Biological Sex Influences The Relationship Between Aortic Stiffness And Cerebrospinal Fluid Neurofilament Light Chain

The presence of neurofilament light chain (NfL) in cerebrospinal fluid (CSF) is a biomarker for axonal damage. Increased aortic stiffness is associated with cognitive decline; however, the relationship between aortic stiffness and biomarkers for neuronal damage, such as NfL, is unclear. PURPOSE: To determine the relationship between aortic stiffness and NfL in cognitively healthy adults, and to evaluate if this association was influenced by biological sex. Further, the influence of cerebral blood flow velocity pulsatility index (PI) on this potential relationship was explored. METHODS: Aortic stiffness (carotid-femoral pulse wave velocity; cf-PWV), CSF NfL, and cerebral PI were measured in a cohort of 43 cognitively healthy individuals with an enriched risk of dementia (30 female; age: 63 ± 4 years; n = 36 with a family history of dementia). Cf-PWV was measured using arterial tonometry and PI was measured in the left middle cerebral artery via transcranial Doppler ultrasound. PI was calculated as (Velocitymax - Velocitymin) / Velocitymean. Data are presented as mean ± SD. RESULTS: The average cf-PWV, CSF NfL, and PI were 8.6 ± 1.6 m/s (males: 9.0 ± 2.1 m/s, females: 8.4 ± 1.6 m/s; p = 0.38), 77.7 ± 24.3 pg/mL (males: 92.7 ± 26.9 pg/mL, females: 71.3 ± 20.1 pg/mL; p = 0.01), and 0.79 ± 0.08 a.u. (males: 0.79 ± 0.05 a.u., females: 0.79 ± 0.09 a.u.; p = 0.83), respectively. There was a positive association between cf-PWV and NfL (r = 0.39, p = 0.01); however, when evaluated by sex, this relationship was only present in the males (males: r = 0.65, p = 0.02; females: r = 0.17, p = 0.38). While PI was not associated with NfL in the individual or combined groups (p > 0.05 for all), the relationship between cf-PWV and NfL in males was no longer significant after covarying by PI (r = 0.61, p = 0.11). CONCLUSIONS: In cognitively healthy individuals with an enriched risk of dementia, cf-PWV is linked with CSF NfL. However, this relationship appears to be sex specific, as the association only existed in the male participants and was no longer significant after controlling for PI. Future studies should evaluate the influence of habitual aerobic exercise on NfL, as it has been shown to have a beneficial effect on central hemodynamics. Alzheimer's Association Research Grant #17-499398 and Wisconsin Alzheimer's Disease Research Center Grant: P30-AG062715