OBJECTIVES/GOALS: Motoric cognitive risk (MCR) is a pre-dementia syndrome characterized by slow gait and subjective cognitive complaints. In the Atherosclerosis Risk in Communities (ARIC) study, we aim to (1) identify plasma proteins and protein modules associated with MCR and (2) compare the proteomic signature of MCR to that of mild cognitive impairment (MCI). METHODS/STUDY POPULATION: Nondemented ARIC participants were classified by MCR status (yes/no) according to a memory questionnaire and 4-meter walk. MCI status (yes/no) was classified by expert diagnosis using standardized criteria. We measured 4,877 proteins in plasma collected at ARIC Visit 5 (late-life) and Visit 2 (midlife) utilizing the SomaScan4 proteomic assay. Multivariable logistic regression”adjusted for demographic variables, kidney function, cardiovascular risk factors, and APOE4 status”related each protein to MCR at late-life. An FDR corrected P RESULTS/ANTICIPATED RESULTS: Proteome-wide association study among 4076 ARIC participants (mean age=75; 58% women, 17% Black, 4% MCR+, 21% MCI+; MCR+ and MCI+ groups overlapped) at late-life identified 26 MCR-associated proteins involved in metabolism, vascular/visceral smooth muscle, and extracellular matrix organization. At an uncorrected P DISCUSSION/SIGNIFICANCE: This proteomic characterization of MCR identifies novel plasma proteins and networks, both distinct from and overlapping with those of MCI, thus highlighting the partially divergent mechanisms underlying these pre-dementia syndromes. These findings may be leveraged toward dementia prognostication and targeted therapeutic approaches.

OBJECTIVES/SPECIFIC AIMS: To identify cardiac structural and function parameters, obtained on usual stroke-care TTE evaluation, associated with cardioembolic stroke (CE) in patients without AF. Hypothesis—left atrial (LA) size and valve dysfunction will be strongly associated with incident CE. METHODS/STUDY POPULATION: Inclusion criteria: July 1, 2013 to July 1, 2015 admission with imaging-confirmed ischemic stroke, no AF, TTE within 1st 7 days. TTE structure/function parameters were recorded. Stroke subtype (CE vs. other) defined using TOAST criteria, blinded to TTE. New AF definition: AF on ECG, telemetry or event monitor. CE/New AF outcome of interest in separate multivariable logistic regression models testing associations with TTE parameters (adjusting for demographics/vascular risk factors). RESULTS/ANTICIPATED RESULTS: Participants (n=332) were ~60 years hypertensive black males with moderate NIHSS and normal ejection fraction. In adjusted models, odds of CE increased with increasing LA systolic diameter (per 0.1 cm), mitral E point velocity(cm/s), mitral valve dysfunction, wall motion abnormality. New AF also associated with increasing LA systolic diameter. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings may suggest cardiac structural changes independent of AF that are on the CE causal pathway. Understanding the relationship between such TTE parameters and stroke subtype would impact clinical practice, as such TTE data is underutilized when considering stroke mechanism and management.

As the older segment of our population grows, cognitive decline and dementia will increase in prevalence, with Alzheimer's disease (AD) as the cause in most cases. Until a cure exists, prevention through the identification and manipulation of modifiable risk factors for dementia, in general, or AD, in particular, will be our only means of reducing dementia prevalence or delaying its onset. Furthermore, it is likely that eventual treatments for AD, when available, will depend on the ability to identify individuals at greatest risk for developing AD. Sleep disturbances are common in later life – roughly half of older adults experience regular insomnia (Ohayon, 2002) and about as many have some degree of sleep-disordered breathing (SDB) (Ancoli-Israel et al., 1991) – and accumulating evidence suggests they may contribute to cognitive decline, at least in part, by promoting the development of AD pathology (Spira et al., 2014). Because they are treatable, sleep disturbances are an important potential target for ongoing study in AD prevention. Moreover, understanding the mechanisms underlying an effect of sleep on subsequent cognitive decline and AD would allow for better identification of opportunities and optimal timing for treatment of sleep disorders, and ultimately perhaps, AD prevention.

Short- and long-term cognitive declines after cardiac surgery with cardiopulmonary bypass have been reported, but the frequency, severity, nature, and etiology of postoperative cognitive changes have been difficult to quantify. Current studies have corrected the principal methodological shortcoming of earlier studies by including control groups, and have shown that while early postoperative cognitive decline does occur in some patients, it is generally mild and reversible by 3 months after surgery. Late cognitive changes do occur, but comparison with patients undergoing off-pump surgery or those being treated medically suggests that these changes are not specific to CABG or more specifically to the use of cardiopulmonary bypass. (JINS, 2010, 16, 221–226.)