Brainstem tissue microstructural properties change across the adult lifespan. However, studies elucidating the biological processes that govern brainstem maturation and degeneration in-vivo are lacking. In the present work, conducted on a large cohort of 140 cognitively unimpaired subjects spanning a wide age range of 21 to 94 years, we implemented a multi-parameter approach to characterize the sex-and age differences. In addition, we examined regional correlations between myelin water fraction (MWF), a direct measure of myelin content, and diffusion tensor imaging indices, and transverse and longitudinal relaxation rates to evaluate whether these metrics provide information complementary to MWF. We observed region-dependent differences in myelin content and axonal density with age and found that both exhibit an inverted U-shape association with age in several brainstem substructures. We emphasize that the microstructural differences captured by our distinct MRI metrics, along with their weak associations with MWF, strongly indicate the potential of using these outcome measures in a multi-parametric approach. Furthermore, our results support the gain-predictsloss hypothesis of tissue maturation and degeneration in the brainstem. Indeed, our results indicate that myelination follows a temporally symmetric time course across the adult life span, while axons appear to degenerate significantly more rapidly than they mature. AGINGTable 2. The slopes and standard error (SE) of the maturation and degeneration phases of the standardized MWF, R1, R2, and DTI indices for six brainstem substructures. Maturation and degeneration slopes ± SE Slope of maturation Slope of degeneration p-value Slope of maturation Slope of degeneration p-value MWF Cerebral peduncle

Background: Central arterial stiffness (CAS) is associated with elevated arterial blood pressure (BP) and is likely associated with stiffening of cerebral artery walls, with attendant cerebral hypoperfusion, neuronal density loss and cognitive decline. Dahl salt-sensitive (Dahl-S) rats exhibit age-associated hypertension and memory loss, even on a normal salt intake. Method: We sought to explore whether central arterial pulse wave velocity (PWV), a marker of CAS, is associated with hippocampal cerebral blood flow (CBF) and neuronal density in hypertensive Dahl-S rats. We measured systolic BP (by tail-cuff plethysmography), aortic PWV (by echocardiography) and CBF and N -acetyl aspartate (NAA) (by magnetic resonance imaging) in 6 month-old male Dahl-S rats ( n = 12). Results: Greater PWV was significantly associated with lower CBF and lower NAA concentration in the hippocampus, supporting a role of CAS in cerebrovascular dysfunction and decline in cognitive performance with aging. Conclusion: These findings implicate increased CAS in cerebral hypoperfusion and loss of neuronal density and function in the Dahl-S model of age-associated cardiovascular dysfunction.

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Background: Aged Dahl salt sensitive rats (DSS) rats represent a model of vascular dementia, i.e., they develop central arterial stiffness (CAS), hypertension, and cognitive decline. DSS rats have compromised renin-angiotensin system (RAS) which is activated with age and contributes to hypertension. This study examined whether angiotensin converting enzyme (ACE) inhibitor, lisinopril, affects CAS and cognitive functions in aged male DSS (n=26). Methods & Results: Following initial measurements at 16-mo of age (baseline; BL), DSS were administered lisinopril through their water (LISI; 15mg/kg/day, n=11) or control treatment (n=15) for 2-mo. Pulse wave velocity (PWV), a marker of CAS, and systolic blood pressure (SBP) were measured at BL and at 18-mo of age. Open field test (OFT) to assess anxiety-like behavior and Morris water maze (MWM) to assess spatial memory were performed at 18-mo, then aortae and hearts were collected and weighed. Aortic wall collagen abundance was estimated by histochemistry. Statistical analyses were performed by 2-way ANOVA mixed effects model and t-test. The data are presented as mean ± SEM. At 18-mo of age, control animals had high SBP similar to BL (187±4 vs. 184±7 mmHg), while LISI-treated DSS had lower SBP by 39±4 mmHg vs. BL (p<0.01). PWV in control rats increased from 16 to 18-mo (7.0±0.6 vs. 10.8±1.0 m/s; p<0.05), while PWV in LISI-treated DSS decreased after 2-mo of treatment (7.1±0.3 vs. 5.4±0.3 m/s; p<0.01). Lower heart weights (2.9±0.1 vs. 3.7±0.3 g/kg BW; p<0.01), aortic weights (4.4±0.1 vs. 5.0±0.2 mg/mm/kg BW; p<0.01), and aortic medial collagen abundance (14.0±0.3 vs. 19.6±1.0 % of total; p<0.01) were observed in the LISI-treated rats vs. control rats. No differences between LISI-treated and control groups at 18-mo (38±10 vs. 25±6 cm traveled in center) were found in OFT. MWM results indicated that neither group at 18-mo of age was able to learn the task and therefore could not be accurately assessed for differences in spatial memory. Conclusion: Initiation of anti-hypertensive treatment in old age was effective in reducing aortic fibrosis and lowering SBP and PWV in DSS rats. Longer treatment may be needed to improve cognitive function in this model of vascular dementia. Supported by the NIH/NIA Intramural Research Program