Exercise: Just What the Doctor Ordered, But Why? Elucidating Mechanisms for Women's Increased High-Density Lipoprotein Benefit From Exercise and for the Health ABC Study.

High-density lipoprotein (HDL) is protective against cardiovascular disease. Exercise can increase HDL concentration, and some evidence suggests that this effect occurs more strongly in women than in men. Both HDL and exercise are associated with inflammation. We hypothesized a sex-by-exercise interaction on HDL level, whereby women would benefit from exercise more strongly than men, and tumor necrosis factor alpha and serum soluble tumor necrosis factor receptor-2 would mediate this relationship. This study included 2,957 older adult participants (1,520 women; 41% Black, 59% White; 73.6-years-old) from the Health, Aging, and Body Composition study. Regression models revealed a positive exercise-HDL relationship in women only (sex-by-exercise interaction: ß = 0.09, p = .013; exercise on HDL in women: ß = 0.07, p = .015), mediated by TNFα (axb = 0.15; CI: 0.01, 0.30), suggesting that exercise may increase HDL levels in women through reduced inflammation. Given that vascular risk contributes to Alzheimer's disease risk, findings have implications for sex differences in AD risk factors.

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment.

The locus coeruleus is the initial site of Alzheimer's disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer's pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer's disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer's disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-ß42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-ß42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer's disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer's disease progression.

NPTX2 and cognitive dysfunction in Alzheimer's Disease.

Memory loss in Alzheimer's disease (AD) is attributed to pervasive weakening and loss of synapses. Here, we present findings supporting a special role for excitatory synapses connecting pyramidal neurons of the hippocampus and cortex with fast-spiking parvalbumin (PV) interneurons that control network excitability and rhythmicity. Excitatory synapses on PV interneurons are dependent on the AMPA receptor subunit GluA4, which is regulated by presynaptic expression of the synaptogenic immediate early gene NPTX2 by pyramidal neurons. In a mouse model of AD amyloidosis, Nptx2-/- results in reduced GluA4 expression, disrupted rhythmicity, and increased pyramidal neuron excitability. Postmortem human AD cortex shows profound reductions of NPTX2 and coordinate reductions of GluA4. NPTX2 in human CSF is reduced in subjects with AD and shows robust correlations with cognitive performance and hippocampal volume. These findings implicate failure of adaptive control of pyramidal neuron-PV circuits as a pathophysiological mechanism contributing to cognitive failure in AD.

Smoking prevalence in urban and rural populations: findings from California between 2001 and 2012.

BACKGROUND: Tobacco smoking and related health problems are still major public health concerns in the United States despite the declining smoking prevalence. OBJECTIVES: This study explored differences in smoking prevalence between urban and rural areas potentially relevant to tobacco control efforts in California. METHODS: Public use adult smoking data from the California Health Interview Survey (CHIS) between 2001 and 2011-2012 were analyzed. A total of 282 931 adults were surveyed across the six CHIS cycles. A ZIP code-based geographic classification (Urban, Second-City, Suburban, and Town/Rural) was used to examine the association between smoking prevalence and area of residency. RESULTS: The overall smoking prevalence in California decreased from 17.0% in 2001 to 13.8% in 2011-2012. Within each CHIS cycle, the Town/Rural areas had the highest smoking prevalence, followed by Urban and Second-City areas, and Suburban areas had the lowest. Pooled data from all CHIS cycles showed a similar pattern, with rates in Urban, Second-City, Suburban and Town/Rural areas being 15.2%, 15.2%, 13.1% and 17.3%, respectively. Weighted multivariate logistic regression analysis indicated significantly higher odds of smoking in Urban, Second-City and Town/Rural areas compared to Suburban areas (all adjusted odds ratios > 1.10), although this trend varied by race/ethnicity, being present in non-Hispanic Whites and not present in Hispanics. CONCLUSIONS: Town/Rural and Urban populations of California are consistently at higher risk of smoking than Suburban populations. These results indicate a need for population-specific tobacco control approaches that address the lifestyle, behavior, and education of disparate populations within the same state or region.

The differential associations of preexisting conditions with trauma-related outcomes in the presence of competing risks.

