Faculty Bibliography

A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer's disease (AD) and related dementias. However, there is limited understanding of the peripheral biological mechanisms relevant in the earliest phases of the disease. Here, we used a large-scale proteomics platform to examine the association of 4877 plasma proteins with 25-year dementia risk in 10,981 middle-aged adults. We found 32 dementia-associated plasma proteins that were involved in proteostasis, immunity, synaptic function, and extracellular matrix organization. We then replicated the association between 15 of these proteins and clinically relevant neurocognitive outcomes in two independent cohorts. We demonstrated that 12 of these 32 dementia-associated proteins were associated with cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, or neuroinflammation. We found that eight of these candidate protein markers were abnormally expressed in human postmortem brain tissue from patients with AD, although some of the proteins that were most strongly associated with dementia risk, such as GDF15, were not detected in these brain tissue samples. Using network analyses, we found a protein signature for dementia risk that was characterized by dysregulation of specific immune and proteostasis/autophagy pathways in adults in midlife ~20 years before dementia onset, as well as abnormal coagulation and complement signaling ~10 years before dementia onset. Bidirectional two-sample Mendelian randomization genetically validated nine of our candidate proteins as markers of AD in midlife and inferred causality of SERPINA3 in AD pathogenesis. Last, we prioritized a set of candidate markers for AD and dementia risk prediction in midlife.

BACKGROUND AND OBJECTIVES/OBJECTIVE:The rapidly aging and diversifying U.S. population is challenged by increases in prevalence of Alzheimer's disease (AD) and aging-related disorders. We conducted a scoping review to assess equitable inclusion of diverse older adult populations in aging research focused on National Institutes of Health (NIH)-sponsored research. RESEARCH DESIGN AND METHODS/METHODS:The scoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-Scr) Protocol. The search was limited to NIH-funded studies focusing on aging, AD and Alzheimer's disease-related dementias (ADRD) and included adults aged 55+. The priority populations and health disparities put forth by the NIA Health Disparities Framework serve as a model for guiding inclusion criteria and for interpreting the representation of these underrepresented groups, including racial ethnic minorities, socioeconomically disadvantaged, rural populations, groups with disabilities, and LGBTQ communities. RESULTS:Our search identified 1,177 records, of which 436 articles were included in the analysis. Inclusion of individuals with ADRD and mild cognitive impairment, racial ethnic minorities, rural populations, socioeconomically disadvantaged, groups with disabilities, and LGBTQ communities were poorly specified in most studies. Studies used multiple recruitment methods, conducting studies in community settings (59%) and hospitals/clinics (38%) most frequently. Incentives, convenience factors, and sustained engagement via community-based and care partners were identified as key strategies for improved retention. DISCUSSION AND IMPLICATIONS/CONCLUSIONS:This scoping review identified gaps in existing literature and aims for future work, including stronger research focus on, better inclusion of, and improved data collection and reporting of older adults from underrepresented groups.

Pregnancy is increasingly considered a period of vulnerability for extreme heat exposure. Multiple lines of evidence support that heat stress is associated with placental insufficiency, poor fetal growth and decreased birth weight. In this narrative review, we first summarize evidence linking ambient temperature or experimentally-induced heat stress with fetal and placental growth outcomes in humans, ruminants and murine species. We then synthesize the literature on putative underlying biological pathways with a focus on the placenta. Reviewed mechanisms include: reduced uterine-placental blood flow, impaired supply of metabolic substrates to the fetus, activation of the maternal stress-response system, and disruption of other endocrine and immune system endpoints. Taken together, this body of evidence supports that exposure to extreme ambient heat likely has adverse consequences for placental development and function. However, research investigating placenta-mediated pathophysiological mechanisms in humans remains extremely limited.

