Investigating the Spatial Associations Between Amyloid-β Deposition, Grey Matter Volume, and Neuroinflammation in Alzheimer’s Disease

Abstract

Background: It has been proposed that amyloid-β (Aβ) plays a causal role in Alzheimer’s disease (AD) by triggering a series of pathologic events—possibly including neuroinflammation—which culminate in progressive brain atrophy. However, the interplay between the two pathological molecular events and how both are associated with neurodegeneration is still unclear. Objective: We aimed to estimate the spatial inter-relationship between neurodegeneration, neuroinflammation and Aβ deposition in a cohort of in 20 mild AD patients and 17 healthy controls. Methods: We resorted to magnetic resonance imaging to measure cortical atrophy, using the radiotracer 11C-PK11195 PET to measure neuroinflammation levels and 11C-PiB PET to assess Aβ levels. Between-group comparisons were computed to explore AD-related changes in the three types of markers. To examine the effects of each one of the molecular pathologic mechanisms on neurodegeneration we computed: 1) ANCOVAs with the anatomic data, controlling for radiotracer uptake differences between groups and 2) voxel-based multiple regression analysis between-modalities. In addition, associations in anatomically defined regions of interests were also investigated. Results: We found significant differences between AD and controls in the levels of atrophy, neuroinflammation, and Aβ deposition. Associations between Aβ aggregation and brain atrophy were detected in AD in a widely distributed pattern, whereas associations between microglia activation and structural measures of neurodegeneration were restricted to few anatomically regions. Conclusion: In summary, Aβ deposition, as opposed to neuroinflammation, was more associated with cortical atrophy, suggesting a prominent role of Aβ in neurodegeneration at a mild stage of the AD.

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

“…Accordingly, our results provide a tantalizing association between neuroinflammation and brain function, as measured for the first time, to the best of our knowledge, using BOLD activation, in a target region of known AD pathophysiology which shows a notable overlap between higher levels of Aβ and neuroinflammation 3 as well as altered functional brain response 10 , 13 , 14 at a mild AD stage.…”

“…In fact, there is some evidence that puts the PCC as an excellent candidate for exploring the interplay between function and AD-related pathophysiological events. For instance, the PCC is a default mode network (DMN) region, involved in cognitive effort and episodic memory 7 , 8 , being also a hotspot for AD-related neuropathological burden 3 , 9 . Previous studies have indeed associated PCC with both early abnormal Aβ deposition 7 , 10 and increased neuroinflammation 3 , 11 , possibly due to its high synaptic activity, which increases the need for adequate autophagic response in order to maintain synaptic homeostasis 10 .…”

“…For instance, the PCC is a default mode network (DMN) region, involved in cognitive effort and episodic memory 7 , 8 , being also a hotspot for AD-related neuropathological burden 3 , 9 . Previous studies have indeed associated PCC with both early abnormal Aβ deposition 7 , 10 and increased neuroinflammation 3 , 11 , possibly due to its high synaptic activity, which increases the need for adequate autophagic response in order to maintain synaptic homeostasis 10 . Evidence of hypometabolism 10 , 12 along with altered resting state functional connectivity in this region has also been reported in AD patients 10 , 13 , 14 .…”

Aging and white matter microstructure and macrostructure: a longitudinal multi-site diffusion MRI study of 1,184 participants

“…Most studies focus on gray matter of the brain, where correlations between cortical volumes and age have been consistently described. These findings provide evidence of heterogenous patterns of normal age-related changes (3)(4)(5)(6)(7)(8), with detectable differences in neurological diseases and disorders (9)(10)(11)(12)(13).…”

Short superficial white matter and aging: a longitudinal multi-site study of 1,293 subjects and 2,711 sessions

“…A large body of magnetic resonance imaging (MRI) research has shown that the structure of the human brain is constantly changing with age. In the gray matter, structural MRI studies have shown heterogenous patterns of normal agerelated changes in cortical volume and thickness [23][24][25][26][27][28][29][30], with detectable differences in abnormal aging and disease [30][31][32][33][34][35]. In the white matter, diffusion tensor imaging (DTI) analysis has shown that fractional anisotropy (FA) is negatively associated with age and mean diffusivity (MD) is positively associated with age across several white matter pathways [36][37][38][39], and tractography analysis has shown that the volume and surface areas of many pathways decreases with age [40].…”