Alzheimer's Disease Biomarker Decision-Making among Patients with Mild Cognitive Impairment and Their Care Partners.

BACKGROUND: Alzheimer's disease (AD) biomarker tests can be ordered as part of the diagnostic workup of patients with mild cognitive impairment (MCI). Little is known about how patients with MCI and their care partners decide whether to pursue testing. OBJECTIVE: To examine factors that influence AD biomarker testing decisions among patients with MCI and their care partners. DESIGN: We performed structured research interviews with patients with MCI and their study partners to assess the importance of eight factors in the decision whether to undergo AD biomarker testing (6-point Likert scale; 1-extremely unimportant to 6-extremely important): cost, fear of testing procedures, learning if AD is the cause of cognitive problems, concern about health insurance, instructing future planning, informing treatment decisions, family members' opinions, and doctor recommendation. SETTING: Two researchers administered interviews with participants in-person (i.e., participant home, research center) or remotely (i.e., telephone, video-conference). PARTICIPANTS: We completed interviews with 65 patients with a diagnosis of MCI and 57 study partners, referred by dementia specialist clinicians from the University of California, Irvine health system. MEASUREMENTS: We used generalized estimating equations (GEE) to examine the mean importance of each factor among patients and study partners, and the mean difference in importance of each factor within dyads. RESULTS: One third of participants reported the patient had previously undergone AD biomarker testing. Fifty-five percent of patients and 65% of study partners who reported no previous testing indicated a desire for the patient to be tested. GEE analyses found that patients and study partners rated the following factors with highest importance: informing treatment decisions (mean score 5.29, 95% CI: 5.06, 5.52 for patients; mean score 5.56, 95% CI: 5.41, 5.72 for partners); doctor recommendation (4.94, 95% CI: 4.73, 5.15 for patients; 5.16, 95% CI: 4.97, 5.34 for partners); and instructing future planning (4.88, 95% CI: 4.59, 5.16 for patients; 5.11, 95% CI: 4.86, 5.35 for partners). High dyadic agreement was observed for all factors except fear of testing, which patients rated with lower importance than their study partners. CONCLUSIONS: Biomarker testing for AD in patients with MCI is a rapidly evolving practice and limited data exist on patient perspectives. In this study, most patients and their care partners were interested in testing to help inform treatment decisions and to plan for the future. Participants placed high importance on clinician recommendations for biomarker testing, highlighting the need for clear communication and education on the options, limitations, risks, and benefits of testing.

Cohort Effects in Alzheimer's Disease Trials: An Empirical Assessment Utilizing Data from the Alzheimer's Disease Cooperative Study.

BACKGROUND: Cohort effects in study populations can impact clinical trial conclusions and generalizability, particularly in trials with planned interim analyses. Long recruitment windows may exacerbate these risks in Alzheimer's disease (AD) trials. OBJECTIVES: To investigate the presence of cohort effects mild-to-moderate AD trials. DESIGN: Retrospective analysis using pooled participant-level data from nine randomized, placebo-controlled trials conducted by the Alzheimer's Disease Cooperative Study (ADCS). SETTING: Trials were multicenter studies conducted by an academic trial network. PARTICIPANTS: The trials enrolled participants with mild, mild-to-moderate, or moderate AD who were over age 50 and had mini mental state exam scores between 12 and 26. Interventions/Exposure: We defined a participant's site-standardized enrollment time as the number of days between their screening date and the first screening date among randomized participants at their site within their study. MAIN OUTCOME(S) AND MEASURE(S): Our primary outcome was the 12-month change in the AD assessment scale - cognitive subscale (ADAS-Cog). Secondary outcomes were participant demographics and time to study discontinuation. RESULTS: The pooled sample consisted of N=2,754 at baseline with N=2,191 participants completing a 12-month visit. We found no meaningful differences in the distributions of sex, race and ethnicity, age, years of education or baseline ADAS-Cog score across enrollment time. We found a significant association between enrollment time and 12-month change in ADAS-Cog, with participants enrolling 100 days later tending to experience an increase on the ADAS-Cog of 0.16 points greater (reflecting greater cognitive decline; 95% CI: (0.021, 0.294), p = 0.02), after controlling for potential confounding factors. CONCLUSION: We found minimal evidence of clinically relevant cohort effects in ADCS trials. Our results reinforce the original findings of these trials.

