Vascular risk factors, cerebrovascular reactivity, and the default-mode brain network.

Cumulating evidence from epidemiologic studies implicates cardiovascular health and cerebrovascular function in several brain diseases in late life. We examined vascular risk factors with respect to a cerebrovascular measure of brain functioning in subjects in mid-life, which could represent a marker of brain changes in later life. Breath-hold functional MRI (fMRI) was performed in 541 women and men (mean age 50.4 years) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Cerebrovascular reactivity (CVR) was quantified as percentage change in blood-oxygen level dependent (BOLD) signal in activated voxels, which was mapped to a common brain template and log-transformed. Mean CVR was calculated for anatomic regions underlying the default-mode network (DMN) - a network implicated in AD and other brain disorders - in addition to areas considered to be relatively spared in the disease (e.g. occipital lobe), which were utilized as reference regions. Mean CVR was significantly reduced in the posterior cingulate/precuneus (ß=-0.063, 95% CI: -0.106, -0.020), anterior cingulate (ß=-0.055, 95% CI: -0.101, -0.010), and medial frontal lobe (ß=-0.050, 95% CI: -0.092, -0.008) relative to mean CVR in the occipital lobe, after adjustment for age, sex, race, education, and smoking status, in subjects with pre-hypertension/hypertension compared to normotensive subjects. By contrast, mean CVR was lower, but not significantly, in the inferior parietal lobe (ß=-0.024, 95% CI: -0.062, 0.014) and the hippocampus (ß=-0.006, 95% CI: -0.062, 0.050) relative to mean CVR in the occipital lobe. Similar results were observed in subjects with diabetes and dyslipidemia compared to those without these conditions, though the differences were non-significant. Reduced CVR may represent diminished vascular functionality for the DMN for individuals with prehypertension/hypertension in mid-life, and may serve as a preclinical marker for brain dysfunction in later life.

Randomized, controlled clinical trial of acoustic stimulation to reduce postconcussive symptoms.

OBJECTIVE: Effective interventions are needed to address postconcussive symptoms. We report the results of randomized, sham-controlled trial of Cereset Research™ Standard Operating Procedures (CR-SOP), a noninvasive, closed-loop, allostatic, acoustic stimulation neurotechnology previously shown to improve insomnia. METHODS: Military service members, veterans, or their spouses with persistent symptoms (Neurobehavioral Symptom Inventory [NSI] Score ≥23) after mTBI 3 months to 10 years ago, were randomized to receive 10 sessions of engineered tones linked to brainwaves (LB, intervention), or random engineered tones not linked to brainwaves (NL, sham control). The primary outcome was change in NSI, with secondary outcomes of heart rate variability and self-report measures of sleep, mood, and anxiety. RESULTS: Participants (n = 106, 22% female, mean age 37.1, 2.8 deployments, 3.8 TBIs) were randomized 1:1 to LB or NL, with no significant differences between groups at baseline. Among all study participants, the NSI declined from baseline 41.0 to 27.2 after (P < 0.0001), with gains largely sustained at 3 months (31.2) and 6 months (28.4). However, there were no significant differences between the LB (NSI declined from 39.9 at baseline to 28.2 post-intervention, 31.5 at 3 months, and 29.4 at 6 months) and NL (NSI declined from 41.5 at baseline to 26.2, 29.9, and 27.3, respectively. Similar patterns were observed for the PCL5 and PHQ-9 and there was no difference in HRV between groups. INTERPRETATION: Ten hours of acoustic stimulation while resting in a zero-gravity chair improves postconcussive symptoms. However, linking tones to brain electrical activity did not reduce symptoms more than random tones. REGISTRATION: ClinicalTrials.gov - NCT03649958.

Internet-Guided Cognitive Behavioral Therapy for Insomnia Among Patients With Traumatic Brain Injury: A Randomized Clinical Trial.

