Age- and time-of-day dependence of glymphatic function in the human brain measured via two diffusion MRI methods

Abstract

Advanced age, accompanied by impaired glymphatic function, is a key risk factor for many neurodegenerative diseases. To study age-related differences in the human glymphatic system, we measured the influx and efflux activities of the glymphatic system via two non-invasive diffusion magnetic resonance imaging (MRI) methods, ultra-long echo time and low-b diffusion tensor imaging (DTIlow–b) measuring the subarachnoid space (SAS) flow along the middle cerebral artery and DTI analysis along the perivascular space (DTI-ALPS) along medullary veins in 22 healthy volunteers (aged 21–75 years). We first evaluated the circadian rhythm dependence of the glymphatic activity by repeating the MRI measurements at five time points from 8:00 to 23:00 and found no time-of-day dependence in the awake state under the current sensitivity of MRI measurements. Further test–retest analysis demonstrated high repeatability of both diffusion MRI measurements, suggesting their reliability. Additionally, the influx rate of the glymphatic system was significantly higher in participants aged >45 years than in participants aged 21–38, while the efflux rate was significantly lower in those aged >45 years. The mismatched influx and efflux activities in the glymphatic system might be due to age-related changes in arterial pulsation and aquaporin-4 polarization.

Circadian Mechanisms in Brain Fluid Biology

“…243 Additionally, the choroid plexus calcifies with age, as does the pineal gland. 244 With aging, glymphatic function is decreased, 55, 245,246 which is exacerbated in Alzheimer disease. [247][248][249][250] There is also age-dependent BBB breakdown in the hippocampus, with worsened phenotype in patients with mild cognitive impairment.…”

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

“…73 The ALPS method has been used to evaluate sleep and cerebral ISF dynamics in several published studies. [74][75][76][77][78] In a study evaluating the correlation between sleep-related indices and the ALPS-index in community-dwelling older adults aged 60 years and older, the ALPS-index correlated with N2 sleep duration and N3 sleep duration. On the other hand, it correlated inversely with the apnea-hypopnea index.…”

“…5). 78 This study is also discussed in "Other methods for evaluation of glymphatic system" and "Consideration for the methodology of DTI-ALPS" sections.…”

“…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.…”

“…The influx rate of the glymphatic system evaluated by DTIlowb was significantly higher in participants aged >45 years than in participants aged 21-38, while the ALPS-index was significantly lower in those aged >45 years. 78 Of course, since this method evaluates CSF outside of the brain, it does not evaluate the entire glymphatic system.…”