PROJECT SUMMARY
We are facing a growing crisis of a greater number of seniors living with a decline in cognitive function as a
common consequence of aging. Once an impairment has reached a level of clinical significance, treatment
options are limited. We propose to examine age-related differences in trait and state autonomic control of heart
rate and their relation to cognitive performance humans and rats. While cognitive changes may be masked by
compensatory efforts, autonomic measures may be more revealing of the underlying age-related changes in the
neural substrates and neurochemistry of aging and its clinical course. We will examine these autonomic
regulation of heart rate, its relation to and modulation by cognitive performance, as a peripheral proxy of early
central alteration of the cholinergic basal forebrain (BF), a progenitor of system-wide neuroanatomical and
neurochemical changes related to aging. To understand the underlying neural mechanistic bases of these
autonomic indices, we will apply a cross-species approach, including human functional neuroimaging as well as
nonhuman neurochemical examinations. Specific Aim 1 will examine whether age-related differences in
cognitive control are associated with altered autonomic regulation of the heart. Approach: We will employ
a cross-sectional examination of inhibitory cognitive control tasks, which we have shown to depend on the
cholinergic BF in rats, in a diverse sample of male and female young, middle-aged, and older adults, examining
how cognitive performance relates to autonomic parasympathetic influences on the heart, reflected in vagally-
mediated heart rate variability(phasic, beat-to-beat heart rate variability). Specific Aim 2 will examine the
specific role of the BF, and its afferent networks, in connecting age-related differences in cognitive
control and autonomic regulation of the heart. Approach: We will employ multi-echo fMRI to acquire high
SNR signal from BF nuclei and autonomic phasic parasympathetic influences on heart, and their relation to
neurocognitive aging, while characterizing and controlling for age-related differences in cerebral blood flow with
arterial spin labelling. Specific Aim 3 will test the hypothesized parallel causal contributions of BF
cholinergic neurons to central cognitive regulation and peripheral autonomic regulation of the heart.
Approach: Using cholinergic immunotoxic lesions, a rat model of cognitive aging will assess the causal role of
the BF to cognitive control and parasympathetic autonomic regulation of heart rate (vmHRV) in male and female
young, middle-aged, and older rats. Revealing peripheral autonomic aspects of age-related differences in brain
integrity and cognitive status would advance our understanding of normative and potentially pathological
neurochemical changes in aging. It will further advance the use of a noninvasive, low-cost peripheral biomarker
for identifying those who may progress to mild neurocognitive disorder (mNCD). Such a readily administered
screen for early mNCD could better afford early detection, monitoring, and potential intervention before the
onset of mNCD and potential conversion to Alzheimer’s Disease.