Age-related memory impairments have been linked to differences in structural brain parameters, including the integrity of the hippocampus (HC) and its distinct hippocampal subfields (HCsf). Imaging methods sensitive to the underlying tissue microstructure are valuable in characterizing age-related HCsf structural changes that may relate to cognitive function. Magnetic resonance elastography (MRE) is a noninvasive MRI technique that can quantify tissue viscoelasticity and may provide additional information about aging effects on HCsf health. Here, we report a high-resolution MRE protocol to quantify HCsf viscoelasticity through shear stiffness, μ, and damping ratio, ξ, which reflect the integrity of tissue composition and organization. HCsf exhibit distinct mechanical properties—the subiculum had the lowest μ and both subiculum and entorhinal cortex had the lowest ξ. Both measures correlated with age: HCsf μ was lower with age (P < 0.001) whereas ξ was higher (P = 0.002). The magnitude of age-related differences in ξ varied across HCsf (P = 0.011), suggesting differential patterns of brain aging. This study demonstrates the feasibility of using MRE to assess HCsf microstructural integrity and suggests incorporation of these metrics to evaluate HC health in neurocognitive disorders.

Aging and neurodegenerative diseases lead to decline in thinking and memory ability. The subfields of the hippocampus (HCsf) play important roles in memory formation and recall. Imaging techniques sensitive to the underlying HCsf tissue microstructure can reveal unique structure–function associations and their vulnerability in aging and disease. The goal of this study was to use magnetic resonance elastography (MRE), a noninvasive MR imaging-based technique that can quantitatively image the viscoelastic mechanical properties of tissue to determine the associations of HCsf stiffness with different cognitive domains across the lifespan. Eighty-eight adult participants completed the study (age 23–81 years, male/female 36/51), in which we aimed to determine which HCsf regions most strongly correlated with different memory performance outcomes and if viscoelasticity of specific HCsf regions mediated the relationship between age and performance. Our results revealed that both interference cost on a verbal memory task and relational memory task performance were significantly related to cornu ammonis 1–2 (CA1–CA2) stiffness (p= 0.018 andp= 0.011, respectively), with CA1–CA2 stiffness significantly mediating the relationship between age and interference cost performance (p= 0.031). There were also significant associations between delayed free verbal recall performance and stiffness of both the dentate gyrus–cornu ammonis 3 (DG–CA3;p= 0.016) and subiculum (SUB;p= 0.032) regions. This further exemplifies the functional specialization of HCsf in declarative memory and the potential use of MRE measures as clinical biomarkers in assessing brain health in aging and disease.SIGNIFICANCE STATEMENTHippocampal subfields are cytoarchitecturally unique structures involved in distinct aspects of memory processing. Magnetic resonance elastography is a technique that can noninvasively image tissue viscoelastic mechanical properties, potentially serving as sensitive biomarkers of aging and neurodegeneration related to functional outcomes. High-resolutionin vivoimaging has invigorated interest in determining subfield functional specialization and their differential vulnerability in aging and disease. Applying MRE to probe subfield-specific cognitive correlates will indicate that measures of subfield stiffness can determine the integrity of structures supporting specific domains of memory performance. These findings will further validate our high-resolution MRE method and support the potential use of subfield stiffness measures as clinical biomarkers in classifying aging and disease states.

Modifiable cardiometabolic risk factors induce the release of pro-inflammatory cytokines and reactive oxygen species from circulating peripheral blood mononuclear cells (PBMCs) resulting in increased cardiovascular disease risk and compromised immune health. These changes may be driven by metabolic reprogramming of PBMCs resulting in impaired mitochondrial respiration; however, this has not been fully tested. We aimed to determine the independent associations between cardiometabolic risk factors, such as blood pressure, BMI, and plasma lipids with impaired mitochondrial respiration in PBMCs isolated from generally healthy individuals (n=21) across the adult lifespan (12 M/ 9 F; age: 56 ± 21 years; age-range: 22-78 year; blood pressure: 123 ± 16 / 72 ± 10 mmHg; low-density lipoprotein cholesterol, LDL-C: 111 ± 22 mg/dL; and high-density lipoprotein cholesterol, HDL-C: 62 ± 16 mg/dL). PBMCs were isolated from whole blood by density dependent centrifugation and used to assess mitochondrial function by respirometry. Primary outcomes included baseline and maximal oxygen consumption rate (OCR) which were subsequently used to determine spare respiratory capacity and OCR metabolic potential. After correcting for HDL-C, SBP, and age, LDL-C was negatively associated with maximal respiration (r=-0.61, P=0.0073), spare respiratory capacity (r=-0.65, P=0.0038) and OCR metabolic potential (r=-0.59, P=0.010), respectively. In addition, there was a strong, but non-significant positive association between HDL-C and maximal respiration (r=0.46, P=0.057) and spare respiratory capacity (r=0.43, P=0.075), after correcting for other covariates. These data suggest a link between blood cholesterol and mitochondrial health that may provide insight into how cardiometabolic risk factors contribute to impaired immune cell function.

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Age-related memory loss shares similar risk factors as cardiometabolic diseases including elevated serum triglycerides (TGs) and low-density lipoprotein cholesterol (LDL-C) and reduced high-density lipoprotein cholesterol (HDL-C). The mechanisms linking these aberrant blood lipids to memory loss are not completely understood but may be partially mediated by reduced integrity of the hippocampus (HC), the primary brain structure for encoding and recalling memories. In this study, we tested the hypothesis that blood lipid markers are independently associated with memory performance and HC viscoelasticity—a noninvasive measure of brain tissue microstructural integrity assessed by high-resolution magnetic resonance elastography (MRE). Twenty-six individuals across the adult lifespan were recruited (14 M/12 F; mean age: 42 ± 15 y; age range: 22–78 y) and serum lipid profiles were related to episodic memory and HC viscoelasticity. All subjects were generally healthy without clinically abnormal blood lipids or memory loss. Episodic memory was negatively associated with the TG/HDL-C ratio. HC viscoelasticity was negatively associated with serum TGs and the TG/HDL-C ratio, independent of age and in the absence of associations with HC volume. These data, although cross-sectional, suggest that subtle differences in blood lipid profiles in healthy adults may contribute to a reduction in memory function and HC tissue integrity.