggest that peripheral tolerance is promoted by the spleen in LC via the up-regulated expression of PD-1 ligands.
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Linfocitos T CD4-Positivos/inmunología , Hepatitis C/complicaciones , Hepatitis C/inmunología , Cirrosis Hepática/inmunología , Cirrosis Hepática/cirugía , Bazo/inmunología , Esplenectomía , Adulto , Anciano , Antígenos CD/biosíntesis , Antígenos CD/genética , Proteínas Reguladoras de la Apoptosis/biosíntesis , Proteínas Reguladoras de la Apoptosis/genética , Antígeno B7-1/biosíntesis , Antígeno B7-H1 , Linfocitos T CD4-Positivos/metabolismo , Antígeno CTLA-4 , Citocinas/biosíntesis , Femenino , Citometría de Flujo , Hepacivirus/inmunología , Humanos , Tolerancia Inmunológica , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Leucocitos Mononucleares/inmunología , Cirrosis Hepática/virología , Recuento de Linfocitos , Subgrupos Linfocitarios/inmunología , Masculino , Persona de Mediana Edad , Proteína 2 Ligando de Muerte Celular Programada 1 , Receptor de Muerte Celular Programada 1 , Bazo/metabolismoRESUMEN
AIM: Dementia with Lewy Bodies (DLB) must be distinguished from other types of dementia because of important differences in patient management and outcome. Both reduction in cardiac 123I-metaiodobenzilguanidine (MIBG) uptake and decreased 123I-FP-CIT binding in basal ganglia have been described in DLB. The aim of this study was to assess the relationship between cardiac sympathetic activity and nigrostriatal degeneration in patients with probable DLB. METHODS: Twenty-eight patients (15 males; mean age 77 years, range 64-88 years) with clinical international criteria of probable DLB were included in the study. All patients underwent a cardiac MIBG scintigraphy and a FP-CIT SPECT. Global cardiac MIBG uptake was semiquantified by means of heart-to-mediastinum ratio (HMR) (normal >1.56). FP-CIT binding in basal ganglia was calculated and compared with an age-matched control group. The relation between cardiac MIBG uptake and FP-CIT uptake in basal ganglia, and the relationship of these two techniques with distinctive symptoms of DLB, features of past medical history and data from the neuropsychological examination were assessed. RESULTS: Cardiac MIBG uptake was decreased in 23 of 28 patients (HMR=1.32, range 0.95-1.85). The FP-CIT binding in basal ganglia was significantly lower than in control group (2.01±0.5 vs 2.62±0.2, P<0.05). All patients with reduced cardiac HMR showed decreased FP-CIT binding in basal ganglia. There was a positive correlation between the HMR and specific binding ratio of striatum (P<0.01). A high correlation between FP-CIT SPECT and the presence of parkinsonism also was found. No correlation between cardiac MIBG uptake and demographic, clinical or neuropsychological data was found. CONCLUSION: In probable DLB cardiac MIBG uptake and FP-CIT binding in basal ganglia are reduced. The positive correlation between both measures suggests that cardiac sympathetic degeneration and nigrostriatal degeneration parallel similarly in patients with probable DLB.
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Cardiopatías/complicaciones , Enfermedad por Cuerpos de Lewy/complicaciones , Degeneración Estriatonigral/complicaciones , Degeneración Estriatonigral/diagnóstico por imagen , Tropanos/metabolismo , 3-Yodobencilguanidina/farmacocinética , Anciano , Anciano de 80 o más Años , Ganglios Basales/diagnóstico por imagen , Ganglios Basales/metabolismo , Femenino , Cardiopatías/diagnóstico por imagen , Humanos , Radioisótopos de Yodo/metabolismo , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Cintigrafía/métodos , Radiofármacos , Estudios Retrospectivos , Sistema Nervioso Simpático/lesiones , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
INTRODUCTION: We describe the 5 year experience of a genetic counselling program for familial dementias (the PICOGEN program). METHODS: The neurologist selected the candidates for genetic testing in the screening visit based on family history and phenotype (Alzheimer disease-AD, frontotemporal lobar degeneration-FTLD, or prion disease). Asymptomatic subjects who decided to know their genetic status were evaluated within a structured protocol by the psychiatrist and psychologist prior to entering the program and followed up afterwards. RESULTS: A total of 87 patients from 72 families were candidates for the genetic study, 20 of the 72 families had a family history of autosomal dominant early-onset dementia (ADEOD). A pathogenic mutation was found in 22 patients (8 PSEN1, 1 PSEN2, 1 APP, 4 MAPT, 8 PRNP), 5 of which had not been previously described. All positive cases, except for 1 PSEN1 (12.5%) and 4 PRNP (50%) showed ADEOD. In 3 ADEOD cases (15%) no pathogenic mutation was found. After individual genetic counselling, 24/54 asymptomatic subjects at risk decided to have the pre-symptomatic study, of whom 10 (42%) were carriers of the pathogenic mutation. In the follow up, no major psychiatric complication was observed. CONCLUSIONS: In our series, family history of ADEOD was a sensitive criterion for the detection of pathogenic mutations in AD and FTLD but not in prion diseases. No genetic anomalies were detected in 15% of the ADEOD cases using conventional diagnostic procedures, and 43% of pre-symptomatic subjects at risk who received individual genetic counselling decided to have the study. The pre-symptomatic diagnosis proved to be safe under these conditions.