Anxiety and Depressive Symptoms and Cortical Amyloid-ß Burden in Cognitively Unimpaired Older Adults.

BACKGROUND: There is evidence of relationships between behavioral symptoms and increased risk for Alzheimer's Disease and/or Alzheimer's Disease biomarkers. However, the nature of this relationship is currently unknown. OBJECTIVES: To evaluate the relationship between anxiety and depressive symptoms and amyloid-ß deposition in cognitively unimpaired older adults, and to assess mediating effects of either objective or subjective cognitive skills. DESIGN: Cross-sectional analysis of screening data from participants enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study (ClinicalTrials.gov Identifier: NCT02008357). SETTING: Data analysis. PARTICIPANTS: 4492 cognitively unimpaired adults, age 65-85, enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study. MEASUREMENTS: We used linear regression to estimate the associations between amyloid-ß standard uptake value ratio (SUVR) and Geriatric Depression Scale (GDS) and State Trait Anxiety Inventory (STAI) scores while adjusting for potential confounding factors as well as for Cognitive Function Index (CFI) or Preclinical Alzheimer's Cognitive Composite (PACC) scores as possible mediational variables. RESULTS: 4399 subjects with complete covariates were included (mean age: 71.3, 59% female), GDS ranged 0-13 (mean: 1.0), and STAI ranged 6-24 (mean: 9.9). Amyloid-ß SUVR was modestly associated with STAI; mean STAI score was estimated to be 0.275 points higher (95% CI: 0.038, 0.526; p-value = 0.023) for each 0.5-point increase in cortical amyloid-ß SUVR. Subjective cognitive decline (CFI) attenuated the relationship between SUVR and STAI, while objective cognitive function (PACC) did not. No statistically significant relationship between SUVR and GDS was observed (p = 0.326). CONCLUSIONS: In cognitively unimpaired adults with low levels of depression and anxiety, cortical amyloid-ß deposition is associated with anxiety but not depressive symptoms. Attenuation of this relationship by subjective cognitive difficulties suggests that anxiety may be partly due to such a perception resulting from cortical amyloid-ß deposition.

Diversifying Recruitment Registries: Considering Neighborhood Health Metrics.

BACKGROUND: Disparities in clinical research participation perpetuate broader health disparities. Recruitment registries are novel tools to address known challenges in accrual to clinical research. Registries may accelerate accrual, but the utility of these tools to improve generalizability is unclear. OBJECTIVE: To examine the diversity of a local on-line recruitment registry using the Area Deprivation Index (ADI), a publicly available metric of neighborhood disadvantage. DESIGN: Retrospective analysis. SETTING: Data were collected in the University of California Irvine Consent-to-Contact Registry. PARTICIPANTS: We categorized N=2,837 registry participants based on the ADI decile (collapsed into quintiles) using a state-based rankings. MEASUREMENTS: We examined the proportion of enrollees per ADI quintile and quantified the demographics of these groups. We assessed willingness to participate in studies involving unique research procedures among the ADI groups. RESULTS: Although registry enrollees represented the full spectrum of the ADI, they disproportionately represented less disadvantaged neighborhoods (lowest to highest quintiles: 42%, 30%, 15%, 6%, 7%). Compared to participants from less disadvantaged neighborhoods, participants from more disadvantaged neighborhoods were more often female, of non-white race, and Hispanic ethnicity. Despite demographic differences, ADI groups were observed to have similar willingness to participate in research studies. CONCLUSIONS: People from more disadvantaged neighborhoods may be underrepresented in recruitment registries, increasing the risk that they will be underrepresented when using these tools to facilitate prospective recruitment to clinical research. Once enrolled in registries, participants from more disadvantaged neighborhoods may be equally willing to participate in research. Efforts to increase representation of participants from disadvantaged neighborhoods in registries could be an important first step toward increasing the generalizability of clinical research.

Is Reluctance to Share Alzheimer's Disease Biomarker Status with a Study Partner a Barrier to Preclinical Trial Recruitment?

