Dual PET-fMRI reveals a link between neuroinflammation, amyloid binding and compensatory task-related brain activity in Alzheimer's disease

The interplay among neuropathological mechanisms underlying Alzheimer's disease (AD), as neuroinflammation and amyloid-beta (A beta), as well their impact on neuronal function remains elusive. A major gap in knowledge is the functional impact of neuroinflammation. The posterior cingulate cortex (PCC), as the most prominent site of amyloid pathology in AD, is a pivotal region to investigate the concomitant presence of pathophysiological mechanisms such as microglia activation, indexing neuroinflammation, and changes in task related activity. Here we used a dual PET approach to simultaneously study A beta load and neuroinflammation (TSPO uptake marker), using C-11-PiB and C-11-PK11195 radiotracers, respectively and fMRI to study task related neural activation in an AD sample (n = 19) and matched controls (n = 19). Here we show significantly increased A beta deposition, neuroinflammation and brain activity related to a visual object working memory task in this key region. Microglia activation was associated with increased brain activity specifically in patients, independently of amyloid binding, raising the possibility that abnormal brain activity might be restored in clinical trials aimed at reducing microglia activation. Multimodal PET-fMRI imaging of Alzheimer's disease patients and healthy controls suggests that microglia activation in the posterior cingulate cortex is associated with increased brain activity in Alzheimer's disease, and independent of amyloid accumulation.