RESUMEN
The primary aim of this observational study was to describe the incidence of postoperative pulmonary complications (PPCs) in 60 consecutive, surgically treated head and neck cancer patients requiring free flap reconstruction and tracheostomy, using both a prospective and a retrospective outcome measure. Secondary aims were to identify risk factors for PPC development, explore the effects of PPC on outcomes, and describe the provision of postoperative physiotherapy in this population. Postoperative pulmonary complications occurred in nine (15%) patients based on the Melbourne Group Scale and 27 (45%) patients based on Health Information Service coding data. The occurrence of a PPC was not statistically correlated with age, smoking history, comorbidities, operative time, or type of resection or free flap. Patients who developed a PPC, compared to those who did not, had a higher preoperative body mass index (P=0.022) and were more likely to be sat out of bed earlier post-surgery (P=0.038). Overall, patients required a median of 9.0 (interquartile range 7.0-11.0) physiotherapy sessions. Patients developing a PPC required significantly more physiotherapy sessions (P=0.007) and additional days of supplemental oxygen (P=0.022) as compared to those without a PPC, despite a similar hospital length of stay. In future, targeted physiotherapy interventions may reduce PPCs in this population.
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Neoplasias de Cabeza y Cuello , Complicaciones Posoperatorias , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Complicaciones Posoperatorias/epidemiología , Estudios Prospectivos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Beclin 1 is a haploinsufficient tumor suppressor that is decreased in many human tumors. The function of beclin 1 in cancer has been attributed primarily to its role in the degradative process of macroautophagy. However, beclin 1 is a core component of the vacuolar protein sorting 34 (Vps34)/class III phosphatidylinositoI-3 kinase (PI3KC3) and Vps15/p150 complex that regulates multiple membrane-trafficking events. In the current study, we describe an alternative mechanism of action for beclin 1 in breast cancer involving its control of growth factor receptor signaling. We identify a specific stage of early endosome maturation that is regulated by beclin 1, the transition of APPL1-containing phosphatidyIinositol 3-phosphate-negative (PI3P(-)) endosomes to PI3P(+) endosomes. Beclin 1 regulates PI3P production in response to growth factor stimulation to control the residency time of growth factor receptors in the PI3P(-)/APPL(+)-signaling-competent compartment. As a result, suppression of BECN1 sustains growth factor-stimulated AKT and ERK activation resulting in increased breast carcinoma cell invasion. In human breast tumors, beclin 1 expression is inversely correlated with AKT and ERK phosphorylation. Our data identify a novel role for beclin 1 in regulating growth factor signaling and reveal a mechanism by which loss of beclin 1 expression would enhance breast cancer progression.
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Proteínas Reguladoras de la Apoptosis/fisiología , Neoplasias de la Mama/metabolismo , Proteínas de la Membrana/fisiología , Receptores de Factores de Crecimiento/fisiología , Transducción de Señal/fisiología , Proteínas Adaptadoras Transductoras de Señales/fisiología , Proteína 5 Relacionada con la Autofagia , Beclina-1 , Neoplasias de la Mama/patología , Fosfatidilinositol 3-Quinasas Clase III/fisiología , Factor de Crecimiento Epidérmico/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/farmacología , Células MCF-7 , Proteínas Asociadas a Microtúbulos/fisiología , Proteínas Nucleares , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factores de TranscripciónRESUMEN
Memory impairment is the cardinal early feature of Alzheimer's disease, a highly prevalent disorder whose causes remain only partially understood. To identify novel genetic predictors, we used an integrative genomics approach to perform the largest study to date of human memory (n=14 781). Using a genome-wide screen, we discovered a novel association of a polymorphism in the pro-apoptotic gene FASTKD2 (fas-activated serine/threonine kinase domains 2; rs7594645-G) with better memory performance and replicated this finding in independent samples. Consistent with a neuroprotective effect, rs7594645-G carriers exhibited increased hippocampal volume and gray matter density and decreased cerebrospinal fluid levels of apoptotic mediators. The MTOR (mechanistic target of rapamycin) gene and pathways related to endocytosis, cholinergic neurotransmission, epidermal growth factor receptor signaling and immune regulation, among others, also displayed association with memory. These findings nominate FASTKD2 as a target for modulating neurodegeneration and suggest potential mechanisms for therapies to combat memory loss in normal cognitive aging and dementia.