BACKGROUND: Preclinical Alzheimer's disease clinical trials test candidate treatments in individuals with biomarker evidence but no cognitive impairment. Participants are required to co-enroll with a knowledgeable study partner, to whom biomarker information is disclosed. OBJECTIVE: We investigated whether reluctance to share biomarker results is associated with viewing the study partner requirement as a barrier to preclinical trial enrollment. DESIGN: We developed a nine-item assessment on views toward the study partner requirement and performed in-person interviews based on a hypothetical clinical trial requiring biomarker testing and disclosure. SETTING: We conducted interviews on campus at the University of California, Irvine. PARTICIPANTS: Two hundred cognitively unimpaired older adults recruited from the University of California, Irvine Consent-to-Contact Registry participated in the study. MEASUREMENTS: We used logistic regression models, adjusting for potential confounders, to examine potential associations with viewing the study partner requirement as a barrier to preclinical trial enrollment. RESULTS: Eighteen percent of participants reported strong agreement that the study partner requirement was a barrier to enrollment. Ten participants (5%) agreed at any level that they would be reluctant to share their biomarker result with a study partner. The estimated odds of viewing the study partner requirement as a barrier to enrollment were 26 times higher for these participants (OR=26.3, 95% CI 4.0, 172.3), compared to those who strongly disagreed that they would be reluctant to share their biomarker result. Overall, participants more frequently agreed with positive statements than negative statements about the study partner requirement, including 76% indicating they would want their study partner with them when they learned biomarker results. CONCLUSIONS: This is one of the first studies to explore how potential preclinical Alzheimer's disease trial participants feel about sharing their personal biomarker information with a study partner. Most participants viewed the study partner as an asset to trial enrollment, including having a partner present during biomarker disclosure.

Association of ultrasound-based measures of fetal body composition with newborn adiposity.

BACKGROUND: Newborns exhibit substantial variation in gestational age-adjusted and sex-adjusted fat mass proportion. The antecedent characteristics of fetal body composition that are associated with newborn fat mass proportion are poorly understood. OBJECTIVE: The aim of this study was to determine whether a composite measure of fetal fat mass is prospectively associated with newborn adiposity. METHODS: In a longitudinal study of 109 low-risk pregnancies, fetal ultrasonography was performed at approximately 12, 20 and 30 weeks gestation. Estimated fetal adiposity (EFA) was derived by integrating cross-sectional arm and thigh per cent fat area and anterior abdominal wall thickness. Newborn per cent body fat was quantified by Dual Energy X-Ray Absorptiometry. The association between EFA and newborn per cent body fat was determined by multiple linear regression. RESULTS: After controlling for confounding factors, EFA at 30 weeks was significantly associated with newborn per cent body fat (standardized ß = 0.41, p < 0.001) and explained 24.0% of its variance, which was substantially higher than that explained by estimated fetal weight (8.1%). The observed effect was driven primarily by arm per cent fat area. CONCLUSIONS: A composite measure of fetal adiposity at 30 weeks gestation may constitute a better predictor of newborn per cent body fat than estimated fetal weight by conventional fetal biometry. Fetal arm fat deposition may represent an early indicator of newborn adiposity. After replication, these findings may provide a basis for an improved understanding of the ontogeny of fetal fat deposition, thereby contributing to a better understanding of its intrauterine determinants and the development of potential interventions.

Using clinical risk factors and bone mineral density to determine who among patients undergoing bone densitometry should have vertebral fracture assessment.

SUMMARY: Vertebral fracture assessment (VFA) is a new method for imaging thoracolumbar spine on bone densitometer. Among patients referred for bone densitometry, the selection of patients for VFA testing can be optimized using an index derived from clinical risk factors and bone density measurement. PURPOSE: VFA, a method for imaging thoracolumbar spine on bone densitometer, was developed because vertebral fractures, although common and predictive of future fractures, are often not clinically diagnosed. The study objective was to develop a strategy for selecting patients for VFA. METHODS: A convenience sample from a university hospital bone densitometry center included 892 subjects (795 women) referred for bone mineral density (BMD) testing. We used questionnaires to capture clinical risk factors and dual-energy X-ray absorptiometry to obtain BMD and VFA. RESULTS: Prevalence of vertebral fractures was 18% in women and 31% in men (p = 0.003 for gender difference). In women, age, height loss, glucocorticoid use, history of vertebral and other fractures, and BMD T-score were significantly and independently associated with vertebral fractures. A multivariate model which included above predictors had an area under the receiver operating curve of 0.85 with 95% confidence interval (CI) of 0.81 to 0.89. A risk factor index was derived from the above multivariate model. Using a level of 2 as a cut-off yielded 93% sensitivity (95% CI 87, 96) and 48% specificity (95% CI 69, 83). Assuming a 15% prevalence of vertebral fractures, this cut-off value had a 24% positive and 97% negative predictive value and required VFA scanning of three women at a cost of $60 (assuming a $20 cost/VFA scan) to detect one with vertebral fracture(s). CONCLUSIONS: Selecting patients for VFA can be optimized using an index derived from BMD measurement and easily obtained clinical risk factors.

