Research Project
9927551
Alzheimer's disease (AD) is a major cause of long-term disability. The prevalence of AD is expected to triple in the next 40 years. AD is a neurodegenerative disorder that develops as a result of multiple cumulative risk factors acting over decades prior to its clinical emergence. Some of these risk factors may start impacting brain-tissue health as early as in adolescence. We seek to understand whether systemic inflammation induced by excess body fat (in particular visceral fat [VF, fat surrounding abdominal organs]) may be one such a risk factor, and whether these processes can be monitored by newly identified biomarkers, i.e., circulating glycerophosphocholines (GPCs). Obesity-induced systemic inflammation promotes neuroinflammation and structural alterations of brain tissue. Microglia, the immune cells of the brain, become activated and enhance production of inflammatory molecules and neglect their care-taking functions, including clearance of myelin debris, which is important for maintenance of myelination. This in turn triggers a cascade of events that can potentiate neuroinflammation and lead to brain-tissue damage ? demyelination, axonal thinning and loss of neurons ? and thus brain atrophy. In white matter, these processes emerge as diffuse microstructural alterations and later as focal lesions. In grey matter, these manifest first as cortical thinning and later as atrophy. Supporting this notion, visceral fat, more so than fat elsewhere in the body, is associated with altered white-matter micro-structure in adolescents and lower brain volume in middle-aged adults, and both these associations involve systemic inflammation. Recent research suggests that circulating GPCs may be useful biomarkers of these processes. Large-scale cohort studies have identified specific circulating GPCs as (a) strong correlates of visceral fat, systemic inflammation and altered white-matter microstructure in adolescents, and (b) predictors of dementia and vascular outcomes related to systemic inflammation in older adults. Our overall objective is to investigate the impact of VF-related systemic inflammation on brain-tissue micro- and macro- structure, and the potential of novel circulating GPCs as biomarkers of these processes, in observational (human cohorts) and experimental (mouse models) settings. Our discovery cohort is 1,000 adolescents and 650 middle-aged adults from the Saguenay Youth Study, a community-based sample with already collected magnetic resonance (MR) imaging of brain structure and VF. Our replication cohort is a subset of 1,000 older adults from the Framingham Heart Study, a community-based sample with also already collected MR imaging of brain structure and VF. To obtain insight into the biology of brain-tissue alterations, parallel preclinical research in specific mouse models will be carried out. Brain micro- and macro-structure will be assessed with the same multimodal MR imaging of the brain (T1W, T2W, MTR, and DTI) and VF (T1W) as in our human studies. Likewise, our new (extensive) panel of circulating GPCs (n=460) will be quantified with advanced mass spectrometry (LC-ESI-MS) as in our human studies. Only in mice, 2-photon brain imaging will be employed to investigate quantity and spatial distribution of activated microglia across the brain; immunohistochemistry will be used to examine myelin and axon diameter. Given the high prevalence of abdominal obesity (high VF) and its potential role in AD, this research is important for early detection and prevention of this disease.
