Serum SAP emerges as strongest marker of white-matter lesions in older CSVD patients

In a single-center cross-sectional study of 382 hospitalized older patients with cerebral small-vessel disease, higher serum homocysteine, serum amyloid P component, neurofilament light chain and carotid plaque Crouse scores were each associated with the presence and greater severity of white-matter hyperintensities. Serum amyloid P component, or SAP, showed the strongest overall association with lesion burden and the best performance in exploratory analyses designed to distinguish patients with white-matter hyperintensities from those without them. The researchers say the findings identify SAP as a promising candidate for further validation as an auxiliary marker, rather than as a diagnostic test ready for independent clinical use.

The study population consisted of consecutively enrolled patients at the Department of Neurology of the North China University of Science and Technology Affiliated Hospital in Tangshan, China, between July 2022 and June 2024. Participants were 60 to 83 years old, with a mean age of 70.32 ± 5.30 years; 184 were men and 198 were women. All met diagnostic criteria for the arteriolosclerotic, or type 1, form of cerebral small-vessel disease, while patients with other recognized subtypes were excluded. Of the 382 participants, 232 had white-matter hyperintensities and 150 did not. The latter group still had cerebral small-vessel disease based on other imaging features, such as lacunar infarcts, cerebral microbleeds or enlarged perivascular spaces.

White-matter hyperintensities were identified on 3-T magnetic resonance imaging as areas that were hyperintense on T2-weighted and fluid-attenuated inversion recovery images, were not obviously bright on diffusion-weighted imaging and had corresponding T1-weighted characteristics. Two radiologists assessed the scans independently while blinded to clinical and laboratory information, resolving disagreements by consensus. Severity was classified with the Fazekas scale: patients with a total score of 1–2 were placed in the mild group, those scoring 3–4 in the moderate group and those scoring 5–6 in the severe group. Among the 232 patients with hyperintensities, 111 had mild disease, 71 moderate disease and 50 severe disease. The weighted Cohen’s kappa for the total Fazekas score was 0.859, indicating excellent agreement between the two readers.

All four investigated indicators were higher on average in patients with white-matter hyperintensities than in those without them. Mean serum homocysteine was 24.28 ± 11.68 μmol/L in the hyperintensity-positive group compared with 13.43 ± 5.79 μmol/L in the negative group. SAP concentrations were 8.80 ± 3.23 μg/L and 4.91 ± 1.50 μg/L, respectively; neurofilament light chain, or NfL, was 117.02 ± 35.77 ng/L versus 101.02 ± 36.75 ng/L; and the carotid plaque Crouse score was 3.06 ± 1.27 points versus 1.55 ± 1.11 points. Age was also higher among patients with hyperintensities, at 72.07 ± 4.83 years compared with 67.62 ± 4.87 years. The two groups did not differ significantly in body mass index, smoking or drinking history, hypertension, diabetes, coronary heart disease, fasting glucose, major blood lipid measures or creatinine.

A clear stepwise pattern emerged when the 232 patients with hyperintensities were divided by lesion severity. Mean homocysteine rose from 20.14 ± 8.18 μmol/L in the mild group to 24.20 ± 9.57 μmol/L in the moderate group and 33.60 ± 15.31 μmol/L in the severe group. SAP increased from 7.72 ± 3.03 μg/L to 8.89 ± 2.30 μg/L and then 11.06 ± 3.63 μg/L. NfL rose from 104.81 ± 31.15 ng/L to 118.29 ± 30.72 ng/L and 142.31 ± 38.88 ng/L, while the Crouse score rose from 2.62 ± 1.28 to 3.20 ± 0.75 and 3.86 ± 1.43 points. Pairwise comparisons showed statistically significant differences between all three severity categories for each indicator. Spearman correlation analysis also found positive relationships with Fazekas severity: SAP had the largest coefficient at 0.451, followed by homocysteine at 0.432, NfL at 0.389 and the Crouse score at 0.366, with all false-discovery-rate-corrected p-values below 0.001.

