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Bladder cancer remains a leading cause of cancer death worldwide and is associated with substantial impacts on patient quality of life, morbidity, mortality, and cost to the healthcare system. Gross hematuria frequently precedes the diagnosis of bladder cancer. Non-muscle-invasive bladder cancer (NMIBC) is managed initially with transurethral resection of a bladder tumor (TURBT), followed by a risk stratified approach to adjuvant intravesical therapy (IVe), and is associated with an overall survival of 90%. However, cure rates remain lower for muscle invasive bladder cancer (MIBC) owing to a variety of factors. NMIBC and MIBC groupings are heterogeneous and have unique pathological and molecular characteristics. Indeed, The Cancer Genome Atlas project identified genetic drivers and luminal and basal molecular subtypes of MIBC with distinct treatment responses. For NMIBC, IVe immunotherapy (primarily BCG) is the gold standard treatment for high grade and high risk NMIBC to reduce or prevent both recurrence and progression after initial TURBT; novel trials incorporate immune checkpoint inhibitors. IVe gene therapy and combination IVe chemotherapy have recently been completed, with promising results. For localized MIBC, essential goals are improving care and reducing morbidity following cystectomy or bladder preserving strategies. In metastatic disease, advances in understanding of the genomic landscape and tumor microenvironment have led to the implementation of immune checkpoint inhibitors, targeted treatments, and antibody-drug conjugates. Defining better selection criteria to identify the patients most likely to benefit from a specific treatment is an urgent need.
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Neoplasias Vesicales sin Invasión Muscular , Neoplasias de la Vejiga Urinaria , Humanos , Inhibidores de Puntos de Control Inmunológico , Calidad de Vida , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/terapia , Inmunoterapia , Cistectomía , Invasividad Neoplásica , Vacuna BCG , Microambiente TumoralRESUMEN
PURPOSE: Erdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer. We characterized the genetic landscape of FGFR-altered urothelial carcinoma and real-world clinical outcomes with erdafitinib, including on-treatment genomic evolution. EXPERIMENTAL DESIGN: Prospectively collected clinical data were integrated with institutional genomic data to define the landscape of FGFR2/3-altered urothelial carcinoma. To identify mechanisms of erdafitinib resistance, a subset of patients underwent prospective cell-free (cf) DNA assessment. RESULTS: FGFR3 alterations predictive of erdafitinib sensitivity were identified in 39% (199/504) of patients with non-muscle invasive, 14% (75/526) with muscle-invasive, 43% (81/187) with localized upper tract, and 26% (59/228) with metastatic specimens. One patient had a potentially sensitizing FGFR2 fusion. Among 27 FGFR3-altered cases with a primary tumor and metachronous metastasis, 7 paired specimens (26%) displayed discordant FGFR3 status. Erdafitinib achieved a response rate of 40% but median progression-free and overall survival of only 2.8 and 6.6 months, respectively (n = 32). Dose reductions (38%, 12/32) and interruptions (50%, 16/32) were common. Putative resistance mutations detected in cfDNA involved TP53 (n = 5), AKT1 (n = 1), and second-site FGFR3 mutations (n = 2). CONCLUSIONS: FGFR3 mutations are common in urothelial carcinoma, whereas FGFR2 alterations are rare. Discordance of FGFR3 mutational status between primary and metastatic tumors occurs frequently and raises concern over sequencing archival primary tumors to guide patient selection for erdafitinib therapy. Erdafitinib responses were typically brief and dosing was limited by toxicity. FGFR3, AKT1, and TP53 mutations detected in cfDNA represent putative mechanisms of acquired erdafitinib resistance.
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Carcinoma de Células Transicionales , Ácidos Nucleicos Libres de Células , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/patología , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Resultado del Tratamiento , GenómicaRESUMEN
Prostate cancer is the second most common cancer among men. Despite advances in diagnosis and management, prostate cancer led to more than 300,000 deaths globally in 2020. Chemotherapy is a cornerstone of therapy for advanced prostate cancer and can prolong survival of patients with both castration-sensitive and castration-resistant disease. Herein, we present a comprehensive review of the data supporting implementation of chemotherapy in the modern treatment of advanced prostate cancer, with special attention to the use of chemotherapy for aggressive variant prostate cancer (e.g., neuroendocrine prostate cancer) and the combination of chemotherapy with androgen signaling inhibitors. As the field of prostate cancer research continues to rapidly evolve yielding novel agents and treatment modalities, chemotherapy continues to play an essential role in prolonging the survival of patients with advanced and metastatic prostate cancer.
