Preclinical Magnetic Resonance Imaging and Spectroscopy Studies of Memory, Aging, and Cognitive Decline

Abstract

Neuroimaging provides for non-invasive evaluation of brain structure and activity and has been employed to suggest possible mechanisms for cognitive aging in humans. However, these imaging procedures have limits in terms of defining cellular and molecular mechanisms. In contrast, investigations of cognitive aging in animal models have mostly utilized techniques that have offered insight on synaptic, cellular, genetic, and epigenetic mechanisms affecting memory. Studies employing magnetic resonance imaging and spectroscopy (MRI and MRS, respectively) in animal models have emerged as an integrative set of techniques bridging localized cellular/molecular phenomenon and broader in vivo neural network alterations. MRI methods are remarkably suited to longitudinal tracking of cognitive function over extended periods permitting examination of the trajectory of structural or activity related changes. Combined with molecular and electrophysiological tools to selectively drive activity within specific brain regions, recent studies have begun to unlock the meaning of fMRI signals in terms of the role of neural plasticity and types of neural activity that generate the signals. The techniques provide a unique opportunity to causally determine how memory-relevant synaptic activity is processed and how memories may be distributed or reconsolidated over time. The present review summarizes research employing animal MRI and MRS in the study of brain function, structure, and biochemistry, with a particular focus on age-related cognitive decline.

Longitudinal Quantification of Metabolites and Macromolecules Reveals Age- and Sex-Related Changes in the Healthy Fischer 344 Rat Brain

“…Previous clinical and preclinical MRS studies of age-related changes have produced mixed findings, particularly for the more commonly reported metabolites such as NAA, tCho, and tCr. Some of the differences between studies may be attributed to reporting metabolite ratios instead of absolute concentrations, different handling of the underlying MM signal, or the study of single sex cohorts (for reviews, see (Haga et al 2009;Cleeland et al 2019;Febo and Foster 2016). Below, we present a brief comparison of our findings to previous studies and an interpretation of the biological relevance of the age-related alterations in the neurochemical profile of the Fischer rat.…”

“…Marjańska et al 2014;Choi et al 2014), rats (Paban, Fauvelle, and Alescio-Lautier 2010;Harris et al 2014;Zhang et al 2009), and humans (Murray et al 2014;Emir et al 2011), reflecting changes in underlying physiological processes and supporting its emergence as an important translational tool in neuroscience research Quantification of at least 18 neurochemicals in the rodent brain is feasible with in vivo 1 H MRS at 7T and above, providing a wide array of potential biomarkers of specific cellular and molecular changes (Pfeuffer et al 1999;Mlynárik et al 2006;Duarte, Do, and Gruetter 2014;Harris et al 2014). Many of these molecular changes are reflective of changes in energy metabolism, inflammation, and antioxidant capacity, processes significantly altered in aging and whose metabolic by-products comprise the Nuclear Magnetic Resonance (NMR)-observable neurochemical profile (McKenna et al 2012;Febo and Foster 2016). In addition to brain metabolites, broad macromolecule (MM) resonances are also detected with 1 H MRS, and have been shown to change with age, brain region, and pathological conditions (Seeger et al 2003;Behar et al 1994;Hofmann et al 2001).…”

Treatment with the mitochondrial‐targeted antioxidant peptide SS‐31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice

“…Importantly, clinical studies suggest that impairment of NVC responses contributes to the age‐related decline in higher cortical functions (Sorond et al., , ). Recent studies demonstrate that BOLD signal is positively correlated with working memory in rodent models and that impaired memory is associated with impaired NVC (reduced BOLD activity) in the hippocampus (Febo & Foster, ). Our recent studies provide strong experimental evidence in support of this concept, demonstrating that impairment of NVC responses and cognitive decline in mice are causally related (Tarantini et al., ).…”

Longitudinal Characterization and Biomarkers of Age and Sex Differences in the Decline of Spatial Memory

“…Studies employing magnetic resonance imaging in animal models have emerged as a valuable strategy for characterizing the relationship between cognitive function and neural circuits that underlie the cognitive process of interest (Liang et al, 2015;Ash et al, 2016). Resting state connectivity provides information on intrinsic functional brain organization, and similar resting state functional connectivity is observed between humans and animal models, including rodents, rabbits, and monkeys (Febo and Foster, 2016). The analysis of brain wide resting state functional connectivity in the rodent brain is facilitated by the use of network science algorithms, which provide insight on the topology of connectivity patterns under normal and disease states (Diaz-Parra et al, 2017).…”