Correlation of microglial activation with white matter changes in dementia with Lewy bodies.

Nicolas Nicastro,W Richard Bevan-Jones,Luca Passamonti,Patricia Vàzquez Rodrìguez,Ajenthan Surendranathan,Tim D Fryer,Franklin I Aigbirhio,Robert Arnold,Young T Hong,John T O'Brien,Li Su,Guy B Williams,James B Rowe,Elijah Mak

doi:10.1016/j.nicl.2020.102200

Abstract

Dementia with Lewy bodies (DLB) is characterized by alpha-synuclein protein deposition with variable degree of concurrent Alzheimer's pathology. Neuroinflammation is also increasingly recognized as a significant contributor to degeneration. We aimed to examine the relationship between microglial activation as measured with [11C]-PK11195 brain PET, MR diffusion tensor imaging (DTI) and grey matter atrophy in DLB. Nineteen clinically probable DLB and 20 similarly aged controls underwent 3T structural MRI (T1-weighted) and diffusion-weighted imaging. Eighteen DLB subjects also underwent [11C]-PK11195 PET imaging and 15 had [11C]-Pittsburgh compound B amyloid PET, resulting in 9/15 being amyloid-positive. We used Computational Anatomy Toolbox (CAT12) for volume-based morphometry (VBM) and Tract-Based Spatial Statistics (TBSS) for DTI to assess group comparisons between DLB and controls and to identify associations of [11C]-PK11195 binding with grey/white matter changes and cognitive score in DLB patients. VBM analyses showed that DLB had extensive reduction of grey matter volume in superior frontal, temporal, parietal and occipital cortices (family-wise error (FWE)-corrected p<0.05). TBSS showed widespread changes in DLB for all DTI parameters (reduced fractional anisotropy, increased diffusivity), involving the corpus callosum, corona radiata and superior longitudinal fasciculus (FWE-corrected p<0.05). Higher [11C]-PK11195 binding in parietal cortices correlated with widespread lower mean and radial diffusivity in DLB patients (FWE-corrected p<0.05). Furthermore, preserved cognition in DLB (higher Addenbrookes Cognitive Evaluation revised score) also correlated with higher [11C]-PK11195 binding in frontal, temporal, and occipital lobes. However, microglial activation was not significantly associated with grey matter changes. Our study suggests that increased microglial activation is associated with a relative preservation of white matter and cognition in DLB, positioning neuroinflammation as a potential early marker of DLB etio-pathogenesis.

Highlights

Dementia with Lewy bodies (DLB) is the second-leading degenerative dementia in older people (Vann Jones and O'Brien, 2014)
Voxel-based Tract-Based Spatial Statistics (TBSS) analyses revealed that the DLB group relative to controls had significant white matter changes in the body and splenium of corpus callosum
This is consistent with our previous data showing that neuroinflammation in fronto-temporo-parietal cortices was more prominent in DLB subjects with milder cognitive impairment, suggesting that central inflammation plays a pivotal role in the early stages of the disease (Surendranathan et al, 2018)

Summary

Introduction

Dementia with Lewy bodies (DLB) is the second-leading degenerative dementia in older people (Vann Jones and O'Brien, 2014). It is characterized by alpha-synuclein protein deposition in the form of intra-neuronal Lewy bodies as well as Lewy neurites, with a variable degree of concurrent Alzheimer's disease (AD) pathology (Spillantini et al, 1997; Gomperts, 2016). Increased microglial activation in MCI was associated with a preserved hippocampal volume (Femminella et al, 2019). Together, these results suggest that neuroinflammation represents an early event in the neurodegeneration process and could be a potential therapeutic target in dementia. An important prerequisite for such an endeavour is a better understanding of the temporal ordering and clinical relevance of protein accumulation, neuroinflammation, and structural brain changes

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