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Hipocampo/fisiología , Memoria/fisiología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Femenino , Estudios de Asociación Genética , Estudio de Asociación del Genoma Completo , Hipocampo/metabolismo , Hipocampo/fisiopatología , Humanos , Estudios Longitudinales , Masculino , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Polimorfismo de Nucleótido Simple , Relación Estructura-ActividadRESUMEN
We aimed to identify cerebrospinal fluid (CSF) biomarkers associated with neurodegeneration in individuals with and without CSF evidence of Alzheimer pathology. We investigated 287 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects (age=74.9±6.9; 22/48/30% with Alzheimer's disease/mild cognitive impairment/controls) with CSF multiplex analyte data and serial volumetric MRI. We calculated brain and hippocampal atrophy rates, ventricular expansion and Mini Mental State Examination decline. We used false discovery rate corrected regression analyses to assess associations between CSF variables and atrophy rates in individuals with and without amyloid pathology, adjusting in stages for tau, baseline volume, p-tau, age, sex, ApoE4 status and diagnosis. Analytes showing statistically significant independent relationships were entered into reverse stepwise analyses. Adjusting for tau, baseline volume, p-tau, age, sex and ApoE4, 4/83 analytes were significantly independently associated with brain atrophy rate, 1/83 with ventricular expansion and 2/83 with hippocampal atrophy. The strongest CSF predictor for the three atrophy measures was low trefoil factor 3 (TFF3). High cystatin C (CysC) was associated with higher whole brain atrophy and hippocampal atrophy rates. Lower levels of vascular endothelial growth factor and chromogranin A (CrA) were associated with higher whole brain atrophy. In exploratory reverse stepwise analyses, lower TFF3 was associated with higher rates of whole brain, hippocampal atrophy and ventricular expansion. Lower levels of CrA were associated with higher whole brain atrophy rate. The relationship between low TFF3 and increased hippocampal atrophy rate remained after adjustment for diagnosis. We identified a series of CSF markers that are independently associated with rate of neurodegeneration in amyloid-positive individuals. TFF3, a substrate for NOTCH processing may be an important biomarker of neurodegeneration across the Alzheimer spectrum.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Amiloidosis/líquido cefalorraquídeo , Amiloidosis/patología , Biomarcadores/líquido cefalorraquídeo , Encéfalo/patología , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/patología , Hipocampo/patología , Péptidos/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Apolipoproteína E4/líquido cefalorraquídeo , Atrofia , Ventrículos Cerebrales/patología , Cistatina C/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Escala del Estado Mental , Estadística como Asunto , Factor Trefoil-3 , Proteínas tau/líquido cefalorraquídeoRESUMEN
ß-amyloid (Aß) plaque accumulation is a hallmark of Alzheimer's disease (AD). It is believed to start many years prior to symptoms and is reflected by reduced cerebrospinal fluid (CSF) levels of the peptide Aß1-42 (Aß42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and Aß metabolism predict the development of Aß plaques, assessed by longitudinal CSF Aß42 decrease in cognitively healthy people. Forty-six healthy people with three to four serial CSF samples were included (mean follow-up 3 years, range 2-4 years). There was an overall reduction in Aß42 from a mean concentration of 211-195 pg ml(-1) after 4 years. Linear mixed-effects models using longitudinal Aß42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for Aß metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal Aß42. The most significant proteins were angiotensin-converting enzyme (ACE, P=0.009), Chromogranin A (CgA, P=0.009) and Axl receptor tyrosine kinase (AXL, P=0.009). Receiver-operating characteristic analysis identified 11 proteins with significant effects on longitudinal Aß42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with Aß42 reduction only in subjects with normal baseline Aß42, and not in subjects with reduced baseline Aß42. We conclude that baseline CSF proteins related to Aß metabolism, microglia activity or synapses predict longitudinal Aß42 reduction in cognitively healthy elders. The finding that some proteins only predict Aß42 reduction in subjects with normal baseline Aß42 suggest that they predict future development of the brain Aß pathology at the earliest stages of AD, prior to widespread development of Aß plaques.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Cromogranina A/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Peptidil-Dipeptidasa A/líquido cefalorraquídeo , Placa Amiloide/metabolismo , Proteínas Proto-Oncogénicas/líquido cefalorraquídeo , Proteínas Tirosina Quinasas Receptoras/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Modelos Lineales , Estudios Longitudinales , Masculino , Microglía , Fragmentos de Péptidos/metabolismo , Curva ROC , Sinapsis , Tirosina Quinasa del Receptor AxlRESUMEN
