Publications

OBJECTIVE: Preeclampsia, a medical complication of pregnancy, is associated with central nervous system (CNS) signs and symptoms, such as headache, hyperexcitability, hyperreflexia, visual disturbances, and seizures (referred to as eclampsia). We hypothesized that markers of neurological injury such as plasma neurofilaments comprising light chains (NfL) and phosphorylated heavy chains (pNfH), would be elevated in preeclampsia and could serve as biomarkers of severity of preeclampsia.

STUDY DESIGN: We first tested NfL and pNfH in nested case-control study from a third trimester plasma bank from patients who delivered at the Beth Israel Deaconess Medical Center (Boston Cohort, N = 288). We then validated the NfL and pNfH alterations in an independent cohort of women who were evaluated for preeclampsia at another tertiary care hospital in South Chicago (Chicago Cohort, N = 393). Data are presented as median (interquartile range) or proportion, and logistic regression was used to estimate risk ratios (RR) and 95 % confidence intervals (CI).

RESULTS: In the Boston cohort, plasma NfL concentrations were 10.8 (8.2, 15.0) pg/ml in normotensive controls versus 15.9 (10.1, 24.8) in preeclampsia (p = 0.002). Likewise, pNfH concentrations were 92.1 (55.6, 148) pg/ml in controls versus 141.5 (93.9, 212.0) in preeclampsia, respectively (p = 0.0004). The adjusted odds ratio (OR) for the risk of preeclampsia in the highest tertile of control NfL and pNfH concentrations, compared with lowest quartiles, was 3.72 (1.70, 8.17) and 3.99 (1.77, 9.03). Similar findings were replicated in the primarily African-American Chicago cohort (OR for NfL: 4.36 [2.46, 7.70] and pNfH: 2.91 [1.66, 5.13]). The risk of preeclampsia with severe features was highest among women who were in the highest quartile of the control distributions for both biomarkers but not for either biomarker alone (adjusted OR for Boston and Chicago cohorts were 7.56 and 5.78 respectively).

CONCLUSION: Markers of neurological injury are markedly elevated in preeclampsia in Caucasians and African Americans. Prospective studies are needed to evaluate whether these markers could herald the onset of eclampsia.

BACKGROUND: Endovascular repair of large diameter infrarenal and complex abdominal aortic aneurysms has been associated with worse outcomes. Whether these associations also apply to thoracoabdominal aortic aneurysms (TAAAs) remains unclear.

METHODS: We identified all patients who underwent endovascular repair for intact TAAAs between July 2010 and July 2024 in the Vascular Quality Initiative. A TAAA was defined as having a proximal aneurysm extent between zones 2 and 6, with at least one renal or visceral artery treated. Locally estimated scatterplot smoothing curves were used to visualize the relationship between preoperative aneurysm diameter and perioperative mortality, which informed the sex-specific definition of large aneurysms. Aneurysm size was categorized based on maximum diameter as follows (females/males): large (>60 mm/>65 mm), small (<50 mm/<55 mm), and medium (50-60 mm/55-65 mm). Perioperative outcomes were assessed using logistic regression models, and 5-year mortality was evaluated using adjusted Kaplan-Meier methods and Cox regression. Both large and small aneurysms were compared with medium-sized aneurysms.

RESULTS: A total of 1309 patients were included; of these, 54% underwent repair for medium-sized aneurysms, 37% for large aneurysms, and 9.1% for small aneurysms. The median follow-up was 345 days. After adjustment, compared with medium-sized aneurysms, large aneurysms were associated with 31% higher odds of any perioperative complication (adjusted odds ratio, 1.31; 95% confidence interval, 1.00-1.72; P = .046) and nearly twice the hazard of 5-year mortality (adjusted hazard ratio, 1.94; 95% confidence interval, 1.43-2.62; P < .01). The odds of perioperative mortality and in-hospital reintervention were similar between medium-sized and large aneurysms. No significant differences in perioperative outcomes or 5-year mortality were observed between patients with small and medium-sized aneurysms.

CONCLUSIONS: After endovascular repair for TAAAs, compared with medium-sized aneurysms, large aneurysms (>60 mm in females, >65 mm in males) were associated with higher odds of any complication and higher 5-year mortality. Patients with small aneurysms (<50 mm in females, <55 mm in males) demonstrated similar perioperative outcomes and 5-year mortality compared with those with medium-sized aneurysms. These findings highlight the need to optimize management strategies for patients with large TAAAs and emphasize the importance of improved screening programs to enable earlier detection.