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INTRODUCTION: Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed. RESULTS: One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (Asunto(s)
Carcinoma de Células Pequeñas
, Neoplasias de la Vejiga Urinaria
, Carcinoma de Células Pequeñas/patología
, Quimioterapia Adyuvante
, Cistectomía
, Genómica
, Humanos
, Terapia Neoadyuvante
, Estudios Retrospectivos
, Vejiga Urinaria/patología
, Neoplasias de la Vejiga Urinaria/tratamiento farmacológico
, Neoplasias de la Vejiga Urinaria/genética
, Proteína de la Xerodermia Pigmentosa del Grupo D
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The Accreditation Council of Graduate Medical Education mandates that all internal medicine residents gain exposure to internal medicine subspecialties including hematology and oncology. While many residents meet this criterion through inpatient oncology rotations, the current structure of many inpatient oncology rotations leaves little opportunity for formal education. We therefore designed a novel oncology curriculum consisting of one-page oncology teaching sheets to increase the number, breadth, and quality of formal teaching sessions on our resident inpatient oncology services. In order to evaluate the curriculum, we conducted pre- and post-intervention surveys of residents. From these surveys, we found that 72.2% of residents used the teaching sheets on their inpatient oncology rotation and that the teaching sheets led to an increase in the number of formal oncology teaching sessions (mean 3.4 ± 2.1 post-implementation vs 2.6 ± 2.0 pre-implementation, p = 0.008), the breadth of oncology topics taught (% reporting ≥ 5 topics; 26.1% vs 16.3%, p = 0.035), the proportion of residents reporting improvement in overall oncology knowledge (80.2% vs 62.4%, p = 0.012), and the proportion of residents reporting improvement in their ability to care for patients (70.8% vs 48.9%, p = 0.013). These results demonstrate that formal oncology teaching can be improved on inpatient oncology rotations through a simple and easily replicable oncology curriculum.
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Internado y Residencia , Humanos , Curriculum , Educación de Postgrado en Medicina , Acreditación , Oncología MédicaRESUMEN
The hallmark of precision medicine involves tailoring the treatment to the patient and/or tumor-specific biomarkers. Candidate biomarkers in bladder cancer are abundant, but few have been validated in clinical practice. Significant obstacles to precision medicine in bladder cancer include the limited predictive value of candidate biomarkers, lack of standardization in biomarker assessment, heterogeneity in biomarker expression and function, and limited insight into the biologic factors that influence biomarker expression and predictive capacity. This review summarizes key biomarkers explored in bladder cancer and outlines innovative trial designs to approach these obstacles.
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Medicina de Precisión , Neoplasias de la Vejiga Urinaria , Biomarcadores de Tumor/genética , Humanos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/terapiaRESUMEN
Metastatic primary cutaneous extramammary Paget disease (EMPD) is a rare clinical entity with a 5-year survival <10% and no standard therapy. We report the first case to our knowledge of metastatic EMPD with treatment response to checkpoint inhibitor immunotherapy. The patient had diffusely metastatic disease and previously progressed on cytotoxic chemotherapy and a molecularly targeted agent. Treatment with four cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg resulted in a durable partial response lasting 7 months. Analysis of metastatic tumor tissue failed to identify known predictors of treatment response to immune checkpoint inhibitors, such as high PD-L1 expression, high tumor mutation burden, or microsatellite instability. These findings support further investigation of immune checkpoint inhibition for the management of metastatic EMPD, which currently has an abysmal prognosis and no standard therapies.
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Background: Energy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study. Methods: Baseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute-sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). P values are 2-sided. Results: Median follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; P nonlinearity < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; P trend = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; P trend < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; P trend < .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS (P nonlinearity = .03). Conclusions: Among patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.
