The main findings of this study were as follows: 1) there was no glymphatic system dysfunction in patients with migraine compared to healthy controls, 2) no differences in glymphatic system function were found between migraine patients with and without aura, 3) there were no significant correlations between the clinical characteristics of migraine and glymphatic system function, and 4) we demonstrated the feasibility of the ALPS method for research in neurological disorders.
Recently, several studies have utilized the ALPS method to evaluate glymphatic system function in various neurological diseases, such as Alzheimer’s disease, normal pressure hydrocephalus, Parkinson’s disease, cerebral small vessel disease, and juvenile myoclonic epilepsy. They successfully demonstrated glymphatic system dysfunction in neurological diseases. In addition, these studies found a significant positive correlation between the ALPS index and cognitive function, and a negative correlation between the ALPS index and age. Our study, along with the previous studies, also proved the usefulness of the ALPS method to assess glymphatic system function, and it is expected that it can be used to investigate glymphatic system function in various neurological diseases in the future. This ALPS method has the advantages of being non-invasive and not requiring gadolinium-based contrast agents.
However, contrary to our initial hypothesis, we found no alterations in glymphatic system function in patients with migraine compared to healthy controls. Although the exact causes are unknown, several possibilities can be considered. First, migraine is not a neurodegenerative disease. Glymphatic system dysfunction is implicated in a variety of neurologic diseases, particularly in neurodegenerative diseases, including dementia, Parkinson’s disease, and normal pressure hydrocephalus. There is little evidence showing that patients with migraine can be prone to any neurodegenerative diseases.[25–27] A previous study prospectively assessed the association between migraine and dementia, and found no association between them. Another study that evaluated whether there was any correlation between headache and Parkinson’s disease revealed no such association. In addition, there is an age-associated decline in glymphatic system function, and this appears to be related to reduced penetrating arterial pulsatility in the aged brain.[28, 24] Prevalence of migraine peaks between the ages of 30 and 39, and falls to reach the lowest prevalence in those 60 and older. Furthermore, there were no significant correlations between the clinical characteristics of migraine and glymphatic system function in our study, which also represented glymphatic system dysfunction actually being absent in patients with migraine. Second, all MRI scans of patients with migraine were performed during the interictal period, and not during migraine attacks, to increase the homogeneity of imaging. The possibility that glymphatic system function differs depending on the presence or absence of a headache attack cannot be excluded. Third, MRI scans were performed during daytime in all participants. Since the glymphatic system function is activated especially during deep sleep stage N, the glymphatic system function between patients with migraine and healthy controls can be different during sleep. To confirm these assumptions, DTI scanning is required during the ictal period and during sleep.
We also found no differences in glymphatic system function between patients with migraine with and without aura. Recently, it was demonstrated that CSD, the neural event that underlies migraine aura, results in the temporary impairment of glymphatic flow in a mouse model via closure of the paravascular spaces for several minutes after the induction of CSD, followed by a gradual recovery over half an hour. Additionally, we recently demonstrated that there were considerable differences in the brain network between migraine patients with and without aura. Thus, we initially thought that there would be differences in glymphatic system function depending on the presence or absence of aura. The present negative results in this study might have originated from the small number of migraine patients with aura, or owing to problems with MRI scanning time, as already mentioned above.
This was the first study to evaluate glymphatic system function in patients with migraine. We enrolled a large number of patients with migraine and healthy controls. However, this study has several limitations. First, we excluded patients with structural brain lesions on MRI. However, migraine is commonly associated with white matter hyperintensities. Although the ALPS index is a ratio of diffusivities and the influence of white matter hyperintensities might be mitigated by this division calculation, white matter hyperintensities would influence the ALPS index. Second, the ALPS index can be affected by several factors, including imaging plane, head position, and motion-proving gradients. However, a previous report showed that the results of the ALPS method were significantly related to glymphatic system function calculated by intrathecal administration of gadolinium-based contrast agent on MRI, and another study successfully demonstrated good test-retest reproducibility and robustness of the ALPS method.