CSF and plasma placental growth factor as a biomarker for small-vessel damage in VCID.

Abstract

Vascular contributions to cognitive impairment and dementia (VCID) is an important and understudied cause of cognitive impairment, often co-morbid with Alzheimer's disease and other neurodegenerative conditions. White matter hyperintensities (WMH) are apparent on magnetic resonance imaging (MRI). WMH has long been considered to be a consequence of cerebrovascular pathology; more specifically cerebral small vessel disease resulting from hypertension and microinfarcts. Much like the pathologic angiogenesis that occurs in retinopathies, pathologic angiogenesis in the brain results in blood-brain barrier leakage and, counterintuitively, tissue ischemia. We have examined plasma and CSF angiogenic mediators in a cohort of 120 research participants who also have a range of cognitive impairments and severity of WMH changes on MRI. We have examined post-mortem autopsy tissue to determine PlGF expression in the human brain. We also performed exosome studies in plasma samples. We found that several members of the vascular endothelial growth factor (VEGF) family, in particular placental growth factor (PlGF), which is significantly associated with WMH growth and cognitive measures, especially executive function measures. We found strong immunostaining in the white matter of individuals with small vessel disease, primarily perivascular labeling. Such staining was significantly less in the brains of age-matched, pathology-free individuals. Using exosomes, we found that the primary source of PlGF in the plasma is astrocytic, and also there is some PlGF in endothelial exosomes. PlGF, and related angiogenic mediators, have a pathological role in cerebral small vessel disease and indicate angiogenic dysregulation as playing a key role in the pathogenesis of small vessel disease.