Asymmetrical glymphatic dysfunction in patients with long Covid associated neurocognitive impairment- correlation with BBB disruption, 2025, Chaganti+

Asymmetrical glymphatic dysfunction in patients with long Covid associated neurocognitive impairment- correlation with BBB disruption
Chaganti, Joga R.; Talekar, Tanush K.; Brew, Bruce James

BACKGROUND AND PURPOSE
The glymphatic system, a waste clearance pathway, has been implicated in several neurological conditions associated with neuroinflammation. COVID-19 associated neurocognitive impairment, part of the post-acute sequelae of SARS-CoV-2 infection (PASC), is strongly associated with neuroinflammation and disrupted blood-brain barrier (BBB). Several studies have implicated a synergistic interaction between the glymphatic system dysfunction and BBB disruption. In this proof-of-concept study, we investigated the role of the MRI metric diffusion along the perivascular spaces DTI (DTI-ALPS) in patients with PASC and correlated this with the BBB capillary permeability metric-K trans derived from Dynamic contrast enhanced (DCE) perfusion.

MATERIALS AND METHODS
14 subjects with PASC who had persisting symptoms of anosmia, ageusia, fatigue, and cognitive impairment (CI) and ten healthy age and sex matched controls were recruited. All PASC subjects underwent routine and advanced MR brain imaging at two time points, (3 months +/-2 weeks) after initial infection -referred as Time Point 1 (TP-1) -and 10 repeated the MRI scan 12 months (+/-2 weeks) later -referred as Time Point 2 (TP-2), while the controls had MR imaging done only at TP-1. All had mild neurocognitive impairment. In the final analysis we included those who had DTI study at both time points (n-10). MR imaging included DCE perfusion and DTI in addition to anatomical imaging.

STATISTICAL ANALYSIS
Given the small size of the sample and nonnormality of data in the descriptive analyses, nonparametric analyses were used for group comparisons. A two-sample Wilcoxon rank sum test was used to show the differences in DTI-ALPS between the patients and controls in the predefined regions of interest. Spearman’s correlation coefficient (rho) was used to assess the correlation between DTI-ALPS index with K trans.

RESULTS
There was significant reduction in the DTI-ALPS index between the patients and controls in the left hemisphere (z = 2.04, p < 0.04). However, there was no significant change over time in the index. There was a strong inverse correlation between the central white matter K trans and DTI-ALPS index (rho = 0.66, p < 0.03).

CONCLUSION
Our study indicates that disordered para vascular drainage, a marker for glymphatic system and BBB damage may contribute to neurocognitive impairment (NCI) among patients with PASC. The DTI-ALPS index, which does not require contrast injection, has the potential to serve as a non-invasive biomarker.

Link | PDF (BMC Neurology) [Open Access]

 

(Step forward acolytes.)

Those are just region-of-interest localiser images. You can see the cursors being placed in order to interrogate the ROIs. The positioning of the ROI is precise in order to capture the signal from the thing you're interested in.

The colour coding shows the direction of non-impaired water diffusion, which indicates the orientation of the nerve fibre bundles (water can move more freely along them but not in other directions). This is diffusion tensor imaging (aka tractography). The idea for DTI-ALPS (diffusion tensor imaging along the perivascular space) is to see how restricted water movement is, solely in the perivascular space, rather than along nerve fibre tracts.

I may be simplifying, but in essence to work that out they look at the signal where they know that other directions are nulled out. To do that they look at the common point between projection fibres (running craniocaudal in the periventricular deep white matter) and association fibres (running anteroposterior). The point where those are at 90° to each other leaves you with a measurement along the lateral-medial axis, that you can isolate. It's a bit like the Lagrange point in astrophysics.

They also need to account for (and exclude) subcortical U fibres which would also partially be in that axis. The end result is you should capture the water movement running alongside the vessels (medullary veins), rather than the nerve fibres. In that way you can see how impaired water motion is in the perivascular space.

 

I think the basic proposal is that this is evidence of neuroinflammation / leaky blood-brain barrier. That the water molecules in the perivascular space are now restricted in Brownian motion. Normally it might be expected to have content mostly like CSF as the current thinking is that CSF washes in and out via the perivascular space (PVS) and interstitial fluid compartment, to exchange solutes and assist waste clearance, as generated from neuronal and glial metabolism. (A lot of that exchange is simply artery -> capillary -> vein so this is a slower, additional process, possibly important during sleep).

So normally the water molecules in the PVS should be able to move relatively freely. But if the material in the perivascular space now consists of more immune cells (having trafficked in as part of neuoinflammation), ± larger proteins (eg amyloid, Tau), then the water molecules in the PVS won't be able to move so freely, because a larger proportion of those water molecules are within cells and so constrained by cell membranes (both internal and external).

