Elevated plasma levels of neuropeptide proenkephalin a predict mortality and functional outcome in ischemic stroke.
OBJECTIVE
The purpose of this study was to investigate neuropeptides in patients presenting with symptoms of acute cerebrovascular disease.


BACKGROUND
The precursor neuropeptides proenkephalin A (PENK-A) and protachykinin (PTA) are markers of blood-brain barrier integrity and have been recently discussed in vascular dementia and neuroinflammatory disorders.


METHODS
In a prospective observational study, we measured plasma PENK-A and PTA concentrations in 189 consecutive patients who were admitted with symptoms of acute stroke. Plasma concentrations were determined by sandwich immunoassay; lower detection limits were 15.6 pmol/l (PENK-A) and 22 pmol/l (PTA). Clinical outcome was assessed at 3 months for mortality, major adverse cerebro/cardiovascular events, and functional outcome (modified Rankin scale).


RESULTS
PENK-A was significantly elevated in patients with ischemic stroke (n = 124; 65.6%) compared to patients with transient ischemic attack (n = 16; 8.5%) and to patients with nonischemic events (n = 49; 25.9%): median (interquartile range), stroke 123.8 pmol/l (93 to 160.5); transient ischemic attack 114.5 pmol/l (85.3 to 138.8); and nonischemic event 102.8 pmol/l (76.4 to 137.6; both groups vs. stroke p < 0.05). High concentrations of PENK-A, but not PTA, were related to severity of stroke as assessed by National Institutes of Health Stroke Scale (NIHSS [r = 0.225; p = 0.002]) and to advanced functional disability (modified Rankin Scale score 3 to 6 vs. 0 to 2: 135.1 pmol/l [99.2 to 174.1] vs. 108.9 pmol/l [88.6 to 139.5]; p = 0.014). After adjusting for age, NIHSS, and brain lesion size (computed tomography), PENK-A predicted mortality (hazard ratio [HR] for log-10 PENK-A in pmol/l: 4.52; 95% confidence interval [CI]: 1.1 to 19.0; p < 0.05) and major adverse cerebro/cardiovascular events (HR: 6.65; 95% CI: 1.8 to 24.9; p < 0.05). Patients in the highest quartile of PENK-A (cutoff >153 pmol/l) had an increased risk of mortality (HR: 2.40; 95% CI: 1.02 to 5.40; p < 0.05) and of major adverse cerebro/cardiovascular events (HR: 2.23; 95% CI: 1.10 to 4.54; p < 0.05).


CONCLUSIONS
PENK-A is a prognostic biomarker in the acute phase of ischemic stroke. Elevated PENK-A concentrations are associated with ischemic stroke, severity of cerebral injury, and may have prognostic value for fatal and nonfatal events.
Center for Stroke Research Berlin, Charité Universitätsmedizin Berlin, Germany. wolfram.doehner@charite.de
Wolfram
W
Doehner
Stephan
S
von Haehling
Jennifer
J
Suhr
Nicole
N
Ebner
Andreas
A
Schuster
Eike
E
Nagel
Arthur
A
Melms
Thomas
T
Wurster
Konstantinos
K
Stellos
Meinrad
M
Gawaz
Boris
B
Bigalke
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood*; D001925:Brain Damage, Chronic / Q000097:blood* / Q000401:mortality*; D002545:Brain Ischemia / Q000097:blood* / Q000401:mortality*; D002423:Cause of Death; D002544:Cerebral Infarction / Q000097:blood* / Q000401:mortality*; D004185:Disability Evaluation; D004745:Enkephalins / Q000097:blood*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D002537:Intracranial Arteriosclerosis / Q000097:blood / Q000401:mortality; D002546:Ischemic Attack, Transient / Q000097:blood / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011498:Protein Precursors / Q000097:blood*; D015320:Tachykinins / Q000097:blood
D015415:Biomarkers; D004745:Enkephalins; D011498:Protein Precursors; D015320:Tachykinins; C029992:proenkephalin; C054618:protachykinin