Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience.

BACKGROUND: While age and the APOE ε4 allele are major risk factors for Alzheimer's disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline. METHODS: We used over 200 "AD resilient" individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs from the linkage peaks that reduced risk for AD in an independent dataset and in a gene-based test. Finally, we experimentally characterized replicated SNPs. RESULTS: Rs142787485 in RAB10 confers significant protection against AD (p value = 0.0184, odds ratio = 0.5853). Moreover, we replicated this association in an independent series of unrelated individuals (p value = 0.028, odds ratio = 0.69) and used a gene-based test to confirm a role for RAB10 variants in modifying AD risk (p value = 0.002). Experimentally, we demonstrated that knockdown of RAB10 resulted in a significant decrease in Aß42 (p value = 0.0003) and in the Aß42/Aß40 ratio (p value = 0.0001) in neuroblastoma cells. We also found that RAB10 expression is significantly elevated in human AD brains (p value = 0.04). CONCLUSIONS: Our results suggest that RAB10 could be a promising therapeutic target for AD prevention. In addition, our gene discovery approach can be expanded and adapted to other phenotypes, thus serving as a model for future efforts to identify rare variants for AD and other complex human diseases.

Vascular risk factors and neuropsychiatric symptoms in Alzheimer's disease: the Cache County Study.

OBJECTIVE: Knowledge of potentially modifiable risk factors for neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) is important. This study longitudinally explores modifiable vascular risk factors for NPS in AD. METHODS: Participants enrolled in the Cache County Study on Memory in Aging with no dementia at baseline were subsequently assessed over three additional waves, and those with incident (new onset) dementia were invited to join the Dementia Progression Study for longitudinal follow-up. A total of 327 participants with incident AD were identified and assessed for the following vascular factors: atrial fibrillation, hypertension, diabetes mellitus, angina, coronary artery bypass surgery, myocardial infarction, cerebrovascular accident, and use of antihypertensive or diabetes medicines. A vascular index (VI) was also calculated. NPS were assessed over time using the Neuropsychiatric Inventory (NPI). Affective and Psychotic symptom clusters were assessed separately. The association between vascular factors and change in NPI total score was analyzed using linear mixed model and in symptom clusters using a random effects model. RESULTS: No individual vascular risk factors or the VI significantly predicted change in any individual NPS. The use of antihypertensive medications more than four times per week was associated with higher total NPI and Affective cluster scores. CONCLUSIONS: Use of antihypertensive medication was associated with higher total NPI and Affective cluster scores. The results of this study do not otherwise support vascular risk factors as modifiers of longitudinal change in NPS in AD.

Avaliação do delírio em pacientes pós-operatórios: validação da versão portuguesa da Nursing Delirium Screening Scale na terapia intensiva / Delirium assessment in postoperative patients: validation of the portuguese version of the Nursing Delirium Screening Scale in critical care / Evaluación del delirio en pacientes postoperatorios: validación de la versión portuguesa de la Nursing Delirium Screening Scale en cuidados intensivos

EXPERIÊNCIA E OBJETIVOS: O objetivo desse estudo foi validar a versão portuguesa da escala Nursing Delirium Screening Scale (Nu-DESC) para uso em anbientes de terapia intensiva. MÉTODOS: Simultânea e independentemente, avaliamos para ocorrência de delírio todos os pacientes pós-operatórios internados em uma Unidade de Terapia Intensiva Cirúrgica (UTIC) ao longo de um período de um mês, utilizando as versões portuguesas de Nu-DESC e da escala Intensive Care Delirium Screening Checklist (ICDSC) dentro de 24 horas a contar da internação, tanto pelo médico da equipe de pesquisa como pelo enfermeiro diretamente encarregado do paciente. Determinamos a acurácia diagnóstica de Nu-DESC utilizando análises de sensibilidade, especificidade e da curva ROC. Avaliamos a confiabilidade entre enfermeiros/médico da equipe de pesquisa para Nu-DESC pelo coeficiente de correlação intraclasse (CCI). Avaliamos concordância e confiabilidade entre Nu-DESC e ICDSC por percentuais globais e específicos de concordância, e por estatística kappa. RESULTADOS: Com base na escala ICDSC, diagnosticamos delírio em 12 dos 78 pacientes. Para o escore Nu-DESC total, consideramos como alta a confiabilidade entre enfermeiros/médico da equipe. Quanto ao diagnóstico, consideramos perfeita a concordância entre enfermeiros e médico da equipe. O percentual de concordância global entre Nu-DESC e ICDSC para o diagnóstico de delírio foi 0,88, e kappa variou de 0,79 a 0,93. A sensibilidade da escala Nu-DESC foi 100%, e a especificidade, 86%. CONCLUSÕES: A versão portuguesa da escala Nu-DESC parece ser instrumento de avaliação e monitoramento acurado e confiável para o diagnóstico de delírio em ambientes de terapia intensiva.

