Zhang Yu, Moore Matthew S, Rahimpour Yashar, Clark J David, Bayley Peter J, Ashford J Wesson, Furst Ansgar J
From the War Related Illness & Injury Study Center (WRIISC) (Y.Z., M.S.M., Y.R., P.J.B., J.W.A., A.J.F), Pain Clinic (J.D.C.), and Polytrauma System of Care (A.J.F.), VA Palo Alto Health Care System, Palo Alto, California, United States; Department of Psychiatry and Behavioral Sciences (M.S.M., Y.R., P.J.B., J.W.A., A.J.F.), Department of Anesthesiology, Perioperative and Pain Medicine (J.D.C.), and Department of Neurology and Neurological Sciences (A.J.F.), Stanford University School of Medicine, Stanford, California, United States.
AJNR Am J Neuroradiol. 2025 Jun 27. doi: 10.3174/ajnr.A8901.
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.
慢性多症状疾病包括疲劳、疼痛、睡眠困难以及神经、呼吸和胃肠道问题等症状，在1990 - 91年海湾战争以及阿富汗和伊拉克战争的退伍军人中尤为常见。淋巴系统功能可能在慢性多症状疾病的病因病理中起重要作用，但尚未得到研究。沿血管周围间隙的扩散张量成像（DTI）分析通过评估血管周围间隙液流状态，为淋巴系统功能提供了一个有前景的替代指标。本研究的目的是比较患有慢性多症状疾病的退伍军人与健康对照者的这种基于DTI的淋巴指数，并揭示该指数与慢性多症状疾病症状严重程度之间的可能相关性。
从多个公共研究数据库中，提取了203名符合慢性多症状疾病临床诊断标准的退伍军人以及224名年龄匹配的健康对照者的成像数据中的DTI衍生指标。慢性多症状疾病的严重程度、睡眠困难、疼痛强度和慢性疲劳程度基于自我报告测量。对MRI扫描仪和扫描部位的差异进行了统一处理。进行统计分析时对人口统计学混杂因素进行了校正。
健康对照者和退伍军人的淋巴指数均随年龄增长而显著降低。在对年龄、性别和教育程度进行校正后，与对照者相比，退伍军人的双侧指数较低（Cohen's d = -0.47；p < 0.001）。在退伍军人的整个样本中，观察到淋巴指数与疼痛强度（r = -0.17；p = 0.01）、睡眠障碍（r = -0.17；p = 0.02）、疲劳程度（r = -0.20；p = 0.006）、慢性多症状疾病严重程度（r = -0.17；p = 0.02）呈负相关，且这些指数与延髓体积呈正相关（r = -0.19；p = 0.007）。请注意，这些显示一组患者有显著结果的结果并不能保证个体患者有相同的结果。
本研究表明，淋巴功能受损与慢性多症状疾病密切相关。这些发现增进了我们对慢性多症状疾病潜在病理机制的理解，并指出基于DTI的指标作为该疾病严重程度的潜在生物标志物。
CMI＝慢性多症状疾病；GWI＝海湾战争疾病；PVS＝血管周围间隙；DTI - ALPS＝沿血管周围间隙的DTI分析；HC＝健康对照；TBI＝创伤性脑损伤；PTSD＝创伤后应激障碍；PSQI＝匹兹堡睡眠质量指数；BPI＝简明疼痛量表；CFS＝慢性疲劳综合征。
