Actigraphic evidence of persistent sleep disruption following repetitive mild traumatic brain injury in a gyrencephalic model.

We studied the effect of multimodal traumatic brain injuries on daily sleep/activity patterns and related histology. Gyrencephalic ferrets wore actigraphs and received military-relevant brain injuries including shockwaves, strong rotational impact, and variable stress, which were evaluated up to 6 months post injury. Sham and Baseline animals exhibited activity patterns occurring in distinct clusters of high activity, interspersed with periods of low activity. In the Injury and Injury + Stress groups, activity clusters diminished and overall activity patterns became significantly more dispersed at 4 weeks post injury with significant sleep fragmentation. Additionally, the Injury + Stress group exhibited a significant decrease in daytime high activity up to 4 months post injury. At 4 weeks post injury, the reactive astrocyte (GFAP) immunoreactivity was significantly greater in both the injury groups compared to Sham, but did not differ at 6 months post injury. The intensity of immunoreactivity of the astrocytic endfeet that surround blood vessels (visualized with aquaporin 4; AQP4), however, differed significantly from Sham at 4 weeks post injury (in both injured groups) and at 6 months (Injury + Stress only). As the distribution of AQP4 plays a key role in the glymphatic system, we suggest that glymphatic disruption occurs in ferrets after the injuries described here.

Quantitative pupillometry as a biomarker for prediction of return to play in mild traumatic brain injury: a Military Traumatic Brain Injury Initiative study.

OBJECTIVE: This study aimed to determine the validity of quantitative pupillometry to predict the length of time for return to full activity/duty after a mild traumatic brain injury (mTBI) in a cohort of injured cadets at West Point. METHODS: Each subject received baseline (T0) quantitative pupillometry, in addition to evaluation with the Balance Error Scoring System (BESS), Standardized Assessment of Concussion (SAC), and Sport Concussion Assessment Tool 5th Edition Symptom Survey (SCAT5). Repeat assessments using the same parameters were conducted within 48 hours of injury (T1), at the beginning of progressive return to activity (T2), and at the completion of progressive return to activity protocols (T3). Pupillary metrics were compared on the basis of length of time to return to full play/duty and the clinical scores. RESULTS: The authors' statistical analyses found correlations between pupillometry measures at T1, including end-initial diameter and maximum constriction velocity, with larger change and faster constriction predicting earlier return to play. There was also an association with maximum constriction velocity at baseline (T0), predicting faster return to play. CONCLUSIONS: The authors conclude that that pupillometry may be a valuable tool for assessing time to return to duty from mTBI by providing a measure of baseline resiliency to mTBI and/or autonomic dysfunction in the acute phase after mTBI.

Investigation of the effect of dietary intake of omega-3 polyunsaturated fatty acids on trauma-induced white matter injury with quantitative diffusion MRI in mice.

Previous studies suggest that long-term supplementation and dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) may have neuroprotective effects following brain injury. The objective of this study was to investigate potential neuroprotective effects of omega-3 PUFAs on white matter following closed-head trauma. The closed-head injury model of engineered rotational acceleration (CHIMERA) produces a reproducible injury in the optic tract and brachium of the superior colliculus in mice. Damage is detectable using diffusion tensor imaging (DTI) metrics, particularly fractional anisotropy (FA), with sensitivity comparable to histology. We acquired in vivo (n = 38) and ex vivo (n = 41) DTI data in mice divided into sham and CHIMERA groups with two dietary groups: one deficient in omega-3 PUFAs and one adequate in omega-3 PUFAs. We examined injury effects (reduction in FA) and neuroprotection (FA reduction modulated by diet) in the optic tract and brachium. We verified that diet did not affect FA in sham animals. In injured animals, we found significantly reduced FA in the optic tract and brachium (~10% reduction, p < 0.001), and Bayes factor analysis showed strong evidence to reject the null hypothesis. However, Bayes factor analysis showed substantial evidence to accept the null hypothesis of no diet-related FA differences in injured animals in the in vivo and ex vivo samples. Our results indicate no neuroprotective effect from adequate dietary omega-3 PUFA intake on white matter damage following traumatic brain injury. Since damage from CHIMERA mainly affects white matter, our results do not necessarily contradict previous findings showing omega-3 PUFA-mediated neuroprotection in gray matter.

Allometric scaling of brain regions to intra-cranial volume: An epidemiological MRI study.