BACKGROUND AND OBJECTIVES: The aim of this study was to validate the Portuguese version of the Nursing Delirium Screening Scale (Nu-DESC) for use in critical care settings. METHODS: We simultaneously and independently evaluated all postoperative patients admitted to a surgical Intensive Care Unit (SICU) over a 1-month period for delirium, using the Portuguese versions of both the Nu-DESC and the Intensive Care Delirium Screening Checklist (ICDSC) within 24 hours of admission by both the research staff physician and one bedside nurse. We determined the diagnostic accuracy of the Nu-DESC using sensitivity, specificity and ROC curve analyses. We assessed reliability between nurses and the research staff physician for Nu-DESC by intraclass correlation coefficient (ICC). We assessed agreement and reliability between Nu-DESC and ICDSC by overall and specific proportions of agreement and by kappa statistics. RESULTS: Based on the ICDSC, we diagnosed delirium in 12 of the 78 patients. Reliability between nurses and the staff physician for total Nu-DESC score was high. Agreement between nurses and staff physician in the delirium diagnosis was perfect. The proportion of overall agreement between Nu-DESC and ICDSC in the delirium diagnosis was 0.88 and the kappa ranged from 0.79 to 0.93. Nu-DESC Sensitivity was 100 and specificity was 86%. CONCLUSIONS: The Portuguese version of the Nu-DESC appears to be an accurate and reliable assessment and monitoring instrument for delirium in critical care settings.

EXPERIENCIA Y OBJETIVOS: El objetivo de este estudio fue validar la versión portuguesa de la escala Nursing Delirium Screening Scale (Nu-DESC) para uso en ambientes de cuidados intensivos. MÉTODOS: Simultánea e independientemente, evaluamos el aparecimiento de delirio en todos los pacientes postoperatorios ingresados en una Unidad de Cuidados Intensivos Quirúgica (UCIQ) a lo largo de un período de un mes, utilizando las versiones portuguesas de Nu-DESC y de la escala Intensive Care Delirium Screening Checklist (ICDSC) dentro de 24 horas a partir del momento del ingreso, tanto por el médico del equipo de investigación, como por el enfermero directamente encargado del paciente. Determinamos la exactitud diagnóstica de Nu-DESC utilizando análisis de sensibilidad, especificidad y de la curva ROC. Evaluamos la confiabilidad entre enfermeros/médico del equipo de investigación para Nu-DESC por el coeficiente de correlación intraclase (CCI). Evaluamos la concordancia y la confiabilidad entre Nu-DESC y ICDSC por porcentajes globales y específicos de concordancia, y por estadística kappa. RESULTADOS: Basándonos en la escala ICDSC, diagnosticamos delirio en 12 de los 78 pacientes. Para la puntuación Nu-DESC total, consideramos como alta la confiabilidad entre enfermeros/médico del equipo. En cuanto al diagnóstico, consideramos perfecta la concordancia entre enfermeros y médico del equipo. El porcentaje de concordancia global entre Nu-DESC y ICDSC para el diagnóstico de delirio fue de 0,88, y kappa varió de 0,79 a 0,93. La sensibilidad de la escala Nu-DESC fue de un 100%, y el de especificidad de un 86%. CONCLUSIONES: La versión portuguesa de la escala Nu-DESC parece ser un instrumento de evaluación y monitoreo exacto y confiable para el diagnóstico del delirio en ambientes de cuidados intensivos.

A prospective, randomized comparison of pain, inflammatory response, and short-term outcomes between single port and laparoscopic cholecystectomy.

