Linking brain micro- and meso-structure with cognitive functioning

National Institute On Aging

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Abstract

In this project we combine pre-clinical and clinical MRI sequences that allows the simultaneous T1, T2, and diffusion encoding (i.e., diffusion-relaxation multidimensional MRI) with complementary histological methods, cognitive assessment, and blood biomarkers, to investigate cellular processes that relate to function, microstructure, and chemical composition in normative aging, mild cognitive impairment, and dementia. The type of data acquisition and approach is novel and is only now starting to be used to investigate the human brain. Below, milestones from this project are summarized: 1. Development, application, and testing of a clinical MD-MRI imaging protocol Sequence and protocol development: We have successfully developed and implemented a novel diffusion-relaxation multidimensional MRI acquisition protocol on a 3T clinical scanner, which simultaneously characterizes micro- and meso-structure and local chemical composition, and importantly, how these properties are coupled within complex tissue that contains multiple microenvironments. This 40 minute scan delivers 2 mm isotropic resolution and allows one to explore both the frequency-dependent and tensorial aspects of diffusion, enabling investigation of frequency/time-dependent changes of diffusion-relaxation correlations measures using a single framework. We first scanned a well-defined physical phantom, demonstrating the robustness of this imaging protocol. We used these data, along with a few healthy volunteers, to design, implement and test a suitable pre-processing pipeline for multidimensional MRI data. Variability and reproducibility of multidimensional diffusion-relaxation MRI estimates in the human brain: Using the clinically feasible whole-brain MD-MRI acquisition protocol we developed, we conducted a comprehensive analysis of the derived multidimensional distributions across various brain regions, including white matter tracts and cortical and subcortical gray matter. The study assessed intrascanner test–retest reliability, repeatability, and reproducibility of MD-MRI parameters in 10 human subjects. Results showed that average diffusion and relaxation values derived from MD-MRI were as reliable and repeatable as those obtained from conventional diffusion tensor imaging (DTI) and quantitative relaxometry. Moreover, the spectral decomposition of MD-MRI data into intra-voxel signal fractions—representing different tissue types—was found to be reproducible. These findings validate the robustness of MD-MRI spectral analysis and highlight its promise for developing novel MRI biomarkers that more accurately reflect the complex structural and chemical makeup of brain tissue. 2. Comprehensive microstructure imaging of brain aging Quantifying cerebral age-related microstructural changes: We used the recently introduced mean apparent propagator (MAP) MRI framework to investigate existing large-scale cross-sectional and longitudinal neuroimaging studies. MAP-MRI comprehensively captures the micro- and mesoscopic complexity of cerebral tissue, encompassing various underlying structural and architectural characteristics. Initially, we explored age-related differences in a cross-sectional cohort of 58 cognitively unimpaired participants from the Baltimore Longitudinal Study of Aging (BLSA) and Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT). This study revealed that MAP-MRI derived parameters contain novel information related to cerebral aging, contributing to the biological interpretation of changes across the adult lifespan. Associating cortical and sub-cortical microstructural changes with neurocognitive aging: We then aimed at exploring the potential of MAP-MRI in unveiling sensitive markers of cortical and subcortical age-related microstructural changes and assessing their associations with cognitive and behavioral deficits. We leveraged the Human Connectome Project-Aging cohort that included 707 unimpaired participants (394 female; median age = 58, range = 36–90 years), along with comprehensive behavioral and cognitive test scores. Both macro- and microstructural cortical and sub-cortical characteristics were strongly associated with age, with widespread significant microstructural correlations reflective of cellular morphological changes, reduced cellular density, increased extracellular volume, and increased membrane permeability. Importantly, when correlating MRI and cognitive test scores, our findings revealed no link between macrostructural volumetric changes and neurobehavioral performance. However, we found that cellular and extracellular alterations in cortical and subcortical regions were associated with neurobehavioral performance. Based on these findings, it is hypothesized that increased microstructural heterogeneity and decreased neurite orientation dispersion precede macrostructural changes, and that they play an important role in subsequent cognitive decline. These alterations are suggested to be early markers of neurocognitive performance that may distinctly aid in identifying the mechanisms underlying phenotypic aging and subsequent age-related functional decline. This work provides valuable insights that could assist in early differentiation of cognitively healthy aging from pathological conditions, including mild cognitive impairment, Alzheimer’s, and other dementia-related disorders.