FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer's disease.

Alzheimer's disease (AD) has been associated with cardiovascular and cerebrovascular risk factors (CVRFs) during middle age and later and is frequently accompanied by cerebrovascular pathology at death. An interaction between CVRFs and genetic variants might explain the pathogenesis. Genome-wide, gene by CVRF interaction analyses for AD, in 6568 patients and 8101 controls identified FMNL2 (p = 6.6 × 10-7). A significant increase in FMNL2 expression was observed in the brains of patients with brain infarcts and AD pathology and was associated with amyloid and phosphorylated tau deposition. FMNL2 was also prominent in astroglia in AD among those with cerebrovascular pathology. Amyloid toxicity in zebrafish increased fmnl2a expression in astroglia with detachment of astroglial end feet from blood vessels. Knockdown of fmnl2a prevented gliovascular remodeling, reduced microglial activity and enhanced amyloidosis. APP/PS1dE9 AD mice also displayed increased Fmnl2 expression and reduced the gliovascular contacts independent of the gliotic response. Based on this work, we propose that FMNL2 regulates pathology-dependent plasticity of the blood-brain-barrier by controlling gliovascular interactions and stimulating the clearance of extracellular aggregates. Therefore, in AD cerebrovascular risk factors promote cerebrovascular pathology which in turn, interacts with FMNL2 altering the normal astroglial-vascular mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain.

Admixture Mapping of Alzheimer's disease in Caribbean Hispanics identifies a new locus on 22q13.1.

Late-onset Alzheimer's disease (LOAD) is significantly more frequent in Hispanics than in non-Hispanic Whites. Ancestry may explain these differences across ethnic groups. To this end, we studied a large cohort of Caribbean Hispanics (CH, N = 8813) and tested the association between Local Ancestry (LA) and LOAD ("admixture mapping") to identify LOAD-associated ancestral blocks, separately for ancestral components (European [EUR], African [AFR], Native American[NA]) and jointly (AFR + NA). Ancestral blocks significant after permutation were fine-mapped employing multi-ethnic whole-exome sequencing (WES) to identify rare variants associated with LOAD (SKAT-O) and replicated in the UK Biobank WES dataset. Candidate genes were validated studying (A) protein expression in human LOAD and control brains; (B) two animal AD models, Drosophila and Zebrafish. In the joint AFR + NA model, we identified four significant ancestral blocks located on chromosomes 1 (p value = 8.94E-05), 6 (p value = 8.63E-05), 21 (p value = 4.64E-05) and 22 (p value = 1.77E-05). Fine-mapping prioritized the GCAT gene on chromosome 22 (SKAT-O p value = 3.45E-05) and replicated in the UK Biobank (SKAT-O p value = 0.05). In LOAD brains, a decrease of 28% in GCAT protein expression was observed (p value = 0.038), and GCAT knockdown in Amyloid-ß42 Drosophila exacerbated rough eye phenotype (68% increase, p value = 4.84E-09). In zebrafish, gcat expression increased after acute amyloidosis (34%, p value = 0.0049), and decreased upon anti-inflammatory Interleukin-4 (39%, p value = 2.3E-05). Admixture mapping uncovered genomic regions harboring new LOAD-associated loci that might explain the observed different frequency of LOAD across ethnic groups. Our results suggest that the inflammation-related activity of GCAT is a response to amyloid toxicity, and reduced GCAT expression exacerbates AD pathology.

Reproductive period, endogenous estrogen exposure and dementia incidence among women in Latin America and China; A 10/66 population-based cohort study.

