Increased CSF biomarkers of angiogenesis in Parkinson disease

The authors of this study have found increased biomarkers of angiogenesis (proteins related to new blood vessel formation) in the CSF of patients with PD and PD with dementia (PDD).

The authors also detected increased CSF/plasma albumin ratio in the patients with PD, which suggests a loss of integrity in the blood-brain barrier in patients with PD. Interestingly, the biomarkers of angiogenesis were correlated with CSF/plasma albumin ratio, leading the authors to suggest that angiogenic factors might contribute to cerebral microbleeds and reduced blood brain barrier function, which could in be involved in the pathogenesis of PD.

This idea that angiogenesis and reduced blood-brain barrier function might contribute to the disease process in PD is not entirely new. A few studies of animal models of PD and post-mortem studies of PD patients' brains have also found increased levels of VEGF (one of the markers of angiogenesis identified by this paper) and signs of vascular proliferation. However, it is a relatively unexplored area.

The study methodology seems robust. The the validation of the associations in a separate validation cohort, is particularly good practice; this helps ensure the initial findings are not due to chance.

I think the paper is a nice example of how biomarker research, though normally aimed at helping improve diagnosis of the condition, can lead to insights into how the disease process actually works and potentially even reveal new targets for disease modifying treatment.

Abstract

Objective: To study biomarkers of angiogenesis in Parkinson disease (PD), and how these are associated with clinical characteristics, blood–brain barrier (BBB) permeability, and cerebrovascular disease.

Methods: In this cross-sectional analysis, 38 elderly controls and 100 patients with PD (82 without dementia and 18 with dementia) were included from the prospective Swedish BioFinder study. CSF samples were analyzed for the angiogenesis biomarkers vascular endothelial growth factor (VEGF); its receptors, VEGFR-1 and VEGFR-2; placental growth factor (PlGF); angiopoietin 2 (Ang2); and interleukin-8. BBB permeability, white matter lesions (WMLs), and cerebral microbleeds (CMB) were assessed. CSF angiogenesis biomarkers were also measured in 2 validation cohorts: (1) 64 controls and 87 patients with PD with dementia; and (2) 35 controls and 93 patients with neuropathologically confirmed diagnosis of PD with and without dementia.

Results: Patients with PD without dementia displayed higher CSF levels of VEGF, PlGF, and sVEGFR-2, and lower levels of Ang2, compared to controls. Similar alterations in VEGF, PlGF, and Ang2 levels were observed in patients with PD with dementia. Angiogenesis markers were associated with gait difficulties and orthostatic hypotension as well as with more pronounced BBB permeability, WMLs, and CMB. Moreover, higher levels of VEGF and PlGF levels were associated with increased CSF levels of neurofilament light (a marker of neurodegeneration) and monocyte chemotactic protein–1 (a marker of glial activation). The main results were validated in the 2 additional cohorts.

Conclusions: CSF biomarkers of angiogenesis are increased in PD, and they are associated with gait difficulties, BBB dysfunction, WMLs, and CMB. Abnormal angiogenesis may be important in PD pathogenesis and contribute to dopa-resistant symptoms.

Janelidze S, Lindqvist D, Francardo V, Hall S, Zetterberg H, Blennow K, Adler CH, Beach TG, Serrano GE, van Westen D, Londos E, Cenci MA, & Hansson O (2015). Increased CSF biomarkers of angiogenesis in Parkinson disease. Neurology PMID: 26511451