Blood-brain barrier-associated biomarker correlated with cerebral small vessel disease and shunt outcome in normal pressure hydrocephalus: a prospective cohort study

Abstract

Background: Blood-brain barrier (BBB) breakdown is associated with neurodegeneration and cognitive impairment. Cerebral small vessel disease (CSVD) is also common in idiopathic normal pressure hydrocephalus (iNPH). Biomarkers in the cerebrospinal fluid (CSF) may reflect the severity of neuropathological damage and indicate a relationship between BBB integrity and iNPH and its surgical outcome. The authors investigated the association of CSVD and comorbidity-related CSF biomarkers with shunt outcomes in iNPH.

Materials and methods: This prospective cohort study recruited 53 patients with iNPH, who were subgrouped by CSVD severity. CSF proteins were analyzed, including soluble platelet-derived growth factor receptor-β (sPDGFR-β), Alzheimer's disease biomarkers, neurofilament light chain (NfL), and triggering receptor expressed on myeloid cells 2 (Trem2). We assessed symptom improvement, investigated its association with biomarkers levels, calculated protein cutoffs for surgical outcomes using receiver operating characteristic (ROC) curves, and compared model predictions using different proteins through hierarchical regression analysis.

Results: Among patients with iNPH, 74% had comorbid CSVD. Patients with severe CSVD exhibited significantly higher sPDGFR-β levels ( P =0.019) and better postoperative performance (β=0.332, t=2.174, P =0.039; r =0.573, P =0.001). Analysis of the predictive potential of the biomarkers showed that sPDGFR-β was predictive of surgical outcomes (area under curve=0.82, sensitivity=66.8%, specificity=94.7%). A Comparison of the models revealed a greater effect of sPDGFR-β (Adjusted R 2 =0.247, ∆R 2 =0.160, ∆F(1, 37)=8.238, P =0.007) on cognitive improvement.

Conclusion: This study highlighted the relevance of CSF biomarkers in assessing CSVD severity and predicting iNPH surgical outcomes. CSF shunt surgery may provide an alternative treatment for neurodegenerative diseases with BBB breakdown and dysfunctional CSF clearance.

Figure 1

Elevated sPDGFR-β levels in iNPH patients with severe CSVD were associated with improvement after surgery. CSVD^NM, n=11, CSVD^MS, n=29. (A, B) MRI of a patient with iNPH showed ventriculomegaly and vascular damage. EI and CA values were calculated according to the iNPH diagnostic guidelines. CSVD scores were determined according to the protocol described in Subjects and Methods. (C) The correlation between sPDGFR-β levels and MRI was analyzed by Spearman correlation coefficient (r). (D) The association between preoperative sPDGFR-β levels and improved symptoms (Score_pre-shunt-Score_post-shunt) was accessed by Spearman correlation after 3 months of follow-up. **P<0.01, significance. CSVD^NM, none to mild cerebral small vessel disease; CSVD^MS, moderate to severe cerebral small vessel disease; EI, Evans index; CA, callosal angle; FLAIR, fluid-attenuated inversion recovery; GRE, gradient echo sequences; EPVS, enlarged perivascular spaces; sPDGFR-β, soluble platelet-derived growth factor receptor-β; iNPHGS, idiopathic normal pressure hydrocephalus grading scale.