title: Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations.
abstract: Dementia with Lewy bodies (DLB) patients frequently experience well formed recurrent complex visual hallucinations (RCVH). This is associated with reduced blood flow or hypometabolism on imaging of the primary visual cortex. To understand these associations in DLB we used pathological and biochemical analysis of the primary visual cortex to identify changes that could underpin RCVH. Alpha-synuclein or neurofibrillary tangle pathology in primary visual cortex was essentially absent. Neurone density or volume within the primary visual cortex in DLB was also unchanged using unbiased stereology. Microarray analysis, however, demonstrated changes in neuropeptide gene expression and other markers, indicating altered GABAergic neuronal function. Calcium binding protein and GAD65/67 immunohistochemistry showed preserved interneurone populations indicating possible interneurone dysfunction. This was demonstrated by loss of post synaptic GABA receptor markers including gephyrin, GABARAP, and Kif5A, indicating reduced GABAergic synaptic activity. Glutamatergic neuronal signalling was also altered with vesicular glutamate transporter protein and PSD-95 expression being reduced. Changes to the primary visual cortex in DLB indicate that reduced GABAergic transmission may contribute to RCVH in DLB and treatment using targeted GABAergic modulation or similar approaches using glutamatergic modification may be beneficial.
authors.affiliation: Edwardson Building, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Westgate Road, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Ahmad A
authors.initials: AA
authors.lastname: Khundakar
authors.affiliation: Medical Toxicology Centre, Newcastle University, Wolfson Building, Claremont Place, Newcastle, NE2 4AA, UK.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hanson
authors.affiliation: Edwardson Building, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Westgate Road, Newcastle upon Tyne, NE4 5PL, UK.|Medical Toxicology Centre, Newcastle University, Wolfson Building, Claremont Place, Newcastle, NE2 4AA, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Erskine
authors.affiliation: Edwardson Building, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Westgate Road, Newcastle upon Tyne, NE4 5PL, UK.|Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Nichola Z
authors.initials: NZ
authors.lastname: Lax
authors.affiliation: Medical Toxicology Centre, Newcastle University, Wolfson Building, Claremont Place, Newcastle, NE2 4AA, UK.
authors.forename: Joseph
authors.initials: J
authors.lastname: Roscamp
authors.affiliation: Medical Toxicology Centre, Newcastle University, Wolfson Building, Claremont Place, Newcastle, NE2 4AA, UK.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Karyka
authors.affiliation: Medical Toxicology Centre, Newcastle University, Wolfson Building, Claremont Place, Newcastle, NE2 4AA, UK.
authors.forename: Eliona
authors.initials: E
authors.lastname: Tsefou
authors.affiliation: Medical Toxicology Centre, Newcastle University, Wolfson Building, Claremont Place, Newcastle, NE2 4AA, UK.
authors.forename: Preeti
authors.initials: P
authors.lastname: Singh
authors.affiliation: Bioinformatics Support Unit, Newcastle University, Leech Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Cockell
authors.affiliation: Medical Toxicology Centre, Newcastle University, Wolfson Building, Claremont Place, Newcastle, NE2 4AA, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Gribben
authors.affiliation: Edwardson Building, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Westgate Road, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Lynne
authors.initials: L
authors.lastname: Ramsay
authors.affiliation: Medical Toxicology Centre, Newcastle University, Wolfson Building, Claremont Place, Newcastle, NE2 4AA, UK.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Blain
authors.affiliation: University Hospital of Old Age Psychiatry, University Bern, CH 3010, Bern, Switzerland.
authors.forename: Urs P
authors.initials: UP
authors.lastname: Mosimann
authors.affiliation: Edwardson Building, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Westgate Road, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Lett
authors.affiliation: Department of Neurology and Clinical Neurophysiology, Academic Hospital Bogenhausen, Technical University of Munich, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Elstner
authors.affiliation: Edwardson Building, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Westgate Road, Newcastle upon Tyne, NE4 5PL, UK.|Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.affiliation: Laboratory of Genetics at the National Institute of Mental Health/National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, MD20892, USA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Xiang
authors.affiliation: Laboratory of Genetics at the National Institute of Mental Health/National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, MD20892, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Brownstein
authors.affiliation: Biomedical Research Building, Institute of Neuroscience, Newcastle University, Newcastle University, Westgate Road, Newcastle upon Tyne, NE4 5PL, UK.|Department of Psychiatry, University of Cambridge School of Clinical Medicine, Box 189, Level E4 Cambridge Biomedical Campus, Cambridge, CB2 0SP, UK.
authors.forename: John T
authors.initials: JT
authors.lastname: O'Brien
authors.affiliation: Biomedical Research Building, Institute of Neuroscience, Newcastle University, Newcastle University, Westgate Road, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Taylor
authors.affiliation: Edwardson Building, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Westgate Road, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Johannes
authors.initials: J
authors.lastname: Attems
authors.affiliation: Biomedical Research Building, Institute of Neuroscience, Newcastle University, Newcastle University, Westgate Road, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Thomas
authors.affiliation: Biomedical Research Building, Institute of Neuroscience, Newcastle University, Newcastle University, Westgate Road, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Ian G
authors.initials: IG
authors.lastname: McKeith
authors.affiliation: Edwardson Building, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Westgate Road, Newcastle upon Tyne, NE4 5PL, UK. c.m.morris@ncl.ac.uk.|Medical Toxicology Centre, Newcastle University, Wolfson Building, Claremont Place, Newcastle, NE2 4AA, UK. c.m.morris@ncl.ac.uk.|Laboratory of Genetics at the National Institute of Mental Health/National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, MD20892, USA. c.m.morris@ncl.ac.uk.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Morris
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006212:Hallucinations / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D020961:Lewy Body Disease / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D046228:Microarray Analysis; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014793:Visual Cortex / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C054369:MAPT protein, human; D012333:RNA, Messenger; C497604:SNCA protein, human; D051844:alpha-Synuclein; D016875:tau Proteins; D005680:gamma-Aminobutyric Acid
keywords: Alzheimer’s disease; Dementia with Lewy bodies; Hallucinations; Primary visual cortex; α-synuclein