Quantifying motor–cognitive reserve using a novel multi-modal stress test

Reserve is a physiological capacity used under demanding situations. The concept was developed to account for the discrepancy between pathology and clinical manifestation. In neuroscience, motor, brain and cognitive reserves are abstract measures, conceptually defined yet elusive to quantify. Reserve is indirectly assessed using proxies such as years of education and brain volume, limiting its utility. Moreover, the dichotomy in definitions of cognitive and motor reserves is artificial, as daily function requires an intricate network of connections between these domains. Here, we assessed the validity of a newly developed graded motor cognitive 'stress test' to quantify the combined motor and cognitive reserve (MCR). The study included <i>144</i> participants (ages between 18 and 85, 50% women) with a range of reserve capacities (i.e. healthy young and older adults and individuals with Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies and mild cognitive impairment). The assessment included walking on a treadmill while negotiating motor and cognitive challenges delivered using virtual reality. To establish an MCR index score, we used a semi-supervised machine learning algorithm. The model includes performance measures from completing the stress test and measures obtained from wearable sensors used during the test. Validation of the proposed MCR index was examined through: (i) model face validity-reflecting decline of performance as challenge increased; (ii) known-groups validity-classification of scores according to neurological status; (iii) construct validity (convergent)-association with common MCRs proxies as well as MRI-derived regional brain volumes. The model's face validity revealed decreased performance with increased motor and cognitive challenges (both domains <i>P</i> < 0.001). The index accurately discriminated between healthy controls and those diagnosed with neurological conditions with an area under the curve of <i>0.89 [95% CI: 0.79-0.99]</i> which was significantly higher than all other commonly used proxies. Statistically significant Spearman's <i>ρ</i> correlations were observed with all commonly used motor and cognitive proxies (0.56 ≤ <i>r</i> ≤ 0.79, after multiplicity correction all <i>P</i> < 0.05), reflecting construct validity. In addition, statistically significant correlations were observed between the MCR index and whole-brain grey matter and white matter volumes (<i>r</i> = 0.63 and 0.55), as well as the pre-defined left and right caudate nucleus (<i>r</i> = 0.56 and 0.68) and inferior-frontal gyrus (<i>r</i> = 0.47 and 0.58). This proof-of-concept study shows that the novel MCR index is valid, with high sensitivity to neurological deficits and is able to quantify reserve on an individual level. This new innovative tool can assist in screening for motor cognitive deficits and potentially, for predicting motor and cognitive decline associated with neurodegenerative disease.