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Neuroinflammation is independently associated with brain network dysfunction in Alzheimer’s disease

Leng, Fangda, Hinz, Rainer, Gentleman, Steve, Hampshire, Adam, Dani, Melanie, Brooks, David J., Edison, Paul·2023·Molecular Psychiatry
DOI 10.1038/s41380-022-01878-zPMC PMC10005956
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Abstract

Brain network dysfunction is increasingly recognised in Alzheimer’s disease (AD). However, the causes of brain connectivity disruption are still poorly understood. Recently, neuroinflammation has been identified as an important factor in AD pathogenesis. Microglia participate in the construction and maintenance of healthy neuronal networks, but pro-inflammatory microglia can also damage these circuits. We hypothesised that microglial activation is independently associated with brain connectivity disruption in AD. We performed a cross-sectional multimodal imaging study and interrogated the relationship between imaging biomarkers of neuroinflammation, Aβ deposition, brain connectivity and cognition. 42 participants (12 Aβ-positive MCI, 14 Aβ-positive AD and 16 Aβ-negative healthy controls) were recruited. Participants had 11 C-PBR28 and 18 F-flutemetamol PET to quantify Aβ deposition and microglial activation, T1-weighted, diffusion tensor and resting-state functional MRI to assess structural network and functional network. 11 C-PBR28 uptake, structural network integrity and functional network orgnisation were compared across diagnostic groups and the relationship between neuroinflammation and brain network was tested in 26 Aβ-positive patients. Increased 11 C-PBR28 uptake, decreased FA, network small-worldness and local efficiency were observed in AD patients. Cortical 11 C-PBR28 uptake correlated negatively with structural integrity (standardised β = −0.375, p = 0.037) and network local efficiency (standardised β = −0.468, p < 0.001), independent of cortical thickness and Aβ deposition, while Aβ was not. Network structural integrity, small-worldness and local efficiency, and cortical thickness were positively associated with cognition. Our findings suggest cortical neuroinflammation coincide with structural and functional network disruption independent of Aβ and cortical atrophy. These findings link the brain connectivity change and pathological process in Alzheimer’s disease, and suggest a pathway from neuroinflammation to systemic brain dysfunction.