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Demencia/genética , Asesoramiento Genético , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Evaluación de Programas y Proyectos de Salud , Factores de TiempoRESUMEN
Inflammation has been associated with the two classic lesions in the Alzheimer's (AD) brain, amyloid deposits and neurofibrillary tangles. Recent data suggest that Triflusal, a compound with potent anti-inflammatory effects in the central nervous system in vivo, might delay the conversion from amnestic mild cognitive impairment to a fully established clinical picture of dementia. In the present study, we investigated the effect of Triflusal on brain Abeta accumulation, neuroinflammation, axonal curvature and cognition in an AD transgenic mouse model (Tg2576). Triflusal treatment did not alter the total brain Abeta accumulation but significantly reduced dense-cored plaque load and associated glial cell proliferation, proinflammatory cytokine levels and abnormal axonal curvature, and rescued cognitive deficits in Tg2576 mice. Behavioral benefit was found to involve increased expression of c-fos and BDNF, two of the genes regulated by CREB, as part of the signal transduction cascade underlying the molecular basis of long-term potentiation. These results add preclinical evidence of a potentially beneficial effect of Triflusal in AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fármacos del Sistema Nervioso Central/farmacología , Salicilatos/farmacología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Axones/efectos de los fármacos , Axones/patología , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuroglía/efectos de los fármacos , Neuroglía/patología , Placa Amiloide/efectos de los fármacos , Placa Amiloide/metabolismo , Placa Amiloide/patología , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
gamma-Secretase is an intramembranous multi-protein complex that cleaves many type-I proteins with critical roles in neuronal function. In Alzheimer's disease (AD) interest in gamma-secretase comes, in part, from the fact that this complex is responsible for the last cleavage step of the amyloid precursor protein (APP) that generates the amyloid-beta peptide (Abeta). Abeta represents the primary component of the amyloid plaque, one of the main pathological hallmarks of AD. Over the last years, considerable efforts have been made to develop drugs to reduce Abeta production with the aim to slow AD progression. Many inhibitors of this protease have been identified, although the clinical use has been limited by concerns about the possible toxicity of these compounds. gamma-secretase inhibitors have been shown to reduce Abeta in vitro and in vivo, but interference with Notch proteolysis causes immunological and gastrointestinal toxicity in animal models. The observation that some nonsteroidal anti-inflammatory drug (NSAID) derivatives are able to specifically lower Abeta42 and the development of inhibitors with Notch-sparing selectivity has revived the interest in gamma-secretase as an attractive target for drug intervention in AD. Despite the fact that all clinical trials with NSAIDs or gamma-secretase modulators in AD have failed to show clinical benefit thus far, the main concern is that the Abeta-lowering potency of the tested compounds may be too low. Active efforts are being made to develop compounds able to penetrate into the brain to lower Abeta at physiological doses without interfering with the cleavage and function of other critical gamma-secretase substrates. These novel inhibitors and modulators may soon offer hope in the Alzheimer's fight.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de Proteasas/uso terapéutico , Enfermedad de Alzheimer/enzimología , Secretasas de la Proteína Precursora del Amiloide/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Diseño de Fármacos , Humanos , Inhibidores de Proteasas/química , Conformación Proteica , Relación Estructura-Actividad , Especificidad por Sustrato , Resultado del TratamientoRESUMEN
Amyloid deposits, neurofibrillary tangles, and neuronal cell death in selectively vulnerable brain regions are the chief hallmarks in Alzheimer's (AD) brains. Glycogen synthase kinase-3 (GSK-3) is one of the key kinases required for AD-type abnormal hyperphosphorylation of tau, which is believed to be a critical event in neurofibrillary tangle formation. GSK-3 has also been recently implicated in amyloid precursor protein (APP) processing/Abeta production, apoptotic cell death, and learning and memory. Thus, GSK-3 inhibition represents a very attractive drug target in AD and other neurodegenerative disorders. To investigate whether GSK-3 inhibition can reduce amyloid and tau pathologies, neuronal cell death and memory deficits in vivo, double transgenic mice coexpressing human mutant APP and tau were treated with a novel non-ATP competitive GSK-3beta inhibitor, NP12. Treatment with this thiadiazolidinone compound resulted in lower levels of tau phosphorylation, decreased amyloid deposition and plaque-associated astrocytic proliferation, protection of neurons in the entorhinal cortex and CA1 hippocampal subfield against cell death, and prevention of memory deficits in this