BACKGROUND/UNASSIGNED:The risk for cannabis use disorder (CUD) is elevated among U.S. adults with chronic pain, and CUD rates are disproportionately increasing in this group. Little is known about the role of medical cannabis laws (MCL) and recreational cannabis laws (RCL) in these increases. Among U.S. Veterans Health Administration (VHA) patients, we examined whether MCL and RCL effects on CUD prevalence differed between patients with and without chronic pain. METHODS/UNASSIGNED:Patients with ≥1 primary care, emergency, or mental health visit to the VHA and no hospice/palliative care within a given calendar year, 2005-2019 (yearly n=3,234,382 to 4,579,994) were analyzed using VHA electronic health record (EHR) data. To estimate the role of MCL and RCL enactment in the increases in prevalence of diagnosed CUD and whether this differed between patients with and without chronic pain, staggered-adoption difference-in-difference analyses were used, fitting a linear binomial regression model with fixed effects for state, categorical year, time-varying cannabis law status, state-level sociodemographic covariates, a chronic pain indicator, and patient covariates (age group [18-34, 35-64; 65-75], sex, and race and ethnicity). Pain was categorized using an American Pain Society taxonomy of painful medical conditions. OUTCOMES/UNASSIGNED:In patients with chronic pain, enacting MCL led to a 0·14% (95% CI=0·12%-0·15%) absolute increase in CUD prevalence, with 8·4% of the total increase in CUD prevalence in MCL-enacting states attributable to MCL. Enacting RCL led to a 0·19% (95%CI: 0·16%, 0·22%) absolute increase in CUD prevalence, with 11·5% of the total increase in CUD prevalence in RCL-enacting states attributable to RCL. In patients without chronic pain, enacting MCL and RCL led to smaller absolute increases in CUD prevalence (MCL: 0·037% [95%CI: 0·03, 0·05]; RCL: 0·042% [95%CI: 0·02, 0·06]), with 5·7% and 6·0% of the increases in CUD prevalence attributable to MCL and RCL. Overall, MCL and RCL effects were significantly greater in patients with than without chronic pain. By age, MCL and RCL effects were negligible in patients age 18-34 with and without pain. In patients age 35-64 with and without pain, MCL and RCL effects were significant (p<0.001) but small. In patients age 65-75 with pain, absolute increases were 0·10% in MCL-only states and 0·22% in MCL/RCL states, with 9·3% of the increase in CUD prevalence in MCL-only states attributable to MCL, and 19.4% of the increase in RCL states attributable to RCL. In patients age 35-64 and 65-75, MCL and RCL effects were significantly greater in patients with pain. INTERPRETATION/UNASSIGNED:In patients age 35-75, the role of MCL and RCL in the increasing prevalence of CUD was greater in patients with chronic pain than in those without chronic pain, with particularly pronounced effects in patients with chronic pain age 65-75. Although the VHA offers extensive behavioral and non-opioid pharmaceutical treatments for pain, cannabis may seem a more appealing option given media enthusiasm about cannabis, cannabis commercialization activities, and widespread public beliefs about cannabis efficacy. Cannabis does not have the risk/mortality profile of opioids, but CUD is a clinical condition with considerable impairment and comorbidity. Because cannabis legalization in the U.S. is likely to further increase, increasing CUD prevalence among patients with chronic pain following state legalization is a public health concern. The risk of chronic pain increases as individuals age, and the average age of VHA patients and the U.S. general population is increasing. Therefore, clinical monitoring of cannabis use and discussion of the risk of CUD among patients with chronic pain is warranted, especially among older patients. RESEARCH IN CONTEXT/UNASSIGNED:

BACKGROUND:Public health experts have urged governments around the world to regulate newly legalized cannabis as they do alcohol to effectively and efficiently protect health. However, research evaluating the alignment of alcohol and cannabis policies is sparse. We assessed similarities and differences in local alcohol and cannabis control policies across California, and characterized localities adopting distinct policy approaches. METHODS:Using standard legal epidemiologic techniques, we collected and coded local alcohol and cannabis control policies relevant to public health for 12 California counties and all incorporated cities within them (N=241). We assessed whether localities were equally stringent on alcohol and cannabis policies by comparing overall restrictiveness (summed policy scores) and 9 specific provisions that applied to both substances. We captured distinct local alcohol-cannabis policy approaches using latent class analysis, and examined this classification in relation to local demographic, socioeconomic, political, and retail market characteristics. RESULTS:All 241 localities permitted alcohol sales, while 71% banned cannabis sales. Among those that did not ban cannabis sales, more stringent alcohol policy scores were associated with more stringent cannabis policy scores (linear regression coefficient: 0.16 [95% CI: 0.07, 0.25]). Local governments rarely adopted the same provisions for alcohol and cannabis (e.g., limits on hours of sale, advertising restrictions), and only two regulated the co-location of cannabis and alcohol outlets. Localities that were restrictive on alcohol yet permissive on cannabis (12%) were more urban, politically progressive, and had more low-income and racial/ethnic minority residents. Localities that were more permissive on alcohol and restrictive on cannabis (51%) were more socioeconomically advantaged. CONCLUSION/CONCLUSIONS:We found few similarities between local alcohol and cannabis control policies. California's experience suggests that, as governments around the world legalize cannabis, lessons learned from regulating alcohol are not routinely applied to cannabis, particularly in communities distinguished by high social and economic advantages.