BACKGROUND: The purpose of this study was to compare the postoperative inflammatory response and severity of pain between single-incision laparoscopic surgery (SILS) cholecystectomy and conventional laparoscopic cholecystectomy (LC). METHODS: Two groups of 20 patients were prospectively randomized to either conventional LC or SILS cholecystectomy. Serum interleukin-6 (IL-6) levels were assayed before surgery, at 4-6 h, and at 18-24 h after the procedure. Serum C-reactive protein (CRP) levels also were assayed at 18-24 h after surgery. Pain was measured at each of three time points after surgery using the visual analogue scale (VAS). The number of analgesia doses administered in the first 24 h after the procedure also was recorded and 30-day surgical outcomes were documented. RESULTS: The groups had equivalent body mass index (BMI), age, and comorbidity distribution. Peak IL-6 levels occurred 4-6 h after surgery, and the median level was 12.8 pg/ml in the LC and 8.9 pg/ml in the SILS group (p = 0.5). The median CRP level before discharge was 1.6 mg/dl in the LC and 1.9 mg/dl in the SILS group (p = 0.38). There was no difference in either analgesic use or pain intensity as measured by the VAS between the two groups (p = 0.72). The length of the surgical procedure was significantly longer in the SILS group (p < 0.001). No intraoperative complications occurred in either group. CONCLUSIONS: Single-incision laparoscopic surgery does not significantly reduce systemic inflammatory response, postoperative pain, or analgesic use compared with LC.

Lifestyle behavior pattern is associated with different levels of risk for incident dementia and Alzheimer's disease: the Cache County study.

OBJECTIVES: To identify distinct behavioral patterns of diet, exercise, social interaction, church attendance, alcohol consumption, and smoking and to examine their association with subsequent dementia risk. DESIGN: Longitudinal, population-based dementia study. SETTING: Rural county in northern Utah, at-home evaluations. PARTICIPANTS: Two thousand four hundred ninety-one participants without dementia (51% male, average age 73.0 ± 5,7; average education 13.7 ± 4.1 years) initially reported no problems in activities of daily living and no stroke or head injury within the past 5 years. MEASUREMENTS: Six dichotomized lifestyle behaviors were examined (diet: high ≥ median on the Dietary Approaches to Stop Hypertension scale; exercise: ≥5 h/wk of light activity and at least occasional moderate to vigorous activity; church attendance: attending church services at least weekly; social Interaction: spending time with family and friends at least twice weekly; alcohol: currently drinking alcoholic beverages ≥ 2 times/wk; nonsmoker: no current use or fewer than 100 cigarettes ever). Latent class analysis (LCA) was used to identify patterns among these behaviors. Proportional hazards regression modeled time to dementia onset as a function of behavioral class, age, sex, education, and apolipoprotein E status. Follow-up averaged 6.3 ± 5.3 years, during which 278 cases of incident dementia (200 Alzheimer's disease (AD)) were diagnosed. RESULTS: LCA identified four distinct lifestyle classes. Unhealthy-religious (UH-R; 11.5%), unhealthy-nonreligious (UH-NR; 10.5%), healthy-moderately religious (H-MR; 38.5%), and healthy-very religious (H-VR; 39.5%). UH-NR (hazard ratio (HR) = 0.54, P = .028), H-MR (HR = 0.56, P = .003), and H-VR (HR = 0.58, P = .005) had significantly lower dementia risk than UH-R. Results were comparable for AD, except that UH-NR was less definitive. CONCLUSION: Functionally independent older adults appear to cluster into subpopulations with distinct patterns of lifestyle behaviors with different levels of risk for subsequent dementia and AD.

Better cognitive performance in elderly taking antioxidant vitamins E and C supplements in combination with nonsteroidal anti-inflammatory drugs: the Cache County Study.

Studies have shown less cognitive decline and lower risk of Alzheimer's disease in elderly individuals consuming either antioxidant vitamins or nonsteroidal anti-inflammatory drugs (NSAIDs). The potential of added benefit from their combined use has not been studied. We therefore analyzed data from 3,376 elderly participants of the Cache County Study who were given the Modified Mini-Mental State examination up to three times during a period of 8 years. Those who used a combination of vitamins E and C supplements and NSAIDs at baseline declined by an average 0.96 fewer points every 3 years than nonusers (P < .05). This apparent effect was attributable entirely to participants with the APOE epsilon4 allele, whose users declined by 2.25 fewer points than nonusers every 3 years (P < .05). These results suggest that among elderly individuals with an APOE epsilon4 allele, there is an association between using antioxidant supplements in combination with NSAIDs and less cognitive decline over time.

