Increased CSF biomarkers of angiogenesis in Parkinson disease.
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.
From the Clinical Memory Research Unit, Department of Clinical Sciences (S.J., E.L., O.H.), Lund University, Malmö; the Department of Clinical Sciences (D.L., S.H.), Division of Psychiatry (D.L.), Department of Experimental Medical Science (V.F., M.A.C.), and Clinical Sciences, Diagnostic Radiology (D.v.W.), Lund University, Lund; Psychiatry Skåne (D.L.), Lund; the Department of Neurology (S.H.) and Memory Clinic (E.L., O.H.), Skåne University Hospital, Lund; Institute of Neuroscience and Physiology (H.Z., K.B.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), London, UK; The Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences (K.B.), Stockholm, Sweden; Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B., G.E.S.), Sun City, AZ; and Imaging and Function (D.v.W.), Skåne University Health Care, Lund, Sweden.
Shorena
S
Janelidze
From the Clinical Memory Research Unit, Department of Clinical Sciences (S.J., E.L., O.H.), Lund University, Malmö; the Department of Clinical Sciences (D.L., S.H.), Division of Psychiatry (D.L.), Department of Experimental Medical Science (V.F., M.A.C.), and Clinical Sciences, Diagnostic Radiology (D.v.W.), Lund University, Lund; Psychiatry Skåne (D.L.), Lund; the Department of Neurology (S.H.) and Memory Clinic (E.L., O.H.), Skåne University Hospital, Lund; Institute of Neuroscience and Physiology (H.Z., K.B.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), London, UK; The Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences (K.B.), Stockholm, Sweden; Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B., G.E.S.), Sun City, AZ; and Imaging and Function (D.v.W.), Skåne University Health Care, Lund, Sweden. Daniel.Lindqvist@med.lu.se.
Daniel
D
Lindqvist
From the Clinical Memory Research Unit, Department of Clinical Sciences (S.J., E.L., O.H.), Lund University, Malmö; the Department of Clinical Sciences (D.L., S.H.), Division of Psychiatry (D.L.), Department of Experimental Medical Science (V.F., M.A.C.), and Clinical Sciences, Diagnostic Radiology (D.v.W.), Lund University, Lund; Psychiatry Skåne (D.L.), Lund; the Department of Neurology (S.H.) and Memory Clinic (E.L., O.H.), Skåne University Hospital, Lund; Institute of Neuroscience and Physiology (H.Z., K.B.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), London, UK; The Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences (K.B.), Stockholm, Sweden; Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B., G.E.S.), Sun City, AZ; and Imaging and Function (D.v.W.), Skåne University Health Care, Lund, Sweden.
Veronica
V
Francardo
From the Clinical Memory Research Unit, Department of Clinical Sciences (S.J., E.L., O.H.), Lund University, Malmö; the Department of Clinical Sciences (D.L., S.H.), Division of Psychiatry (D.L.), Department of Experimental Medical Science (V.F., M.A.C.), and Clinical Sciences, Diagnostic Radiology (D.v.W.), Lund University, Lund; Psychiatry Skåne (D.L.), Lund; the Department of Neurology (S.H.) and Memory Clinic (E.L., O.H.), Skåne University Hospital, Lund; Institute of Neuroscience and Physiology (H.Z., K.B.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), London, UK; The Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences (K.B.), Stockholm, Sweden; Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B., G.E.S.), Sun City, AZ; and Imaging and Function (D.v.W.), Skåne University Health Care, Lund, Sweden.
Sara
S
Hall
From the Clinical Memory Research Unit, Department of Clinical Sciences (S.J., E.L., O.H.), Lund University, Malmö; the Department of Clinical Sciences (D.L., S.H.), Division of Psychiatry (D.L.), Department of Experimental Medical Science (V.F., M.A.C.), and Clinical Sciences, Diagnostic Radiology (D.v.W.), Lund University, Lund; Psychiatry Skåne (D.L.), Lund; the Department of Neurology (S.H.) and Memory Clinic (E.L., O.H.), Skåne University Hospital, Lund; Institute of Neuroscience and Physiology (H.Z., K.B.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), London, UK; The Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences (K.B.), Stockholm, Sweden; Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B., G.E.S.), Sun City, AZ; and Imaging and Function (D.v.W.), Skåne University Health Care, Lund, Sweden.
Henrik
H
Zetterberg
From the Clinical Memory Research Unit, Department of Clinical Sciences (S.J., E.L., O.H.), Lund University, Malmö; the Department of Clinical Sciences (D.L., S.H.), Division of Psychiatry (D.L.), Department of Experimental Medical Science (V.F., M.A.C.), and Clinical Sciences, Diagnostic Radiology (D.v.W.), Lund University, Lund; Psychiatry Skåne (D.L.), Lund; the Department of Neurology (S.H.) and Memory Clinic (E.L., O.H.), Skåne University Hospital, Lund; Institute of Neuroscience and Physiology (H.Z., K.B.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), London, UK; The Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences (K.B.), Stockholm, Sweden; Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B., G.E.S.), Sun City, AZ; and Imaging and Function (D.v.W.), Skåne University Health Care, Lund, Sweden.
Kaj
K
Blennow
From the Clinical Memory Research Unit, Department of Clinical Sciences (S.J., E.L., O.H.), Lund University, Malmö; the Department of Clinical Sciences (D.L., S.H.), Division of Psychiatry (D.L.), Department of Experimental Medical Science (V.F., M.A.C.), and Clinical Sciences, Diagnostic Radiology (D.v.W.), Lund University, Lund; Psychiatry Skåne (D.L.), Lund; the Department of Neurology (S.H.) and Memory Clinic (E.L., O.H.), Skåne University Hospital, Lund; Institute of Neuroscience and Physiology (H.Z., K.B.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), London, UK; The Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences (K.B.), Stockholm, Sweden; Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B., G.E.S.), Sun City, AZ; and Imaging and Function (D.v.W.), Skåne University Health Care, Lund, Sweden.
