Greater physical fitness ( VO 2 max ) in healthy older adults associated with increased integrity of the locus coeruleus-noradrenergic system

Abstract

Aim: Physical activity (PA) is a key component for brain health and Reserve, and it is among the main dementia protective factors. However, the neurobiological mechanisms underpinning Reserve are not fully understood. In this regard, a noradrenergic (NA) theory of cognitive reserve (Robertson, 2013) has proposed that the upregulation of NA system might be a key factor for building reserve and resilience to neurodegeneration because of the neuroprotective role of NA across the brain. PA elicits an enhanced catecholamine response, in particular for NA. By increasing physical commitment, a greater amount of NA is synthetised in response to higher oxygen demand. More physically trained individuals show greater capabilities to carry oxygen resulting in greater ${\mathrm{Vo}}_{2_{\max }}$ - a measure of oxygen uptake and physical fitness (PF).

Methods: We hypothesized that greater ${\mathrm{Vo}}_{2_{\max }}$ would be related to greater Locus Coeruleus (LC) MRI signal intensity. In a sample of 41 healthy subjects, we performed Voxel-Based Morphometry analyses, then repeated for the other neuromodulators as a control procedure (Serotonin, Dopamine and Acetylcholine).

Results: As hypothesized, greater ${\mathrm{Vo}}_{2_{\max }}$ related to greater LC signal intensity, and weaker associations emerged for the other neuromodulators.

Conclusion: This newly established link between ${\mathrm{Vo}}_{2_{\max }}$ and LC-NA system offers further understanding of the neurobiology underpinning Reserve in relationship to PA. While this study supports Robertson's theory proposing the upregulation of the NA system as a possible key factor building Reserve, it also provides ground for increasing LC-NA system resilience to neurodegeneration via ${\mathrm{Vo}}_{2_{\max }}$ enhancement.

Keywords: aging; brain age; locus Coeruleus; Vo 2 max ; neuroimaging; neuromodulators; voxel‐based morphometry.

Figure1 –

Plasma noradrenaline concentration in relation to intensity and duration of exercise. Figure adapted from Kjaer et al. 1987 with permission of Prof. Michael Kjaer

Figure 2 –

The neuromodulatory subcortical system: the main nuclei synthetizing and projecting to the cortex the main neuromodulators involved in cognition. The figure shows a 3D MRI reconstruction of the five neuromodulators’ seeds within the whole brain.

Figure 3 –

a) shows the relationship between Vo2max and locus coeruleus signal intensity in a sample of 41 healthy subjects (age range 60–72). Results are covaried for Age, Gender, Education, Total Intracranial Volume and max heart rate for P<0.001*. b) The significant LC voxels for P<0.01 and P<0.001 clusters are displayed in a 3D-reconstruction of the brain from a midline frontal point of view. c) The LC clusters associated with Vo2max are shown in comparison with the previously published LC atlases and masks displayed on the LC omni-comprehensive mask by Plini et al. 2021.

Figure 4 –

a) Bayesian sequential analyses for the association between locus coeruleus signal intensity and Vo2max. The sequential analyses reports “very strong” evidence supporting H1 (BF₁₀ 52.98). b) ANCOVA scattered box plot displays the mean difference between the 2 levels of Vo2max (individuals above Vo2max of 20 VS individual below Vo2max of 20).

Figure 5 –

proposed neurobiological mechanisms between Vo2Max, LC-NA system and brain and cognitive health. Based on the Noradrenergic theory of Cognitive Reserve (Robertson 2013 & 2014). Physical activity (measured with Vo2Max), by up-regulating the LC-NA system, would support brain and cognitive health via NA, BDNF and Galanin metabolism. In this framework, the neuroprotective and anti-inflammatory effects of NA may act in combination with Galanin and BDNF levels elicited by Physical activity. Galanin, particularly in the LC, would be protective against stress promoting dendrite density. Similarly, greater BDNF levels would contribute maintaining LC dendrites while promoting overall brain plasticity.