Neuroinflammation in dementia with Lewy bodies: a human post-mortem study

Jay Amin,Delphine Boche,Emanuele Tommasino,Clive Holmes,Daisy M Williams,James A R Nicoll,Robert B Dorey,Yuri R Casal,Charles Dupuy

doi:10.1038/s41398-020-00954-8

Abstract

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative cause of dementia, behind Alzheimer’s disease (AD). It is now established that cerebral inflammation has a key role in the aetiology and progression of AD, but this has yet to be confirmed in DLB. We aimed to determine the neuroinflammatory profile in the cerebral cortex of a large cohort of DLB cases. Thirty post-mortem confirmed DLB cases and twenty-nine matched controls were immunolabelled (Brodmann area 21) and quantified for: neuropathology—αSYN, Aβ, P-tau; microglial phenotype—Iba1, HLA-DR, CD68, FcƴR (CD64, CD32a, CD32b, CD16); presence of T lymphocytes—CD3; and anti-inflammatory markers—IL4R, CHI3L1. Status spongiosis, as a marker of neuropil degeneration, was quantified using Haematoxylin and Eosin staining. We found no significant difference between groups in protein load for Iba1, HLA-DR, CD68, CD64, CD32b, IL4R, or CHI3L1, despite increased neuropathology in DLB. CD32a load was significantly lower, and CD16 load higher, in DLB compared with controls. There was no difference in status spongiosis between groups. Significantly more DLB cases than controls showed T-lymphocyte recruitment. Overall, we conclude that microglial activation is not a prominent feature of DLB, and that this may be associated with the relatively modest neuropil degeneration observed in DLB. Our findings, based on the largest post-mortem cohort to date exploring neuroinflammation in DLB, demonstrate a dissociation between protein deposition, neurodegeneration and microglial activation. The relative preservation of cortical structures in DLB suggests the dementia could be more amenable to potential therapies.

Highlights

Introduction Dementia withLewy bodies (DLB) is the second most common neurodegenerative cause of dementia, behind Alzheimer’s disease (AD)[1], accounting for 4.2–7.5% of dementia cases[2]
Neuropathology Immunostaining for αSYN detected a variable degree of LB and Lewy neurites (LN) in deep cortical layers in the Dementia with Lewy bodies (DLB) group (Figs. 1a and 1b), with no specific αSYN-positive structures observed in control cases
Quantification of neuropathology revealed significantly higher Lewy-related pathology (LRP) (P < 0.001), Aβ load (P = 0.039) and P-tau load (P = 0.031) in DLB compared with control cases

Summary

Introduction

Introduction Dementia withLewy bodies (DLB) is the second most common neurodegenerative cause of dementia, behind Alzheimer’s disease (AD)[1], accounting for 4.2–7.5% of dementia cases[2]. At post-mortem examination of the cerebral cortex, DLB is characterised by the. Lewy bodies (LB) and Lewy neurites (LN), formed primarily of alpha-synuclein (αSYN). Amyloid-beta (Aβ) plaques, and to a lesser extent hyperphosphorylated tau (P-tau) tangles, are present[6]. The innate immune cells of the brain, are highly dynamic cells that display different phenotypes in response to their microenvironment[7]. Whilst in AD neuroinflammation has been widely explored in the form of activated microglia[8], present around Aβ plaques[9], the role of inflammation in DLB is yet to be established owing to inconsistent findings. Numbers of activated microglia, immunostained for HLA-DR (Human leukocyte antigen–antigen D related) in post-mortem brain tissue have been shown to be either increased in DLB10,11, or unchanged compared with healthy controls[12]

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