Importance: Many military service members and veterans report insomnia after sustaining traumatic brain injury (TBI). Limitations of first-line treatment, cognitive-behavioral therapy for insomnia (CBT-I), include availability of qualified clinicians, low completion rates, and cost. Objective: To investigate the feasibility and efficacy of internet-guided CBT-I (eCBT-I) in military service members and veterans with insomnia and a history of TBI. Design, Setting, and Participants: This randomized clinical trial of fully remote internet-based interventions and evaluations was conducted from September 1, 2020, to June 30, 2021, with 3 months of follow-up. Participants included a volunteer sample of military service members and veterans aged 18 to 64 years with a history of mild TBI/concussion and at least moderately severe insomnia defined as an insomnia severity index (ISI) score of greater than 14 and Pittsburgh Sleep Quality Index of greater than 4. Self-reported race, ethnicity, and educational level were generally representative of the US military. Data were analyzed from October 21, 2021, to April 29, 2024. Intervention: Internet-based CBT-I delivered over 6 weekly lesson modules with assigned homework activities. Main Outcomes and Measures: The prespecified primary outcome measure was change in ISI score over time. Prespecified secondary outcome measures included self-reported measures of depression symptoms, posttraumatic stress disorder (PTSD) symptoms, sleep quality, migraine impact, and fatigue. Results: Of 204 people screened, 125 were randomized 3:1 to eCBT-I vs online sleep education, and 106 completed baseline evaluations (83 men [78.3%]; mean [SD] age, 42 [12] years). Of these, 22 participants (20.8%) were Hispanic or Latino and 78 (73.6%) were White. Fifty participants completed postintervention evaluations, and 41 completed the 3-month follow-up. Baseline mean (SD) ISI scores were 19.7 (4.0) in those randomized to eCBT-I and 18.9 (5.0) in those randomized to sleep education. After intervention, mean (SD) ISI scores were 13.7 (5.6) in those randomized to eCBT-I and 16.6 (5.7) in those randomized to sleep education. The difference in the extent of reduction in ISI scores between groups was 3.5 (95% CI,-6.5 to -0.4 [P = .03]; Cohen d, -0.32 [95% CI, -0.70 to -0.04]). In the eCBT-I group, the extent of insomnia improvement correlated with the extent of depressive symptom improvement (Spearman ρ = 0.68 [P < .001]), PTSD symptoms (ρ = 0.36 [P = .04]), sleep quality (ρ = 0.54 [P = .001]), and fatigue impact (ρ = -0.58 [P < .001]) but not migraine-related disability. Conclusions and Relevance: The findings of this randomized clinical trial suggest that fully remote eCBT-I was moderately feasible and effective for self-reported insomnia and depression symptoms in military service members and veterans with a history of TBI. There is great potential benefit for eCBT-I due to low availability and cost of qualified CBT-I clinicians, although optimization of completion rates remains a challenge. Future studies may use home-based objective sleep assessments and should increase study retention. Trial Registration: ClinicalTrials.gov Identifier: NCT04377009.

Associations between respiratory illnesses and secondhand smoke exposure in flight attendants: A cross-sectional analysis of the Flight Attendant Medical Research Institute Survey.

ABSTRACT: BACKGROUND: Secondhand tobacco smoke (SHS) is associated with increased risk of respiratory illness, cancer, and cardiovascular disease. Prior to smoking bans on airlines in the late 1980s, flight attendants were exposed to a significant amount of SHS. In the present study, we examine associations between flight attendant SHS exposure and development of respiratory illnesses and cardiovascular disease. METHODS: Between December 2006 and October 2010, three hundred sixty-two flight attendants completed an online questionnaire with information regarding experience as a flight attendant, medical history, smoking history, and SHS exposure. Rates of illnesses in flight attendants were compared with an age and smoking history matched population sample from NHANES 2005-2006. Logistic regression analysis was used to examine the association of reported medical conditions and pre-ban years of exposure. RESULTS: Compared with the sample from NHANES 2005-2006, flight attendants had increased prevalence of chronic bronchitis (11.7% vs. 7.2%, p < 0.05), emphysema/COPD (3.2% vs. 0.9%, p < 0.03), and sinus problems (31.5% vs. 20.9%, p < 0.002), despite a lower prevalence of medical illnesses including high blood pressure, diabetes, high cholesterol, heart failure, cancer, and thyroid disease. Amongst flight attendants who reported never smoking over their lifetimes, there was not a significant association between years of service as a flight attendant in the pre-smoking ban era and illnesses. However, in this same group, there was a significantly increased risk of daily symptoms (vs. no symptoms) of nasal congestion, throat, or eye irritation per 10-year increase of years of service as a flight attendant prior to the smoking ban (OR 2.14, 95% CI 1.41 - 3.24). CONCLUSIONS: Flight attendants experience increased rates of respiratory illnesses compared to a population sample. The frequency of symptoms of nasal congestion, throat or eye irritation is associated with occupational SHS exposure in the pre-smoking ban era.

