Association between Serum Alkaline Phosphatase Level and Cerebral Small Vessel Disease

<div><p>Background</p><p>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).</p><p>Methods</p><p>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.</p><p>Results</p><p>Subjects with SLI (odds ratio [OR]: 2.09; 95% confidence interval [CI]: 1.27–3.42; <i>p</i> = 0.004) and MS-cWMH (OR: 1.48; 95% CI; 1.03–2.13, <i>p</i> = 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; <i>p</i> = 0.003) or MS-cWMH (OR: 1.03 per 10 IU/L increase in ALP; 95% CI: 1.00–1.06; <i>p</i> = 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.</p><p>Conclusions</p><p>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.</p></div

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

<p>(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. * <i>p</i> < 0.05. ALP: Alkaline phosphatase; SLI, silent lacunar infarct; MS-cWMH, moderate-to-severe cerebral white matter hyperintensities.</p

Logistic regression analysis of serum ALP in the presence of SLI and MS-cWMH.

<p>Logistic regression analysis of serum ALP in the presence of SLI and MS-cWMH.</p

Logistic regression analysis of the presence of SLI, MS-cWMH, LCAS, ICAS, and ECAS in 1,011 Korean participants according to serum ALP tertile.

<p>Logistic regression analysis of the presence of SLI, MS-cWMH, LCAS, ICAS, and ECAS in 1,011 Korean participants according to serum ALP tertile.</p

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

<p>(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.</p

Demographic and laboratory data of 1,011 study participants according to serum ALP tertile.

<p>Demographic and laboratory data of 1,011 study participants according to serum ALP tertile.</p

Table_1_Differential Impact of Plasma Homocysteine Levels on the Periventricular and Subcortical White Matter Hyperintensities on the Brain.docx

Background: The clinical significance of cerebral white matter hyperintensities (WMH) on brain magnetic resonance imaging (MRI) has recently increased, and recognized now as a risk factor for future stroke and dementia. High levels of plasma homocysteine (Hcyt) are associated with cerebral WMH. Recent studies suggest a different anatomy and physiology in the arteriolar system may be supplied to the periventricular and deep subcortical white matter. We hypothesize that plasma Hcyt levels have differing impacts on periventricular WMH (PVWMH) than on deep subcortical WMH (DSWMH).Methods: We evaluated plasma Hcyt levels from 937 neurologically healthy participants. The severity of PVWMH and DSWMH was evaluated by the use of a manual grading scale. Moderate to severe PVWMH and DSWMH levels were defined when the Fazekas score was two or three, respectively. Predominant PVWMH (pred-PVWMH) and predominant DSWMH (pred-DSWMH) were defined as having a difference of Fazekas score between PVWMH and DSWMH of two or more. Other confounding variables including age, sex, vascular risk factors, and estimated glomerular filtration rate (eGFR) were also analyzed.Results: Logistic regression revealed that, after adjusting for the confounding variables, PVWMH was associated with old age, hypertension, diabetes mellitus, low eGFR, and high plasma Hcyt levels. DSWMH was associated with old age, hypertension, and hypercholesterolemia but not with plasma Hcyt levels. Plasma Hcyt levels were associated with pred-PVWMH but not with pred-DSWMH.Conclusions: High plasma Hcyt levels are strongly associated with the development of PVWMH but not DSWMH. Our results suggest the possibility that different pathogeneses exist for PVWMH and DSWMH and that dysregulated Hcyt metabolism associated with the development of PVWMH.</p

Results of univariate logistic regression for the severity of leukoaraiosis.

<p>Results of univariate logistic regression for the severity of leukoaraiosis.</p

Red blood cell distribution on the presence of severe degree of leukoaraiosis.

<p>Red blood cell distribution on the presence of severe degree of leukoaraiosis.</p

Relationship between red blood cell distribution width and leukoaraiosis.

<p>A) Boxplot for RDW according to the Fazekas scale. In each boxplot, the lower and upper ends of the box represent the 25^th and 75^th percentiles (interquartile range, IQR) and the line inside the box represents the median. An asterisk indicates the mean value. The ends of the vertical lines represent the lowest and the highest value within the range from 25^th percentile– 1.5 x IQR to 75^th percentile + 1.5 x IQR. B) Regression spline curve of estimated probability for severe degree of leukoaraiosis according to the level of RDW. The black lines and gray shadows represent the estimated probability and the 95% confidence intervals for the presence of severe degree of leukoaraiosis (Fazekas scale ≥2) at the RDW level, based on the generalized additive model with splines. Adjustments were made on the variables listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0150308#pone.0150308.t003" target="_blank">Table 3</a>. The x-axis is limited from the 5^th to the 95^th percentile of RDW to avoid overfitting by rare extremes. RDW indicates red blood cell distribution width.</p