INTRODUCTION: Pre-existing chronic conditions (PECs) pose a unique problem for the care of aging trauma populations. However, the relationships between specific conditions and outcomes after injury are relatively unknown. Evaluation of trauma patients is further complicated by their discharge to care facilities, where mortality risk remains high. Traditional approaches for evaluating in-hospital mortality do not account for the discharge of at-risk patients, which constitutes a competing risk event to death. The objective of this study was to evaluate associations between 40 PECs and two clinical outcomes in the context of competing risks among older trauma patients. METHODS: This retrospective study evaluated blunt-injured patients aged 55 years and older admitted to a level I trauma centre in 2006-2012. Outcomes were hospital length of stay (HLOS) and in-hospital mortality. Survivors were classified as discharges home or discharges to care facilities. Competing risks regression was used to evaluate each PEC with in-hospital mortality, accounting for discharges to care facilities as competing events. Competing risk estimates were compared to Cox model estimates, for which all survivors to discharge were non-events. Analyses were stratified using injury-based mortality risk at a 50% cutpoint (high versus low). RESULTS: Among 4653 patients, 176 died in-hospital, 3059 were discharged home, and 1418 were discharged to a care facility. Most patients (98%) were classified with a low mortality risk. Only haemophilia and coagulopathy were consistently associated with longer HLOS. In the low-risk subgroup, in-hospital mortality was most strongly associated with liver diseases, haemophilia, and coagulopathy. In the high-risk group, Parkinson's disease, depression, and cancers showed the strongest associations. Accounting for the competing event altered estimates for 12 of 19 significant conditions. CONCLUSIONS: Excess mortality among patients expected to survive their injuries may be attributable to complications resulting from PECs. Discharges to care facilities constitute a bias in the evaluation of in-hospital mortality and should be considered for the accurate calculation of risk. In conjunction with injury measures, consideration of PECs provides physicians with a foundation to plan clinical decisions in older trauma patients.

Pulse pressure in relation to tau-mediated neurodegeneration, cerebral amyloidosis, and progression to dementia in very old adults.

IMPORTANCE: Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear. OBJECTIVES: To determine the relationship between pulse pressure and cerebral spinal fluid biomarker profiles of preclinical Alzheimer disease, investigate whether observed relationships are stronger in adults with more advanced arterial age (≥80 years of age), and examine the relationship between pulse pressure and progression to dementia. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, 877 participants without dementia (55-91 years of age) from the Alzheimer's Disease Neuroimaging Initiative underwent baseline health assessment, including blood pressure assessment and lumbar puncture for determination of cerebral spinal fluid phosphorylated tau (P-tau) and ß-amyloid 1-42. Participants have been followed up longitudinally since 2005. The last date of examination was October 15, 2013. Clinical follow-up between 6 and 96 months tracked progression to dementia. MAIN OUTCOMES AND MEASURES: Regression and analysis of covariance analyses investigated relationships between pulse pressure and distinct cerebral spinal fluid biomarker profiles. Very old participants (80 years or older) were compared with younger participants (55-79 years of age) on clinical measures and pulse pressure × age group interactions were investigated. Survival analysis examined the effect of baseline pulse pressure on progression to dementia. Covariates were age, sex, apolipoprotein E genotype, body mass index, vascular risk factors, and antihypertensive medication use. RESULTS: Individuals with a P-tau-positive biomarker profile exhibited mean (SD) elevated pulse pressure regardless of age (62.0 [15.6] mm Hg for a P-tau-positive biomarker vs 57.4 [14.0] mm Hg for P-tau-negative biomarker; P = .04). In very old participants, a further increase in pulse pressure was observed in those exhibiting both P-tau elevation and ß-amyloid 1-42 reduction vs either biomarkers alone (69.7 [16.0] mm Hg for both positive biomarkers vs 63.18 [13.0] mm Hg for P-tau alone vs 60.1 [16.4] mm Hg for ß-amyloid 1-42 alone vs 56.6 [14.5] mm Hg for negative biomarkers; P = .003). Those with higher baseline pulse pressure progressed to dementia more rapidly (95% CI, 1.000-1.048; P = .05; hazard ratio = 1.024). Systolic pressure exhibited similar relationships with Alzheimer disease biomarkers and progression to dementia in the very old subgroup (P < .05) but showed no associations in the young old subgroup (P > .10). Diastolic pressure was reduced in young old participants with isolated phosphorylated tau elevation (P = .04). CONCLUSIONS AND RELEVANCE: Pulse pressure, an index of vascular aging, was associated with neurodegenerative change prior to the onset of dementia across a broad age range. Among those with more advanced age, higher pulse pressure was also associated with cerebral amyloidosis in the presence of neurodegeneration and more rapid progression to dementia. Diastolic contributions to these biomarker associations were limited to young old participants whereas systolic contributions were found only in very old participants.