Secondhand smoke, vascular disease, and dementia incidence: findings from the cardiovascular health cognition study.

Recent studies have found that smoking is associated with an increased risk of dementia, but the effects of secondhand smoke (SHS) on dementia risk are not known to have previously been studied. The authors used Cox proportional hazards marginal structural models to examine the association between self-reported lifetime household SHS exposure and risk of incident dementia over 6 years among 970 US participants in the Cardiovascular Health Cognition Study (performed from 1991 to 1999) who were never smokers and were free of clinical cardiovascular disease (CVD), dementia, and mild cognitive impairment at baseline. In addition, because prior studies have found that SHS is associated with increased risk of CVD and that CVD is associated with increased risk of dementia, the authors tested for interactions between SHS and measures of clinical and subclinical CVD on dementia risk. Moderate (16-25 years) and high (>25 years) SHS exposure levels were not independently associated with dementia risk; however, subjects with >25 years of SHS exposure and >25% carotid artery stenosis had a 3-fold increase (hazard ratio = 3.00, 95% confidence interval: 1.03, 9.72) in dementia risk compared with subjects with no/low (0-15 years) SHS exposure and < or =25% carotid artery stenosis. High lifetime SHS exposure may increase the risk of dementia in elderly with undiagnosed CVD.

A cross-validation deletion-substitution-addition model selection algorithm: Application to marginal structural models.

The cross-validation deletion-substitution-addition (cvDSA) algorithm is based on data-adaptive estimation methodology to select and estimate marginal structural models (MSMs) for point treatment studies as well as models for conditional means where the outcome is continuous or binary. The algorithm builds and selects models based on user-defined criteria for model selection, and utilizes a loss function-based estimation procedure to distinguish between different model fits. In addition, the algorithm selects models based on cross-validation methodology to avoid "over-fitting" data. The cvDSA routine is an R software package available for download. An alternative R-package (DSA) based on the same principles as the cvDSA routine (i.e., cross-validation, loss function), but one that is faster and with additional refinements for selection and estimation of conditional means, is also available for download. Analyses of real and simulated data were conducted to demonstrate the use of these algorithms, and to compare MSMs where the causal effects were assumed (i.e., investigator-defined), with MSMs selected by the cvDSA. The package was used also to select models for the nuisance parameter (treatment) model to estimate the MSM parameters with inverse-probability of treatment weight (IPTW) estimation. Other estimation procedures (i.e., G-computation and double robust IPTW) are available also with the package.

Secondhand smoke exposure, pulmonary function, and cardiovascular mortality.

PURPOSE: Cardiovascular disease and obstructive lung disease are leading global causes of death. Despite this, the impact of secondhand smoke (SHS) exposure on pulmonary function and cardiovascular disease remains uncertain. Our goal was to elucidate the association between baseline SHS exposure and the risk of lung function decline and cardiovascular mortality over a period of nearly a decade. METHODS: We used data from a longitudinal cohort study of 1,057 older adults to study the association between baseline SHS exposure and the risk of lung function decline and cardiovascular mortality. The effect of SHS exposure on cardiovascular mortality may be mediated by its influence on FEV1 and biological processes captured by measurement of FEV1. Alternatively, the effect of SHS may be mediated by baseline cardiovascular disease status, which reflects the combined effects of traditional cardiovascular risk factors. To correctly estimate the effect of SHS and FEV1 on cardiovascular mortality, we used marginal structural models (MSMs) that took into account the mediating effects of FEV1 and baseline cardiovascular disease in the causal pathway. RESULTS: In longitudinal multivariate analyses, lifetime cumulative home and work SHS exposure were associated with a greater decline of FEV1 (-15 mL/s; 95% CI, -29 to -1.3 mL/s and -41 mL/s; 95% CI, -55 to -28 mL/s per 10-year cumulative exposure, respectively). Lifetime home SHS exposure was associated with a greater risk of cardiovascular mortality in both conventional multivariate analysis (HR, 1.10 per 10 years of exposure; 95% CI, 0.99 to 1.24) and the MSM for FEV1 (HR, 1.06; 95% CI, 0.95 to 1.19) and baseline cardiovascular disease (HR for subjects with no baseline cardiovascular disease, 1.39; 95% CI, 1.17 to 1.66). CONCLUSIONS: Lifetime SHS exposure appears to result in a greater decline in lung function and risk of cardiovascular mortality, taking into account confounders and the mediating effect of FEV1 and baseline cardiovascular disease.