Charles H
CH
Adler
From the Clinical Memory Research Unit, Department of Clinical Sciences (S.J., E.L., O.H.), Lund University, Malmö; the Department of Clinical Sciences (D.L., S.H.), Division of Psychiatry (D.L.), Department of Experimental Medical Science (V.F., M.A.C.), and Clinical Sciences, Diagnostic Radiology (D.v.W.), Lund University, Lund; Psychiatry Skåne (D.L.), Lund; the Department of Neurology (S.H.) and Memory Clinic (E.L., O.H.), Skåne University Hospital, Lund; Institute of Neuroscience and Physiology (H.Z., K.B.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), London, UK; The Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences (K.B.), Stockholm, Sweden; Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B., G.E.S.), Sun City, AZ; and Imaging and Function (D.v.W.), Skåne University Health Care, Lund, Sweden.
Thomas G
TG
Beach
From the Clinical Memory Research Unit, Department of Clinical Sciences (S.J., E.L., O.H.), Lund University, Malmö; the Department of Clinical Sciences (D.L., S.H.), Division of Psychiatry (D.L.), Department of Experimental Medical Science (V.F., M.A.C.), and Clinical Sciences, Diagnostic Radiology (D.v.W.), Lund University, Lund; Psychiatry Skåne (D.L.), Lund; the Department of Neurology (S.H.) and Memory Clinic (E.L., O.H.), Skåne University Hospital, Lund; Institute of Neuroscience and Physiology (H.Z., K.B.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), London, UK; The Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences (K.B.), Stockholm, Sweden; Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B., G.E.S.), Sun City, AZ; and Imaging and Function (D.v.W.), Skåne University Health Care, Lund, Sweden.
Geidy E
GE
Serrano
From the Clinical Memory Research Unit, Department of Clinical Sciences (S.J., E.L., O.H.), Lund University, Malmö; the Department of Clinical Sciences (D.L., S.H.), Division of Psychiatry (D.L.), Department of Experimental Medical Science (V.F., M.A.C.), and Clinical Sciences, Diagnostic Radiology (D.v.W.), Lund University, Lund; Psychiatry Skåne (D.L.), Lund; the Department of Neurology (S.H.) and Memory Clinic (E.L., O.H.), Skåne University Hospital, Lund; Institute of Neuroscience and Physiology (H.Z., K.B.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), London, UK; The Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences (K.B.), Stockholm, Sweden; Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B., G.E.S.), Sun City, AZ; and Imaging and Function (D.v.W.), Skåne University Health Care, Lund, Sweden.
Danielle
D
van Westen
From the Clinical Memory Research Unit, Department of Clinical Sciences (S.J., E.L., O.H.), Lund University, Malmö; the Department of Clinical Sciences (D.L., S.H.), Division of Psychiatry (D.L.), Department of Experimental Medical Science (V.F., M.A.C.), and Clinical Sciences, Diagnostic Radiology (D.v.W.), Lund University, Lund; Psychiatry Skåne (D.L.), Lund; the Department of Neurology (S.H.) and Memory Clinic (E.L., O.H.), Skåne University Hospital, Lund; Institute of Neuroscience and Physiology (H.Z., K.B.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), London, UK; The Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences (K.B.), Stockholm, Sweden; Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B., G.E.S.), Sun City, AZ; and Imaging and Function (D.v.W.), Skåne University Health Care, Lund, Sweden.
Elisabet
E
Londos
From the Clinical Memory Research Unit, Department of Clinical Sciences (S.J., E.L., O.H.), Lund University, Malmö; the Department of Clinical Sciences (D.L., S.H.), Division of Psychiatry (D.L.), Department of Experimental Medical Science (V.F., M.A.C.), and Clinical Sciences, Diagnostic Radiology (D.v.W.), Lund University, Lund; Psychiatry Skåne (D.L.), Lund; the Department of Neurology (S.H.) and Memory Clinic (E.L., O.H.), Skåne University Hospital, Lund; Institute of Neuroscience and Physiology (H.Z., K.B.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), London, UK; The Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences (K.B.), Stockholm, Sweden; Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B., G.E.S.), Sun City, AZ; and Imaging and Function (D.v.W.), Skåne University Health Care, Lund, Sweden.
M Angela
MA
Cenci
From the Clinical Memory Research Unit, Department of Clinical Sciences (S.J., E.L., O.H.), Lund University, Malmö; the Department of Clinical Sciences (D.L., S.H.), Division of Psychiatry (D.L.), Department of Experimental Medical Science (V.F., M.A.C.), and Clinical Sciences, Diagnostic Radiology (D.v.W.), Lund University, Lund; Psychiatry Skåne (D.L.), Lund; the Department of Neurology (S.H.) and Memory Clinic (E.L., O.H.), Skåne University Hospital, Lund; Institute of Neuroscience and Physiology (H.Z., K.B.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), London, UK; The Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences (K.B.), Stockholm, Sweden; Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B., G.E.S.), Sun City, AZ; and Imaging and Function (D.v.W.), Skåne University Health Care, Lund, Sweden.
Oskar
O
Hansson
D000368:Aged; D043925:Angiogenesis Inducing Agents / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D010300:Parkinson Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D011446:Prospective Studies; D015203:Reproducibility of Results
D043925:Angiogenesis Inducing Agents; D015415:Biomarkers