Benzodiazepines are potentially inappropriate medications for older adults, and deprescribing interventions are needed. We describe the development of a psychologist-led, mindfulness-informed cognitive-behavioural therapy (CBT) intervention to pair with pharmacist-led tapering to support benzodiazepine deprescribing in older adults. Based on previous research, we first developed an intervention conceptual model. The aim of this study was to (1) gather stakeholder feedback on previous experiences with benzodiazepine tapering and on our intervention model and proposed intervention, and (2) integrate this qualitative feedback to develop an intervention manual. We conducted (a) semistructured individual interviews with older adults (N = 8) who previously attempted to taper their benzodiazepines, and (b) a focus group with members (N = 5) from a national deprescribing patient stakeholder group. Overlapping themes emerged, including support for the mindfulness-informed CBT intervention, the importance of control over taper pace, the need for a goal- and skills-oriented intervention, the importance of normalizing side effects of the taper and building confidence to manage side effects and the utility of fostering acceptance during the taper. These findings informed the development of a final intervention manual, named Confidence-Building Strategies for Reducing Sedative Medications (CSTARS), to be tested in a single-arm pilot feasibility trial.

INTRODUCTION: Contrasting active treatment against a placebo has long been the gold standard in clinical medicine. The possible impact of placebo responses in surgery has recently been investigated using sham surgery. Despite indications that both genuine and placebo surgeries may lead to positive outcomes, no investigation into the differential routes to improvement has been performed.

OBJECTIVES: To assess the mechanisms involved in improvements seen in patients with sacroiliac joint pain who undergo genuine or placebo surgery.

METHODS: This randomized controlled trial incorporated both subjective and objective assessments, including functional magnetic resonance imaging and experimental pain testing, at baseline and 6-month follow-up in a surgical trial including patients with chronic pain. Twenty-three patients were randomized to receive genuine surgery (sacroiliac joint fusion) or placebo (sham). An additional 7 patients were included as observational controls.

RESULTS: There was a significant reduction in weekly pain intensity for both the genuine and placebo groups at follow-up, with greater reductions in the genuine group compared with placebo (P = 0.04). The difference was driven by a few "super-responders" in the genuine group. Clinical improvements correlated with experimental pain outcomes at the operated sacroiliac joint. Functional brain connectivity between the somatosensory cortex and the default mode network decreased more in the genuine group compared with the placebo group.

CONCLUSION: Preliminary findings indicate decreased connectivity between somatosensory and default mode networks for patients in the genuine vs sham group, demonstrating the first findings of differential neural processing in pain-relevant brain networks after genuine vs placebo surgery using objective measures. Understanding the active mechanisms of surgery may lead to personalized treatments, more effective pain reduction, and less side effects for patients with pain.

INTRODUCTION: Dementia has been strongly linked with cardiovascular disease, but the relationships between cardiovascular disease and brain health at subclinical stages have not been fully explored. We investigated the associations between subclinical cardiac dysfunction, defined by cardiac biomarkers and echocardiography, and novel neurobiomarkers associated with the brain injury in older adults.

METHODS: We included 962 participants from the Cardiovascular Health Study who had no history of stroke, transient ischemic attack, atrial fibrillation, heart failure, or myocardial infarction. We analyzed cross-sectional associations using linear regression. Outcomes variables were serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), two markers of subclinical brain injury. Exposure variables were serum N-terminal pro-brain-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) and subclinical cardiac measures including echocardiographic left atrial reservoir strain, left ventricular average longitudinal strain, early diastolic strain rate of the left ventricle, decreased left ventricular ejection fraction, average E/e', percent predicted left ventricular mass, and left atrial diameter.

RESULTS: Among 844 participants with serum biomarkers, hs-cTnT was significantly associated with NfL (β = 1.881, 95 % CI: (0.729, 3.032), p = 0.001), and this association remained significant even after mutual adjustment for NT-proBNP (β = 1.781, 95 % CI: (0.626, 2.937), p = 0.003). NT-proBNP was also associated with NfL (β = 1.170, 95 % CI: (0.047, 2.293), p = 0.041), although this association was slightly attenuated and not statistically significant after adjustment for hs-cTnT (β = 1.004, 95 % CI: (-0.119, 2.126), p = 0.08). There were no significant associations observed for either circulating marker with GFAP, nor were echocardiographic variables associated with NfL or GFAP.