Longitudinal changes in aerobic capacity: implications for concepts of aging.

BACKGROUND: Whereas aerobic capacity declines with age, major factors responsible for such decline have been poorly defined by past studies. METHODS: Participants were relatively healthy older individuals (339 women, 253 men) in whom demographic information and cardiopulmonary physiological measurements were obtained at baseline and biannually for three additional measurements. RESULTS: The study identified progressive declines in both forced expiratory volume in 1 second (FEV(1)) and in maximal exercise heart rate as two variables that accounted primarily for the longitudinal decline of aerobic performance in this cohort of relatively fit older persons who achieved high respiratory exchange ratios (RER; mean = 1.08 for women, 1.12 for men). Whereas women achieved a peak oxygen consumption (VO(2peak)) only 77% that of men, oxygen uptake became similar to men (to 95%) when measured per kilogram of lean body mass rather than per kilogram of total body mass. During the 6 years of the study (four time points) aerobic capacity declined in both sexes, however, less steeply for women than for men (18% vs 24% per decade, respectively). The rate of decline was independent of baseline variables such as body composition (e.g., lean body mass, lean/fat ratio), smoking status, medications, or concomitant health conditions, even though these variables strongly influenced baseline aerobic performance. Inclusion of FEV(1) and maximal exercise heart rate into the statistical models, however, accounted for most of the longitudinal decline of aerobic performance. When adjusted for these two variables, aerobic capacity declined 9.7% and 10.4% per decade in women and men, respectively. CONCLUSIONS: Our findings emphasize the primary importance of declining FEV(1) and declining maximal exercise heart rate in accounting for the "aging effect" on aerobic capacity. Thus, when comparing longitudinal studies, all estimates of aerobic decline should be interpreted with respect to the specific variables included in the models, which also need to include FEV(1) and maximal exercise heart rate.

Brain Volume as an Integrated Marker for the Risk of Death in a Community-Based Sample: Age Gene/Environment Susceptibility--Reykjavik Study.

BACKGROUND: Total brain volume is an integrated measure of health and may be an independent indicator of mortality risk independent of any one clinical or subclinical disease state. We investigate the association of brain volume to total and cause-specific mortality in a large nondemented stroke-free community-based cohort. METHODS: The analysis includes 3,543 men and women (born 1907-1935) participating in the Age, Gene, Environment Susceptibility-Reykjavik Study. Participants with a known brain-related high risk for mortality (cognitive impairment or stroke) were excluded from these analyses. Quantitative estimates of total brain volume, white matter, white matter lesions, total gray matter (GM; cortical GM and subcortical GM separately), and focal cerebral vascular disease were generated from brain magnetic resonance imaging. Brain atrophy was expressed as brain tissue volume divided by total intracranial volume, yielding a percentage. Mean follow-up duration was 7.2 (0-10) years, with 647 deaths. Cox regression was used to analyze the association of mortality to brain atrophy, adjusting for demographics, cardiovascular risk factors, and cerebral vascular disease. RESULTS: Reduced risk of mortality was significantly associated with higher total brain volume (hazard ratio, 95% confidence interval = 0.71, 0.65-0.78), white matter (0.85, 0.78-0.93), total GM (0.74, 0.68-0.81), and cortical GM (0.78, 0.70-0.87). Overall, the associations were similar for cardiovascular and noncardiovascular-related deaths. CONCLUSIONS: Independent of multiple risk factors and cerebral vascular damage, global brain volume predicts mortality in a large nondemented stroke-free community-dwelling older cohort. Total brain volume may be an integrated measure reflecting a range of health and with further investigation could be a useful clinical tool when assessing risk for mortality.

