Abstract
BackgroundThe human brain has high energy requirements that continuously support healthy neuronal activity and cognition. A disruption in brain energy metabolism (BEM) may contribute to early neuropathological changes such as accumulation of β-amyloid and tau in vulnerable populations. One such population is amnestic mild cognitive impairment (aMCI) where some individuals are at risk for developing dementia, i.e. Alzheimer’s disease (AD). Recent advances in imaging technology are providing new avenues to measure BEM accurately using 31phosphorus magnetic resonance spectroscopy (31P MRS) at ultra-high-field (UHF) magnetic strength 7-Tesla. This study investigates whether a methodology using partial volume-coil 31P MRS at 7T over parieto-occipital lobes can accurately quantify high-energy phosphate and membrane phospholipid metabolites in aMCI. A secondary objective was to explore BEM and membrane phospholipid indices’ correspondence with cognitive performance in domains of executive function (EF), memory, attention, and visuospatial skills in aMCI, a heterogeneous population.Methods19 aMCI participants enrolled in the study completed cognitive assessment and 31P MRS scan. BEM indices were measured using three energy indicators: energy reserve (PCr/t-ATP), energy consumption (intracellular_Pi/t-ATP), and metabolic state (PCr/intracellular_Pi) along with regulatory co-factors of BEM-intracellular Mg2 + and pH; whereas the ratio of phosphomonoesters (PMEs) to phosphodiesters (PDEs) – membrane phospholipid indicator.Results31P MRS scan showed thirteen well-resolved peaks with precise quantification of the phosphorus metabolites at UHF. The higher BEM indices were associated with lower cognitive performance of memory [(energy reserve indicator: CVLT p = 0.004), (metabolic state indicator: CVLT p = 0.007)], executive function [(metabolic state indicator: TOSL (p = 0.044)], and attention [(pH: selective auditory task, p = 0.044)]. The finding of an inverse relationship observed in the parieto-occipital lobes suggests an association between neuronal energy markers with cognition in aMCI.ConclusionThe significant contribution of this preliminary research was to establish the feasibility of utilizing a methodology at UHF to accurately measure high-energy phosphate and membrane phospholipid metabolites in a population with heterogeneous outcomes. This work offers a novel approach for future work to further elucidate early dementia biomarkers or precursors to the downstream accumulation of amyloid and tau using the combination of MRS-PET imaging modalities in AD.
Highlights
Mild cognitive impairment (MCI) represents a heterogeneous clinical condition that is definable and objectively classifiable; its nature is unstable
We investigated the relationships across brain energy metabolism (BEM) indices measured using PCr/t-adenosine triphosphate (ATP), Pi/t-ATP, and PCr/Pi and its regulatory co-factors followed by membrane phospholipid metabolite index
The extracellular-Pi/t-ATP ratio was inversely related with performance of attention [selective auditory attention-trail 2: (b = −0.0018, t = −2.254, p = 0.038)]; whereas intracellular-Pi/t-ATP ratio was trending to be inversely proportional with the performance on the executive function (EF) domain of inhibition and switching [Trails B: (b = −13.867, t = −2.029, p = 0.0585)]
Summary
Mild cognitive impairment (MCI) represents a heterogeneous clinical condition that is definable and objectively classifiable; its nature is unstable. This varying range of MCI progression to dementia, or reversal back to normal, supports a plausible hypothesis that the biological mechanisms involved are heterogeneous and unstable As such, this classifiable group may provide a valuable population to explore the early biomarkers of neuronal function that affect cognition before the diagnosis of dementia. A disruption in brain energy metabolism (BEM) may contribute to early neuropathological changes such as accumulation of β-amyloid and tau in vulnerable populations One such population is amnestic mild cognitive impairment (aMCI) where some individuals are at risk for developing dementia, i.e. Alzheimer’s disease (AD). A secondary objective was to explore BEM and membrane phospholipid indices’ correspondence with cognitive performance in domains of executive function (EF), memory, attention, and visuospatial skills in aMCI, a heterogeneous population
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