For background, this is related to, but a little different from, the diffusion restriction you would see in an acute cerebral infarct (stroke). In that situation you still have the same number of cells initially, but their Na/K pumps are failing due to lack of O2 etc so the cells swell. Extracellular fluid moves to intracellular where water molecules can't now move freely. As a technical point you later get a period of pseudonormalisation when the cells are well dead but their membranes are breaking down, releasing the water back to the extracellular space where it can move more freely again.

Spoiler: Some references

Impaired glymphatic function as a biomarker for subjective cognitive decline: An exploratory dual cohort study (2024, Alzheimer's & Dementia)

Longitudinal assessment of glymphatic changes following mild traumatic brain injury: Insights from perivascular space burden and DTI-ALPS imaging (2024, Frontiers in Neurology)

Increased glymphatic system activity in migraine chronification by diffusion tensor image analysis along the perivascular space (2023, The Journal of Headache and Pain)

Reproducibility of diffusion tensor image analysis along the perivascular space DTI-ALPS for evaluating interstitial fluid diffusivity and glymphatic function: CHanges in Alps index on Multiple conditiON acquIsition eXperiment CHAMONIX study (2021, Japanese Journal of Radiology)

Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space DTI-ALPS in Alzheimer’s disease cases (2017, Japanese Journal of Radiology)

Glymphatic system impairment in sleep disruption: diffusion tensor image analysis along the perivascular space DTI-ALPS (2023, Japanese Journal of Radiology)

Glymphatic system dysfunction in recovered patients with mild COVID-19: A DTI-ALPS study (2023, iScience)

Impaired glymphatic system as evidenced by low diffusivity along perivascular spaces is associated with cerebral small vessel disease: a population-based study (2023, Stroke and Vascular Neurology)

Evaluation of glymphatic system activity by diffusion tensor image analysis along the perivascular space DTI-ALPS in dementia patients (2023, The British Journal of Radiology)

 

$1m question!

I use the term with the expectation that inflammation affecting the CNS is a bit different and is worth distinguishing due to the unique aspects of the intracranial compartment in particular. With typical inflammation (rubor, calor, dolor and tumor) there is a cellular infiltration through leaky blood vessels and you get swelling. The brain is in an enclosed box so brain swelling has a narrow envelope of tolerance. Beyond that you get significant neurological deficits, ultimately leading to intracranial compartment shift, vascular compromise in distant regions and herniation that fatally impairs brainstem function. So I think the ideas have developed along the lines that the inflammation process needs to be a bit different in most contexts.

You can certainly have the more classical version, eg cerebral abscess. But often what we see is a varying degree of brain swelling and then later a reduction in brain volume in the affected region, with mature gliosis (as opposed to liquefactive necrosis). We also see clinically (and often but not always on imaging) dramatic immune/inflammatory disorders (eg autoimmune encephalitis) that doesn't seem to have significant brain swelling on imaging, maybe mild. But maybe we shouldn't be saying "immune/inflammatory" and "encephalitis" and just "autoimmune" etc.

Jo may have some comments But in the meantime I found this recent opinion piece that on a quick scan may be nicely readable. They argue for using a term like "neuroimmune defence" rather than "neuroinflammation". I'll have a read later and maybe it's worth its own post.

Neuroinflammation: The Abused Concept (2023)
Elena Galea; Manuel B. Graeber

Spoiler: Abstract

Scientific progress requires the relentless correction of errors and refinement of hypotheses. Clarity of terminology is essential for clarity of thought and proper experimental interrogation of nature. Therefore, the application of the same scientific term to different and even conflicting phenomena and concepts is not useful and must be corrected.

Such abuse of terminology has happened and is still increasing in the case of “neuroinflammation,” a term that until the 1990s meant classical inflammation affecting the central nervous system (CNS) and thereon was progressively used to mostly denote microglia activation. The resulting confusion is very wasteful and detrimental not only for scientists but also for patients, given the numerous failed clinical trials in acute and chronic CNS diseases over the last decade with “anti-inflammatory” drugs.

Despite this failure, reassessments of the “neuroinflammation” concept are rare, especially considering the number of articles still using the term. This undesirable situation motivates this article. We review the origins and evolution of the term “neuroinflammation,” discuss the unique tissue defense and repair strategies in the CNS, define CNS immunity, and emphasize the notion of gliopathies to help readdress, if not bury, the term “neuroinflammation” as it stands in the way of scientific progress.

Link | PDF (ASN Neuro) [Open Access]