The latest buzzword in MS research---"smo(u)ldering"

MS researchers are considering the ongoing deterioration that occurs in the MS brain, even when patients are treated with current MS medications.  This leads to ongoing progression, damage beyond lesions and relapses which may be related to gray matter atrophy. The new term used to describe this underlying process is "smoldering (or smouldering) disease".  Literally, smoke, but no flame.

Maybe you've also seen many articles on this new "discovery"--which has come about because the current MS drugs are not arresting disease progression, and this offers a new drug target.

Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition of "progression independent of relapsing activity." We propose the concept of smouldering-associated-worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering pathological processes, which remain unmet therapeutic targets. We provide a consensus-based framework of possible pathological substrates and manifestations of smouldering MS, and we discuss clinical, radiological, and serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, we share considerations for optimizing disease surveillance and implications for clinical trials to promote the integration of smouldering MS into routine practice and future research efforts.  https://pubmed.ncbi.nlm.nih.gov/39051525/

Long time readers of the blog will recognize my questioning this very situation----the ongoing disease progression and loss of grey matter in "treated" MS patients.  In 2012,  I put together a theory of hypoperfusion and reperfusion injury to address the ongoing, unseen disease progression.  

Hypoperfusion/Reperfusion Injury in MS

 https://ccsviinms.blogspot.com/2013/09/multiple-sclerosis-hypoperfusionreperfu.html

Even though I am not currently writing for this blog, I do check it occasionally--and have noted that people are still finding it and reading the posts.  In fact, over a million readers from all over the globe have read a variety of posts since I began writing.  Just today, there were 259 readers, yesterday there were 1223.  Over 30,000 unique readers check out the blog posts each month.  Obviously, there is still an interest in the vascular connection to MS.  

In this new era of AI--I am able to ask the computer/hive mind what it thinks about "smoldering disease" in MS being related to hypoperfusion and hypoxia in the MS brain.  

And AI seems to think it might be something worth exploring!  Perhaps this theory might be worth investigating.  

Yes, there's a strong connection between 

smoldering disease in Multiple Sclerosis (MS) and hypoperfusion (reduced blood flow) leading to hypoxic injury (damage caused by a lack of oxygen). 

Here's how they are related:

• Smoldering lesions: These are chronic, active MS lesions characterized by ongoing low-grade inflammation and tissue damage, contributing significantly to disease progression and disability accumulation, even when there are no outward signs of a relapse.
• Hypoperfusion in MS: Research indicates that many individuals with MS experience widespread cerebral hypoperfusion, meaning reduced blood flow to their brain. This hypoperfusion can lead to areas of oxygen deficiency (hypoxia).
• Hypoxia and Inflammation Cycle: Hypoxia and inflammation are closely intertwined in MS. Hypoxia can exacerbate inflammation, while inflammation can trigger hypoxia by damaging blood vessels and impairing blood flow regulation. This creates a vicious cycle that contributes to MS disease progression.
• Smoldering Lesions and Hypoxia: Hypoxia may play a crucial role in the development and persistence of smoldering lesions, particularly pattern III lesions which show similarities to hypoxic/ischemic lesions. Studies suggest that chronic inflammation associated with smoldering lesions, especially those containing iron-laden microglia/macrophages at their edge, could contribute to local tissue hypoxia and chronic damage. 

In summary: The concept of smoldering MS highlights the chronic, ongoing nature of the disease and suggests that mechanisms like hypoperfusion and subsequent hypoxia are likely involved in driving this persistent damage and contributing to long-term disability, even in the absence of relapses. 

Increasing drainage to save the brain

Researchers at Keck's School of Medicine at USC are looking at a compound (Piezo1) which increases the diameter of lymphatic vessels which drain the brain of toxins and metabolites.  Dr. Young-Kwon Hong has discovered a potential breakthrough which may help those with diseases of neurodegeneration. 

Hong’s team theorized that they could speed up the draining of fluid and waste from the brain. “Think about a kitchen sink that’s draining too slowly because it has a two-inch pipe,” he said. “We can give you a four-inch pipe.” Hong and his team first developed the idea of manually stimulating the drainage process, and then they developed a compound that triggers an increase in the diameter of the lymphatic vessels. Hong’s research was published in Nature Neuroscience in March of this year, and he and his team continue to move forward with this exciting development.

https://keck.usc.edu/news/usc-researcher-discovers-drug-that-may-delay-onset-of-alzheimers-and-parkinsons-disease-and-treat-hydrocephalus/

Here is the published research in Nature.

Piezo1 regulates meningeal lymphatic vessel drainage and alleviates excessive CSF accumulation

https://www.nature.com/articles/s41593-024-01604-8

Adequate lymphatic drainage of the brain is essential for brain health. 

