Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations

Ahmad A. Khundakar, Peter S. Hanson, Daniel Erskine, Nichola Z. Lax, Joseph Roscamp, Evangelia Karyka, Eliona Tsefou, Preeti Singh, Simon J. Cockell, Andrew Gribben, Lynne Ramsay, Peter G. Blain, Urs P. Mosimann, Deborah J. Lett, Matthias Elstner, Douglass M. Turnbull, Charles C. Xiang, Michael J. Brownstein, John T. O’Brien, John-Paul Taylor, Johannes Attems, Alan J. Thomas, Ian G. McKeith, Christopher M. Morris

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.