Vascular factors and risk for neuropsychiatric symptoms in Alzheimer's disease: the Cache County Study.

OBJECTIVE: To examine, in an exploratory analysis, the association between vascular conditions and the occurrence of neuropsychiatric symptoms (NPS) in a population-based sample of incident Alzheimer's disease (AD). METHODS: The sample consisted of 254 participants, identified through two waves of assessment. NPS were assessed using the Neuropsychiatric Inventory. Prior to the onset of AD, data regarding a history of stroke, hypertension, hyperlipidemia, heart attack or coronary artery bypass graft (CABG), and diabetes were recorded. Logistic regression procedures were used to examine the relationship of each vascular condition to individual neuropsychiatric symptoms. Covariates considered were age, gender, education, APOE genotype, dementia severity, and overall health status. RESULTS: One or more NPS were observed in 51% of participants. Depression was most common (25.8%), followed by apathy (18.6%), and irritability (17.7%). Least common were elation (0.8%), hallucinations (5.6%), and disinhibition (6.0%). Stroke prior to the onset of AD was associated with increased risk of delusions (OR = 4.76, p = 0.02), depression (OR = 3.87, p = 0.03), and apathy (OR = 4.48, p = 0.02). Hypertension was associated with increased risk of delusions (OR = 2.34, p = 0.02), anxiety (OR = 4.10, p = 0.002), and agitation/aggression (OR = 2.82, p = 0.01). No associations were observed between NPS and diabetes, hyperlipidemia, heart attack or CABG, or overall health. CONCLUSIONS: Results suggest that a history of stroke and hypertension increase the risk of specific NPS in patients with AD. These conditions may disrupt neural circuitry in brain areas involved in NPS. Findings may provide an avenue for reduction in occurrence of NPS through the treatment or prevention of vascular risk conditions.

Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County study.

Vascular risk factors for Alzheimer disease (AD) and vascular dementia (VaD) have been evaluated; however, few studies have compared risks by dementia subtypes and sex. We evaluated relationships between cardiovascular risk factors (hypertension, high cholesterol, diabetes mellitus, and obesity), events (stroke, coronary artery bypass graft surgery, and myocardial infarction), and subsequent risk of AD and VaD by sex in a community-based cohort of 3264 Cache County residents aged 65 or older. Cardiovascular history was ascertained by self-report or proxy-report in detailed interviews. AD and VaD were diagnosed using standard criteria. Estimates from discrete-time survival models showed no association between self-reported history of hypertension and high cholesterol and AD after adjustments. Hypertension increased the risk of VaD [adjusted hazard ratio (aHR) 2.42, 95% confidence interval (CI) 0.95-7.44]. Obesity increased the risk of AD in females (aHR 2.23, 95% CI 1.09-4.30) but not males. Diabetes increased the risk of VaD in females after adjustments (aHR 3.33, 95% CI 1.03-9.78) but not males. The risk of VaD after stroke was increased in females (aHR 16.90, 95% CI 5.58-49.03) and males (aHR 10.95, 95% CI 2.48-44.78). The results indicate that vascular factors increase risks for AD and VaD differentially by sex. Future studies should focus on specific causal pathways for each of these factors with regard to sex to determine if sex differences in the prevalence of vascular factors have an influence on sex differences in dementia risk.

A population-based study of the association between coronary artery bypass graft surgery (CABG) and cognitive decline: the Cache County study.

BACKGROUND: The relationship between coronary artery bypass graft (CABG) surgery and cognitive decline remains uncertain, in particular with regard to whether there is delayed cognitive decline associated with this procedure. METHODS: This was a population-based cohort study involving participants in the Cache County Study of Memory Health and Aging. At baseline the study enrolled 5,092 persons age 65 and older and followed them up three years later and again four years after that. Individuals who reported having undergone CABG surgery at study baseline or had this surgery in between follow-up waves were compared to individuals who never reported having the surgery. The main outcome measure was the Modified Mini Mental State (3MS). Multilevel models were used to examine the relationship between CABG surgery and cognitive decline over time. RESULTS: Study participants who had CABG surgery evidenced 0.95 points of greater decline relative to baseline on the 3MS at the first follow-up interview after CABG, and an average of 1.9 points of greater decline at the second follow-up interview, than those without CABG (t = -2.51, df = 2,316, p = 0.0121), after adjusting for several covariates, including number of vascular conditions. This decline was restricted to individuals who were more than five years past the procedure and was not evident in the early years after the surgery. CONCLUSIONS: CABG surgery is associated with accelerated cognitive decline more than five years after the procedure in a long-lived population. This decline is small and its clinical significance is uncertain. We could not find an association between CABG and decline in the first five post-operative years.

Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study.

BACKGROUND: Antioxidants may protect the aging brain against oxidative damage associated with pathological changes of Alzheimer disease (AD). OBJECTIVE: To examine the relationship between antioxidant supplement use and risk of AD. DESIGN: Cross-sectional and prospective study of dementia. Elderly (65 years or older) county residents were assessed in 1995 to 1997 for prevalent dementia and AD, and again in 1998 to 2000 for incident illness. Supplement use was ascertained at the first contact. SETTING: Cache County, Utah. PARTICIPANTS: Among 4740 respondents (93%) with data sufficient to determine cognitive status at the initial assessment, we identified 200 prevalent cases of AD. Among 3227 survivors at risk, we identified 104 incident AD cases at follow-up. MAIN OUTCOME MEASURE: Diagnosis of AD by means of multistage assessment procedures. RESULTS: Analyses of prevalent and incident AD yielded similar results. Use of vitamin E and C (ascorbic acid) supplements in combination was associated with reduced AD prevalence (adjusted odds ratio, 0.22; 95% confidence interval, 0.05-0.60) and incidence (adjusted hazard ratio, 0.36; 95% confidence interval, 0.09-0.99). A trend toward lower AD risk was also evident in users of vitamin E and multivitamins containing vitamin C, but we saw no evidence of a protective effect with use of vitamin E or vitamin C supplements alone, with multivitamins alone, or with vitamin B-complex supplements. CONCLUSIONS: Use of vitamin E and vitamin C supplements in combination is associated with reduced prevalence and incidence of AD. Antioxidant supplements merit further study as agents for the primary prevention of AD.

An adaptation of the modified mini-mental state examination: analysis of demographic influences and normative data: the cache county study.

OBJECTIVES: To present a new version of the Modified Mini-Mental State Examination (3MS-R), provide normative information extending to individuals in the 10th decade, and examine the effects of demographic variables on test performance. BACKGROUND: The Modified Mini-Mental State Examination, based originally on the Mini-Mental State Examination, has been used to screen populations for dementia. Providing normative information and an analysis of demographic variables on test performance for this version would support broader use in clinical and other settings. METHODS: Two thousand, nine hundred thirteen elderly individuals determined to be free of dementia and other neurologic and psychiatric conditions served as subjects. An analysis of variance was conducted to examine the effects of age, gender, and education on test performance. Descriptive statistics (means, standard deviations, and percentile ranks) were calculated to summarize the range of normal performance. To examine the sensitivity/specificity of the suggested cut-off points at the 7th and 10th percentiles, two subsamples of elderly individuals, on whom clinical dementia assessments were available, were used to classify individuals with regard to dementia status. RESULTS: Lower age, higher education, and female gender were associated with higher 3MS-R scores. Gender effects were among the weakest, but most important at lower levels of education. Education effects were most prominent in the youngest age groups. Selection of a cut-off point at the 7th percentile revealed 69%-70% sensitivity for detecting dementia, and higher sensitivity for individuals in the youngest age groups. Specificity at this cut-off point was 89%. Raising the cut-off point to the 10th percentile improved sensitivity to 73%-76%, but reduced specificity to 85%-86%. CONCLUSION: We present a version of the Modified Mini-Mental State Examination that has demonstrated utility in screening a population for dementia. An analysis of normative information and the effects of demographic influences suggest that the 7th percentile cut-off point performs very well in detecting dementia in 65-79-year-old individuals but less well for individuals in their 80s and 90s. To increase the sensitivity of the 3MS-R to detect dementia or other forms of cognitive impairment, particularly among the "old-old," the test user may wish to raise the cut-off point for impairment in some demographic groups or to supplement the test with additional cognitive measures.