Vascular and inflammatory plasma biomarkers correlate with human post‐mortem cerebral vascular pathology

Abstract

AbstractBackgroundVascular Cognitive Impairment and Dementia (VCID) is a common cause of dementia in Western populations. Small‐vessel disease (SVD), a VCID subtype, can present as arteriolosclerosis and microinfarcts. Currently, identifying this pathology clinically is limited to MRI, which is expensive, limited in terms of small vessel resolution and not widely available. Therefore, a more accessible screening tool is needed to clinically evaluate SVD. Here, we evaluate the relationships between vascular and inflammatory plasma biomarkers with global levels of SVD pathology in human brain.MethodPlasma and brain tissue samples were obtained from the University of Kentucky Alzheimer’s Disease Research Center (UK‐ADRC) Brain Bank. Cases were selected from participants who had an available plasma sample from within two years of death. These plasma samples were analyzed using a digital immunoassay (Quanterix Simoa) to determine biomarker levels of placental growth factor (PlGF), matrix metalloproteinase 9 (MMP9), and tumor necrosis factor α (TNFα). Biomarker levels were categorized by quartiles. Pathological evaluation was performed by UK‐ADRC neuropathologists, blind to clinical data. The association of plasma markers with neuropathology was estimated via multinomial and binary logistic regressions adjusted for age and sex. Global arteriosclerosis was examined using a scale of none/mild/moderate/severe, with none being the reference. Presence or absence of microinfarcts was also examined.ResultIncluded cases (n=93) were age 82.0±9.2 years at death; 46.7% were female. Higher plasma placental growth factor (PlGF) levels were associated with less severe arteriolosclerosis: odds ratio (OR)=0.8 (95% CI 0.5‐1.3), 0.8 (0.5‐1.5), and 0.6 (0.2‐1.7); higher plasma MMP9 levels were associated with more severe arteriolosclerosis (OR=1.0 (0.5‐2.1), 0.7 (0.3‐1.5), 0.7 (0.2‐2.4), comparing odds of mild, moderate, and severe to none, respectively), though these results were not statistically significant. Lower plasma PlGF and MMP9, and higher TNFa, were associated with higher odds of microinfarction: OR=0.59 (0.33‐1.02), 0.74 (0.38‐1.42), and 2.28 (0.84‐6.20), respectively.ConclusionOur results, while based on a small sample, suggest plasma PlGF and MMP9 levels have an inverse relationship with global SVD pathology, while plasma TNFa is positively correlated with increased global SVD pathology. These results provide support for potential use of plasma biomarkers as a clinical screening tool for SVD pathology.