Abstract
Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer's disease. We test the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment.
We combined [11C]PK11195 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in 28 humans (12 females/16 males) with clinical diagnosis of probable Alzheimer's disease or mild cognitive impairment with positive PET biomarker for amyloid, and 14 age-, sex-, and education-matched healthy humans (8 females/6 males). Source-based ‘inflammetry' was used to extract principal components of [11C]PK11195 PET signal variance across all participants. rs-fMRI data were pre-processed via independent component analyses to classify neuronal and non-neuronal signals. Multiple linear regression models identified sources of signal co-variance between neuroinflammation and brain connectivity profiles, in relation to group and cognitive status.
Patients showed significantly higher [11C]PK11195 binding relative to controls, in a distributed spatial pattern including the hippocampus, medial, and inferior temporal cortex. Patients with enhanced loading on this [11C]PK11195 binding distribution displayed diffuse abnormal functional connectivity. The expression of a stronger association between such abnormal connectivity and higher levels of neuroinflammation correlated with worse cognitive deficits.
Our study suggests that neuroinflammation relates to the pathophysiological changes in network function that underlie cognitive deficits in Alzheimer's disease. Neuroinflammation, and its association with functionally-relevant reorganisation of brain networks, is proposed as a target for emerging immuno-therapeutic strategies aimed at preventing or slowing the emergence of dementia.
SIGNIFICANCE STATEMENT
Neuroinflammation is an important aspect of Alzheimer's disease (AD), but it was not known whether the influence of neuroinflammation on brain network function in humans was important for cognitive deficit.
Our study provides clear evidence that in vivo neuroinflammation in AD impairs large-scale network connectivity; and that the link between inflammation and functional network connectivity is relevant to cognitive impairment.
We suggest that future studies should address how neuroinflammation relates to network function as AD progresses; and whether the neuroinflammation in AD is reversible, as the basis of immunotherapeutic strategies to slow the progression of AD.
Footnotes
We thank our volunteers and the radiographers/technologists at WBIC and PET/CT, Addenbrooke's Hospital, for their invaluable support in data acquisition. We thank the NIHR Eastern Dementias and Neurodegenerative Diseases Research Network for help with subject recruitment. We thank Dr Istvan Boros and others at WBIC RPU for the manufacture of [11C]PK11195 and [11C]PiB. This study was funded by the National Institute for Health Research Cambridge Biomedical Research Centre and Biomedical Research Unit in Dementia (NIHR, RG64473), the Wellcome Trust (JBR 103838), and the Medical Research Council (RG91365/SUAG/004 and MR/P01271X/1). Dr. Li Su is supported by Alzheimer's Research UK. L. Passamonti, K. Tsvetanov, W.R. Bevan-Jones, P.S. Jones, R. Arnold, R. Borchert, E. Mak, and L. Su report no financial disclosures or conflict of interest relevant to the manuscript. J.T. O'Brien has served as deputy editor of International Psychogeriatrics, received grant support from Avid (Lilly), and served as a consultant for Avid and GE Healthcare, all for matters not related to the current study. J.B. Rowe serves as editor to Brain, has been a consultant for Asceneuron and Syncona, and has received academic grant funding from AZ-MedImmune, Janssen, and Lilly, unrelated to this study.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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