CONCLUSIONS: In older adults without clinically identified cardiovascular disease, subclinical cardiac dysfunction identified through hs-cTnT and, to a lesser extent, NT-proBNP, was associated with higher levels of NfL, a marker of brain injury. This novel insight suggests that even subclinical cardiac disease is linked to brain health.

BACKGROUND: While mindfulness meditation (MM) apps have gained popularity as a tool for promoting sleep, research focusing on bedtime mindfulness practice and app usage is limited.

OBJECTIVE: As the first step toward understanding the efficacy and mechanisms of such bedtime practice and to inform future investigations, the goal of this pilot study was to explore the feasibility of app-guided bedtime MM practice with both in-lab and at-home physiological and self-report sleep remote assessments.

METHODS: We conducted a single-arm, prospective mixed methods pilot study that included both standard in-lab sleep studies and remote at-home assessments of individuals with insomnia disorder with self-reported difficulty falling asleep. Participants practiced MM guided by a commercially available smartphone app at bedtime for 4 weeks. Pre-post assessments included a battery of sleep-related and psychological health questionnaires, objective physiological sleep measures (polysomnography and actigraphy), and daily sleep logs. We also conducted qualitative exit interviews to further assess feasibility and acceptability. Transcripts were analyzed for dominant themes using inductive and deductive qualitative methods.

RESULTS: We recruited 13 participants with chronic insomnia (symptoms ≥3 nights weekly for ≥3 months) to complete the study protocol within 8 months (retention rate 77%). We were able to collect analyzable physiological and psychometric data with overall completion rates of more than 90%. The study was deemed feasible, meeting a priori benchmarks including recruitment, retention, completion, and adherence. The 10 participants retained in the program had excellent engagement (95% completion of in-lab studies, 100% completion of questionnaires, and 91% compliance with use of the app). Our preliminary analysis of subjective measures indicated improvement in sleep quality, insomnia severity, and presleep arousal, including Pittsburgh Sleep Quality Index change of -3.7 (95% CI -6.7 to -0.7), Insomnia Severity Index change of -4.5 (95% CI -7.7 to -1.4), Pre-Sleep Arousal Scale change of -7.7 (95% CI -13.1 to -2.3), and trend toward improvement in the Ford Insomnia Response to Stress Test indicated by a change of -2.5 (95% CI -5.9 to 0.9). From qualitative data, we identified domains that inform the feasibility and acceptability of the study, including (1) barriers to sleep prior to the study, (2) benefits and skills imparted by mindfulness, and (3) feedback on app use. Benefits and skills imparted by mindfulness included decreased catastrophizing, acceptance and nonreactivity, body awareness and relaxation, self-kindness, awareness of sleep hygiene and bedtime routine, earlier defusing of stress, increased focus and presence, and calm throughout the day.

CONCLUSIONS: Bedtime app-guided MM as an intervention in patients with insomnia and the hybrid study design with in-lab and at-home assessments are feasible and acceptable. This study informs the design of future clinical and mechanistic research examining app-guided MM to impact insomnia severity and presleep arousal.

AIMS: Circulating ketone bodies (KB) are an important source of metabolic fuel for the myocardium under physiological and pathological conditions. Prior studies have linked KB levels with adverse cardiovascular outcomes. However, their relationship with atrial fibrillation (AF) risk remains unknown. The objective is to evaluate the association of KB levels with the risk of incident AF.

METHODS AND RESULTS: This prospective, multicentre cohort study recruited patients without baseline AF from the Multi-Ethnic Study of Atherosclerosis (MESA) and the UK Biobank (UKB), respectively. Total KB levels were measured by nuclear magnetic resonance spectroscopy in both studies. The associations between total and individual KB and incident AF were evaluated using multivariable-adjusted Cox proportional hazard models. Prespecified interaction analyses were performed for smoking status, history of diabetes mellitus, history of hypertension, body mass index, and self-reported race/ethnicity (to represent a social construct). A total of 6783 participants [mean (standard deviation, SD) age 62 (10) years, 52% women, 38% White, 27.5% Black, 21.8% Hispanic, and 11.6% Chinese American] from MESA and 116 480 participants [mean (SD) age 56.5 (8) years, 54% women, 94% White] from the UKB were included. Over a median follow-up of 16.5 (10.3-17.4) years in MESA and 13.6 (12.8-14.4) years in the UKB, higher levels of total KB were associated with a higher risk of incident AF. In MESA, each doubling of baseline total KB levels was associated with a 1.08-fold increased hazard of incident AF on follow-up [95% confidence interval (CI): 1.00-1.16] after adjustment for confounding factors. Consistent results were obtained in a subgroup analysis stratified by different types of KB (β-hydroxybutyrate, acetoacetate, and acetone). There was a significant interaction with current smoking, such that per doubling of total KB levels was associated with a 1.32-fold increased hazard for incident AF in current smokers (95% CI: 1.08-1.61), but this association was not seen among former/never smokers [hazard ratio (95% CI): 1.05 (0.95-1.13)]. These results were replicated in the UKB.