There is growing evidence that sub-structures of the brain scale allometrically to total brain size, that is, in a non-proportional and non-linear way. Here, scaling of different volumes of interest (VOI) to intra-cranial volume (ICV) was examined. It was assessed whether scaling was allometric or isometric and whether scaling coefficients significantly differed from each other. We also tested to what extent allometric scaling of VOI was introduced by the automated segmentation technique. Furthermore, reproducibility of allometric scaling was studied different age groups and study populations. Study samples included samples of cognitively healthy adults from the community-based Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik Study) (N = 3,883), the Coronary Artery Risk Development in Young Adults Study (CARDIA) (N =709), and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 180). Data encompassed participants with different age, ethnicity, risk factor profile, and ICV and VOI obtained with different automated MRI segmentation techniques. Our analysis showed that (1) allometric scaling is a trait of all parts of the brain, (2) scaling of neo-cortical white matter, neo-cortical gray matter, and deep gray matter structures including the cerebellum are significantly different from each other, and (3) allometric scaling of brain structures cannot solely be explained by age-associated atrophy, sex, ethnicity, or a systematic bias from study-specific segmentation algorithm, but appears to be a true feature of brain geometry. Hum Brain Mapp 38:151-164, 2017. © 2016 Wiley Periodicals, Inc.

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.

Quantitative Pupillometry Predicts Return to Play and Tracks the Clinical Evolution of Mild Traumatic Brain Injury in US Military Academy Cadets: A Military Traumatic Brain Injury Initiative Study.

BACKGROUND AND OBJECTIVES: The objective of this study was to determine the utility of the pupillary light reflex use as a biomarker of mild traumatic brain injury (mTBI). METHODS: This prospective cohort study was conducted at The US Military Academy at West Point. Cadets underwent a standard battery of tests including Balance Error Scoring System, Sports Concussion Assessment Tool Fifth Edition Symptom Survey, Standard Assessment of Concussion, and measure of pupillary responses. Cadets who sustained an mTBI during training events or sports were evaluated with the same battery of tests and pupillometry within 48 hours of the injury (T1), at the initiation of a graded return to activity protocol (T2), and at unrestricted return to activity (T3). RESULTS: Pupillary light reflex metrics were obtained in 1300 cadets at baseline. During the study period, 68 cadets sustained mTBIs. At T1 (<48 hours), cadets manifested significant postconcussion symptoms (Sports Concussion Assessment Tool Fifth Edition P < .001), and they had decreased cognitive performance (Standardized Assessment of Concussion P < .001) and higher balance error scores (Balance Error Scoring System P < .001) in comparison with their baseline assessment (T0). The clinical parameters showed normalization at time points T2 and T3. The pupillary responses demonstrated a pattern of significant change that returned to normal for several measures, including the difference between the constricted and initial pupillary diameter (T1 P < .001, T2 P < .05), dilation velocity (T1 P < .01, T2 P < .001), and percent of pupillary constriction (T1 P < .05). In addition, a combination of dilation velocity and maximum constriction velocity demonstrates moderate prediction ability regarding who can return to duty before or after 21 days (area under the curve = 0.71, 95% CI [0.56-0.86]). CONCLUSION: This study's findings indicate that quantitative pupillometry has the potential to assist with injury identification and prediction of symptom severity and duration.

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.

Plasma Biomarker Concentrations Associated With Return to Sport Following Sport-Related Concussion in Collegiate Athletes-A Concussion Assessment, Research, and Education (CARE) Consortium Study.

Importance: Identifying plasma biomarkers associated with the amount of time an athlete may need before they return to sport (RTS) following a sport-related concussion (SRC) is important because it may help to improve the health and safety of athletes. Objective: To examine whether plasma biomarkers can differentiate collegiate athletes who RTS in less than 14 days or 14 days or more following SRC. Design, Setting, and Participants: This multicenter prospective diagnostic study, conducted by the National Collegiate Athletics Association-Department of Defense Concussion Assessment, Research, and Education Consortium, included 127 male and female athletes who had sustained an SRC while enrolled at 6 Concussion Assessment, Research, and Education Consortium Advanced Research Core sites as well as 2 partial-Advanced Research Core military service academies. Data were collected between February 2015 and May 2018. Athletes with SRC completed clinical testing and blood collection at preseason (baseline), postinjury (0-21 hours), 24 to 48 hours postinjury, time of symptom resolution, and 7 days after unrestricted RTS. Main Outcomes and Measures: A total of 3 plasma biomarkers (ie, total tau protein, glial fibrillary acidic protein [GFAP], and neurofilament light chain protein [Nf-L]) were measured using an ultrasensitive single molecule array technology and were included in the final analysis. RTS was examined between athletes who took less than 14 days vs those who took 14 days or more to RTS following SRC. Linear mixed models were used to identify significant interactions between period by RTS group. Area under the receiver operating characteristic curve analyses were conducted to examine whether these plasma biomarkers could discriminate between RTS groups. Results: The 127 participants had a mean (SD) age of 18.9 (1.3) years, and 97 (76.4%) were men; 65 (51.2%) took less than 14 days to RTS, and 62 (48.8%) took 14 days or more to RTS. Linear mixed models identified significant associations for both mean (SE) plasma total tau (24-48 hours postinjury, <14 days RTS vs ≥14 days RTS: -0.65 [0.12] pg/mL vs -0.14 [0.14] pg/mL; P = .008) and GFAP (postinjury, 14 days RTS vs ≥14 days RTS: 4.72 [0.12] pg/mL vs 4.39 [0.11] pg/mL; P = .04). Total tau at the time of symptom resolution had acceptable discrimination power (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.63-0.86; P < .001). We also examined a combined plasma biomarker panel that incorporated Nf-L, GFAP, and total tau at each period to discriminate RTS groups. Although the analyses did reach significance at each time period when combined, results indicated that they were poor at distinguishing the groups (area under the receiver operating characteristic curve, <0.7). Conclusions and Relevance: The findings of this study suggest that measures of total tau and GFAP may identify athletes who will require more time to RTS. However, further research is needed to improve our ability to determine recovery following an SRC.

