Early microglial activation and peripheral inflammation in dementia with Lewy bodies.

Ajenthan Surendranathan,Franklin I Aigbirhio,John T O’Brien,James B Rowe,Li Su,Tim D Fryer,Luca Passamonti,Susannah A E Brain,Robert Arnold,Young T Hong,William R Bevan-Jones,Patricia Vázquez Rodríguez,Elijah Mak

doi:10.1093/brain/awy265

Ajenthan Surendranathan, Franklin I Aigbirhio + Show 11 more

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https://doi.org/10.1093/brain/awy265

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Abstract

Inflammation is increasingly recognized as part of the pathology of neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, but its role in dementia with Lewy bodies remains unclear. Using multimodal imaging and peripheral cytokine analysis, we therefore investigated central and peripheral inflammation in this common form of dementia. Nineteen participants with probable dementia with Lewy bodies and 16 similarly aged controls underwent 3 T MRI and PET imaging with 11C-PK11195, a marker of microglial activation in vivo. Peripheral blood inflammatory cytokines were also measured in all subjects, as well as in an additional 10 controls, using the Mesoscale Human Cytokine 36 plex panel and additional assays for high sensitivity c-reactive protein, tumour necrosis factor receptor 1, IL-34, YKL-40 (chitinase-3-like protein 1) and colony stimulating factor 1. To test for the presence of in vivo amyloid, 11C-Pittsburgh compound B PET imaging was also performed in 16 of the dementia with Lewy body participants. Microglial activation was elevated in dementia with Lewy bodies subjects with mild disease when compared to those with moderate/severe impairment, where disease severity was indexed by cognitive performance on the revised Addenbrooke's Cognitive Examination. In patients, strong correlations were found between cognitive performance and 11C-PK11195 non-displaceable binding potential in several regions including the caudate nucleus (R = 0.83, P = 0.00008) and cuneus (R = 0.77, P = 0.0005). Several inflammatory cytokines were altered in the patients compared to controls, with elevated macrophage inflammatory protein-3 (P = 0.001), IL-17A (P = 0.008) and IL-2 (P = 0.046) and reduced IL-8 (P = 0.024). There was no correlation between cortical 11C-Pittsburgh compound B standardized uptake value ratio and clinical features, regional 11C-PK11195 binding or peripheral cytokine levels. Nor was there any regional correlation between 11C-PK11195 non-displaceable binding potentials and 11C-Pittsburgh compound B standardized uptake value ratios. Our findings provide evidence for both central and peripheral inflammatory changes in dementia with Lewy bodies, with microglial activation occurring early in the disease in key regions known to be associated with pathology, before declining as cognition declines. Raised peripheral cytokines associated with T cell function further suggest a role for the adaptive immune system in the pathogenesis of the disease.

Highlights

Dementia with Lewy bodies (DLB) is the second commonest degenerative form of dementia in older people (Fujimi et al, 2008; Jellinger and Attems, 2011) and is characterized by synuclein protein aggregations in the form of Lewy bodies within neurons and Lewy neurites
Neuroinflammation is increasingly considered as a contributor to dementia pathogenesis (Amor et al, 2014), and a potential target for novel disease-modifying therapeutic strategies. -Synuclein aggregates are reported to interact with a range of components of the immune system including microglia (Surendranathan et al, 2015), potentially providing the substrate for an inflammatory response
This study provides evidence of both central and peripheral inflammation in dementia with Lewy bodies and establishes their correlation with clinical severity

Summary

Introduction

Dementia with Lewy bodies (DLB) is the second commonest degenerative form of dementia in older people (Fujimi et al, 2008; Jellinger and Attems, 2011) and is characterized by synuclein protein aggregations in the form of Lewy bodies within neurons and Lewy neurites. -Synuclein aggregates are reported to interact with a range of components of the immune system including microglia (Surendranathan et al, 2015), potentially providing the substrate for an inflammatory response. In diseases closely related to DLB, through shared or comorbid pathology, such as Parkinson’s disease (Dobbs et al, 1999; Imamura et al, 2003; Wahner et al, 2007; Brochard et al, 2009; Hamza et al, 2010), and Alzheimer’s disease (Lee et al, 2010; McGeer and McGeer, 2013; Morales et al, 2014; Latta et al, 2015; Lai et al, 2017; Passamonti et al, 2018), inflammation has been identified with a range of methodologies, including pathological, genetic, epidemiological and with cytokine assessment. Inflammation is reported in the early stages of Alzheimer’s disease as well as in mild cognitive impairment even before the onset of dementia (Okello et al, 2009; Hamelin et al, 2016). Patients affected by rapid eye movement (REM) sleep behaviour disorder, which is recognized as a prodromal stage of synucleinopathies (Hogl et al, 2018), show elevated microglial activation in the substantia nigra (Stokholm et al, 2017)

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