Here is a wonderful review of the research from Glasgow-- this area of study is just beginning, but there are links to be found in impaired (g)lymphatic drainage and MS.

https://www.sciencedirect.com/science/article/pii/S221103482400035X

Multiple sclerosis (MS) is a complex autoimmune disorder that affects the central nervous system, resulting in demyelination and an array of neurological manifestations. Recently, there has been significant scientific interest in the glymphatic system, which operates as a waste-clearance system for the brain. This article reviews the existing literature, and explores potential links between the glymphatic system and MS, shedding light on its evolving significance in the context of MS pathogenesis. The authors consider the pathophysiological implications of glymphatic dysfunction in MS, the impact of disrupted sleep on glymphatic function, and the bidirectional relationship between MS and sleep disturbances. By offering an understanding of the intricate interplay between the glymphatic system and MS, this review provides valuable insights which may lead to improved diagnostic techniques and more effective therapeutic interventions.

Vascular endothelial dysfunction associated with severity in MS

I wanted to provide a recent research round-up on the connection of MS to vascular health, specifically how endothelial dysfunction contributes to MS progression.  

As I've explained in another blog post, I do not feel it is appropriate for me to be dispensing medical advice as a layperson.  But I am still interested in seeing the exploration of the vascular connection to MS, and happy to share that the research continues. 

Jeff is now 15 years out from his MS diagnosis, and has shown no further MS disease progression.  His most recent MRI from last June shows continued healing of old lesions and completely healthy, normal gray matter.  And he's still composing, conducting, traveling, teaching, biking, jogging, living.  As his new GP recently commented, he's an incredibly healthy 59 year old man.  The fact that he has had MS for 15 years astonishes her.  Me too.

Here's a short research wrap up:

1. A group of Japanese neurologists examined the level of endothelial dysfunction exhibited by people with MS and found a correlation between lower flow mediated dilation (FMD), endothelial dysfunction, and MS progression.  FMD is lowered when we do not have enough endogenous nitric oxide.

Twenty-seven patients with MS and 24 healthy controls were enrolled. FMD was significantly lower in MS subjects than in control subjects (6.0 ± 0.6 vs. 8.6 ± 0.7, p = 0.006); furthermore, BHI was similarly lower in MS than in controls, but insignificant. Remarkably, FMD was significantly lower in secondary progressive MS subjects than in relapse-remitting MS subjects (3.7 ± 1.3 vs. 6.7 ± 0.7, p = 0.045). In addition, FMD was inversely correlated with the disability score as per the expanded disability status scale (R2 = 0.170, p = 0.033) and modified Rankin scale (R2 = 0.187, p = 0.027).

https://www.msard-journal.com/article/S2211-0348(21)00402-8/fulltext#%20

2. Russian neurologists are looking at how homocysteine decreases endothelial health, and contributes to MS progression. 

The effect of homocysteine on endothelial dysfunction was shown in vitro. It was reported that homocysteine (500 µM) decreases the viability and induces the apoptosis of human vascular endothelial cells. Increases in reactive oxygen species in endothelial cells treated with homocysteine were also found [70]. Increasing concentrations of reactive oxygen species in endothelial cells homocysteine may induce vascular inflammation [19,28]. 

https://www.mdpi.com/2076-3425/10/9/637/htm

I first wrote about the danger of elevated homocysteine levels as part of the Endothelial Health Program

Anemia/low vit. B12 creates high levels of homocysteine in the blood (a sulfur containing amino acid) which damages the endothelium A strict vegetarian diet that excludes all meat, fish, dairy and eggs, or an unbalanced diet of processed foods could create low vit. B12 levels and damage the endothelium (10)

https://ccsviinms.blogspot.com/2016/04/the-endothelial-health-program-8-years.html

3. Our friends from the ISNVD, Dr. Mark Haacke and Dr. Yulin Ge, continue to look at the MS brain, to study the vasculature.  This group is noting a new venous vascular sign in lesions, which they are calling multiple vessel sign (MVS).  Using a new contrast agent called Ferumoxytol, the researchers were able to see enhanced images of MS lesions, and noticed many more small vessel abnormalities.  Rindfleisch's discovery of the dilated blood vessel, the central vein sign, continues to be explored.

 The total number of lesions with vascularity on pre- and post-contrast data were 287 and 488, respectively. The lesions with abnormal vascular behavior were broken up into following categories: small lesions appearing only at the vessel boundary; dilated vessels within the lesions; and developmental venous angiomas. These vessel abnormalities observed within lesions increased from 55 on pre-contrast data to 153 on post-contrast data. Finally, across all the patients, the periventricular lesional vessel density was significantly higher (p < 0.05) than that of the periventricular NAWM.

https://pubmed.ncbi.nlm.nih.gov/33338965/

4. And finally, here is a fabulously thorough review from the ISNVD 2020 meeting, published in 2021.  This paper can serve as a primer for any medical researcher interested in learning more about the vascular connection to MS.  It's all here.  

https://www.frontiersin.org/articles/10.3389/fneur.2021.561458/full

stay well,

Joan