Vascular risk factors and astrocytic marker for the glymphatic system activity

Abstract

Objectives Glymphatic system maintains brain fluid circulation via active transportation of astrocytic aquaporin-4 in perivascular space. The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) is an established method measuring perivascular glymphatic activity, but comprehensive investigations into its influential factors are lacking. Methods Community-dwelling older adults underwent brain MRI scans, neuropsychiatric, and multi-domain assessments. Blood biomarker tests included glial fibrillary acidic protein (GFAP) for astrocyte injury. Results In 71 enrolled participants, the DTI-ALPS index was associated with modifiable factors, including lipid profile (high-density lipoprotein, r = 0.396; very-low-density lipoprotein, r = − 0.342), glucose intolerance (diabetes mellitus, standardized mean difference (SMD) = 0.7662; glycated hemoglobin, r = − 0.324), obesity (body mass index, r = − 0.295; waist, r = − 0.455), metabolic syndrome (SMD = − 0.6068), cigarette-smoking (SMD = − 0.6292), and renal clearance (creatinine, r = − 0.387; blood urea nitrogen, r = − 0.303). Unmodifiable associative factors of DTI-ALPS were age (r = − 0.434) and sex (SMD = 1.0769) (all p < 0.05). A correlation of DTI-ALPS and blood GFAP was noticed (r = − 0.201, one-tailed t-test for the assumption that astrocytic injury impaired glymphatic activity, p = 0.046). Their cognitive correlations diverged, domain-specific for DTI-ALPS (Facial Memory Test, r = 0.272, p = 0.022) but global cognition-related for blood GFAP (MoCA, r = − 0.264, p = 0.026; ADAS-cog, r = 0.304, p = 0.010). Conclusion This correlation analysis revealed multiple modifiable and unmodifiable association factors to the glymphatic image marker. The DTI-ALPS index correlated with various metabolic factors that are known to increase the risk of vascular diseases such as atherosclerosis. Furthermore, the DTI-ALPS index was associated with renal indices, and this connection might be a link of water regulation between the two systems. In addition, the astrocytic biomarker, plasma GFAP, might be a potential marker of the glymphatic system; however, more research is needed to confirm its effectiveness.

Diffusion Tensor Image Analysis ALong the Perivascular Space (DTI-ALPS): Revisiting the Meaning and Significance of the Method

“…This is also a problem that has been pointed out in a number of papers. 27,28,30,47,61,82,90,163,173,184,185 This problem is an inherent weakness of the ALPS method and cannot be solved. However, other methods discussed in this review also do not evaluate the whole system.…”

“…A number of studies using the DTI-ALPS method have evaluated the association between age and ALPSindex. 4,17,18,[27][28][29]36,43,56,61,70,74,78,[80][81][82][83][84][85][86][87][88][89][90][91][92] Among these reports, a number of them showed negative correlations between age and ALPS-index. McKnight et al showed a negative correlation between the ALPS-index and age in a group of subjects with PD or essential tremor aged approximately 40−80 years, with a correlated Spearman's rank correlation coefficient of −0.203.…”

Exploring neurodegenerative disorders using advanced magnetic resonance imaging of the glymphatic system

“…The glymphatic system is active during sleep and primarily driven by arterial pulsation and the aquaporin-4 (AQP4) s maintains health by efficiently removing waste products and distributing essential nutrients ( 1 ). The significance of the glymphatic system is stressed by its association with several neurological disorders, including neurodegenerative disorders (NDs), traumatic brain injury, and stroke, among others ( 3 – 6 ).…”

“…For many years, the lack of a lymphatic system in the brain led to questions about how waste products were removed ( 7 ). The discovery of the glymphatic system revealed a robust waste removal system intimately linked with the brain’s vascular system ( 3 ). This finding has also highlighted the importance of sleep for brain health, given that the glymphatic system is highly active during sleep ( 8 ).…”

Diffusion magnetic resonance imaging of cerebrospinal fluid dynamics: Current techniques and future advancements

“…where the authors observed that a decrease in the ALPS index was correlated with worse cognitive function and an increase in age. 68 Because of the simplicity of the measurement and the ability to retrospectively calculate the ALPS index in large clinical datasets, it has been quickly adopted to study many cerebral health conditions, including neurodegeneration, 68,[93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110] cerebrovascular pathologies, [111][112][113][114][115][116][117] hydrocephalus, [118][119][120][121] epilepsy, [122][123][124][125][126][127][128] migraines, 129,130 sleep disorders, [131][132][133][134] and traumatic brain injury. [135][136]…”