DTI-Derived Evaluation of Glymphatic System Function in Veterans with Chronic Multisymptom Illness, 2025, Zhang et al.

SNT Gatchaman

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DTI-Derived Evaluation of Glymphatic System Function in Veterans with Chronic Multisymptom Illness
Yu Zhang; Matthew S. Moore; Yashar Rahimpour; J. David Clark; Peter J. Bayley; J. Wesson Ashford; Ansgar J. Furst

BACKGROUND AND PURPOSE
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.

MATERIALS AND METHODS
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.

RESULTS
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.

CONCLUSIONS
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.

ABBREVIATIONS
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.

Link | PDF | American Journal of Neuroradiology [Paywall]
 
ABBREVIATIONS
CMI= Chronic multisymptom illness; GWI= Gulf War Illness; PVS= perivascular space; DTI-ALPS= DTI-analysis along the perivascular space;
:) An abbreviation section and I still don't know what DTI stands for.

DTI-ALPS, or Diffusion Tensor Imaging along Perivascular Spaces, is an MRI technique used to assess the dynamics of fluid movement within the brain, particularly the glymphatic system, which is involved in waste removal.

Interesting, worth a look. I wonder if they blinded the analysis.

AI summary of how DTI-ALPS works - may or may not be right, but looks plausible:
Glymphatic System and Waste Removal:
The glymphatic system, a glial-dependent waste clearance system in the brain, plays a crucial role in removing metabolic waste products and maintaining brain homeostasis.

DTI-ALPS Principle:
The DTI-ALPS method relies on the principle that water molecules diffuse more readily along the perivascular spaces compared to other directions within the white matter.

Measuring Diffusivity:
DTI-ALPS measures the diffusivity of water molecules in different directions within the brain, specifically focusing on the direction of perivascular spaces.

Perpendicular Directions:
At the level of the lateral ventricles, the perivascular spaces run roughly perpendicular to the projection and association fibers. DTI-ALPS analyzes diffusivity in these perpendicular directions, which are thought to reflect glymphatic activity.

Correlation with Glymphatic Function:
Lower DTI-ALPS values are generally associated with reduced glymphatic activity, potentially indicating impaired waste clearance.

Non-Invasive Assessment:
DTI-ALPS offers a non-invasive method for assessing glymphatic function, unlike invasive tracer-based methods.

The technique looks to have been used in quite a range of diseases, although it sounds as though it is still a research technique, rather than being used clinically.

Of course, the glymphatic system was only discovered in 2012.
 
What is the evidence for glymphatics being important in 'metabolic waste removal'?
Metabolic waste is normally reabsorbed through venules, not cleared by lymphatics.
In what sense do glymphatics maintain 'homeostasis'?

What if veterans who fit diagnostic criteria for 'chronic multisystem illness' are just generally a mixed bag of people whose physiology isn't that hot and are ill for all sorts of reasons? They are almost certainly going to be biased in that direction.
 
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