Title: The trajectory of functional status before and after vascular events
Description: Background: Previous studies that have examined functional status in relation to vascular events have focused on the short term after events and have measured functional status a limited number of times. The trajectories of functional status before and after vascular events are not well characterized, and the factors influencing these trajectories are not well known. Methods: A comprehensive, structured, narrative review was performed on the topic of trajectories of disability and cognition surrounding vascular events. Then using 2 large population-based epidemiologic cohorts, the Northern Manhattan Study (NOMAS) and the Cardiovascular Health Study (CHS), trajectories of functional status were examined. In Analysis A, in NOMAS, the effect of inflammatory biomarkers (interleukin-6 [IL6], tumor necrosis factor receptor-1 [TNFR1], C-reactive protein [CRP], and lipoprotein-associated phospholipase-A2 [LpPLA2]) on the intercept and slope of functional status was determined over a median of 13 years, measured with yearly assessments by the Barthel index.

In Analysis B, in NOMAS, a similar modeling strategy was used to examine whether subclinical ischemic disease on brain MRIs, measured by subclinical brain infarct (SBI) and white matter hyperintensity volume (WMHV), was associated with functional trajectories. In Analysis C, in CHS, participants had yearly assessments of disability with a combined activities of daily living (ADL) and instrumental ADL scale. The slope of change in disability was compared before and after vascular events (stroke and myocardial infarction [MI]). Results: In Analysis A, CRP (-0.41 BI points per 1 SD increase, 95% CI -0.82 to 0.002) and LpPLA2 (-0.40, 95% CI -0.75 to -0.04) were associated with baseline BI but not change over time. TNFR1 was associated with baseline BI (-0.93, 95% CI -1.59 to -0.26) and change over time (-0.36 BI points per year, 95% CI -0.69 to -0.03). In Analysis B, functional change was -0.85 BI points per year (95%CI -1.01 to -0.69); among those with SBI there were -0.88 additional points annually (-1.44 to -0.32).

In WMHV models, annual functional change was -1.04 points (-1.2 to -0.88), with -0.74 additional points annually per SD WMHV increase (-0.99 to -0.49). In Analysis C, stroke (0.88, 95% CI 0.57-1.20, p<0.0001) was associated with a greater acute increase in disability than MI (0.20, 0.06-0.35, p=0.006). The annual increase in disability before stroke (0.06 points per year, 0.002-0.12, p=0.04) more than tripled after stroke (0.15 additional points per year, 0.004-0.30, p=0.04). The annual increase in disability before MI (0.04 points per year, 0.004-0.08, p=0.03) did not change significantly after MI (0.02 additional points per year, -0.07-0.11, p=0.7). Conclusions: In these large population-based studies with repeated measures of functional status and disability over long-term follow-up, several trajectories were found. In Analysis A, TNFR1 predicted worse overall functional status as well as accelerated decline over time. In Analysis B, both SBI and WMHV were associated with accelerated decline.

In Analysis C, there was a steeper decline in function after stroke but not MI. These findings help to elucidate the course and potential etiologies of long-term functional decline related to vascular events, and they suggest directions for future research in this area.