title: Deep-brain stimulation associates with improved microvascular integrity in the subthalamic nucleus in Parkinson's disease.
abstract: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become an accepted treatment for motor symptoms in a subset of Parkinson's disease (PD) patients. The mechanisms why DBS is effective are incompletely understood, but previous studies show that DBS targeted in brain structures other than the STN may modify the microvasculature. However, this has not been studied in PD subjects who have received STN-DBS. Here we investigated the extent and nature of microvascular changes in post-mortem STN samples from STN-DBS PD patients, compared to aged controls and PD patients who had not been treated with STN-DBS. We used immunohistochemical and immunofluorescent methods to assess serial STN-containing brain sections from PD and STN-DBS PD cases, compared to similar age controls using specific antibodies to detect capillaries, an adherens junction and tight junction-associated proteins as well as activated microglia. Cellular features in stained sections were quantified by confocal fluorescence microscopy and stereological methods in conjunction with in vitro imaging tools. We found significant upregulation of microvessel endothelial cell thickness, length and density but lowered activated microglia density and striking upregulation of all analysed adherens junction and tight junction-associated proteins in STN-DBS PD patients compared to non-DBS PD patients and controls. Moreover, in STN-DBS PD samples, expression of an angiogenic factor, vascular endothelial growth factor (VEGF), was significantly upregulated compared to the other groups. Our findings suggest that overexpressed VEGF and downregulation of inflammatory processes may be critical mechanisms underlying the DBS-induced microvascular changes.
authors.affiliation: Centre for Neuroinflammation & Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom. Electronic address: i.pienaar@imperial.ac.uk.
authors.forename: Ilse S
authors.initials: IS
authors.lastname: Pienaar
authors.affiliation: The Sir William Dunn School of Pathology, South Parks Road, University of Oxford, Oxford OX1 3RE, United Kingdom.
authors.forename: Cecilia Heyne
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne NE1 3BZ, United Kingdom; Centre for Human Metabonomics, North-West University, Potchefstroom, South Africa.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Elson
authors.affiliation: Centre for Neuroinflammation & Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom.
authors.forename: Louisa
authors.initials: L
authors.lastname: McGuinness
authors.affiliation: Centre for Neuroinflammation & Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Gentleman
authors.affiliation: Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, United Kingdom.
authors.forename: Raj N
authors.initials: RN
authors.lastname: Kalaria
authors.affiliation: Centre for Neuroinflammation & Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom.
authors.forename: David T
authors.initials: DT
authors.lastname: Dexter
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D046690:Deep Brain Stimulation; D042783:Endothelial Cells / Q000473:pathology* / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007150:Immunohistochemistry; D008297:Male; D017628:Microglia / Q000473:pathology / Q000502:physiology; D055806:Microvessels / Q000473:pathology* / Q000503:physiopathology; D009929:Organ Size; D010300:Parkinson Disease / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D020531:Subthalamic Nucleus / Q000098:blood supply* / Q000473:pathology* / Q000503:physiopathology; D062725:Tight Junction Proteins / Q000378:metabolism; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051272:Glucose Transporter Type 1; D007074:Immunoglobulin G; C495677:SLC2A1 protein, human; D062725:Tight Junction Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Deep-brain stimulation; Growth factor; Parkinson's disease; Subthalamic nucleus; Tight junction proteins; Vasculature