Intravenous BU divided four times daily (q6 h) has been shown to be safe and effective in pediatric allo-SCT recipients. Though less frequent dosing is desirable, pharmacokinetic (PK) data on twice daily (q12 h) i.v. BU administration in pediatric allo-SCT recipients is limited. We prospectively examined the PK results in a cohort of pediatric allo-SCT recipients receiving i.v. BU q12 h as part of conditioning before allo-SCT. BU levels were obtained after the first dose of conditioning. PK parameter analysis (n=49) yielded the following 95% confidence intervals (CI95): weight-normalized volume of distribution: 0.65-0.73 L/kg; t(1/2): 122-147 min; weight-normalized clearance (CL(n)): 3.4-4.3 mL/min/kg; and area under the curve: 1835-2180 mmol × min/L. From these results, a steady state concentration was calculated with CI95 between 628-746 ng/mL. Comparison between recipients ≤4 vs >4 years old revealed significant differences in t(1/2) (mean: 115 vs 146 min, P=0.008) and CL(n) (mean: 4.4 vs 3.5 mL/min/kg, P=0.038). Intravenous BU q12 h had a comparable PK to i.v. BU q6 h PK seen in the literature, and in pediatric allo-SCT recipients, is a feasible, attractive alternative to i.v. q6h dosing.
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Antineoplásicos Alquilantes/farmacocinética , Busulfano/farmacocinética , Agonistas Mieloablativos/farmacocinética , Trasplante de Células Madre/efectos adversos , Acondicionamiento Pretrasplante/efectos adversos , Adolescente , Factores de Edad , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/sangre , Busulfano/administración & dosificación , Busulfano/efectos adversos , Busulfano/sangre , Niño , Preescolar , Estudios de Cohortes , Esquema de Medicación , Quimioterapia Combinada/efectos adversos , Femenino , Estudios de Seguimiento , Supervivencia de Injerto/efectos de los fármacos , Semivida , Humanos , Lactante , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Agonistas Mieloablativos/administración & dosificación , Agonistas Mieloablativos/efectos adversos , Agonistas Mieloablativos/sangre , Trasplante HomólogoRESUMEN
BACKGROUND: Anxiety, apathy and depression are common in subjects with mild cognitive impairment (MCI) and may herald Alzheimer's disease (AD). We investigated whether these symptoms correlated with cerebrospinal fluid (CSF) markers for AD in subjects with MCI. Method Subjects with MCI (n=268) were selected from the 'Development of screening guidelines and criteria for pre-dementia Alzheimer's disease' (DESCRIPA) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies. We measured amyloid ß(1-42) protein (Aß42) and total tau (t-tau) in CSF. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory. RESULTS: Depressive symptoms were reported by 55 subjects (21%), anxiety by 35 subjects (13%) and apathy by 49 subjects (18%). The presence of anxiety was associated with abnormal CSF Aß42 [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.6-3.3] and t-tau (OR 2.6, 95% CI 1.9-3.6) concentrations and with the combination of abnormal concentrations of both Aß42 and t-tau (OR 3.1, 95% CI 2.0-4.7). The presence of agitation and irritability was associated with abnormal concentrations of Aß42 (agitation: OR 1.6, 95% CI 1.1-2.3; irritability: OR 2.2, 95% CI 1.5-3.3). Symptoms of depression and apathy were not related to any of the CSF markers. CONCLUSIONS: In subjects with MCI, symptoms of anxiety, agitation and irritability may reflect underlying AD pathology, whereas symptoms of depression and apathy do not.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Ansiedad/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/psicología , Ansiedad/epidemiología , Apatía , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/psicología , Estudios de Cohortes , Intervalos de Confianza , Depresión/epidemiología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Genio Irritable/fisiología , Masculino , Pruebas Neuropsicológicas , Oportunidad RelativaRESUMEN
The pathophysiology of negative affect states in older adults is complex, and a host of central nervous system and peripheral systemic mechanisms may play primary or contributing roles. We conducted an unbiased analysis of 146 plasma analytes in a multiplex biochemical biomarker study in relation to number of depressive symptoms endorsed by 566 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) at their baseline and 1-year assessments. Analytes that were most highly associated with depressive symptoms included hepatocyte growth factor, insulin polypeptides, pregnancy-associated plasma protein-A and vascular endothelial growth factor. Separate regression models assessed contributions of past history of psychiatric illness, antidepressant or other psychotropic medicine, apolipoprotein E genotype, body mass index, serum glucose and cerebrospinal fluid (CSF) τ and amyloid levels, and none of these values significantly attenuated the main effects of the candidate analyte levels for depressive symptoms score. Ensemble machine learning with Random Forests found good accuracy (~80%) in classifying groups with and without depressive symptoms. These data begin to identify biochemical biomarkers of depressive symptoms in older adults that may be useful in investigations of pathophysiological mechanisms of depression in aging and neurodegenerative dementias and as targets of novel treatment approaches.
