Cardiorespiratory Fitness Modifies the Association of Cerebral Pulsatility on CSF Biomarkers Related to Neurodegeneration, Synaptic Dysfunction, and Neuroinflammation

Abstract Background Cerebral pulsatility (PI) is reportedly higher in individuals with AD and MCI compared to age matched controls and has been associated with greater beta‐amyloid (Aß) burden, but its relationship to other neurodegenerative biomarkers is unknown. Higher cardiorespiratory fitness (CRF) positively affects vascular function and is associated with lower PI in several large cerebral vessels. The relationship between PI, CRF, and biomarkers for neurodegeneration have not yet been characterized. Our objective was to examine a potential CRF modification of the relationship between PI and cerebrospinal fluid (CSF) biomarkers of neurodegeneration, synaptic dysfunction, and neuroinflammation. Methods Cognitively unimpaired adults (n=32, Mean Age=64) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center who met selection criteria were included. PI from bilateral MCA vessels were measured using 4D flow MRI and averaged (PI‐MCA AVG ). CRF was measured as peak VO 2PEAK during a graded exercise treadmill test. CSF was obtained via lumbar puncture and measured using the NeuroToolKit, a panel of robust prototype assays (Roche Diagnostics International Ltd). The toolkit included measures of: neurodegeneration [α‐synuclein (α‐syn) and neurofilament light polypeptide (NfL)], synaptic dysfunction [neurogranin (Ng), synaptosomal‐associated protein 5 (SNAP‐25), and neuronal activity related protein 2 (nptx2)], and neuroinflammation [glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed in myeloid cells (sTREM2), and chitinase‐3‐like protein 1 (YKL‐40)]. A single multivariate regression model, adjusted for sex, age, and APOE4, examined whether the association between PI‐MCA AVG and CSF biomarkers varied as a function of CRF. Results There was a significant interaction between PI and VO 2PEAK on α‐syn (ß = ‐22.66, p=0.04), Ng (ß =‐171.46, p=0.01), SNAP‐25 (ß = ‐0.35, p= 0.02), STREM2 (ß =‐1.04, p=0.02), and nptx2 (ß =‐1037, p=0.04) indicating more favorable profiles of CSF biomarkers with increasing VO 2PEAK despite elevated PI. No significant interactions were found for NfL, GFAP, or YKL40 (all p’s > 0.05). Conclusion Our findings support the hypothesis that increased CRF influences the relationship between cerebral PI and CSF biomarkers related to neurodegeneration, synaptic dysfunction, and neuroinflammation indicating that improved CRF may offer protection against cerebrovascular alterations known to coincide with biomolecular changes in various types of dementia.