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

• Published in: Molecular psychiatry 2023-03, Vol.28 (3), p.1303-1311
• Main Authors: Leng, Fangda, Hinz, Rainer, Gentleman, Steve, Hampshire, Adam, Dani, Melanie, Brooks, David J., Edison, Paul
• Format: Article
• Language: English
• Subjects: 59; 59/36; 59/57; 59/78; 631/378; 692/699; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Atrophy; Behavioral Sciences; Biological Psychology; Brain - metabolism; Cognition; Cognitive Dysfunction - metabolism; Cross-Sectional Studies; Efficiency; Functional magnetic resonance imaging; Humans; Inflammation; Medicine; Medicine & Public Health; Microglia; Neural networks; Neurodegenerative diseases; Neuroimaging; Neuroinflammatory Diseases; Neurosciences; Pharmacotherapy; Positron emission tomography; Positron-Emission Tomography - methods; Psychiatry; Structure-function relationships
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-022-01878-z

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