The relationship of respiratory and cardiovascular hospital admissions to the southern California wildfires of 2003.

OBJECTIVE: There is limited information on the public health impact of wildfires. The relationship of cardiorespiratory hospital admissions (n = 40 856) to wildfire-related particulate matter (PM(2.5)) during catastrophic wildfires in southern California in October 2003 was evaluated. METHODS: Zip code level PM(2.5) concentrations were estimated using spatial interpolations from measured PM(2.5), light extinction, meteorological conditions, and smoke information from MODIS satellite images at 250 m resolution. Generalised estimating equations for Poisson data were used to assess the relationship between daily admissions and PM(2.5), adjusted for weather, fungal spores (associated with asthma), weekend, zip code-level population and sociodemographics. RESULTS: Associations of 2-day average PM(2.5) with respiratory admissions were stronger during than before or after the fires. Average increases of 70 microg/m(3) PM(2.5) during heavy smoke conditions compared with PM(2.5) in the pre-wildfire period were associated with 34% increases in asthma admissions. The strongest wildfire-related PM(2.5) associations were for people ages 65-99 years (10.1% increase per 10 microg/m(3) PM(2.5), 95% CI 3.0% to 17.8%) and ages 0-4 years (8.3%, 95% CI 2.2% to 14.9%) followed by ages 20-64 years (4.1%, 95% CI -0.5% to 9.0%). There were no PM(2.5)-asthma associations in children ages 5-18 years, although their admission rates significantly increased after the fires. Per 10 microg/m(3) wildfire-related PM(2.5), acute bronchitis admissions across all ages increased by 9.6% (95% CI 1.8% to 17.9%), chronic obstructive pulmonary disease admissions for ages 20-64 years by 6.9% (95% CI 0.9% to 13.1%), and pneumonia admissions for ages 5-18 years by 6.4% (95% CI -1.0% to 14.2%). Acute bronchitis and pneumonia admissions also increased after the fires. There was limited evidence of a small impact of wildfire-related PM(2.5) on cardiovascular admissions. CONCLUSIONS: Wildfire-related PM(2.5) led to increased respiratory hospital admissions, especially asthma, suggesting that better preventive measures are required to reduce morbidity among vulnerable populations.

Survival advantage of pediatric recipients of a first kidney transplant among children awaiting kidney transplantation.

The mortality rate in children with ESRD is substantially lower than the rate experienced by adults. However, the risk of death while awaiting kidney transplantation and the impact of transplantation on long-term survival has not been well characterized in the pediatric population. We performed a longitudinal study of 5961 patients under age 19 who were placed on the kidney transplant waiting list in the United States. Of these, 5270 received their first kidney transplant between 1990 and 2003. Survival was assessed via a time-varying nonproportional hazards model adjusted for potential confounders. Transplanted children had a lower mortality rate (13.1 deaths/1000 patient-years) compared to patients on the waiting list (17.6 deaths/1000 patient-years). Within the first 6 months of transplant, there was no significant excess in mortality compared to patients remaining on the waiting list (adjusted Relative Risk (aRR) = 1.01; p = 0.93). After 6 months, the risk of death was significantly lower: at 6-12 months (aRR = 0.37; p < 0.001) and at 30 months (aRR 0.26; p < 0.001). Compared to children who remain on the kidney transplant waiting list, those who receive a transplant have a long-term survival advantage. With the potential for unmeasured bias in this observational data, the results of the analysis should be interpreted conservatively.

Vascular access survival and incidence of revisions: a comparison of prosthetic grafts, simple autogenous fistulas, and venous transposition fistulas from the United States Renal Data System Dialysis Morbidity and Mortality Study.