transgenic mouse model. These results show that this novel GSK-3 inhibitor has a dual impact on amyloid and tau alterations and, perhaps even more important, on neuronal survival in vivo further suggesting that GSK-3 is a relevant therapeutic target in AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Inhibidores Enzimáticos/farmacología , Neuronas/efectos de los fármacos , Neuronas/patología , Tiadiazoles/farmacología , Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Astrocitos/fisiología , Muerte Celular/efectos de los fármacos , Corteza Entorrinal/efectos de los fármacos , Corteza Entorrinal/patología , Inhibidores Enzimáticos/sangre , Femenino , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta , Hipocampo/efectos de los fármacos , Hipocampo/patología , Humanos , Masculino , Memoria/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/patología , Ratones , Ratones Transgénicos , Nexinas de Proteasas , Receptores de Superficie Celular/genética , Percepción Espacial/efectos de los fármacos , Tiadiazoles/sangre , Proteínas tau/genéticaRESUMEN
Early-onset Alzheimer's disease (EOAD) is a clinically and genetically heterogeneous condition in which the typical features appear significantly earlier in life (before 65 years). Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in autosomal dominant forms of EOAD. However, in about 50% of Mendelian cases and in most of the sporadic EOAD patients, no mutations have been found. We present clinical characteristics of an Israeli family comprising two affected siblings with EOAD born to neurologically healthy parents who were first cousins (both parents died after 90 years old). Sequence analysis of PSEN1, PSEN2, APP, TAU, PGRN, and PRNP failed to reveal any mutations in the affected siblings. Because the disease in this family is consistent with an autosomal recessive mode of inheritance we identified all homozygous regions identical by descent (IBD) in both siblings, by high-density SNP genotyping. We provide here the first catalog of autozygosity in EOAD and suggest that the regions identified are excellent candidate loci for a recessive genetic lesion causing this disease.
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Enfermedad de Alzheimer/genética , Consanguinidad , Familia , Genoma , Edad de Inicio , Anciano , Anciano de 80 o más Años , Femenino , Genes Recesivos , Genotipo , Humanos , Israel , Masculino , Persona de Mediana Edad , Mutación , Linaje , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADNRESUMEN
During the last decade, interest has grown in the beneficial effects of non-steroidal anti-inflammatory drugs (NSAIDs) in neurodegeneration, particularly in pathologies such as Alzheimer's (AD) and Parkinson's (PD) disease. Evidence from epidemiological studies has indicated a decreased risk for AD and PD in patients with a history of chronic NSAID use. However, clinical trials with NSAIDs in AD patients have yielded conflicting results, suggesting that these drugs may be beneficial only when used as preventive therapy or in early stages of the disease. NSAIDs may also have salutary effects in other neurodegenerative diseases with an inflammatory component, such as multiple sclerosis and amyotrophic lateral sclerosis. In this review we analyze the molecular (cyclooxygenases, secretases, NF-kappaB, PPAR, or Rho-GTPasas) and cellular (neurons, microglia, astrocytes or endothelial cells) targets of NSAIDs that may mediate the therapeutic function of these drugs in neurodegeneration.
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Antiinflamatorios no Esteroideos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Antiinflamatorios no Esteroideos/metabolismo , Antiinflamatorios no Esteroideos/uso terapéutico , Células Endoteliales/metabolismo , Humanos , FN-kappa B/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/prevención & control , Neuroglía/metabolismo , Neuronas/metabolismo , PPAR gamma/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Proteínas de Unión al GTP rho/metabolismoRESUMEN
Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects approximately 4.5 million people in the United States. The mainstays of current pharmacotherapy for AD are compounds aimed at increasing the levels of acetylcholine in the brain, thereby facilitating cholinergic neurotransmission through inhibition of the cholinesterases. These drugs, known as acetylcholinesterase inhibitors (AChEIs), were first approved by the U.S. Food and Drug Administration (FDA) in 1995 based on clinical trials showing modest symptomatic benefit on cognitive, behavioral, and global measures. In 2004 the FDA approved memantine, an NMDA antagonist, for treating dementia symptoms in moderate to severe AD cases. In clinical practice, memantine may be co-administered with an AChEI, although neither drug individually or in combination affects the underlying pathophysiology of dementia. Dementia in AD results from progressive synaptic loss and neuronal death. As knowledge of the mechanisms responsible for neurodegeneration in AD increases, it is anticipated that neuroprotective drugs to slow or prevent neuronal dysfunction and death will be developed to complement current symptomatic treatments.