Smokers who report smoking but do not consider themselves smokers: a phenomenon in need of further attention.

BACKGROUND: Heightened stigma surrounding the action of smoking may decrease the likelihood that individuals who engage in smoking identify with the label 'smoker'. Non-identifying smokers (NIS) may undermine accurate smoking prevalence estimates and can be overlooked by tobacco control efforts. OBJECTIVE: We sought to characterise NIS in a cross-sectional study using a sample representative of the population of adults (>18 years) in California who reported smoking at least 100 cigarettes in their lifetime, smoking at least some days and at least once in the last 30 days (n=1698). Individuals were considered NIS if they met the above criteria and answered 'no' when asked if they 'considered themselves a smoker'. RESULTS: We estimate that 395 928 (SD=54 126) NIS were living in California in 2011 (a prevalence of 12.3% of all smokers in California). The odds of being NIS were higher among non-daily smokers who were previously daily smokers (adjusted OR (AOR)=7.63, 95% CI 2.67 to 21.8) or were never previously daily smokers (AOR=7.14, CI 2.78 to 18.3) compared with daily smokers. The odds of being an NIS were also higher among those who did not believe they were addicted to cigarettes (AOR=3.84, CI 1.68 to 9.22), were older than 65 years (vs less than 45 years) (AOR=3.35, CI 1.16 to 9.75) or were from ethnic minorities including Black and Asian (vs non-Hispanic white) (AOR=3.16, CI 1.19 to 8.49). CONCLUSIONS: Smoking surveillance should restructure selection criteria to more accurately account for NIS in areas with high stigma toward smokers. Targeted interventions may be needed for NIS including educating healthcare providers to enquire more deeply into smoking habits.

Smoking ban policies and their influence on smoking behaviors among current California smokers: a population-based study.

OBJECTIVE: To assess whether smoking ban policies are associated with smoking reduction and quit attempts among California smokers. METHODS: Data were examined for 1718 current smokers from follow-up telephone interviews conducted in 2011 of persons previously identified as smokers in a representative sample of the adult population of California. Population weighted logistic regressions controlling for demographic and other variables were used to evaluate the association between smoking ban policies (home, work, and town) and changes in tobacco use (past year quit attempt or reduction in smoking rate). RESULTS: Living in a home with a total ban was significantly associated with smoking reduction (adjusted odds ratio, AOR: 2.4, 95% CI: 1.4-4.2) and making a quit attempt (AOR: 2.3, 95% CI: 1.3-3.9) compared to living in a home with no home ban. Self-reported perception of an outdoor ban in one's city/town was associated with smoking reduction (AOR: 1.7, 95% CI: 1.02-2.7) and making a quit attempt (AOR: 1.8, 95% CI: 1.05-2.9). CONCLUSION: These results indicate that smoking bans not only protect nonsmokers from the harms of secondhand smoke, but are also associated with smoking reduction and cessation.

Cigarette smoking initiation during college predicts future alcohol involvement: a matched-samples study.

OBJECTIVE: Little is known about the relationship between cigarette smoking initiation and subsequent alcohol involvement. To address this question, the present study compared alcohol use between students who initiated smoking during college and a matched sample of never-smoking students. We hypothesized greater increases in alcohol involvement among smoking initiators, mediated by exposure to cigarette use situations. METHOD: Included in the present study were 104 Chinese American and Korean American undergraduates who at baseline (freshman year) reported never having smoked a cigarette. Subjects were drawn from 433 participants in a naturalistic longitudinal study of tobacco use who were assessed annually each year in college. Cigarette smoking status was assessed annually as part of a structured interview. Initiators and never-smokers were matched on gender, ethnicity, baseline alcohol use, parental smoking status, and behavioral undercontrol. RESULTS: As predicted, participants who initiated smoking during college reported significantly greater increases in the number of past-30-day total drinks consumed (p < .001) and reported greater prevalence of heavy drinking episodes (p < .05). The effect of smoking initiation on the change in the number of past-30-day drinks at the final assessment was partially mediated by exposure to smoking (p < .05). Exploratory analyses indicated that greater recent smoking significantly predicted increased alcohol consumption over and above the effect of exposure. CONCLUSIONS: Students who initiate smoking during college appear at risk for increased alcohol involvement. Part of this risk is explained by environmental contextual factors, specifically exposure to situations involving other smokers that also may result in greater exposure to alcohol use.

