Disambiguating natural aging from Alzheimer's disease through changes in oral neuromechanics

PROJECT SUMMARY
Many age-related oral health problems, such as masticatory dysfunction, dysphagia, periodontal disease, and tooth loss
have been associated with Alzheimer’s disease (AD). How cortical and biomechanical changes in oromotor behavior
contribute to the onset and progression of AD and age-related dementias (ARD) are widely unknown. This is largely
because of a fundamental gap in understanding the neuromechanical processes, at the level of large-scale activity of single
neurons and neuronal networks, that underlie healthy aging. This represents an important problem because until they
are understood, the cortical mechanisms underlying pathological aging in AD/ARD will remain largely incomprehensible.
The goal of the proposed research is to investigate changes in the orofacial sensorimotor-cognitive neuronal network that
underlie healthy age-related sensorimotor changes and how these cortical correlates are affected by absent sensory inputs
to oral structures and by the presence of AD-like impairments (‘pathological aging’) in old rhesus macaques. The central
hypothesis is that differential patterns of the dynamics of large-scale neural activity and connectivity in the orofacial
sensorimotor cortex (OSMcx) and the ventrolateral frontal cortex (VLFcx) will help disambiguate healthy and pathological
aging. This hypothesis will be tested by pursuing three specific aims: (1) to identify the neuronal correlates of healthy age-
related changes in feeding behavior, (2) to identify changes in cortical representations of oral somatosensation following
sensory nerve block, and (3) to identify changes in neuronal responses and cortical interactions in OSMcx-VLFcx networks
following drug-induced AD-like impairments. Thus, we can evaluate and compare the added burden of sensory loss and
AD-like impairments on aging. The proposed research uses an innovative approach that leverages the unique sensory
innervation of the oral region by different cranial nerves and the use of a pharmacological model to induce AD-like
impairments in old rhesus macaques. We will record cortical activity from multiple chronically implanted microelectrode
arrays in OSMcx-VLFcx simultaneously with 3D tracking of tongue and jaw kinematics using biplanar videoradiography and
the XROMM workflow (X-ray Reconstruction of Moving Morphology) while young and old subjects engage in natural
feeding behavior. The proposed research is significant for (1) defining cortical, biomechanical, and immunohistological
profiles of healthy and pathological aging, (2) determining potential contributing factors to the onset and progression of
AD, and (3) identifying cortical regions that are vulnerable to AD. Using old rhesus macaques has direct translational value
to evaluate potential avenues for pharmacological or cortical therapies for AD. The knowledge gained from the proposed
study has important implications for earlier identification of individuals with chronic oral health issues who may be at risk
for developing AD or ARDs. It may also inform the development of more effective interventions focused on enhancing oral
health outcomes in this group and thus preventing the onset or allaying the progression of AD or ARD.

Grant Number: 5R01AG069227-05
NIH Institute/Center: NIH
Principal Investigator: Fritzie Arce-McShane