First in last out: how development informs neurodegeneration

Washington University, Saint Louis MO

Investigators

Abstract

PROJECT SUMMARY In Alzheimer Disease (AD), magnetic resonance imaging shows early atrophy and loss of functional connectivity in the medial temporal lobes, which then spreads to the posterior temporal lobe, parietal lobe, and finally the frontal lobe with relative sparing of the sensorimotor cortex. It is unclear what biological properties drive these different spatiotemporal patterns. At the other end of the lifespan, over the first few years of life the brain undergoes rapid cortical expansion and maturation. Whereas primary sensory regions are relatively stable from birth, there is tremendous cortical expansion in the temporal, parietal, and frontal regions. The networks that are most plastic mirror those regions most sensitive to AD pathology later in late. Further, adverse developmental conditions and structural and social determinants of health (SSDOH) such as low birthweight, poverty, and trauma can negatively impact the development of these networks, and increasing evidence indicates the repercussions persist throughout the lifespan. This raises the question whether degenerative processes in AD reflect downstream consequences of adverse developmental trajectories. The most frequent attempt to consider development and aging together has largely been qualitative in the recognition of the “first in last out” mirroring between regional changes in the brain. There has been minimal research testing hypotheses linking early development and degeneration together empirically. We posit two main theories. First, regions with high plasticity in early life have unique biological properties that inherently make them more susceptible to pathological changes later in life. Second, the detrimental impact of SSDOH on these regions during development are long-lasting and will contribute to adverse aging trajectories. Our goal is to determine the degree to which our understanding of healthy and pathological aging in the brain can be informed by early neurodevelopment. To accomplish this goal, the project will leverage multiple rich longitudinal datasets with advanced neuroimaging, deep clinical and cognitive phenotyping, and in-depth genotyping. In Aim1, we will quantify similarities and differences in the spatiotemporal progression of brain development and degeneration using neuroimaging to empirically test the spatiotemporal patterns predicted by the “first in last out” hypothesis. In Aim 2, we will determine the impact of deprivation and genetic risk on functional and structural brain development and degeneration. Finally, in Aim 3, we will elucidate early-life contributions to accelerated brain aging and susceptibility to degenerative diseases using genetic risk, neighborhood deprivation, birthweight, and early childhood trauma. Aims 1 and 2 will harmonize large, extant neuroimaging datasets including birth to three years of age (eLABE, BCP) and aging and degeneration (ADNI, SORTOUT-AB, HABS-HD) to directly test how normal and abnormal cortical expansion and brain connectivity development during childhood are reflected in healthy and pathological aging. In Aim 3, we will leverage lifespan, population level data from the UK Biobank. This proposal brings together a diverse team with expertise in both brain development, degeneration, and SSDOH.