The parent grant for this administrative supplement, R01 AG039684, is designed to investigate structural and functional brain connectivity, and cognitive performance, in the context of healthy aging. In this administrative supplement application, in response to NOT-AG-20-008, we propose to apply the imaging techniques, developed in the parent R01, to develop an additional focus on Alzheimer's disease (AD). The overall goal is to investigate the potential value of regional brain iron as a novel biomarker of AD. Currently, postmortem histology is needed for a definite determination of AD, However, validated, in vivo biomarkers from cerebrospinal fluid (CSF) and neuroimaging exist that are proxies for the neuropathologic changes and can provide a diagnosis of probable AD. Because these biomarkers are either relatively invasive (e.g., lumbar puncture) or involve radioactivity exposure during imaging, a critical need exists for less invasive and widely available biomarkers that may be predictive of AD. Non-heme iron, which is the most abundant metal in the brain, is a contributor to essential neurobiological processes, including oxygen transportation, mitochondrial respiration, myelin synthesis, and neurotransmitter synthesis and metabolism. Excess iron, however, promotes spontaneous release of highly neurotoxic free iron, which leads to the harmful formation of highly reactive radical species, thus drastically exacerbating oxidative stress and neuronal death. Postmortem histological studies have demonstrated increases in the level of iron within deep gray matter and neocortical regions during aging and neurodegenerative disease, including AD and related forms of dementia. The regional distribution of iron co- localizes with the plaques and neurofibrillary tangles definitive of AD. Magnetic resonance imaging (MRI) can estimate iron deposition through analyses of the susceptibility data in diffusion weighted imaging (DWI), without obtaining CSF or using a radioactive imaging tracer. Previous MRI studies suggest that AD is associated with increased iron in deep gray matter and cortical regions, as well as a decline in functional brain connectivity. These previous studies, however, have typically been conducted at a conventional level of spatial resolution and have not as yet demonstrated a relation of iron to AD-related decline in functional connectivity. In this project, we propose to use high-resolution (sub-millimeter) quantitative susceptibility mapping (QSM) to estimate regional brain iron in 30 individuals diagnosed with probable AD and 30 healthy, age- matched controls. The increased spatial resolution will allow the estimation of iron across cortical depth. We will characterize AD-related differences in brain iron within deep gray matter and cortical regions (Aim 1) and test for the potential influence of brain iron on AD-related decline in functional brain connectivity (Aim 2).
These aims are within the scope of the parent R01 but develop a new direction that will be relevant for understanding AD and related dementias.
The disruption of brain iron homeostasis is known to contribute to neurodegeneration, and previous research suggests that increasing brain iron is a prominent feature of Alzheimer's disease (AD) and related forms of dementia. Little information, however, is available regarding either the profile of regional brain iron associated with AD, or whether the AD-related increase in iron influences functional brain connectivity. The proposed research would fill that scientific gap and contribute new information that can potentially guide diagnosis and new interventions for AD and related disorders.
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