BACKGROUND:Although studies to date have broadly shown that cardiovascular disease (CVD) increases cognitive and physical impairment risk, there is still limited understanding of the magnitude of this risk among relevant CVD subtypes or age cohorts. METHODS:We analyzed longitudinal data from 16 679 U.S. Health and Retirement Study participants who were aged ≥65 years at study entry. Primary endpoints were physical impairment (activities of daily living impairment) or cognitive impairment (Langa-Weir Classification of dementia). We compared these endpoints among participants who developed incident CVD versus those who were CVD free, both in the short term (<2-year postdiagnosis) and long term (>5 years), controlling for sociodemographic and health characteristics. We then analyzed the effects by CVD subtype (atrial fibrillation, congestive heart failure, ischemic heart disease, and stroke) and age-at-diagnosis (65-74, 75-84, and ≥85). RESULTS:Over a median follow-up of 10 years, 8 750 participants (52%) developed incident CVD. Incident CVD was associated with significantly higher adjusted odds (aOR) of short-term and long-term physical and cognitive impairment. The oldest (≥85) age-at-diagnosis subgroup had the highest risk of short-term physical (aOR 3.01, 95% confidence interval [CI]: 2.40-3.77) and cognitive impairment (aOR 1.96, 95% CI: 1.55-2.48), as well as long-term impairment. All CVD subtypes were associated with higher odds of physical and cognitive impairment, with the highest risk for patients with incident stroke. CONCLUSIONS:Incident CVD was associated with an increased risk of physical and cognitive impairment across CVD subtypes. Impairment risk after CVD was highest among the oldest patients (≥85 years) who should therefore remain a target for prevention efforts.

BACKGROUND:Hearing loss is highly prevalent in older ages and has several health consequences. Some cardiovascular risk factors are associated with worse hearing at older ages. Still, the role of midlife leisure-time physical activity (PA) as a risk factor for hearing loss is yet to be investigated. METHODS:Among 3 198 participants of the Atherosclerosis Risk in Communities study, we investigated the associations of midlife and change from mid- to late-life PA (assessed via modified Baecke questionnaire) with hearing loss (audiometric battery [worse-ear pure-tone average, and speech-in-noise test]) at older ages. We used regression analyses, adjusted for demographics, medical conditions, and noise exposure, to estimate differences in hearing between those who met and did not meet PA recommendations at midlife and at late life. RESULTS:A total of 1 386 (43.3%) participants met PA recommendations at midlife. These participants, compared to those who did not meet recommendations, had lower (better) pure-tone average by 1.51 (0.46, 2.55) decibels, identified 0.37 (0.01, 0.74) more words (better score) in the speech-in-noise test, and had a lower relative risk of having hearing loss at older ages (eg, relative risk ratio for severe hearing loss vs normal hearing = 0.70 [0.52, 0.95]). Similarly, those who persistently met PA recommendations from mid- to late life had, compared with those who did not, a better hearing at older ages. CONCLUSIONS:Meeting PA public health recommendations in midlife and mid- to late life was associated with better hearing at older ages and reduced risk of hearing loss. Promoting adequate levels of PA may be an essential component of hearing care.

Relatively few studies on the adverse health impacts of outdoor air pollution have been conducted in Latin American cities, whose pollutant mixtures and baseline health risks are distinct from North America, Europe, and Asia. This study evaluates respiratory morbidity risk associated with ambient air pollution in Quito, Ecuador, and specifically evaluates if the local air quality index accurately reflects population-level health risks. Poisson generalized linear models using air pollution, meteorological, and hospital admission data from 2014 to 2015 were run to quantify the associations of air pollutants and index values with respiratory outcomes in single- and multi-pollutant models. Significant associations were observed for increased respiratory hospital admissions and ambient concentrations of fine particulate matter (PM_2.5), ozone (O₃), nitrogen dioxide (NO₂), and sulfur dioxide (SO₂), although some of these associations were attenuated in two-pollutant models. Significant associations were also observed for index values, but these values were driven almost entirely by daily O₃ concentrations. Modifications to index formulation to more fully incorporate the health risks of multiple pollutants, particularly for NO₂, have the potential to greatly improve risk communication in Quito. This work also increases the equity of the existing global epidemiological literature by adding new air pollution health risk values from a highly understudied region of the world.

OBJECTIVES/OBJECTIVE:This study aimed to examine trends in cannabis-positive urine drug screens (UDSs) among emergency department (ED) patients from 2008 to 2019 using data from the Veterans Health Administration (VHA) health care system, and whether these trends differed by age group (18-34, 35-64, and 65-75 years), sex, and race, and ethnicity. METHOD/METHODS:VHA electronic health records from 2008 to 2019 were used to identify the percentage of unique VHA patients seen each year at an ED, received a UDS, and screened positive for cannabis. Trends in cannabis-positive UDS were examined by age, race and ethnicity, and sex within age groups. RESULTS:Of the VHA ED patients with a UDS, the annual prevalence positive for cannabis increased from 16.42% in 2008 to 27.2% in 2019. The largest increases in cannabis-positive UDS were observed in the younger age groups. Male and female ED patients tested positive for cannabis at similar levels. Although the prevalence of cannabis-positive UDS was consistently highest among non-Hispanic Black patients, cannabis-positive UDS increased in all race and ethnicity groups. DISCUSSION/CONCLUSIONS:The increasing prevalence of cannabis-positive UDS supports the validity of previously observed population-level increases in cannabis use and cannabis use disorder from survey and administrative records. Time trends via UDS results provide additional support that previously documented increases in self-reported cannabis use and disorder from surveys and claims data are not spuriously due to changes in patient willingness to report use as it becomes more legalized, or due to greater clinical attention over time.