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Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/sangre , Trastorno Depresivo/sangre , Trastorno Depresivo/diagnóstico , Anciano , Anciano de 80 o más Años , Inteligencia Artificial , Femenino , Estudios de Seguimiento , Factor de Crecimiento de Hepatocito/sangre , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Proteína Plasmática A Asociada al Embarazo/metabolismo , Valores de Referencia , Estadística como Asunto , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
We used pharmacokinetic (PK) targeting of BU in 145 consecutive patients treated with fludarabine and i.v. BU. BU was given once daily at 130 mg/m(2) per day on days 1 and 2; doses for days 3 and 4 were adjusted in 92 patients (63%) to an average daily area under the concentration-time curve (AUC) of 5300 µM/min. In the remaining 53 patients, the first-dose AUC was within the target range and no dosing adjustments were required. First-dose AUC, maximum concentration and clearance were not correlated with age, race, ethnicity, performance status, or hematopoietic cell transplant comorbidity index. Women had higher clearance than men (median 2.9 vs 2.5 mL/min/kg; P=0.001). BU toxicities were not associated with first-dose AUC or any other PK parameter measured. First-dose BU AUC was not associated with non-relapse mortality (NRM) or survival, but higher AUC was predictive of relapse. We did not find an increased risk of toxicity or NRM in patients with high first-dose AUC presumably because of the dose adjustment. We conclude that PK targeting of BU as described here provides a simple, safe and effective method of delivering high BU doses before transplantation in a wide variety of patients.
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Busulfano/farmacocinética , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/farmacocinética , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Adulto , Anciano , Área Bajo la Curva , Busulfano/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/administración & dosificación , Recurrencia , Estudios Retrospectivos , Vidarabina/administración & dosificaciónRESUMEN
OBJECTIVES: CSF levels of Aß1-42, t-tau, and p-tau181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (Aß1-42, t-tau, p-tau181p, p-tau181p/Aß1-42, and t-tau/Aß1-42). METHODS: A total of 374 non-Hispanic Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative cohort with quality-controlled CSF and genotype data were included in this analysis. The main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed on each of 5 CSF biomarkers. The p values of all SNPs for each CSF biomarker were adjusted for multiple comparisons by the Bonferroni method. We focused on SNPs with corrected p<0.01 (uncorrected p<3.10×10(-8)) and secondarily examined SNPs with uncorrected p values less than 10(-5) to identify potential candidates. RESULTS: Four SNPs in the regions of the APOE, LOC100129500, TOMM40, and EPC2 genes reached genome-wide significance for associations with one or more CSF biomarkers. SNPs in CCDC134, ABCG2, SREBF2, and NFATC4, although not reaching genome-wide significance, were identified as potential candidates. CONCLUSIONS: In addition to known candidate genes, APOE, TOMM40, and one hypothetical gene LOC100129500 partially overlapping APOE; one novel gene, EPC2, and several other interesting genes were associated with CSF biomarkers that are related to AD. These findings, especially the new EPC2 results, require replication in independent cohorts.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/genética , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/genética , Treonina/metabolismo , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Antígenos de Neoplasias/líquido cefalorraquídeo , Antígenos de Neoplasias/genética , Apolipoproteínas E/genética , Trastornos del Conocimiento/líquido cefalorraquídeo , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Estudios de Cohortes , Diagnóstico por Imagen , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Proteínas de Transporte de Membrana/líquido cefalorraquídeo , Proteínas de Transporte de Membrana/genética , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Fosforilación , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
