Abstract
BackgroundActivation of indoleamine 2,3-dioxygenase (IDO) and higher concentrations of several kynurenine metabolites have been observed post-stroke, where they have been associated with increased mortality. While lower tryptophan or a higher ratio of kynurenine/tryptophan (K/T) in peripheral blood have been associated with dementia and the severity of cognitive symptoms in Alzheimer's disease, the association between K/T ratios and post-stroke cognitive impairment (PSCI) has not been investigated.MethodsPatients were recruited from the acute stroke unit of a general hospital within 1 month post-stroke. Assessments included the Standardized Mini-Mental State Examination (sMMSE) for cognition, the National Institutes of Health Stroke Scale (NIHSS) for stroke severity, and the Center for Epidemiological Studies-Depression Scale (CES-D) for depressive symptoms. Tryptophan and kynurenine concentrations were determined by high-performance liquid chromatography.ResultsA total of 41 patients with ischemic stroke ([mean ± SD] age 72.3 ± 12.2 years, 53.7% male, sMMSE 25.6 ± 4.1, NIHSS 7.27 ± 5.55) were recruited. Higher K/T ratios were associated with lower post-stroke global cognition (i.e. sMMSE scores; β = -.327, P = .037). A backward stepwise elimination linear regression (F1,40=6.15, P=.005, adjusted R2=.205) showed that the highest K/T ratio tertile (β = -.412, P = .006) predicted lower sMMSE scores, controlling for age (β = -.253, p = .081), with NIHSS (β = -.027, P = 0.859), and lesion volume (β = -.066, P = 0.659) removed from the model. In receiver operating characteristic analysis, a K/T ratio of 78.3 μmol/mmol (top tertile) predicted significant cognitive impairment (sMMSE score ≤ 24) with 67% sensitivity and 86% specificity (area under the curve = 0.730, p = .022).ConclusionsThese data suggest an inflammatory response characterized by IDO activation may be relevant to the development of PSCI. Since the neuroactivity of kynurenine metabolites may be amenable to pharmacotherapeutic intervention, the K/T ratio may be a clinically important biomarker.
Highlights
Activation of indoleamine 2,3-dioxygenase (IDO) and higher concentrations of several kynurenine metabolites have been observed post-stroke, where they have been associated with increased mortality
We have recently demonstrated a relationship between post-stroke cognitive impairment (PSCI) and two inflammatory biomarkers, C-reactive protein (CRP) and interleukin-6 (IL-6) [13]
Stroke severity and lesion volume did not significantly modify this relationship suggesting that the clinical importance of the K/T ratio may extend beyond their relationships with these established risk factors for PSCI
Summary
Activation of indoleamine 2,3-dioxygenase (IDO) and higher concentrations of several kynurenine metabolites have been observed post-stroke, where they have been associated with increased mortality. For older patients with ischemic stroke, post-stroke cognitive impairment (PSCI) is Disease-10 (ICD-10) criteria, within 1 year after stroke [7]. The prevalence of post-stroke MMSE scores less than 24, indicative of significant cognitive impairment, was much higher than the prevalence of dementia diagnosed by standard criteria, which included the DSM-IV or ICD-10 [7]. The majority of these and other known risk factors for PSCI including older age, lower level of education, family history of dementia [8] are not readily amenable to treatment. There is considerable need to identify pathophysiological mechanisms that may contribute to PSCI
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