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Adiponectina/sangre , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/mortalidad , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Anciano , Péptido C/sangre , Neoplasias Colorrectales/genética , Intervalos de Confianza , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/sangre , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Estudios ProspectivosRESUMEN
BACKGROUND: In nonmetastatic colorectal cancer, overweight and mild-to-moderately obese patients experience improved outcomes compared with other patients. Obesity's influence on advanced or metastatic colorectal cancer (mCRC) is relatively unexplored. METHODS: We conducted a prospective body mass index (BMI) companion study in Cancer and Leukemia Group B (now Alliance)/SWOG 80405, a phase III metastatic colorectal cancer (mCRC) treatment trial. BMI was measured at trial registration. Primary and secondary endpoints were overall and progression-free survival, respectively. To minimize confounding by poor and rapidly declining health, we used Cox proportional hazards regression to adjust for known prognostic factors, comorbidities, physical activity, and weight loss during the 6 months prior to study entry. We also examined weight loss prior to enrollment as an independent predictor of patient outcome. All statistical tests were two-sided. RESULTS: Among 2323 patients with mCRC, there were no statistically significant associations between BMI and overall or progression-free survival (adjusted P trend = .12 and .40, respectively). Weight loss during the 6 months prior to study entry was associated with shorter overall and progression-free survival; compared with individuals with stable weight ±4.9%, individuals with weight loss greater than 15% experienced an adjusted hazard ratio of 1.52 for all-cause mortality (95% confidence interval [CI] = 1.26 to 1.84; P trend < .001) and of 1.23 for disease progression or death (95% CI = 1.02 to 1.47; P trend = .006). CONCLUSIONS: In this prospective study of patients with mCRC, BMI at time of first-line chemotherapy initiation was not associated with patient outcome. Weight loss prior to study entry was associated with increased risk of patient mortality and disease progression.
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PURPOSE: Regular physical activity is associated with reduced risk of recurrence and mortality in patients with nonmetastatic colorectal cancer. Its influence on patients with advanced/metastatic colorectal cancer (mCRC) has been largely unexplored. PATIENTS AND METHODS: We conducted a prospective cohort study nested in Cancer and Leukemia Group B (Alliance)/SWOG 80405 (ClinicalTrials.gov identifier: NCT00265850), a National Cancer Institute-sponsored phase III trial of systemic therapy for mCRC. Within 1 month after therapy initiation, patients were invited to complete a validated questionnaire that reported average physical activity over the previous 2 months. On the basis of responses, we calculated metabolic equivalent task (MET) hours per week to quantify physical activity. The primary end point of the clinical trial and this companion study was overall survival (OS). Secondary end points included progression-free survival (PFS) and first grade 3 or greater treatment-related adverse events. To minimize confounding by poor and declining health, we excluded patients who experienced progression or died within 60 days of activity assessment and used Cox proportional hazards regression analysis to adjust for known prognostic factors, comorbidities, and weight loss. RESULTS: The final cohort included 1,218 patients. Compared with patients engaged in less than 3 MET hours per week of physical activity, patients engaged in 18 or more MET hours per week experienced an adjusted hazard ratio for OS of 0.85 (95% CI, 0.71 to 1.02; PTrend = .06) and for PFS of 0.83 (95% CI, 0.70 to 0.99; PTrend = .01). Compared with patients engaging in less than 9 MET hours per week, patients engaging in 9 or more MET hours per week experienced an adjusted hazard ratio for grade 3 or greater treatment-related adverse events of 0.73 (95% CI, 0.62 to 0.86; PTrend < .001). CONCLUSION: Among patients with mCRC in Cancer and Leukemia Group B (Alliance)/SWOG 80405, association of physical activity with OS was not statistically significant. Greater physical activity was associated with longer PFS and lower adjusted risk for first grade 3 or greater treatment-related adverse events.
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Neoplasias Colorrectales/mortalidad , Ejercicio Físico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Estudios de Cohortes , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Encuestas y Cuestionarios , Estados Unidos/epidemiologíaRESUMEN
PURPOSE: Observational studies have demonstrated increased colon cancer recurrence and mortality in states of excess energy balance, as denoted by factors including sedentary lifestyle, diabetes, increased dietary glycemic load, and increased intake of sugar-sweetened beverages. Nonetheless, the relation between artificially sweetened beverages, a popular alternative for sugar-sweetened beverages, and colon cancer recurrence and survival is unknown. METHODS: We analyzed data from 1,018 patients with stage III colon cancer who prospectively reported dietary intake during and after chemotherapy while enrolled in a National Cancer Institute-sponsored trial of adjuvant chemotherapy. Using Cox proportional hazards regressions, we assessed associations of artificially sweetened beverage intake with cancer recurrence and mortality. RESULTS: Patients consuming one or more 12-ounce servings of artificially sweetened beverages per day experienced an adjusted hazard ratio for cancer recurrence or mortality of 0.54 (95% confidence interval, 0.36 to 0.80) when compared to those who largely abstained (Ptrend = .004). Similarly, increasing artificially sweetened beverage intake was also associated with a significant improvement in both recurrence-free survival (Ptrend = .005) and overall survival (Ptrend = .02). Substitution models demonstrated that replacing a 12-ounce serving of a sugar-sweetened beverage with an isovolumetric serving of an artificially sweetened beverage per day was associated with a 23% lower risk of cancer recurrence and mortality (relative risk, 0.77; 95% confidence interval, 0.63 to 0.95; P = .02). CONCLUSION: Higher artificially sweetened beverage consumption may be associated with significantly reduced cancer recurrence and death in patients with stage III colon cancer. This association may be mediated by substitution for sugar-sweetened alternatives. Further studies are needed to confirm these findings.