OBJECTIVE: The study's aim was to evaluate access patency and incidence of revisions in patients initiating hemodialysis and to determine differences in access performance by type of access among patient subgroups. METHODS: The study used data from the United States Renal Data System Dialysis Morbidity and Mortality Study Wave 2, which contained a random sample of dialysis patients initiating dialysis in 1996 and early 1997. Failures and revisions were evaluated among 2247 newly placed hemodialysis accesses by using Cox proportional hazards regression model and Poisson regression. Primary and secondary patency rates were estimated using the Kaplan-Meier method. RESULTS: Fifteen hundred seventy-four prosthetic grafts, 492 simple autogenous fistulas, and 181 venous transposition fistulas were available for evaluation. Prosthetic grafts had a 41% greater risk of primary failure compared with simple fistulas (relative risk, 1.41; 95% CI, 1.22-1.64; P < .001) and a 91% higher incidence of revision (relative risk, 1.91; 95% CI, 1.60-2.28; P <.001). At 2 years, autogenous fistulas demonstrated superior primary patency (39.8% versus 24.6%, P < .001) and equivalent secondary patency (64.3% versus 59.5%, P = .24) compared with prosthetic grafts. When compared with simple fistulas, vein transpositions demonstrated equivalent secondary patency at 2 years (61.5% versus 64.3%, P = .43) but inferior primary patency (27.7% versus 39.8%, P = .008) and had a 32% increased incidence of revision (P = .04). Autogenous fistulas had superior primary patency compared with prosthetic grafts in all patient subgroups except for patients with previously failed access. Vein transpositions showed the greatest benefit in terms of patency and incidence of revision in women and in patients with previously failed access. CONCLUSIONS: The preferential placement of autogenous fistulas may increase primary patency and decrease the incidence of revisions. Vein transpositions had similar secondary patency compared with simple fistulas, but required more revisions. The greatest benefit of a vein transposition fistula was seen in women and in patients with a history of access failure.

Assessment of a policy to reduce placement of prosthetic hemodialysis access.

BACKGROUND: The aim of this study was to evaluate the determinants of access patency and revision, including the effects of reducing the placement of prosthetic hemodialysis access. METHODS: A retrospective cohort study of all hemodialysis accesses placed at the Veteran's Administration Puget Sound Health Care System between 1992 and 1999 was conducted. A policy was instituted in 1996 that maximized the use of autogenous hemodialysis access. The impacts of the policy change, demographics, and comorbid factors on access type and patency, were examined. Primary and secondary patency rates were examined using the Kaplan--Meier method, and factors associated with failure and revision were examined using Cox proportional hazard models and Poisson regression. RESULTS: During the study, 104 accesses (61 prosthetic grafts and 43 autogenous fistulas) were placed prior to 1996, and 118 (31 prosthetic grafts and 87 autogenous fistulas) were placed after 1996. There was a significant increase in autogenous fistulas placed after 1996 (87 out of 118) compared with before 1996 (43 out of 104, P < 0.001). At one year, autogenous fistulas demonstrated superior primary patency (56 vs. 36%, P = 0.001) and secondary patency (72 vs. 58%, P = 0.003) compared with prosthetic grafts. After adjustment for age, race, side of access placement, and history of prior access placement, patients with a prosthetic graft were estimated to experience a 78% increase in the risk of primary access failure when compared with similar patients having an autogenous access [adjusted relative risk (aRR) = 1.78, 95% CI 1.21--2.62, P = 0.003)]. Similarly, the adjusted relative risk of secondary access failure for comparing prosthetic grafts with autogenous fistulas was estimated to be 2.21 (95% CI 1.38--3.54, P = 0.001). The adjusted risk of access revision was 2.89-fold higher for prosthetic grafts than for autogenous fistulas (95% CI 1.88--4.44, P < 0.001). CONCLUSIONS: Autogenous conduits demonstrated superior performance when compared with prosthetic grafts in terms of primary and secondary patency and number of revisions. A policy emphasizing the preferential placement of autogenous fistulas over prosthetic grafts may result in improved patency and a reduction in the number of procedures required to maintain dialysis access patency.

Risk factors for hip fracture among patients with end-stage renal disease.

