Background: The role of inflammation in cerebral small vessel disease remains uncertain. Tumor necrosis factor-alpha receptor 1 (TNFR1) has been associated with atherosclerosis and risk of stroke. We hypothesized that TNFR1 concentrations would be associated with cerebral white matter disease (WMD) and subclinical infarcts in patients with recent lacunar stroke.
Methods: Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) was an international, multicenter, ancillary biomarker study nested within the Secondary Prevention of Small Subcortical Strokes trial (SPS3; http://www.clinicaltrials.gov unique identifier: NCT00059306), a Phase III trial in patients with recent lacunar stroke. Patients had blood samples collected at enrollment, and concentrations of inflammatory biomarkers, including TNFR1, were measured using ELISA at a central laboratory. Enrollment MRI scans were read centrally and interpreted for silent infarcts and burden of WMD using semi-quantitative scales. We compared proportions of patients with prior infarcts and WMD scores across quartiles of TNFR1, and used logistic regression to estimate odds ratios and 95% confidence intervals (OR, 95%CI) to examine the relationship between TNFR1 and subclinical disease after adjusting for demographics and comorbidities.
Results: Among 1004 lacunar stroke patients with TNFR1 data (mean age 63.3 ± 10.8 years), 407 (40%) had infarcts besides the qualifying infarct; half the cohort had 0-4 white matter lesions, 27% had 5-8 lesions, and 23% had >=9 lesions. TNFR1 levels were associated with WMD score >=9 (OR per standard deviation (SD) TNFR1=1.2, 95%CI 1.0-1.4). Larger proportions of those in the top quartile of TNFR1, compared to those in the lowest, had ≥9 white matter lesions (29% versus 19%, p=0.026) and additional infarcts (45% versus 37%, p=0.28). After adjusting for demographics and comorbidities, the effect of TNFR1 on WMD score >=9 (adjusted OR per SD=1.1, 95%CI 1.0-1.3) and additional infarcts (adjusted OR 1.2, 95%CI 1.0-1.3) attenuated.
Conclusions: Among recent lacunar stroke patients, TNFR1 concentrations were associated with prior or subclinical cerebrovascular disease. Future studies of TNF and TNF inhibitors in cerebral ischemic disease may be warranted.