DTI-Derived Evaluation of Glymphatic System Function in Veterans with Chronic Multisymptom Illness

Abstract

Background and purpose: Chronic multisymptom illness (CMI) includes symptoms of fatigue, pain, and sleep difficulties, as well as neurologic, respiratory, and gastrointestinal problems and is particularly common in veterans from the 1990-1991 Gulf War and the Afghanistan and Iraq Wars. Glymphatic system function may play an important role in the etiopathology of CMI but has not been addressed. DTI-derived analysis along the perivascular space provides a promising proxy for glymphatic system function by evaluating the status of perivascular space fluid flow. The objective of this study was to compare this DTI-derived glymphatic index in veterans with CMI and healthy controls, and to reveal possible correlations between this index and the severity of CMI symptoms.

Materials and methods: DTI-derived indices were extracted from imaging data of 203 veterans who met clinical diagnostic criteria for CMI, and 224 age-matched healthy control subjects from multiple public research databases. Severity of CMI, sleep difficulty, pain intensity, and the degree of chronic fatigue were based on self-report measures. MRI scanner and site variations were harmonized. Statistical analyses were performed adjusting for demographic confounding factors.

Results: Both healthy controls and veterans showed significantly reduced glymphatic indices associated with increased age. Compared with controls, veterans showed bilaterally lower indices (Cohen d = -0.47; P < .001) after adjusting for age, sex, and education. Across the entire sample of veterans, negative correlations were observed between glymphatic indices and pain intensities (r = -0.17; P = .01), sleep disturbances (r = -0.17; P = 0.02), degree of fatigue (r = -0.20; P = 0.006), severity of CMI (r = -0.17; P = 0.02), and the indices were positively correlated with medullar volumes (r = -0.19; P = .007). Note, these results showing significant outcomes for a group of patients do not guarantee the same outcome for individual patients.

Conclusions: This study suggests that impaired glymphatic functions are strongly associated with CMI. These findings improve our understanding of the pathologic mechanism underlying CMI and point to DTI-based metrics as a potential biomarker for disease severity in this condition.