BACKGROUND: Although bone disease is well described among end-stage renal disease (ESRD) patients, little attention has been paid to the occurrence of fracture. We sought to identify factors that are associated with hip fracture among ESRD patients. METHODS: Data from patients who participated in the United States Renal Data System Dialysis Morbidity and Mortality Study Wave 1 were used for this study. Hip fractures occurring among these patients between 1993 and 1996 were identified from Medicare claims data available from the United States Renal Data System. Cox proportional hazards models were used to estimate the risk of hip fracture associated with demographic and medical variables. RESULTS: Of the 4952 patients included in this analysis, 103 sustained a hip fracture. In the multivariate analysis, age (per increasing decade, RR = 1.40, 95% CI 1.20, 1.64), female gender (RR = 2.26, 95% CI 1.48, 3.44), race (blacks compared with whites, RR = 0.58, 95% CI 0.37, 0.91), body mass index (per 1 unit increase, RR 0.89, 95% CI 0.86, 0.93), and the presence of peripheral vascular disease (RR 1.94, 95% CI 1.29, 2.92) were independently associated with hip fracture. Serum intact parathyroid hormone (iPTH), aluminum, diabetes, and bicarbonate levels did not appreciably influence the risk of hip fracture. CONCLUSIONS: Demographic and other characteristics that predict risk of hip fracture in the population at large also do so in ESRD patients. However, we could identify no characteristics of ESRD or its treatment that were independently related to hip fracture incidence.

Anthropometric measures and risk of death in children with end-stage renal disease.

We evaluated the association between anthropometric measurements and death among pediatric patients with end-stage renal disease (ESRD) using data from the Pediatric Growth and Development Special Study (PGDSS) from the US Renal Data System. Height, growth velocity, and body mass index (BMI) were used for the analysis of 1,949 patients in the PGDSS. To standardize these measurements, SD scores (SDSs) were calculated using population data from the Third National Health and Nutrition Examination Survey. Using Cox proportional hazards models, we assessed the association between anthropometric measures and death, controlling for demographic factors and stratifying by age. Multivariate analysis showed that each decrease by 1 SDS in height was associated with a 14% increase in risk for death (adjusted relative risk [aRR], 1.14; 95% confidence interval [CI], 1.02 to 1.27; P = 0.017). For each 1 SDS decrease in growth velocity among patients in our sample, the risk for death increased by 12% (aRR, 1.12; 95% CI, 1.00 to 1.25; P = 0.043). There was a statistically significant U-shaped association between BMI and death (P = 0.001), with relatively low and high BMIs associated with an increased risk for death. In children with ESRD, growth delay and extremes in BMI are associated with an increased risk for mortality.

Increased risk of hip fracture among patients with end-stage renal disease.

BACKGROUND: Although patients with end-stage renal disease (ESRD) are at increased risk for bone loss, the risk of hip fracture in this population is not known. We compared the risk of hip fracture among dialysis patients with the general population. METHODS: We used data from the United States Renal Data System (USRDS) to identify all new Caucasian dialysis patients who began dialysis between January 1, 1989, and December 31, 1996. All hip fractures occurring during this time period were ascertained. The observed number of hip fractures was compared with the expected number based on the experience of residents of Olmstead County (MN, USA). Standardized incidence ratios were calculated as the ratio between observed and expected. The risk attributable to ESRD was calculated as the difference between the observed and expected rate of hip fracture per 1000 person-years. RESULTS: The number of dialysis patients was 326,464 (55.9% male and 44.1% female). There were 6542 hip fractures observed during the follow-up period of 643, 831 patient years. The overall incidence of hip fracture was 7.45 per 1000 person years for males and 13.63 per 1000 person years for females. The overall relative risk for hip fracture was 4.44 (95% CI, 4.16 to 4.75) for male dialysis patients and 4.40 (95% CI, 4.17 to 4.64) for female dialysis patients compared with people of the same sex in the general population. While the age-specific relative risk of hip fracture was highest in the youngest age groups, the added risks of fracture associated with dialysis rose steadily with increasing age. The relative risk of hip fracture increased as time since first dialysis increased. CONCLUSIONS: The overall risk of hip fracture among Caucasian patients with ESRD is considerably higher than in the general population, independent of age and gender.