We report the results of a pilot study of a BU-fludarabine-alemtuzumab (BFA)-reduced toxicity conditioning (RTC) followed by allogeneic hematopoietic SCT (AlloHSCT) in 12 children and adolescents (<21 years) with malignant and non-malignant diseases. Stem cell sources were: two unrelated cord blood, one unrelated BM, two related and seven unrelated PBSC. Positive CD34 selection was performed in five unrelated PBSC grafts. RCT was carried out with BFA, and GVHD prophylaxis was FK506 and mycophenolate mofetil. The median time for neutrophil and platelet engraftment was 16 and 31 days, respectively. The P of developing ≥ grade II, ≥ grade III aGVHD and cGVHD was 41.6, 25 and 9%, respectively. Only 1 out of 12 developed ≥ grade III toxicity. There was one primary and no secondary graft failure. Mixed donor chimerism on day 100 and 1 year was median 99 and 96%, respectively; ≥ 90% of recipients achieved ≥ 80% donor chimerism. The 3-year overall survival (OS) in all patients was 91.7 ± 8% (100% for malignant vs. 80% for non-malignant diseases, ns). In all, 11 (91%) patients remain alive at median 2.8 (0.3-6.8) years. RTC followed by AlloHSCT, based on BFA conditioning, is feasible and tolerable in children and adolescents, and results in prompt achievement of durable mixed donor chimerism and excellent OS.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Adolescente , Alemtuzumab , Anticuerpos Monoclonales , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos , Busulfano , Niño , Preescolar , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/clasificación , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Proyectos Piloto , Análisis de Supervivencia , Quimera por Trasplante , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Homólogo , Vidarabina/análogos & derivados , Adulto JovenRESUMEN
OBJECTIVE: To identify antemortem CSF diagnostic biomarkers that can potentially distinguish between the 2 main causes of frontotemporal lobar degeneration (FTLD), i.e., FTLD with TDP-43 pathology (FTLD-TDP) and FTLD with tau pathology (FTLD-tau). METHODS: CSF samples were collected antemortem from 23 patients with FTLD with known pathology to form a autopsy cohort as part of a comparative biomarker study that additionally included 33 living cognitively normal subjects and 66 patients with autopsy-confirmed Alzheimer disease (AD). CSF samples were also collected from 80 living patients clinically diagnosed with frontotemporal dementia (FTD). Levels of 151 novel analytes were measured via a targeted multiplex panel enriched in neuropeptides, cytokines, and growth factors, along with levels of CSF biomarkers for AD. RESULTS: CSF levels of multiple analytes differed between FTLD-TDP and FTLD-tau, including Fas, neuropeptides (agouti-related peptide and adrenocorticotropic hormone), and chemokines (IL-23, IL-17). Classification by random forest analysis achieved high sensitivity for FTLD-TDP (86%) with modest specificity (78%) in the autopsy cohort. When the classification algorithm was applied to a living FTD cohort, semantic dementia was the phenotype with the highest predicted proportion of FTLD-TDP. When living patients with behavioral variant FTD were examined in detail, those predicted to have FTLD-TDP demonstrated neuropsychological differences vs those predicted to have FTLD-tau in a pattern consistent with previously reported trends in autopsy-confirmed cases. CONCLUSIONS: Clinical cases with FTLD-TDP and FTLD-tau pathology can be potentially identified antemortem by assaying levels of specific analytes that are well-known and readily measurable in CSF.
