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

Chronic Multisymptom Illness includes symptoms of fatigue, pain, sleep difficulties, as well as neurological, respiratory, and gastrointestinal problems and is particularly common in veterans from the 1990-91 Gulf War and the Afghanistan and Iraq Wars. Glymphatic system function may play an important role in the etiopathology of Chronic Multisymptom Illness 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. DTI-derived indices were extracted from imaging data of 203 veterans who met clinical diagnostic criteria for Chronic Multisymptom Illness, and 224 age-matched healthy control subjects from multiple public research databases. Severity of Chronic Multisymptom Illness, 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. Both healthy controls and veterans showed significantly reduced glymphatic indices associated with increased age. Compared to controls, veterans showed bilaterally lower indices (Cohen's d = -.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 = -.17; p = .01), sleep disturbances (r = -.17; p = .02), degree of fatigue (r = -.20; p = .006), severity of Chronic Multisymptom Illness (r = -.17; p = .02), and the indices were positively correlated with medullar volumes (r = -.19; p = .007). Note, these results showing significant outcomes for a group of patients do not guarantee the same outcome for individual patients. This study suggests that impaired glymphatic functions are strongly associated with Chronic Multisymptom Illness. These findings improve our understanding of the pathological mechanism underlying Chronic Multisymptom Illness and point to DTI-based metrics as a potential biomarker for disease severity in this condition. CMI＝ Chronic multisymptom illness; GWI＝ Gulf War Illness; PVS＝ perivascular space; DTI-ALPS＝ DTI-analysis along the perivascular space; HC＝ healthy control; TBI＝ traumatic brain injury; PTSD＝ post-traumatic stress disorder; PSQI＝ Pittsburgh sleep quality index; BPI＝ brief pain inventory; CFS＝ chronic fatigue syndrome.