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Cited by 150Parkinson's Disease Mechanisms and TreatmentsNeurological Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration Mechanisms

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Increased CSF biomarkers of angiogenesis in Parkinson disease

Open access
Janelidze, Shorena, Lindqvist, Daniel, Francardo, Veronica, Hall, Sara, Zetterberg, Henrik, Blennow, Kaj, Adler, Charles H., Beach, Thomas G., Serrano, Geidy E., van Westen, Danielle, Londos, Elisabet, Cenci, M. Angela, Hansson, Oskar·2015·Neurology
DOI 10.1212/wnl.0000000000002151PMC PMC4662706
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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.

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Figure 1 Angiogenesis biomarkers in CSF of healthy controls, PDND, and PDD patients (cohort 1) Vascular endothelial growth factor (VEGF) (A), placental growth factor (PlGF) (B), sVEGFR-2 (C), angiopoietin 2 (Ang2) (D), VEGF/sVEGFR-1 ratio (E), and PlGF/sVEGFR-1 ratio (F) are altered in patients with Parkinson disease without dementia (PDND) and patients with Parkinson disease with dementia (PDD) compared to controls. Angiogenesis biomarkers were skewed and therefore ln-transformed before statistical analyses; p values are from analysis of covariance adjusting for age and sex as described in the Methods; data are presented as mean ± 95% confidence interval.
Figure 1 Angiogenesis biomarkers in CSF of healthy controls, PDND, and PDD patients (cohort 1) Vascular endothelial growth factor (VEGF) (A), placental growth factor (PlGF) (B), sVEGFR-2 (C), angiopoietin 2 (Ang2) (D), VEGF/sVEGFR-1 ratio (E), and PlGF/sVEGFR-1 ratio (F) are altered in patients with Parkinson disease without dementia (PDND) and patients with Parkinson disease with dementia (PDD) compared to controls. Angiogenesis biomarkers were skewed and therefore ln-transformed before statistical analyses; p values are from analysis of covariance adjusting for age and sex as described in the Methods; data are presented as mean ± 95% confidence interval.CC BY-NC-ND · PubMed Central
Figure 2 Angiogenesis biomarkers, blood–brain barrier, and WMLs in controls, PDND, and PDD (cohort 1) (A) The CSF/plasma albumin ratio is higher in patients with Parkinson disease without dementia (PDND) and patients with Parkinson disease with dementia (PDD) than in controls. (B–E) Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are associated with the CSF/plasma albumin ratio and white matter lesions (WMLs) in patients with Parkinson disease. Angiogenesis biomarkers were skewed and therefore ln-transformed before statistical analyses; p values are from analysis of covariance (A) and from liner regression (B–E) adjusting for age and sex as described in the Methods; data in (A) are presented mean ± 95% confidence interval.
Figure 2 Angiogenesis biomarkers, blood–brain barrier, and WMLs in controls, PDND, and PDD (cohort 1) (A) The CSF/plasma albumin ratio is higher in patients with Parkinson disease without dementia (PDND) and patients with Parkinson disease with dementia (PDD) than in controls. (B–E) Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are associated with the CSF/plasma albumin ratio and white matter lesions (WMLs) in patients with Parkinson disease. Angiogenesis biomarkers were skewed and therefore ln-transformed before statistical analyses; p values are from analysis of covariance (A) and from liner regression (B–E) adjusting for age and sex as described in the Methods; data in (A) are presented mean ± 95% confidence interval.CC BY-NC-ND · PubMed Central
Figure 3 CSF levels of angiogenesis biomarkers (cohorts 2 and 3) (A–C) Placental growth factor (PlGF), vascular endothelial growth factor (VEGF)/sVEGFR-1 ratio, and PlGF/sVEGFR-1 ratio are higher in patients with Parkinson disease with dementia (PDD)/patients with dementia with Lewy bodies (DLB) than in controls in cohort 2. (D, E) VEGF and PlGF levels are elevated in patients with Parkinson disease without dementia (PDND) and patients with PDD compared to controls in cohort 3 with neuropathologically confirmed diagnosis. Angiogenesis biomarkers were skewed and therefore ln-transformed before statistical analyses; p values are from analysis of covariance adjusting for age and sex as described in the Methods; data are presented as mean ± 95% confidence interval.
Figure 3 CSF levels of angiogenesis biomarkers (cohorts 2 and 3) (A–C) Placental growth factor (PlGF), vascular endothelial growth factor (VEGF)/sVEGFR-1 ratio, and PlGF/sVEGFR-1 ratio are higher in patients with Parkinson disease with dementia (PDD)/patients with dementia with Lewy bodies (DLB) than in controls in cohort 2. (D, E) VEGF and PlGF levels are elevated in patients with Parkinson disease without dementia (PDND) and patients with PDD compared to controls in cohort 3 with neuropathologically confirmed diagnosis. Angiogenesis biomarkers were skewed and therefore ln-transformed before statistical analyses; p values are from analysis of covariance adjusting for age and sex as described in the Methods; data are presented as mean ± 95% confidence interval.CC BY-NC-ND · PubMed Central

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Citations

Cites

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Metadata

Authors
Janelidze, S., Lindqvist, D., Francardo, V., Hall, S., Zetterberg, H., Blennow, K., Adler, C. H., Beach, T. G., Serrano, G. E., van Westen, D., Londos, E., Cenci, M. A., & Hansson, O.
Affiliations
Mayo Clinic (US)
Corresponding author
Lindqvist, Daniel
ORCID
Venue
Neurology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2015-11-24
Volume
85
Issue
21
Pages
1834-1842
ISSN
  • 0028-3878 (ISSN-L)
  • 1526-632X
DOI
10.1212/wnl.0000000000002151
PMC
PMC4662706
OpenAlex
W2173706022
Cited by
150
References
8
Citations by year
2026: 7 · 2025: 13 · 2024: 22 · 2023: 15 · 2022: 9 · 2021: 21 · 2020: 17 · 2019: 12 · 2018: 12 · 2017: 11 · 2016: 10 · 2015: 1
FWCI
7.99
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Neurology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Lunds Universitet
  • Vetenskapsrådet
  • National Institute on Aging (P30-AG-19610, P30AG019610)
  • National Institute of Neurological Disorders and Stroke (U24NS072026)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Parkinson's disease, angiogenic biomarkers, cerebrospinal fluid, vascular endothelial growth factor, placental growth factor, angiopoietin-2, VEGFR2, blood-brain barrier permeability, white matter lesions, cerebral microbleeds, Parkinson's disease dementia, gait disturbance, orthostatic hypotension, neurofilament light chain, MCP-1
MeSH terms
Aged, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Neovascularization, Pathologic, Parkinson Disease, Prospective Studies, Reproducibility of Results, Cohort Studies, Biomarkers, Angiogenesis Inducing Agents

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