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Biomarcadores/líquido cefalorraquídeo , Proteínas de Unión al ADN/metabolismo , Degeneración Lobar Frontotemporal/líquido cefalorraquídeo , Tauopatías/líquido cefalorraquídeo , Hormona Adrenocorticotrópica/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Estudios de Cohortes , Femenino , Degeneración Lobar Frontotemporal/complicaciones , Humanos , Interleucina-17/líquido cefalorraquídeo , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estadísticas no Paramétricas , Tauopatías/complicacionesRESUMEN
OBJECTIVE: Cognitive decline associated with Parkinson disease (PD) is common and highly disabling. Biomarkers that help identify patients at risk for cognitive decline would be useful additions to the clinical management of the disease. METHODS: A total of 45 patients with PD were enrolled in this prospective cohort study and had at least 1 yearly longitudinal follow-up evaluation. CSF was collected at baseline and cognition was assessed at baseline and follow-up visits using the Mattis Dementia Rating Scale (DRS-2). CSF was tested for amyloid ß 1-42 (Aß(1-42)), p-tau(181p), and total tau levels using the Luminex xMAP platform. Mixed linear models were used to test for associations between baseline CSF biomarker levels and change in cognition over time. RESULTS: Lower baseline CSF Aß(1-42) was associated with more rapid cognitive decline. Subjects with CSF Aß(1-42) levels ≤192 pg/mL declined an average of 5.85 (95% confidence interval 2.11-9.58, p = 0.002) points per year more rapidly on the DRS-2 than subjects above that cutoff, after adjustment for age, disease duration, and baseline cognitive status. CSF total tau and p-tau(181p) levels were not significantly associated with cognitive decline. CONCLUSIONS: Reduced CSF Aß(1-42) was an independent predictor of cognitive decline in patients with PD. This observation is consistent with previous research showing that Alzheimer disease pathology contributes to cognitive impairment in PD. This biomarker may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD.
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Péptidos beta-Amiloides/líquido cefalorraquídeo , Trastornos del Conocimiento/líquido cefalorraquídeo , Progresión de la Enfermedad , Enfermedad de Parkinson/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Anciano , Biomarcadores/líquido cefalorraquídeo , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/psicología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/psicología , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To compare the annual change in MRI and CSF biomarkers in cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer disease (AD). Comparisons were based on intergroup discrimination, correlation with concurrent cognitive/functional changes, relationships to APOE genotype, and sample sizes for clinical trials. METHODS: We used data from the Alzheimer's Disease Neuroimaging Initiative study consisting of CN, aMCI, and AD cohorts with both baseline and 12-month follow-up CSF and MRI. The annual change in CSF (total-tau [t-tau], Abeta(1-42)) and MRI (change in ventricular volume) was obtained in 312 subjects (92 CN, 149 aMCI, 71 AD). RESULTS: There was no significant average annual change in either CSF biomarker in any clinical group except t-tau in CN; moreover, the annual change did not differ by clinical group in pairwise comparisons. In contrast, annual increase in ventricular volume increased in the following order, AD > aMCI > CN, and differences were significant between all clinical groups in pairwise comparisons. Ventricular volume increase correlated with concurrent worsening on cognitive/functional indices in aMCI and AD whereas evidence of a similar correlation with change in CSF measures was unclear. The annual changes in MRI differed by APOE epsilon4 status overall and among aMCI while annual changes in CSF biomarkers did not. Estimated sample sizes for clinical trials are notably less for MRI than the CSF or clinical measures. CONCLUSIONS: Unlike the CSF biomarkers evaluated, changes in serial structural MRI are correlated with concurrent change on general cognitive and functional indices in impaired subjects, track with clinical disease stage, and are influenced by APOE genotype.