Physical functioning and mortality in older women: an assessment of energy costs and level of difficulty.

OBJECTIVE: We tested the hypothesis that the types of activity and the energy equivalent assigned to each activity affect the relationship between self-reported physical functioning and mortality. METHODS: We analyzed the relationship between physical functioning and cardiovascular and noncardiovascular mortality in 1230 women (median age 70 years) observed for 7.5 years. We evaluated five separate scores of physical functioning that differed in the method of scoring the responses. Cox proportional hazard models included baseline age, self-reported physical functioning, medical morbidity, and assessment of health. RESULTS: For cardiac and noncardiovascular mortality, greater self-reported functioning was associated independently with a decreased hazard of death. The effects of physical functioning were sensitive to the form of the score used; that is, a score based on ordinal responses was associated with a greater reduction in hazard of death difference in survival between high and low function score: Ordinal: -15.2% (95% confidence interval [CI] -25.2--4.0); dichotomous: -11.6% (95%CI -18.9--3.9). CONCLUSION: There is a consistent relationship between functional limitation and all causes of mortality. The association is sensitive to the form of the score. Future physical function scores should be based on ordinal responses to individual items used in the scores.

Living arrangements and participation in leisure-time physical activities in an older population.

OBJECTIVES: This is a cross-sectional investigation of living arrangements, social contacts, and level of leisure-time physical activity (LTPA) among residents of Sonoma, California, aged 55 and older. METHODS: The odds of different levels of LTPA were assessed by living arrangements and social contacts following adjustment for measures of health, functioning, physical performance, selected health behaviors, and socioeconomic status for men and women separately (n = 2,073). Level of LTPA also was examined among married couples only (subset of sample, n = 511 spouse pairs). RESULTS: The relationship between living arrangements, social contacts, and LTPA varied by gender and level of LTPA. Among married couples, the LTPA of the partner was the most significant predictor of the LTPA of the participant, with the exception of those who engaged in less than brisk activity. DISCUSSION: Living arrangements and social contacts are important determinants of LTPA and should serve as the basis for future interventions.

Dissociable effects of Alzheimer disease and white matter hyperintensities on brain metabolism.

IMPORTANCE: Cerebrovascular disease and Alzheimer disease (AD) frequently co-occur and seem to act through different pathways in producing dementia. OBJECTIVE: To examine cerebrovascular disease and AD markers in relation to brain glucose metabolism in patients with mild cognitive impairment. DESIGN AND SETTING: Cohort study among the Alzheimer Disease Neuroimaging Initiative clinical sites in the United States and Canada. PARTICIPANTS: Two hundred three patients having amnestic mild cognitive impairment (74 of whom converted to AD) with serial imaging during a 3-year follow-up period. MAIN OUTCOMES AND MEASURES: Quantified white matter hyperintensities (WMHs) represented cerebrovascular disease, and cerebrospinal fluid ß-amyloid represented AD pathology. Brain glucose metabolism in temporoparietal and frontal brain regions was measured using positron emission tomography with fluorodeoxyglucose F18. RESULTS: In converters, greater WMHs were associated with decreased frontal metabolism (-0.048; 95% CI, -0.067 to -0.029) but not temporoparietal metabolism (0.010; 95% CI, -0.010 to 0.030). Greater cerebrospinal fluid ß-amyloid (per 10-pg/mL increase) was associated with increased temporoparietal metabolism (0.005; 95% CI, 0.000-0.010) but not frontal metabolism (0.002; 95% CI, -0.004 to 0.007) in the same patients. In nonconverters, similar relationships were observed except for a positive association of greater WMHs with increased temporoparietal metabolism (0.051; 95% CI, 0.027-0.076). CONCLUSIONS AND RELEVANCE: The dissociation of WMHs and cerebrospinal fluid ß-amyloid in relation to regional glucose metabolism suggests that these pathologic conditions operate through different and independent pathways in AD that reflect dysfunction in different brain systems. The positive association of greater WMHs with temporoparietal metabolism suggests that these pathologic processes do not co-occur in nonconverters.

