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

Ahmad Khundakar ,Joseph Roscamp,Nichola Z Lax,Johannes Attems,Evangelia Karyka,Peter S Hanson,Lynne Ramsay,Preeti Singh,Daniel Erskine,Eliona Tsefou,Matthias Elstner,Christopher M Morris,Peter G Blain,Ian G Mckeith,Michael J Brownstein,Andrew Gribben,Simon Cockell ,John T O′Brien ,Urs Peter Mosimann ,Charles Xiang ,Alan Thomas ,Deborah Lett ,John‐Paul Taylor ,Doug M Turnbull

doi:10.1186/s40478-016-0334-3

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0334-3) contains supplementary material, which is available to authorized users.

Highlights

Dementia with Lewy bodies (DLB) accounts for up to 20 % of all dementia cases at autopsy [1]
Cases of DLB had the presence of visual hallucinations documented by patient and informant interview through standard clinical interview according to consensus criteria [3] or were without any documented recurrent complex visual hallucinations (RCVH) (1 case), whilst Alzheimer’s disease (AD) cases showed an absence of any prior history of RCVH
Transcripts for α-synuclein mRNA were not significantly altered in DLB compared to controls, and protein analysis of α-synuclein monomer (18 kDa) showed no significant change in expression in DLB, and comparable levels of expression were observed between control and AD subjects, consistent with previous studies [58]

Summary

Introduction

Dementia with Lewy bodies (DLB) accounts for up to 20 % of all dementia cases at autopsy [1]. DLB subjects do show hypoperfusion and glucose hypometabolism in the medial occipital lobe including the primary and secondary visual cortices [10,11,12], which is associated with the visuoperceptual problems common to both DLB and PDD and may lead to misidentification or misinterpretation of objects and images [13]. Such visuoperceptual problems may indicate parietal and occipital dysfunction and relate to the RCVH experienced in DLB.

Methods

Results

Conclusion