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Bebidas/análisis , Neoplasias del Colon/diagnóstico , Sacarosa en la Dieta/efectos adversos , Recurrencia Local de Neoplasia/diagnóstico , Edulcorantes/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/etiología , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Ingestión de Energía/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/etiología , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Apathy is a common neuropsychiatric symptom in Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI). Detecting apathy accurately may facilitate earlier diagnosis of AD. The Apathy Evaluation Scale (AES) is a promising tool for measurement of apathy in prodromal and possibly preclinical AD. OBJECTIVE: To compare the three AES sub-scales - subject-reported (AES-S), informant-reported (AES-I), and clinician-reported (AES-C) - over time in individuals at risk for AD due to MCI and advanced age (cognitively normal [CN] elderly). METHODS: Mixed effects longitudinal models were used to assess predictors of score for each AES sub-scale. Cox proportional hazards models were used to assess which AES sub-scales predict progression from MCI to AD dementia. RESULTS: Fifty-seven MCI and 18 CN subjects (ages 53-86) were followed for 1.4 ± 1.2 years and 0.7 ± 0.7 years, respectively. Across the three mixed effects longitudinal models, the common findings were associations between greater apathy and greater years in study, a baseline diagnosis of MCI (compared to CN), and male gender. CN elderly self-reported greater apathy compared to that reported by informants and clinicians, while individuals with MCI under-reported their apathy compared to informants and clinicians. Of the three sub-scales, the AES-C best predicted transition from MCI to AD dementia. CONCLUSION: In a sample of CN elderly and elderly with MCI, apathy increased over time, particularly in men and those with MCI. AES-S scores may be more sensitive than AES-I and AES-C scores in CN elderly, but less reliable if subjects have MCI. Moreover, the AES-C sub-scale predicted progression from MCI to AD dementia.
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Envejecimiento/psicología , Apatía , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Escalas de Valoración Psiquiátrica , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Disfunción Cognitiva/fisiopatología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Percepción , Modelos de Riesgos Proporcionales , Factores SexualesRESUMEN
PURPOSE: Observational studies have demonstrated increased colon cancer recurrence in states of relative hyperinsulinemia, including sedentary lifestyle, obesity, and increased dietary glycemic load. Greater coffee consumption has been associated with decreased risk of type 2 diabetes and increased insulin sensitivity. The effect of coffee on colon cancer recurrence and survival is unknown. PATIENTS AND METHODS: During and 6 months after adjuvant chemotherapy, 953 patients with stage III colon cancer prospectively reported dietary intake of caffeinated coffee, decaffeinated coffee, and nonherbal tea, as well as 128 other items. We examined the influence of coffee, nonherbal tea, and caffeine on cancer recurrence and mortality using Cox proportional hazards regression. RESULTS: Patients consuming 4 cups/d or more of total coffee experienced an adjusted hazard ratio (HR) for colon cancer recurrence or mortality of 0.58 (95% CI, 0.34 to 0.99), compared with never drinkers (Ptrend = .002). Patients consuming 4 cups/d or more of caffeinated coffee experienced significantly reduced cancer recurrence or mortality risk compared with abstainers (HR, 0.48; 95% CI, 0.25 to 0.91; Ptrend = .002), and increasing caffeine intake also conferred a significant reduction in cancer recurrence or mortality (HR, 0.66 across extreme quintiles; 95% CI, 0.47 to 0.93; Ptrend = .006). Nonherbal tea and decaffeinated coffee were not associated with patient outcome. The association of total coffee intake with improved outcomes seemed consistent across other predictors of cancer recurrence and mortality. CONCLUSION: Higher coffee intake may be associated with significantly reduced cancer recurrence and death in patients with stage III colon cancer.