BACKGROUND: Exposure to endogenous estrogen may protect against dementia, but evidence remains equivocal. Such effects may be assessed more precisely in settings where exogenous estrogen administration is rare. We aimed to determine whether reproductive period (menarche to menopause), and other indicators of endogenous estrogen exposure are inversely associated with dementia incidence. METHODS: Population-based cohort studies of women aged 65 years and over in urban sites in Cuba, Dominican Republic, Puerto Rico and Venezuela, and rural and urban sites in Peru, Mexico and China. Sociodemographic and risk factor questionnaires were administered to all participants, including ages at menarche, birth of first child, and menopause, and parity, with ascertainment of incident 10/66 dementia, and mortality, three to five years later. RESULTS: 9,428 women participated at baseline, with 72-98% responding by site. The 'at risk' cohort comprised 8,466 dementia-free women. Mean age varied from 72.0 to 75.4 years, lower in rural than urban sites and in China than in Latin America. Mean parity was 4.1 (2.4-7.2 by site), generally higher in rural than urban sites. 6,854 women with baseline reproductive period data were followed up for 26,463 person years. There were 692 cases of incident dementia, and 895 dementia free deaths. Pooled meta-analysed fixed effects, per year, for reproductive period (Adjusted Sub-Hazard Ratio [ASHR] 1.001, 95% CI 0.988-1.015) did not support any association with dementia incidence, with no evidence for effect modification by APOE genotype. No association was observed between incident dementia and; ages at menarche, birth of first child, and menopause: nulliparity; or index of cumulative endogenous estrogen exposure. Greater parity was positively associated with incident dementia (ASHR 1.030, 95% CI 1.002-1.059, I2 = 0.0%). CONCLUSIONS: We found no evidence to support the theory that natural variation in cumulative exposure to endogenous oestrogens across the reproductive period influences dementia incidence in late life.

Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals.

OBJECTIVES: To identify novel loci for late-onset Alzheimer disease (LOAD) in Caribbean Hispanic individuals and to replicate the findings in a publicly available data set from the National Institute on Aging Late-Onset Alzheimer's Disease Family Study. DESIGN: Nested case-control genome-wide association study. SETTING: The Washington Heights-Inwood Columbia Aging Project and the Estudio Familiar de Influencia Genetica de Alzheimer study. PARTICIPANTS: Five hundred forty-nine affected and 544 unaffected individuals of Caribbean Hispanic ancestry. INTERVENTION: The Illumina HumanHap 650Y chip for genotyping. MAIN OUTCOME MEASURE: Clinical diagnosis or pathologically confirmed diagnosis of LOAD. RESULTS: The strongest support for allelic association was for rs9945493 on 18q23 (P=1.7×10(-7)), but 22 additional single-nucleotide polymorphisms (SNPs) had a P value less than 9×10(-6) under 3 different analyses: unadjusted and stratified by the presence or absence of the APOE ε4 allele. Of these SNPs, 5 SNPs (rs4669573 and rs10197851 on 2p25.1; rs11711889 on 3q25.2; rs1117750 on 7p21.1; and rs7908652 on 10q23.1) were associated with LOAD in an independent cohort from the National Institute on Aging Late-Onset Alzheimer's Disease Family Study. We also replicated genetic associations for CLU, PICALM, and BIN1. CONCLUSIONS: Our genome-wide search of Caribbean Hispanic individuals identified several novel genetic variants associated with LOAD and replicated these associations in a white cohort. We also replicated associations in CLU, PICALM, and BIN1 in the Caribbean Hispanic cohort.

Cancer disparities between mainland and island Puerto Ricans.

OBJECTIVES: Examination of cancer rates in a single Hispanic subgroup-Puerto Ricans- and comparison of incidence rates among mainland Puerto Ricans living in the United States, island Puerto Ricans in Puerto Rico, and U.S. non-Hispanic whites to reveal ethnic-specific cancer patterns and disparities in Puerto Ricans. METHODS: Incidence data were obtained from the cancer registries of Puerto Rico and three U.S. northeastern states (New York, New Jersey, and Connecticut) with a high density of mainland Puerto Ricans. Age-adjusted rates were compared by standardized rate ratios (SRRs). RESULTS: Total cancer incidence was the lowest in island Puerto Ricans, intermediate for mainland Puerto Ricans, and highest in U.S. non-Hispanic whites. Compared to mainland Puerto Ricans, islanders had significantly lower rates (p<0.05) for major cancers-lung (SRRs=0.36 in males and 0.29 in females), prostate (SRR=0.71), female breast (SRR=0.73), and colon-rectum (SRRs=0.74 in males and 0.65 in females)-as well as several less common cancers (urinary bladder; non-Hodgkin lymphoma; liver; kidney and renal pelvis; pancreas; thyroid; leukemia; and skin melanoma). Overall cancer rates in mainland Puerto Ricans were modestly lower than those in U.S. non-Hispanic whites, but mainland Puerto Ricans had the highest rates for stomach, liver, and cervical cancers among the three populations. CONCLUSION: Despite socioeconomic disadvantages, island Puerto Ricans have relatively low cancer incidence. Identifying contributing factors would be informative for cancer research, and understanding the reasons for increased cancer risk in their mainland counterparts would facilitate the development of ethnic-specific intervention programs.