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Fig. 1 Voxel-wise group comparisons of 11C-PBR28 PET images. A Increased 11C-PBR28 uptake ratio in the Alzheimer’s dementia patients compared to healthy controls; (B) Increased 11C-PBR28 uptake ratio in the Aβ+ mild cognitive impairment patients compared to healthy controls.
Fig. 1 Voxel-wise group comparisons of 11C-PBR28 PET images. A Increased 11C-PBR28 uptake ratio in the Alzheimer’s dementia patients compared to healthy controls; (B) Increased 11C-PBR28 uptake ratio in the Aβ+ mild cognitive impairment patients compared to healthy controls.CC BY · PubMed Central
Fig. 2 Voxel-wise analysis of FA values on TBSS skeletons. A Decreased FA values in Alzheimer’s dementia patients compared to healthy controls, age and gender adjusted; (B) Significant negative relationship between 11C-PBR28 uptake (11C-PBR28 PC1) and FA values in Aβ+ patients, corrected for age, gender, cortical thickness and 18F-flutemetamol uptake. Significant clusters (FDR corrected) are shown in blue (negative association); TBSS skeleton is shown in green.
Fig. 2 Voxel-wise analysis of FA values on TBSS skeletons. A Decreased FA values in Alzheimer’s dementia patients compared to healthy controls, age and gender adjusted; (B) Significant negative relationship between 11C-PBR28 uptake (11C-PBR28 PC1) and FA values in Aβ+ patients, corrected for age, gender, cortical thickness and 18F-flutemetamol uptake. Significant clusters (FDR corrected) are shown in blue (negative association); TBSS skeleton is shown in green.CC BY · PubMed Central
Fig. 3 Group comparisons and partial correlations. A–C Group comparisons of functional network topology metrics found reduced small-worldness and local efficiency in patients with Alzheimer’s dementia compared to healthy controls; (D) patients with Alzheimer’s disease had significantly lower cortical thickness compared to healthy controls and mild cognitive impairment participants. E, F Cortical 11C-PBR28 uptake has significant negative correlations with PC1 and PC2 of FA values in Aβ+ patients; (G) cortical 11C-PBR28 uptake has significant negative correlation with local efficiency; (H) FA PC2 positively correlates with local efficiency; (I) cortical thickness positively correlates with small-worldness; (J–L) FA PC2, local efficiency and cortical thickness positively correlate with mini-mental state examination scores. AD Alzheimer’s dementia, MCI mild cognitive impairment, HC healthy controls, PC principal component, FA fractional anisotropy. *p < 0.05 in pairwise comparisons; ****p < 0.0001 in pairwise comparisons.
Fig. 3 Group comparisons and partial correlations. A–C Group comparisons of functional network topology metrics found reduced small-worldness and local efficiency in patients with Alzheimer’s dementia compared to healthy controls; (D) patients with Alzheimer’s disease had significantly lower cortical thickness compared to healthy controls and mild cognitive impairment participants. E, F Cortical 11C-PBR28 uptake has significant negative correlations with PC1 and PC2 of FA values in Aβ+ patients; (G) cortical 11C-PBR28 uptake has significant negative correlation with local efficiency; (H) FA PC2 positively correlates with local efficiency; (I) cortical thickness positively correlates with small-worldness; (J–L) FA PC2, local efficiency and cortical thickness positively correlate with mini-mental state examination scores. AD Alzheimer’s dementia, MCI mild cognitive impairment, HC healthy controls, PC principal component, FA fractional anisotropy. *p < 0.05 in pairwise comparisons; ****p < 0.0001 in pairwise comparisons.CC BY · PubMed Central
Fig. 4 Hypothetical framework of pathological events leading to structural and functional network impairment and cognitive decline in Alzheimer’s disease. The initial amyloid deposition, together with other inflammatory risk factors (including systemic inflammation, traumatic brain injuries, and genetic risk factors, etc.) initiate neuroinflammation, which could cause neuronal damage via production of reactive oxygen species, pro-inflammatory cytokines, reduced trophic support and direct synaptic pruning. These aforementioned events could then directly damage neuronal circuits and cause abnormal neuronal activity, resulting in disruption of structural and functional brain connectivity. On the other hand, these events could also facilitate the propagation of hyperphosphorylated tau species and formation of intracellular neurofibrillary tangles (NFT). NFT formation further causes neuronal dysfunction, axonal destabilisation and neuronal death, hence cortical atrophy and network dysfunction. This cascade of events eventually leads to cognitive impairment in Alzheimer’s disease.
Fig. 4 Hypothetical framework of pathological events leading to structural and functional network impairment and cognitive decline in Alzheimer’s disease. The initial amyloid deposition, together with other inflammatory risk factors (including systemic inflammation, traumatic brain injuries, and genetic risk factors, etc.) initiate neuroinflammation, which could cause neuronal damage via production of reactive oxygen species, pro-inflammatory cytokines, reduced trophic support and direct synaptic pruning. These aforementioned events could then directly damage neuronal circuits and cause abnormal neuronal activity, resulting in disruption of structural and functional brain connectivity. On the other hand, these events could also facilitate the propagation of hyperphosphorylated tau species and formation of intracellular neurofibrillary tangles (NFT). NFT formation further causes neuronal dysfunction, axonal destabilisation and neuronal death, hence cortical atrophy and network dysfunction. This cascade of events eventually leads to cognitive impairment in Alzheimer’s disease.CC BY · PubMed Central

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Citations

Cites

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Metadata

Authors
Leng, F., Hinz, R., Gentleman, S., Hampshire, A., Dani, M., Brooks, D. J., & Edison, P.
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2022-12-06
Volume
28
Issue
3
Pages
1303-1311
ISSN
  • 1359-4184
  • 1476-5578
DOI
10.1038/s41380-022-01878-z
PMC
PMC10005956
Cited by
120
References
14
Language
en
Licence
Funders
  • RCUK | Medical Research Council (WMCN_P33428)
  • Alzheimer’s Research UK (WMCN_P23750)
  • China Scholarship Council (201806010427)

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