The Relationship Between Resting Cerebral Blood Flow, Neurometabolites, Cardio-Respiratory Fitness and Aging-Related Cognitive Decline

Abstract

Older adults typically experience a decline in cognitive function, but improvements in physical health and lifestyle can be neuroprotective across the human lifespan. The primary objective of this study is to advance our basic understanding of how cardiorespiratory fitness and neurophysiological attributes relate to cognitive decline. While cerebral blood flow (CBF) is critical for the supply of nutrients to the tissue, the brain's major neurotransmitters (i.e., gamma-aminobutyric acid, GABA, and glutamate-glutamine complex, Glx) are closely linked to oxidative metabolism. Within the context of flow-metabolism coupling, the critical question is how these neurophysiological parameters interplay, resulting in cognitive decline. Further, how cardiorespiratory fitness may impact aging neurophysiology and cognition is not well understood. To address these questions, we recruited 10 younger and 12 older cognitively intact participants to collect GABA and Glx using magnetic resonance spectroscopy (MRS), CBF using pseudo-continuous arterial spin labeling Magnetic Resonance Imaging (MRI), VO2max as a measure of cardiorespiratory fitness using the YMCA submax test, and cognitive and motor-cognitive measures using a battery of behavioral assessments. We observed expected differences in GABA+, Glx, and CBF between younger and older participants in pre-SMA, a frontal domain-general region. When GABA+ and Glx were related to CBF via multiple linear regression, Glx was identified as the main contributor to the model. For higher-order executive function (i.e., inhibition versus color naming), GABA*Glx*CBF interaction was critical in younger, while only Glx was involved in older participants. For unimanual motor dexterity, GABA*Glx interaction was the common denominator across both groups, but younger participants' brain also engages CBF. In terms of selective motor inhibition, CBF from younger participants was the only major neurophysiological factor. In terms of fitness, cardiorespiratory fitness was significantly related to GABA, Glx, and motor performance when combining cohorts, but no group-specific relationships were observed. Taken together, our results indicate that Glx and CBF coupling decreases with aging, perhaps due to altered glial oxidative metabolism. Our data suggest that GABA, Glx, and CBF are engaged and weighted differently for different cognitive measures sensitized to aging, and higher fitness allows for a more efficient metabolic shift that facilitates improved performance on cognitive-motor tasks.

Keywords: GABA; MRS; aging; cardiorespirarory fitness; cerebral blood blow; cognition; glutamate-glutamine (Glx); pre-SMA.