Relative contributions of biomarkers in Alzheimer's disease.

PURPOSE: To assess relationships between biomarkers for Alzheimer's disease (AD) and their potential contributions to AD. METHODS: Biomarkers and cognitive evaluations were assessed longitudinally in 179 patients with mild cognitive impairment, from the Alzheimer's Disease Neuroimaging Initiative from 2003 to 2006, and were used to examine, at any given time, the joint contributions of hippocampal volume, whole brain volume, and brain glucose metabolism on clinical AD progression, using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). Marginal structural models were applied, and an inverse-probability of treatment weight estimation was used to account for time-dependent confounding between study variables. RESULTS: At any given time, population-level differences (e.g., 1-standard deviation [SD] increase) in brain glucose metabolism (-1.036; 95% confidence interval [95% CI], -1.608, -0.464) and hippocampal volume (-1.537; 95% CI, -2.399, -0.674) independently reduced mean (ADAS-Cog), whereas a 1-SD increase in whole brain volume did not (0.372; 95% CI, -0.283, 1.027). The effects of brain glucose metabolism differed in subgroups defined by baseline covariates (e.g., age), but no subgroup effects were observed for hippocampal volume and brain volume. CONCLUSIONS: Brain glucose metabolism and hippocampal volume represent relevant biological markers in subjects at risk for AD.

Effects of age and ß-amyloid on cognitive changes in normal elderly people.

Age-related decline is common in multiple cognitive domains. ß-amyloid (Aß) deposition, a pathological hallmark of Alzheimer's disease, is also associated with cognitive changes in many older people. In this study, we examined a wide range of cognitive function in order to differentiate the effect of age and Aß on cognition during aging. Using positron emission tomography (PET) imaging with the radiotracer Pittsburgh Compound B (PIB), we classified normal older subjects as High PIB-Old and Low PIB-Old and applied sequential multivariate analyses (i.e., principal components analysis [PCA] and discriminant analysis) to obtain summary measures of cognitive tests encompassing multiple cognitive domains. Among 5 cognitive components, a significant age effect was observed in component scores of visual memory and executive functions, regardless of the level of Aß. Discriminant scores (weighted scores of the 5 cognitive components) revealed a significant effect of both age and Aß and were further associated with quantitative PIB counts. The results of the current study highlight both effects of age and Aß on cognitive changes in normal elderly.

Asymptomatic Left Bundle Branch Block Predicts New-Onset Congestive Heart Failure and Death From Cardiovascular Diseases.

BACKGROUND: Left bundle branch block (LBBB) has been proposed as a risk factor for cardiovascular morbidity and mortality. We sought to characterize the strength of these associations in a population without preexisting clinical heart disease. METHODS: The association between LBBB and new-onset congestive heart failure (CHF) or death from cardiovascular diseases was examined in 1,688 participants enrolled in the SPPARCS study who were free of known CHF or previous myocardial infarction. SPPARCS is a community-based cohort study in residents of Sonoma, California that are > 55 years. Medical history and 12-lead ECGs were obtained every 2 years for up to 6 years of follow-up. LBBB at enrollment or year 2 was considered "baseline" and assessed as a predictor of CHF and cardiovascular death ascertained at years 4 and 6. RESULTS: The prevalence of LBBB at baseline was 2.5% (n = 42). During 6 years of follow-up, 70 (4.8%) people developed new CHF. Incidence of CHF was higher in patients with LBBB than in participants without LBBB. This association persisted after controlling for potential confounders (odds ratio (OR): 2.85; 95% confidence interval (CI): 1.01 - 8.02; P = 0.047). A higher mortality from cardiovascular diseases was also found in participants with LBBB after adjusting for potential confounders (OR: 2.35, 95%CI: 1.02 - 5.41; P = 0.044). CONCLUSIONS: LBBB in the absence of a clinically detectable heart disease is associated with new-onset CHF and death from cardiovascular diseases. Further study is warranted to determine if additional diagnostic testing or earlier treatment in patients with asymptomatic LBBB can decrease cardiovascular morbidity or mortality.