Asunto(s)
Envejecimiento/líquido cefalorraquídeo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Encéfalo/patología , Trastornos del Conocimiento/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Factores de Edad , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Envejecimiento/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquídeo , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Valores de Referencia , Análisis de Regresión , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: A variety of measurements have been individually linked to decline in mild cognitive impairment (MCI), but the identification of optimal markers for predicting disease progression remains unresolved. The goal of this study was to evaluate the prognostic ability of genetic, CSF, neuroimaging, and cognitive measurements obtained in the same participants. METHODS: APOE epsilon4 allele frequency, CSF proteins (Abeta(1-42), total tau, hyperphosphorylated tau [p-tau(181p)]), glucose metabolism (FDG-PET), hippocampal volume, and episodic memory performance were evaluated at baseline in patients with amnestic MCI (n = 85), using data from a large multisite study (Alzheimer's Disease Neuroimaging Initiative). Patients were classified as normal or abnormal on each predictor variable based on externally derived cutoffs, and then variables were evaluated as predictors of subsequent conversion to Alzheimer disease (AD) and cognitive decline (Alzheimer's Disease Assessment Scale-Cognitive Subscale) during a variable follow-up period (1.9 +/- 0.4 years). RESULTS: Patients with MCI converted to AD at an annual rate of 17.2%. Subjects with MCI who had abnormal results on both FDG-PET and episodic memory were 11.7 times more likely to convert to AD than subjects who had normal results on both measures (p Asunto(s)
Enfermedad de Alzheimer/complicaciones
, Apolipoproteína E4/genética
, Trastornos del Conocimiento/líquido cefalorraquídeo
, Trastornos del Conocimiento/etiología
, Trastornos del Conocimiento/genética
, Anciano
, Anciano de 80 o más Años
, Enfermedad de Alzheimer/genética
, Péptidos beta-Amiloides/líquido cefalorraquídeo
, Trastornos del Conocimiento/diagnóstico por imagen
, Progresión de la Enfermedad
, Femenino
, Fluorodesoxiglucosa F18
, Estudios de Seguimiento
, Hipocampo/diagnóstico por imagen
, Humanos
, Imagen por Resonancia Magnética/métodos
, Masculino
, Trastornos de la Memoria/etiología
, Persona de Mediana Edad
, Pruebas Neuropsicológicas
, Fragmentos de Péptidos/líquido cefalorraquídeo
, Tomografía de Emisión de Positrones/métodos
, Valor Predictivo de las Pruebas
, Curva ROC
, Estadísticas no Paramétricas
, Factores de Tiempo
, Proteínas tau/líquido cefalorraquídeo
RESUMEN
Cerebrospinal fluid (CSF) and structural magnetic resonance imaging (MRI) show patterns of change in Alzheimer's disease (AD) that precede dementia. The Alzheimer's Disease Neuroimaging Initiative (ADNI) studied normal controls (NC), subjects with mild cognitive impairment (MCI), and subjects with AD to identify patterns of biomarkers to aid in early diagnosis and effective treatment of AD. Two hundred twenty-two NC underwent baseline MRI and clinical examination at baseline and at least one follow-up. One hundred twelve also provided CSF at baseline. Unsupervised clustering based on initial CSF and MRI measures was used to identify clusters of participants with similar profiles. Repeated measures regression modeling assessed the relationship of individual measures, and of cluster membership, to cognitive change over 3 years. Most individuals showed little cognitive change. Individual biomarkers had limited predictive value for cognitive decline, but membership in the cluster with the most extreme profile was associated with more rapid decline in ADAS-cog. Subtypes among NC based on multiple biomarkers may represent the earliest stages of subclinical cognitive decline and AD.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Trastornos del Conocimiento/líquido cefalorraquídeo , Trastornos del Conocimiento/patología , Imagen por Resonancia Magnética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/clasificación , Biomarcadores/líquido cefalorraquídeo , Trastornos del Conocimiento/clasificación , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , Masculino , Valor Predictivo de las Pruebas , Estudios ProspectivosRESUMEN
BACKGROUND: Neuroimaging measures and chemical biomarkers may be important indices of clinical progression in normal aging and mild cognitive impairment (MCI) and need to be evaluated longitudinally. OBJECTIVE: To characterize cross-sectionally and longitudinally clinical measures in normal controls, subjects with MCI, and subjects with mild Alzheimer disease (AD) to enable the assessment of the utility of neuroimaging and chemical biomarker measures. METHODS: A total of 819 subjects (229 cognitively normal, 398 with MCI, and 192 with AD) were enrolled at baseline and followed for 12 months using standard cognitive and functional measures typical of clinical trials. RESULTS: The subjects with MCI were more memory impaired than the cognitively normal subjects but not as impaired as the subjects with AD. Nonmemory cognitive measures were only minimally impaired in the subjects with MCI. The