Association between Serum Alkaline Phosphatase Level and Cerebral Small Vessel Disease

Abstract

Background: Serum alkaline phosphatase (ALP) is a marker of vascular calcification. A high serum ALP level is associated with an increase in cardiovascular events, and predicts poor functional outcome in patients with stroke. We investigated whether serum ALP was associated with cerebral small vessel disease (cSVD) and large cerebral artery stenosis (LCAS).

Methods: We evaluated vascular risk factors, brain magnetic resonance images (MRIs), and MR angiograms from 1,011 neurologically healthy participants. The presence of silent lacunar infarction (SLI) and moderate-to-severe cerebral white matter hyperintensities (MS-cWMH) were evaluated as indices of cSVD on brain MRIs. Findings of extracranial arterial stenosis (ECAS) or intracranial arterial stenosis (ICAS) were considered to be indices of LCAS on MR angiograms.

Results: Subjects with SLI (odds ratio [OR]: 2.09; 95% confidence interval [CI]: 1.27-3.42; p = 0.004) and MS-cWMH (OR: 1.48; 95% CI; 1.03-2.13, p = 0.036) were significantly more likely to have ALP levels in the third tertile (ALP ≥ 195 IU/L) than the first tertile (ALP ≤ 155 IU/L), after adjusting for cardiovascular risk factors. The mean serum ALP level was significantly higher in patients with SLI or MS-cWMH compared to patients without those findings. After adjustment for confounding factors, the multivariate model found that the statistical significance of serum ALP remained when the presence of SLI (OR: 1.05 per 10 IU/L increase in ALP; 95% CI: 1.02-1.08; p = 0.003) or MS-cWMH (OR: 1.03 per 10 IU/L increase in ALP; 95% CI: 1.00-1.06; p = 0.025) were added to the model. There were no differences in the proportions of patients with LCAS, ICAS, and ECAS across the serum ALP tertiles.

Conclusions: Our study of neurologically healthy participants found a positive association between serum ALP level and indicators of cSVD, but no association between serum ALP level and the indicators of LCAS.

Fig 1. Mean concentration of serum ALP in participants with SLI and MS-cWMH.

(A) Serum ALP levels between SLI and no SLI groups. (B) Serum ALP levels between four cWMH groups according to Fazekas score. Error bar indicates standard deviation. * p < 0.05. ALP: Alkaline phosphatase; SLI, silent lacunar infarct; MS-cWMH, moderate-to-severe cerebral white matter hyperintensities.

Fig 2. Spline curves of the relationship between ALP level and the presence of SLI and MS-cWMH†.

(A) Relationship between ALP level and SLI. (B) Relationship between ALP level and MS-cWMH. The black lines and gray shadows represent the estimated probability and 95% confidence intervals for the presence of SLI and MS-cWMH, and were drawn using the generalized additive model. The x-axis is limited from the 1^th to 99^th percentile of ALP. †Adjusted for age, gender, hypertension, diabetes, hyperlipidemia, coronary artery occlusive disease, and smoking. ALP: Alkaline phosphatase; SLI, silent lacunar infarct; MS-cWMH, moderate-to-severe cerebral white matter hyperintensities.