Neuroinflammation Co-localizes Highly with Tau in Mild Cognitive Impairment from Early Onset Alzheimer’s Disease
Johanna Appleton1, Quentin Funk1, Paolo Zanotti Fregonara2, Meixiang Yu1, Alirexa Faridar3, Mohammad Nakawah4, Maria Carrillo5, Bradford Dickerson6, Gil Rabinovici7, Liana Apostolova8, Joseph Masdeu9, Belen Pascual4
1Houston Methodist, 2Molecular Imaging Branch, National Institute of Mental Health, 3Methodist Neurological Institute, 4Houston Methodist Hospital, 5Alzheimer's Association, 6Massachusetts General Hospital, 7UCSF Memory & Aging Center, 8Indiana University School of Medicine, 9Houston Methodist Neurological Institute
Objective:
To study neuroinflammation in early-onset Alzheimer’s disease (AD) and its brain topography, compared with that of tau and amyloid.
Background:
Neuroinflammation is a potential therapeutic target in AD. Translocator protein (TSPO) positron emission tomography (PET) is useful to image neuroinflammation, but most “second generation” inflammation tracers cannot image subjects with a low-binder TSPO rs6971 genotype. However, participants with any TSPO genotype can be imaged with a novel tracer, [11C]ER176, with a high binding potential and more favorable metabolite profile than other TSPO tracers. We postulated that using [11C]ER176 we would be able to detect brain inflammation in mild cognitive impairment (MCI) caused by early-onset AD.
Design/Methods:
We studied 25 patients with early-onset amnestic MCI and 23 healthy controls, both groups with a similar proportion of all three TSPO-binding affinities. [11C]ER176 total distribution volume (VT), obtained with an arterial input function, was determined using voxel-wise and region-wise analyses. Most MCI patients had amyloid (n=23), and tau (n=21) PETs, for which standard uptake value ratios (SUVRs) were calculated using cerebellar grey matter as reference region. Regional correlations among the three tracers were determined for each patient and an average was calculated. All data were corrected for partial volume effect.
Results:
In MCI caused by early-onset AD, there was bilateral neuroinflammation in precuneus and lateral temporal and parietal association cortex, and in the right amygdala. The localization of amyloid and tau in the brain were correlated (r= 0.55±0.25), as well as the topography of neuroinflammation and amyloid (0.43±0.22). However, neuroinflammation and tau were even more strongly spatially correlated (r= 0.63 ± 0.24).
Conclusions:
Our data highlight the importance of neuroinflammation, a potential therapeutic target, in the AD process. Furthermore, they support the notion that, as shown in experimental tissue and animal models, the propagation of tau in humans is associated with neuroinflammation.