Leisure-time physical activity and all-cause mortality in an elderly cohort.

BACKGROUND: Physical activity is one of the mainstays of secondary prevention in people with heart disease. It is not well understood, however, how the presence of heart disease or a history of habitual exercise prior to the study modify any mortality-sparing effects of leisure-time physical activity. METHODS: We analyzed data from a well-described cohort of subjects aged 54 years and older at intake (median age, 70 years) from Sonoma, CA, studied between 1993 and 2001 with mortality follow-up until 2003. A history-adjusted marginal structural model was used to obtain counterfactual excess risk estimates that were pooled across the different time points. Additive interaction was examined by comparing these excess risk estimates across strata of age, heart disease, and precohort physical activity. RESULTS: Estimates of the excess risk for 2-year all-cause mortality comparing Centers for Disease Control and Prevention-recommended levels of current physical activity to lower levels of activity ranged from -0.7% to -4.9% among subjects younger than 75 years of age and from -7.8% to -14.8% among older subjects. Heart disease or precohort physical activity were not found to modify the effect of leisure-time physical activity. CONCLUSIONS: Our data are consistent with the view that the mortality-sparing effect of recent physical activity is independent of the presence or absence of underlying cardiac disease and the pattern of past physical activity.

Cigarette smoking and gray matter brain volumes in middle age adults: the CARDIA Brain MRI sub-study.

Cigarette smoking has been associated with dementia and dementia-related brain changes, notably gray matter (GM) volume atrophy. These associations are thought to reflect the co-morbidity of smoking and vascular, respiratory, and substance use/psychological conditions. However, the extent and localization of the smoking-GM relationship and the degree to which vascular, respiratory, and substance use/psychological factors influence this relationship remain unclear. In the Coronary Artery Risk Development in Young Adults CARDIA cohort (n = 698; 52% women; 40% black participants; age = 50.3 (SD = 3.5)), we examined the associations of smoking status with total GM volume and GM volume of brain regions linked to neurocognitive and addiction disorders. Linear regression models were used to adjust for vascular, respiratory, and substance use/psychological factors and to examine whether they modify the smoking-GM relationship. Compared to never-smokers, current smokers had smaller total GM volume (-8.86 cm3 (95%CI = -13.44, -4.29). Adjustment for substance use/psychological - but not vascular or respiratory - factors substantially attenuated this association (coefficients = -5.54 (95% CI = -10.32, -0.76); -8.33 (95% CI = -12.94, -3.72); -7.69 (95% CI = -6.95, -4.21), respectively). There was an interaction between smoking and alcohol use such that among alcohol non-users, smoking was not related to GM volumes and among alcohol users, those who currently smoked had -12 cm3 smaller total GM, specifically in the frontal and temporal lobes, amygdala, cingulate, and insula. Results suggest a large-magnitude association between smoking and smaller GM volume at middle age, accounting for vascular, respiratory, and substance use/psychological factors, and that the association was strongest in alcohol users. Regions suggested to be most vulnerable are those where cognition and addiction processes overlap.

Cigarette smoking and cerebral blood flow in a cohort of middle-aged adults.