Cancer disparities between mainland and island Puerto Ricans / Disparidades en la incidencia de cáncer en puertorriqueños residentes en los Estados Unidos y Puerto Rico

OBJECTIVES: Examination of cancer rates in a single Hispanic subgroup-Puerto Ricans-and comparison of incidence rates among mainland Puerto Ricans living in the United States, island Puerto Ricans in Puerto Rico, and U.S. non-Hispanic whites to reveal ethnic-specific cancer patterns and disparities in Puerto Ricans. METHODS: Incidence data were obtained from the cancer registries of Puerto Rico and three U.S. northeastern states (New York, New Jersey, and Connecticut) with a high density of mainland Puerto Ricans. Age-adjusted rates were compared by standardized rate ratios (SRRs). RESULTS: Total cancer incidence was the lowest in island Puerto Ricans, intermediate for mainland Puerto Ricans, and highest in U.S. non-Hispanic whites. Compared to mainland Puerto Ricans, islanders had significantly lower rates (p < 0.05) for major cancers-lung (SRRs = 0.36 in males and 0.29 in females), prostate (SRR = 0.71), female breast (SRR = 0.73), and colon-rectum (SRRs = 0.74 in males and 0.65 in females)-as well as several less common cancers (urinary bladder; non-Hodgkin lymphoma; liver; kidney and renal pelvis; pancreas; thyroid; leukemia; and skin melanoma). Overall cancer rates in mainland Puerto Ricans were modestly lower than those in U.S. non-Hispanic whites, but mainland Puerto Ricans had the highest rates for stomach, liver, and cervical cancers among the three populations. CONCLUSION: Despite socioeconomic disadvantages, island Puerto Ricans have relatively low cancer incidence. Identifying contributing factors would be informative for cancer research, and understanding the reasons for increased cancer risk in their mainland counterparts would facilitate the development of ethnic-specific intervention programs.

OBJETIVOS: Se analizaron las tasas de cáncer en un subgrupo de hispanos residentes en los Estados Unidos de América -los puertorriqueños (PRREUA) y se compararon sus tasas de incidencia con las de los puertorriqueños que residen en Puerto Rico (PRRPR) y la población estadounidense blanca sin ascendencia hispana (EUBNH) a fin de encontrar patrones de cáncer y disparidades de orden étnico específicos para los puertorriqueños. MÉTODOS: Se obtuvieron los datos de incidencia de los registros de cáncer de Puerto Rico y tres estados del nordeste de los Estados Unidos (New York, New Jersey y Connecticut) que tienen una elevada densidad de PRREUA. Se compararon las tasas ajustadas por la edad mediante las razones de las tasas estandarizadas (SRR). RESULTADOS: La incidencia total de cáncer fue menor en los PRRPR, intermedia en los PRREUA y mayor en los EUBNH. Los PRRPR presentaron tasas significativamente menores que los PRREUA (P < 0,05) en los principales tipos de cáncer -de pulmón (SRR = 0,36 en hombres; SRR = 0,29 en mujeres), próstata (SRR = 0,71), mama (SRR = 0,73) y colorrectal (SRR = 0,74 en hombres y SRR = 0,65 en mujeres)- así como en algunos tipos de cáncer menos frecuentes (de vejiga, hígado, riñón y pelvis renal, páncreas, tiroides, linfomas no Hodgkin, leucemia y melanoma de piel). En general, las tasas de cáncer en los PRREUA fueron ligeramente menores que las de los EUBNH, aunque de las tres poblaciones los PRREUA tuvieron las mayores tasas de cáncer de estómago, hígado y cervicouterino. CONCLUSIONES: A pesar de las desventajas socioeconómicas, los PRRPR tienen una menor incidencia relativa de cáncer. La identificación de los factores que contribuyen a ello podría ayudar en las investigaciones sobre cáncer, y comprender las razones del mayor riesgo de cáncer en los PRREUA podría facilitar el desarrollo de programas de intervención específicos para esta población.

Contrast associated nephropathy in the elderly.