Multivariable analyses supported the same pattern. In binary logistic regression, each of the four indicators remained associated with the presence of white-matter hyperintensities after adjustment for measured confounders. The reported adjusted odds ratios were 1.219 per unit of homocysteine, 2.496 per unit of SAP, 1.015 per unit of NfL and 1.819 per unit of Crouse score; age also remained independently associated with hyperintensity presence. All five associations remained significant after false-discovery-rate correction. Ordinal logistic regression, with sex and creatinine included as prespecified potential confounders, likewise found independent positive associations with increasing severity. Adjusted odds ratios for a more severe WMH category were 1.109 for homocysteine, 1.133 for SAP, 1.024 for NfL and 2.157 for the Crouse score, while age had an odds ratio of 1.163. A parallel-lines test did not reject the proportional-odds assumption, with p = 0.56.

Exploratory receiver operating characteristic analyses produced an area under the curve of 0.880 for SAP, with a reported optimal cutoff of 6.18 μg/L, sensitivity of 85.3% and specificity of 84.5%. The Crouse score followed with an area under the curve of 0.822 and homocysteine with 0.813; both had relatively low sensitivity and high specificity. Age achieved an area under the curve of 0.744, while NfL had the weakest discrimination at 0.667, despite a sensitivity of 84.1%. These ROC results were treated as exploratory and did not receive the same false-discovery-rate correction as the regression and correlation tests. The findings therefore describe how well each measure separated groups in this particular hospitalized cohort, not their accuracy in an unselected population or their ability to predict future lesions.

The four indicators represent different biological dimensions. Homocysteine is a metabolism-related intermediate whose elevation has been linked in preclinical and previous clinical research to endothelial injury, oxidative stress, vascular inflammation and small-artery changes. NfL is a structural axonal protein that can enter peripheral blood after axonal injury, making it a marker of neuronal damage rather than one specific to cerebral small-vessel disease. The Crouse score sums the maximum thickness of discrete carotid plaques and therefore measures extracranial atherosclerotic burden; it does not describe plaque stability. SAP is a liver-produced pentraxin-family glycoprotein involved in immune and inflammatory responses. Prior evidence discussed by the researchers suggests that blood–brain-barrier disruption may permit circulating SAP to enter injured brain tissue, where experimental studies report inflammatory and potentially neurotoxic effects. The present data did not measure cerebrospinal-fluid markers or directly test any of these mechanisms.

Several limitations constrain the interpretation and generalizability of the findings. The study was conducted at one hospital among selected older inpatients, all of whom were of East Asian ancestry, so selection bias and residual confounding are possible and the results may not represent community-dwelling older adults. Its cross-sectional design cannot establish whether elevated biomarkers precede white-matter damage, contribute causally to it or merely co-occur with existing lesions. Blood concentrations may also differ from concentrations within the brain, particularly for SAP and NfL, and the Crouse score captures plaque thickness rather than the full vascular process. Validation in larger, multicenter and prospective cohorts is therefore needed to determine whether SAP or combinations of these markers can improve screening or severity assessment. The findings do not establish that lowering any biomarker, treating plaque or altering vascular risk factors will prevent or reduce white-matter lesions, and the authors draw no therapeutic conclusions from these data.

Subject of Research: Associations of four blood and vascular markers with white-matter hyperintensities in older adults with cerebral small-vessel disease

Article Title: Associations of serum Hcy, SAP, NfL, and carotid plaque Crouse score with white-matter hyperintensities in older patients with cerebral small-vessel disease

Article References: Ren, B., Ma, Y., Mao, W., & Wu, X. (2026). Associations of serum Hcy, SAP, NfL, and carotid plaque Crouse score with white-matter hyperintensities in older patients with cerebral small-vessel disease. Frontiers in Neurology, 17, 1977360. https://doi.org/10.3389/fneur.2026.1977360

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1977360

Keywords: cerebral small-vessel disease, white-matter hyperintensities, serum amyloid P component, homocysteine, neurofilament light chain, carotid plaque Crouse score, cerebrovascular biomarkers, brain MRI, older adults, Associations, serum, carotid