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.

Determinants of cerebral blood flow and arterial transit time in healthy older adults

“…17,19,27,86 However, the present data found no association between cardiorespiratory fitness and global or regional CBF. Other cross-sectional ASL studies report no global effect, 33,52,54 but positive regional associations are generally observed. 33,36–39 Previously reported regional effects often relate to much smaller regions than those examined in the present study (e.g., occipitoparietal area, posterior cingulate cortex, precuneus, middle frontal gyrus), and CBF was not adjusted for ATT differences in those studies.…”

“…40 Furthermore, aerobic exercise training in older adults has been shown to increase CBF 28,[41][42][43][44][45] or CBv. [46][47][48][49] In contrast, a negative association between cardiorespiratory fitness and CBF has also been found 50,51 or a complete lack of association between cardiorespiratory fitness and CBF [52][53][54] or CBv. [55][56][57][58][59] Interestingly, reported changes in CBF are not usually global, but instead confined to specific regions of the brain.…”

ASL MRI informs blood flow to chronic stroke lesions in patients with aphasia

“…Such a result, though counterintuitive, is not beyond the realm of possibility. A theoretical, yet empirically elusive, construct in the stroke literature is the concept of diaschisis ( Carrera and Tononi, 2014 )—defined as “neurophysiological changes that occur distant to a focal brain lesion.” It may be that loss of input and output to a region distal to the lesion may cause an increase in blood flow due to a reduction in inhibitory tone ( Blicher et al, 2015 ), which together (i.e., GABA and CBF) influence cognitive decline ( Krishnamurthy V. et al, 2022 ; Krishnamurthy L. C. et al, 2022 ). Therefore, an increased CBF distal to the lesion may indicate a failure of the network and lead to worse behavioral outcomes.…”

The association between language-based task-functional magnetic resonance imaging hemodynamics and baseline GABA+ and glutamate–glutamine measured in pre-supplementary motor area: A pilot study in an aging model

“…Specifically, multi-modal neuroimaging approaches that combine magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging (fMRI) are highly informative in such endeavors (for a descriptive review see ( 5 ) and a comprehensive meta-analysis see ( 6 )), but all reports to date examine younger or midlife populations. While we recently showed that the flow-metabolism coupling (i.e., associations between neurometabolites and cerebral blood flow) is critical in aging-related cognitive decline ( 7 ), the role of neurometabolites in task engagement is yet to be explored in an aging model, Furthermore, most reports relate MRS measures with task-BOLD amplitude, but the shape of the hemodynamic response is also of great importance when relating to neurochemistry ( 8 ), especially in an aging model.…”

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and Krishnamurthy V (2022) The association between language-based task-functional magnetic resonance imaging hemodynamics and baseline GABA+ and glutamate-glutamine measured in pre-supplementary motor area: A pilot study in an aging model.

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