CONCLUSION: Higher concentrations of KB are associated with an increased risk of AF in predominantly healthy, community-based cohorts, acknowledging that many participants also had comorbidities such as hypertension and diabetes, particularly among smokers. Ketone bodies could serve as a potential biomarker for identifying populations at risk for AF.

BACKGROUND: Exposure to lipopolysaccharide (LPS), a potent proinflammatory glycolipid derived from gut microbiota, may be linked to the development of coronary heart disease (CHD). However, evidence from human studies is limited.

OBJECTIVES: We aimed to investigate prospective relationships between 2 plasma biomarkers of LPS exposures-LPS-binding protein (LBP) and soluble cluster of differentiation 14 (sCD14)-in relation to incident CHD among United States males and females.

METHODS: A prospective nested 1:1 matched case-control study of CHD was conducted among participants in the Nurses' Health Study II (NHSII) and Health Professionals Follow-up Study (HPFS). Plasma concentrations of LBP and sCD14 were measured in 496 HPFS male CHD case-control pairs and 212 NHSII female pairs.

RESULTS: Among controls, plasma concentrations of LBP exhibited positive correlations with age, body mass index, and C-reactive protein (CRP) concentrations and an inverse correlation with high-density lipoprotein cholesterol concentrations. For sCD14, positive correlations with age and CRP were only observed in HPFS controls. Neither elevated LBP nor sCD14 concentrations were significantly associated with incident CHD in HPFS. In NHSII, higher sCD14 concentrations, but not LBP, were significantly associated with higher risk of CHD, with a risk ratio of 3.01 [95% confidence interval (CI): 1.28, 7.11] when comparing extreme quintiles. Collectively, CRP and the total cholesterol/ high-density lipoprotein cholesterol ratio explained 27.9% (95% CI: 7.1%, 66.1%; P = 0.01) of the positive association between sCD14 and CHD in NHSII females. These associations were not modified by physical activity, alcohol intake, body mass index, inflammation markers, family history of CHD, or the presence of hypertension, hyperlipidemia, or type-2 diabetes.

CONCLUSION: Higher concentrations of sCD14 may be associated with an increased risk of CHD in females, whereas LBP concentrations are not associated with CHD in either sex. These data do not support that LPS exposure in initially healthy individuals is a contributing CHD risk factor, although the potential sex difference should be explored further.

INTRODUCTION: The present study examined the dimensional structure of the neuropsychological test batteries from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) versions 2.0 and 3.0 and measurement equivalence across UDS versions and race/ethnicity groups.

METHODS: There were 49,895 participants included in the present study. The best-fitting model was developed and tested in separate samples. Multiple group confirmatory factor analysis (CFA) evaluated measurement equivalence across UDS versions and race/ethnicity groups.

RESULTS: Results identified a best-fitting four-factor model with residual structure. Multiple group CFA supported partial scalar invariance by UDS version and race/ethnicity group. Regarding race/ethnicity groups, the Language and Attention domains had more non-invariant intercepts, which most affected the White group.

DISCUSSION: A four-factor model effectively summarizes the UDS neuropsychological test batteries across UDS versions and race/ethnicity groups. Crucial differences in measurement parameters must be accounted for in studies using these neuropsychological tests as outcomes.

HIGHLIGHTS: A four-factor model summarizes cognition across Uniform Data Set (UDS) versions and race/ethnicity groups. Measurement invariance exists across race/ethnicity groups. Model fit differs between cognitively impaired and unimpaired samples. Accounting for differences in measurement parameters across groups is essential. Tailored normative data are crucial for certain UDS tests, including category fluency.