MRI connectivity-based spread of microglial activation in early Alzheimer's disease

Abstract

Background: Alzheimer′s disease (AD) is characterized by amyloid-β; (Aβ) plaques, neurofibrillary tau tangles and neuroinflammation leading to brain functional connectivity changes and cognitive decline. There is evidence, that microglial activity is increased in AD and cognitive decline. Aβ and tau pathology appear to spread along pathways of highly connected brain regions, but it remains elusive if microglial activation follows a similar distribution pattern. Methods: Thirty-two early AD subjects and 18 age-matched healthy cognitively normal controls were included from the prospective ActiGliA study. Differences between the diagnostic groups were explored for translocator protein (TSPO) positron emission tomography (PET) microglial activation, diffusion tensor imaging (DTI) structural connectivity and magnetic resonance imaging (MRI) functional connectivity. Associations between PET microglial activation with cognitive impairment, dementia severity and MRI connectivity measures were investigated within the diagnostic groups. Results: AD patients showed increased TSPO PET tracer uptake bilaterally in the parahippocampal region compared to cognitively normal controls. Higher TSPO PET was associated with cognitive impairment and dementia severity in a disease stage dependent fashion. Inter-regional covariance in TSPO PET and standardized uptake value ratio (SUVR) was found to be preferentially distributed along functionally highly connected brain regions, with MRI structural connectivity showing a weaker association with microglial activation. Conclusion: Neuroinflammation in AD is associated with clinical disease presentation, and like tau pathology, microglial activation seems to spread preferentially along highly connected brain regions. These findings support the important role of microglia in neurodegeneration and suggest that disease spreading throughout the brain along vulnerable connectivity pathways could guide future interventional anti-inflammatory therapy approaches to prevent disease progression.

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

“…TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and can act as a surrogate for activated microglia. Several TSPO radioligands allow monitoring neuroinflammation in AD and 4R-tauopathies (18) and we were able to show that [ 18 F]GE-180 recapitulates expected topology of microglial activation in 4RTs (22) and AD (43). However, [ 18 F]GE-180 has recently been criticized for limited uptake across the bloodbrain-barrier (22,80), since blood-brain integrity can be disturbed in neurodegenerative disorders with a potential impact on tracer kinetics (81, 82).…”

“…Group level TSPO-PET data of this cohort was previously published for patients with AD, 4RTs and controls (31,32). Group level tau-PET data of this cohorts was partially published for patients with AD, AD-CBS, 4RTs and controls (21).…”

“…Using the Brainnetome atlas (40), the brain was parcellated into 210 cortical and 36 subcortical volume-of-interests (VOIs) and standardized-uptake-valueratios (SUVr) were calculated for all four PET read-outs. Per subject, the standardized regional deviation of SUVr (z-score) was calculated versus previously established age-and sex-matched normal cohorts for [ 18 Three-dimensional T1-weighted (T1w) MRI data were collected for the majority (60/72) of the cohort as reported previously (43). The data were coregistered into the MNI standard space using PNEURO tool (V3.9; PMOD Technologies LLC) and segmented into all 246 Brainnetome atlas VOIs.…”

“…Three-dimensional T1-weighted (T1w) MRI data were collected for the majority (60/72) of the cohort as reported previously (43). The data were coregistered into the MNI standard space using PNEURO tool (V3.9; PMOD Technologies LLC) and segmented into all 246 Brainnetome atlas VOIs.…”