Dataset Information

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

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.

SUBMITTER: Nicastro N

PROVIDER: S-EPMC7005463 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Nicastro Nicolas N Mak Elijah E Williams Guy B GB Surendranathan Ajenthan A Bevan-Jones W Richard WR Passamonti Luca L Vàzquez Rodrìguez Patricia P Su Li L Arnold Robert R Fryer Tim D TD Hong Young T YT Aigbirhio Franklin I FI Rowe James B JB O'Brien John T JT

NeuroImage. Clinical 20200128

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 [<sup>11</sup>C]-PK11195 brain PET, MR diffusion tensor imaging (DTI) and grey matter atrophy in DLB. Nineteen clinically probable DLB and 20 similarly aged controls underwent ...[more]

PMID: 32032816

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Project description: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.

Project description:Patients who have dementia with Lewy bodies and Alzheimer's disease show early degeneration of the cholinergic nucleus basalis of Meynert. However, how white matter projections between the nucleus basalis of Meynert and the cortex are altered in neurodegenerative disease is unknown. Tractography of white matter pathways originating from the nucleus basalis of Meynert was performed using diffusion-weighted imaging in 46 patients with Alzheimer's disease dementia, 48 with dementia with Lewy bodies, 35 with mild cognitive impairment with Alzheimer's disease, 38 with mild cognitive impairment with Lewy bodies and 71 control participants. Mean diffusivity of the resulting pathways was compared between groups and related to cognition, attention, functional EEG changes and dementia conversion in the mild cognitive impairment groups. We successfully tracked a medial and a lateral pathway from the nucleus basalis of Meynert. Mean diffusivity of the lateral pathway was higher in both dementia and mild cognitive impairment groups than controls (all P < 0.03). In the patient groups, increased mean diffusivity of this pathway was related to more impaired global cognition (β = -0.22, P = 0.06) and worse performance on an attention task (β = 0.30, P = 0.03). In patients with mild cognitive impairment, loss of integrity of both nucleus basalis of Meynert pathways was associated with increased risk of dementia progression [hazard ratio (95% confidence interval), medial pathway: 2.51 (1.24-5.09); lateral pathway: 2.54 (1.24-5.19)]. Nucleus basalis of Meynert volume was reduced in all clinical groups compared to controls (all P < 0.001), but contributed less strongly to cognitive impairment and was not associated with attention or dementia conversion. EEG slowing in the patient groups as assessed by a decrease in dominant frequency was associated with smaller nucleus basalis of Meynert volumes (β = 0.22, P = 0.02) and increased mean diffusivity of the lateral pathway (β = -0.47, P = 0.003). We show that degeneration of the cholinergic nucleus basalis of Meynert in Alzheimer's disease and dementia with Lewy bodies is accompanied by an early reduction in integrity of white matter projections that originate from this structure. This is more strongly associated with cognition and attention than the volume of the nucleus basalis of Meynert itself and might be an early indicator of increased risk of dementia conversion in people with mild cognitive impairment.

Dataset Information

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

Publications

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

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