Pulse pressure is associated with Alzheimer biomarkers in cognitively normal older adults.

OBJECTIVE: The current study examined the association between pulse pressure (PP) and CSF-based biomarkers for Alzheimer disease, including ß-amyloid 1-42 (Aß1-42) and phosphorylated tau (P-tau) protein, in cognitively normal older adults. METHODS: One hundred seventy-seven cognitively normal, stroke-free older adult participants (aged 55-100 years) underwent blood pressure assessment for determination of PP (systolic - diastolic blood pressure) and lumbar puncture for measurement of CSF Aß1-42 and P-tau. Pearson correlations and multiple linear regression, controlling for age, sex, APOE genotype, and body mass index, evaluated the relationship between PP and Alzheimer disease biomarkers. RESULTS: PP elevation was associated with increased P-tau (r = 0.23, p = 0.002), reduced Aß1-42 (r = -0.19, p = 0.01), and increased P-tau to Aß1-42 ratio (r = 0.27, p < 0.001). After controlling for covariates, PP remained associated with P-tau (ß = 0.18, p = 0.0196) and P-tau to Aß1-42 ratio (ß = 0.0016, p < 0.001) but was no longer associated with Aß1-42 (ß = -0.1, p = 0.35). Post hoc multivariate analyses indicated that increased PP was associated with all biomarkers in younger participants (aged 55-70 years) (Aß1-42: p = 0.050; P-tau: p = 0.003; P-tau to Aß ratio: p = 0.0007) but not older participants (aged 70-100 years). CONCLUSIONS: PP elevation is associated with increased CSF P-tau and decreased Aß1-42 in cognitively normal older adults, suggesting that pulsatile hemodynamics may be related to amyloidosis and tau-related neurodegeneration. The relationship between PP and CSF biomarkers is age-dependent and observed only in participants in the fifth and sixth decades of life.

Perceived price sensitivity by ethnicity and smoking frequency among California Hispanic and non-Hispanic white smokers.

OBJECTIVES: Little is currently known about price sensitivity across ethnic groups as well as for non-daily smokers. To address this issue, this study compared perceived price sensitivity across smoking status (daily and non-daily) and within ethnicity (Hispanic and non-Hispanic White) in a recent representative population survey of California smokers. METHODS: This study employed data from the 2008 California Tobacco Survey (CTS), a large population-based random-digit-dialed telephone survey. Participants were 1,777 non-Hispanic White and 450 Hispanic respondents who had smoked at least 100 cigarettes and currently smoked daily or on some days. RESULTS: Differences in perceived price sensitivity were found by ethnicity when controlling for age, gender, and cigarette consumption. Comparisons across ethnic groups indicated that Hispanic smokers, in general, have more price-sensitive perceptions than non-Hispanic White smokers. However, daily versus non-daily status had no effect on price sensitivity when controlling for cigarette quantity. CONCLUSIONS: These findings indicate that pricing increases may be differentially influential for Hispanic compared with non-Hispanic White smokers across smoking status categories.

Increasing hookah use in California.

Hookah use is gaining popularity nationwide. We determined the correlates and trends for hookah use from the California Tobacco Survey. Between 2005 and 2008 hookah use increased more than 40%, and in 2008, 24.5% of young men reported ever using a hookah. Hookah use was more common among the young (18-24 years), the educated, the non-Hispanic Whites, and the cigarette smokers. Hookah use is increasing in California, especially among young adults, and in 2008 reached the highest prevalence ever reported for both genders.

Determinants of hookah use among high school students.