Contrast medium studies have become an important tool for management and diagnosis in many medical specialties. As we age, the need for such studies increase in presence of multiple comorbidities as coronary artery disease and diabetes mellitus. Nephropathy induced by iodine contrast medium is an important complication of radiological procedures, most common in the aged, and a potentially preventable one. For this reason, the understanding and prevention of contrast associated nephropathy is of prime importance to prevent morbidity and mortality in the geriatric population.

Health disparities between island and mainland Puerto Ricans.

OBJECTIVE: To detect health disparities among three populations--Puerto Ricans living in Puerto Rico as well as Puerto Ricans and non-Hispanic whites living on the United States (U.S.) mainland. METHODS: Data from two similarly designed surveys conducted in 1999-2000 were analyzed. The Behavioral Risk Factor Surveillance System (BRFSS) provided data on Puerto Ricans living on the island and on non-Hispanic whites in the U.S. Another survey of Puerto Ricans living in New York City provided data on mainland Puerto Ricans. The age- and sex-standardized weighted prevalences of various health parameters (e.g., obesity, diabetes, smoking, and physical illness) and indicators of access to health care (e.g., frequencies of routine checkups and diabetes care) were compared between populations by means of standardized rate ratios (SRR). RESULTS: Puerto Ricans living on the mainland and those living on the island had a similar prevalence of obesity (21% to 22%). Compared with islanders, mainland Puerto Ricans had a higher prevalence of diabetes (SRR = 1.4; 95% confidence interval [95% CI] = 1.01 to 2.0); those with diabetes also showed higher prevalences of smoking (SRR = 4.2; 95% CI = 2.3 to 7.7) and physical illness (SRR = 1.5; 95% CI = 1.1 to 2.0) than Puerto Ricans living on the island. While mainland Puerto Ricans were similar to non-Hispanic whites in terms of their utilization of primary prevention and diabetes care, island Puerto Ricans trailed behind significantly. CONCLUSIONS: Puerto Ricans living on the U.S. mainland and those living in Puerto Rico both need to target lowering their prevalence of obesity and diabetes. For island Puerto Ricans, improved education about the significance of primary prevention and diabetes care is needed. For mainland Puerto Ricans, the accessibility of the primary health care system renders it a potentially effective venue for interventions, particularly for smoking cessation. More studies are warranted to identify factors associated with the poor health status observed in mainland Puerto Ricans.

Health disparities between island and mainland Puerto Ricans

OBJETIVO: Detectar disparidades de salud entre tres poblaciones: puertorriqueños que viven en Puerto Rico, así como puertorriqueños y personas no hispanas de raza blanca que viven en tierra firme estadounidense. MÉTODOS: Se analizaron los datos obtenidos mediante dos encuestas de similar diseño que se realizaron en 1999–2000. El Sistema de Vigilancia de Factores de Riesgo Conductuales proporcionó datos acerca de los puertorriqueños radicados en la isla y de residentes de Estados Unidos de raza blanca que no son hispanos. Otra encuesta de puertorriqueños radicados en la Ciudad de Nueva York aportó datos acerca de los puertorriqueños que residían en tierra firme estadounidense. Se usaron las razones de las tasas estandarizadas (standardized rate ratios, SRR) para hacer las comparaciones interpoblacionales de las prevalencias ponderadas, estandarizadas por edad y sexo, de varios parámetros (obesidad, diabetes, tabaquismo y dolencias físicas) y de indicadores de acceso a la atención sanitaria (frecuencia de los exámenes de rutina y de la atención de la diabetes). RESULTADOS: Los puertorriqueños que vivían en tierra firme estadounidense y los que vivían en la isla tuvieron una prevalencia de obesidad parecida (21% a 22%). Comparados con los habitantes de la isla, los puertorriqueños radicados en tierra firme tuvieron una prevalencia de diabetes más alta (SRR = 1,4; intervalo de confianza de 95% [IC95%]: 1,01 a 2,0); los que tenían diabetes también mostraron una mayor prevalencia de tabaquismo (SRR = 4,2; IC 95%: 2,3 a 7,7) y de dolencias físicas (SRR = 1,5%; IC95%: 1,1 a 2,0) que los puertorriqueños que vivían en la isla. Mientras que los puertorriqueños en tierra firme se asemejaron a los blancos que no eran hispanos en cuanto a la utilización de servicios de prevención primaria y de atención de la diabetes, los puertorriqueños en la isla tenían cifras de utilización mucho más bajas...