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Café , Neoplasias del Colon/tratamiento farmacológico , Recurrencia Local de Neoplasia , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cafeína/uso terapéutico , Quimioterapia Adyuvante/métodos , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Terapia Combinada/métodos , Dieta , Femenino , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Encuestas y Cuestionarios , Té , Adulto JovenRESUMEN
BACKGROUND: Neuropsychiatric symptoms (NPS), such as apathy and depression, commonly accompany cognitive and functional decline in early Alzheimer's disease (AD). Prior studies have shown associations between affective NPS and neurodegeneration of medial frontal and inferior temporal regions in mild cognitive impairment (MCI) and AD dementia. OBJECTIVE: To investigate the association between functional connectivity in four brain networks and NPS in elderly with MCI. METHODS: NPS were assessed using the Neuropsychiatric Inventory in 42 subjects with MCI. Resting-state functional connectivity in four networks (default mode network, fronto-parietal control network (FPCN), dorsal attention network, and ventral attention network) was assessed using seed-based magnetic resonance imaging. Factor analysis was used to identify two factors of NPS: Affective and Hyperactivity. Linear regression models were utilized with the neuropsychiatric factors as the dependent variable and the four networks as the predictors of interest. Covariates included age, gender, premorbid intelligence, processing speed, memory, head movement, and signal-to-noise ratio. These analyses were repeated with the individual items of the affective factor, using the same predictors. RESULTS: There was a significant association between greater Affective factor symptoms and reduced FPCN connectivity (pâ=â0.03). There was no association between the Hyperactivity factor and any of the networks. Secondary analyses revealed an association between greater apathy and reduced FPCN connectivity (pâ=â0.005), but none in other networks. CONCLUSIONS: Decreased connectivity in the FPCN may be associated with greater affective symptoms, particularly apathy, early in AD. These findings extend prior studies, using different functional imaging modalities in individuals with greater disease severity.
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Apatía , Encéfalo/irrigación sanguínea , Disfunción Cognitiva/patología , Trastornos del Humor/patología , Vías Nerviosas/irrigación sanguínea , Vías Nerviosas/patología , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Modelos Lineales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Escalas de Valoración PsiquiátricaRESUMEN
Apathy is a common neuropsychiatric symptom in Alzheimer's disease dementia and amnestic mild cognitive impairment and is associated with cortical atrophy in Alzheimer's disease dementia. This study investigated possible correlations between apathy and cortical atrophy in 47 individuals with mild cognitive impairment and 19 clinically normal elderly. Backward elimination multivariate linear regression was used to evaluate the cross-sectional relationship between scores on the Apathy Evaluation Scale and thickness of several cortical regions and covariates. Lower inferior temporal cortical thickness was predictive of greater apathy. Greater anterior cingulate cortical thickness was also predictive of greater apathy, suggesting an underlying reactive process.
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Envejecimiento/patología , Apatía , Disfunción Cognitiva/patología , Disfunción Cognitiva/fisiopatología , Lóbulo Temporal/patología , Estimulación Acústica , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Modelos Lineales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Aprendizaje Verbal/fisiologíaRESUMEN
White matter pathology has been documented in the brains of familial Alzheimer's disease (FAD)-afflicted individuals during presymptomatic and preclinical stages of AD. How these defects in myelination integrity arise and what roles they may play in AD pathophysiology have yet to be fully elucidated. We previously demonstrated that triple-transgenic AD (3xTg-AD) mice, which harbor the human amyloid precursor Swedish mutation, presenilin-1 M146V (PS1(M146V) ) knock-in mutation, and tau(P301L) mutation, exhibit myelin abnormalities analogous to FAD patients and that Aß(1-42) contributes to these white matter deficits. Herein, we demonstrate that the PS1(M146V) mutation predisposes mouse oligodendrocyte precursor (mOP) cells to Aß(1-42) -induced alterations in cell differentiation in vitro. Furthermore, PS1(M146V) expression compromised mOP cell function and MBP protein distribution, a process that is further aggravated with exposure to Aß(1-42) . We found that the myelination defect and MBP subcellular mislocalization triggered by PS1(M146V) and Aß(1-42) can be effectively prevented by treatment with the GSK-3ß inhibitor, TWS119, thereby implicating GSK-3ß kinase activity in this pathogenic cascade. Overall, this work provides further mechanistic insights into PS1(M146V) and Aß(1-42) -driven oligodendrocyte dysfunction andmyelin damage during early presymptomatic stages of AD, and provides a new target in oligodendrocytes for developing therapies designed to avert AD-related white matter pathology.