Association Between Nerve Growth Factor and Clinical Stroke and Covert Brain Infarcts: The FHS

Nerve growth factor (NGF) is associated with neuroprotection and neural repair. However, whether NGF is associated with future stroke in humans is unknown. We determined the association between late midlife serum NGF and subsequent risk of clinical stroke, covert brain infarcts, and white matter hyperintensity volume on magnetic resonance imaging.

A total of 1709 stroke-free participants from the FHS (Framingham Heart Study) Offspring and Omni 1 cohorts who attended Offspring examination 7/Omni 1 examination 2, respectively (1998-2001), with baseline serum NGF were included. The primary outcomes were incident all-cause and ischemic stroke. Secondary outcomes included covert brain infarct and white matter hyperintensity volume on magnetic resonance imaging. Serum NGF was analyzed continuously and by tertiles, adjusting for age, sex, and vascular risk factors. Cox proportional hazards regression models were used to assess the association between serum NGF and all-cause and ischemic stroke risk. Linear and logistic regression models were used to evaluate the association between serum NGF levels and white matter hyperintensity volume and covert brain infarct.

Mean age was 60.6±9.6 years, and 47.6% were men. The median follow-up for incident stroke was 19.2 (interquartile range, 14.7-21.3) years. The highest tertile (tertile 3) of NGF, compared with the bottom tertile (tertile 1), was associated with a reduced risk of incident all-cause stroke (hazard ratio [HR], 0.59 [95% CI, 0.37-0.94]; P=0.03) and ischemic stroke (HR, 0.50 [95% CI, 0.27-0.77]; P=0.003). Tertile 3 versus tertile 1 of NGF was also associated with a reduced risk of covert brain infarct (odds ratio, 0.57 [95% CI, 0.34-0.97]; P=0.04).

Higher serum NGF in late midlife demonstrates a protective association with future risk of silent and clinically overt stroke.