subjects with MCI progressed to dementia in 12 months at a rate of 16.5% per year. Approximately 50% of the subjects with MCI were on antidementia therapies. There was minimal movement on the Alzheimer's Disease Assessment Scale-Cognitive Subscale for the normal control subjects, slight movement for the subjects with MCI of 1.1, and a modest change for the subjects with AD of 4.3. Baseline CSF measures of Abeta-42 separated the 3 groups as expected and successfully predicted the 12-month change in cognitive measures. CONCLUSION: The Alzheimer's Disease Neuroimaging Initiative has successfully recruited cohorts of cognitively normal subjects, subjects with mild cognitive impairment (MCI), and subjects with Alzheimer disease with anticipated baseline characteristics. The 12-month progression rate of MCI was as predicted, and the CSF measures heralded progression of clinical measures over 12 months.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Diagnóstico por Imagen/normas , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/metabolismo , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: PET imaging using [(18)F]fluorodeoxyglucose (FDG) and [(11)C]Pittsburgh compound B (PIB) have been proposed as biomarkers of Alzheimer disease (AD), as have CSF measures of the 42 amino acid beta-amyloid protein (Abeta(1-42)) and total and phosphorylated tau (t-tau and p-tau). Relationships between biomarkers and with disease severity are incompletely understood. METHODS: Ten subjects with AD, 11 control subjects, and 34 subjects with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative underwent clinical evaluation; CSF measurement of Abeta(1-42), t-tau, and p-tau; and PIB-PET and FDG-PET scanning. Data were analyzed using continuous regression and dichotomous outcomes with subjects classified as "positive" or "negative" for AD based on cutoffs established in patients with AD and controls from other cohorts. RESULTS: Dichotomous categorization showed substantial agreement between PIB-PET and CSF Abeta(1-42) measures (91% agreement, kappa = 0.74), modest agreement between PIB-PET and p-tau (76% agreement, kappa = 0.50), and minimal agreement for other comparisons (kappa <0.3). Mini-Mental State Examination score was significantly correlated with FDG-PET but not with PIB-PET or CSF Abeta(1-42). Regression models adjusted for diagnosis showed that PIB-PET was significantly correlated with Abeta(1-42), t-tau, and p-tau(181p), whereas FDG-PET was correlated only with Abeta(1-42). CONCLUSIONS: PET and CSF biomarkers of Abeta agree with one another but are not related to cognitive impairment. [(18)F]fluorodeoxyglucose-PET is modestly related to other biomarkers but is better related to cognition. Different biomarkers for Alzheimer disease provide different information from one another that is likely to be complementary.
Asunto(s)
Envejecimiento/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Biomarcadores/metabolismo , Trastornos del Conocimiento/diagnóstico por imagen , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Compuestos de Anilina/metabolismo , Biomarcadores/líquido cefalorraquídeo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Estudios de Casos y Controles , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/metabolismo , Femenino , Fluorodesoxiglucosa F18/metabolismo , Humanos , Masculino , Fragmentos de Péptidos/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Escalas de Valoración Psiquiátrica , Tiazoles/metabolismo , Proteínas tau/líquido cefalorraquídeoRESUMEN
OBJECTIVE: To assess the correlations of both MRI and CSF biomarkers with clinical diagnosis and with cognitive performance in cognitively normal (CN) subjects and patients with amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD). METHODS: This is a cross-sectional study with data from the Alzheimer's Disease Neuroimaging Initiative, which consists of CN subjects, subjects with aMCI, and subjects with AD with both CSF and MRI. Baseline CSF (t-tau, Abeta(1-42), and p-tau(181P)) and MRI scans were obtained in 399 subjects (109 CN, 192 aMCI, 98 AD). Structural Abnormality Index (STAND) scores, which reflect the degree of AD-like anatomic features on MRI, were computed for each subject. RESULTS: We found no significant correlation between CSF biomarkers and cognitive scores in any of the 3 clinical groups individually. Conversely, STAND scores correlated with both Clinical Dementia Rating-sum of boxes and Mini-Mental State Examination in aMCI and AD (p < or = 0.01). While STAND and all CSF biomarkers were predictors of clinical group membership (CN, aMCI, or AD) univariately (p < 0.001), STAND was more predictive than CSF both univariately and in combined models. CONCLUSIONS: CSF and MRI biomarkers independently contribute to intergroup diagnostic discrimination and the combination of CSF and MRI provides better prediction than either source of data alone. However, MRI provides greater power to effect cross-sectional groupwise discrimination and better correlation with general cognition and functional status cross-sectionally. We therefore conclude that although MRI and CSF provide complementary information, MRI reflects clinically defined disease stage better than the CSF biomarkers tested.