Cigarette smoking is often associated with dementia. This association is thought to be mediated by hypoperfusion; however, how smoking behavior relates to cerebral blood flow (CBF) remains unclear. Using data from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort (mean age = 50; n = 522), we examined the association between smoking behavior (status, cumulative pack-years, age at smoking initiation, and years since cessation) and CBF (arterial spin labeling) in brain lobes and regions linked to dementia. We used adjusted linear regression models and tested whether associations differed between current and former-smokers. Compared to never-smokers, former-smokers had lower CBF in the parietal and occipital lobes, cuneus, precuneus, putamen, and insula; in contrast, current-smokers did not have lower CBF. The relationship between pack-years and CBF was different between current and former-smokers (p for interaction < 0.05): Among current-smokers, higher pack-years were associated with higher occipital, temporal, cuneus, putamen, insula, hippocampus, and caudate CBF; former-smokers had lower caudate CBF with increasing pack-years. Results show links between smoking and CBF at middle-age in regions implicated in cognitive and compulsive/addictive processes. Differences between current and former smoking suggest that distinct pathological and/or compensatory mechanisms may be involved depending on the timing and history of smoking exposure.

Associations of plasma clusterin and Alzheimer's disease-related MRI markers in adults at mid-life: The CARDIA Brain MRI sub-study.

BACKGROUND: Clinical and epidemiological studies of older persons have implicated clusterin in Alzheimer's disease (AD) pathogenesis. In the context of identifying early biomarkers of risk, we examined associations of plasma clusterin and characteristics of AD in middle-aged individuals from the community. MATERIALS AND METHODS: Subjects were 639 cognitively normal individuals (mean age 50 ± 3.5) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Clusterin was quantified using ELISA (mean 255± 31 ng/ml). Associations were assessed between clusterin and volumes of brain regions known to atrophy in early AD, including entorhinal cortex (ECV), hippocampus (HV), and medial temporal lobe (MTLV) volumes (cm3). Total brain volume (TBV) and volumes of structures affected in later AD were examined for comparison. RESULTS: In multivariable models, higher clusterin had a negative non-linear association with ECV (combined left and right hemispheres), and this association was influenced by the highest clusterin levels. Compared to mean clusterin, 1 and 2 standard deviation (SD) level increases in clusterin were associated with -2.1% (95% CI: -3.3,-0.9) and -7.3% (95% CI: -11.3,-3.3) lower ECV, respectively. Similar relationships were observed between clusterin and HV, although the relationship was stronger for left-side HV than the right-side. However, the association was not significant after adjusting for covariates. Negative non-linear associations between clusterin and MTLV were strongest for the left side: compared to mean clusterin, 1 and 2 SD level increases in clusterin were associated with -0.9% (95% CI: -1.9, 0.1) and -3.7% (95% CI: -7.1, -0.3) lower MTLV. There were no significant associations between clusterin and brain structures affected in later AD. CONCLUSIONS: In middle-aged adults unselected for AD, plasma clusterin was associated with lower volume of the entorhinal cortex, an area that atrophies early in AD. Clusterin could be informative as part of a multi-component preclinical marker for AD.

White matter microstructure, white matter lesions, and hypertension: An examination of early surrogate markers of vascular-related brain change in midlife.

Objective: We examined imaging surrogates of white matter microstructural abnormalities which may precede white matter lesions (WML) and represent a relevant marker of cerebrovascular injury in adults in midlife. Methods: In 698 community-dwelling adults (mean age 50 years ±3.5 SD) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study, WML were identified on structural MR and fractional anisotropy (FA), representing WM microstructural integrity, was derived using Diffusion Tensor Imaging. FA and WML maps were overlaid on a parcellated T1-template, based on an expert-delineated brain atlas, which included 42 WM tract ROIs. Analyses occurred in stages: 1) WML were quantified for the different tracts (i.e., frequency, volume, volume relative to tract size); 2) the interdependence of FA in normal appearing WM (NAWM) and WML was examined across tracts; 3) associations of NAWM FA and hypertension status were assessed controlling for WML volume. In the latter analysis, both overall hypertension (i.e. hypertension vs. normotension and prehypertension vs. normotension) and hypertension categorized by antihypertensive treatment status (yes/no) and blood pressure control (e.g., diastolic <90 mmHg, systolic <140 mmHg), were assessed. Results: WML were widely distributed across different WM tracts, however, WML volume was small. Mean NAWM FA was lower in participants with vs. participants without WML in given tracts. Hypertension was significantly associated with lower mean NAWM FA globally across tracts, both before and after adjustment for WML volume. Moreover, the magnitude of this association differed by treatment status and the level of control of the hypertension. Conclusions: In middle-aged adults, NAWM FA could represent a relevant marker of cerebrovascular injury when WML are minimally present.

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.