INTRODUCTION: Hookah use is increasing among young people, but there are limited data on its use among high school-age populations. We examined hookah use initiation, prevalence, cessation, and psychosocial risk factors of hookah use among high school students. METHODS: A cross-sectional survey of 689 students from three high schools in San Diego County was used to compare characteristics of hookah ever-users to nonusers and factors associated with current and former hookah use. RESULTS: Hookah ever-use in the study population was 26.1%, previous month hookah use was 10.9%, and current hookah use was 10.3%. Most students first learned about hookah from friends (50.3%) or saw a hookah lounge (20.9%). Students believed hookah to be more socially acceptable than cigarettes and less harmful than cigarettes, cigars, and smokeless tobacco. Hookah ever-users were significantly more likely than nonusers to have smoked cigarettes, to know of a hookah lounge in their community, and to believe hookah is safer and more socially acceptable than cigarettes. In comparison to former users, current users were more likely to have recently smoked a cigarette, to know of a hookah lounge in their community, and to believe hookah is more socially acceptable than cigarettes. CONCLUSIONS: Hookah use is becoming a commonly acceptable behavior among adolescents, and risk perception is a significant factor. Presence of hookah lounges are associated with increased hookah use among high school students and should be a target of further regulation.

ADCS Prevention Instrument Project: pharmacoeconomics: assessing health-related resource use among healthy elderly.

BACKGROUND: The Prevention Instrument project of the Alzheimer's Disease Cooperative Study (ADCS) seeks to develop instruments to assess treatment efficacy including potential economic benefit. The Resource Use Inventory (RUI) is an instrument that has been used to capture resource utilization and costs in populations with Alzheimer disease (AD). However, resource utilization and costs for healthy, cognitively intact elderly as they begin to demonstrate cognitive deterioration are not well understood. In addition, the loss that relates to the subjects' own time as they transition through cognitive impairment is not well documented. OBJECTIVES: To evaluate the utility of the RUI in a sample of cognitively intact elderly individuals living in the community and enrolled in AD prevention trials. METHODS: The RUI was administered to 644 subjects and their study partners either at home or in the clinic. For half of each sample, 3-month retesting was carried out. The RUI consisted of 9 questions. The first part of the RUI captured subjects' use of direct medical care (eg, hospitalizations) and nonmedical care (eg, home health aides). The second part of the RUI captured the time caregivers spend providing care to the subjects. The third part of the RUI captured subjects' participation in volunteer work and employment. The assessment interval for each question was the past 3 months. RESULTS: The percentage of RUI forms returned incomplete or inaccurate for both in-clinic and at-home groups was extremely low. There were no differences in utilization rates between in-clinic and at-home group for all items in the RUI. Except for use of outpatient procedures, tests, or treatments, there were no differences in utilization rates between subjects who filled out the RUI with the help of their study partners or by themselves. Items in the RUI were sensitive to subjects' cognitive and functional status and demographic characteristics. CONCLUSIONS: Home-based completion of the RUI by participants in an AD prevention study is feasible, and seems to provide data that are reliable and valid. The instrument will be useful for tracking resource and time use through transition from healthy to cognitive impairment.

Incidence and causes of nondegenerative nonvascular dementia: a population-based study.

BACKGROUND: Information on the incidence of nondegenerative and nonvascular dementia is limited. DESIGN: We used the records-linkage system of the Rochester Epidemiology Project to ascertain incident cases of dementia in Rochester, Minn, from January 1, 1990, through December 31, 1994. To define causes of dementia, we reviewed all diagnoses, imaging study results, laboratory test results, and clinical courses, as recorded historically in the patient dossier. RESULTS: We found 560 incident cases of dementia, and 60 of them (10.7%) had onset before the age of 70 years (younger-onset group). Forty-three cases (7.7%) were due to nondegenerative nonvascular causes and represented 30.0% of the total in the younger-onset group, but only 5.0% of the total in the older-onset group (aged 70-99 years). The most common nondegenerative nonvascular causes were cancer with or without brain metastases (n = 13), chronic alcoholism (n = 7), and chronic mental illness (n = 11). There were no cases of dementia due to normal-pressure hydrocephalus, subdural hematoma, hypothyroidism, vitamin B12 deficiency, or neurosyphilis. There were 2 individuals with acute confusion due to subdural hematoma and 1 with hypothyroidism whose cognition normalized with therapy. CONCLUSIONS: Nondegenerative nonvascular causes were more common than expected in patients with a younger onset of dementia. None of the patients with dementia reverted to normal with treatment of the putative reversible cause.