Secondary progressive multiple sclerosis (MS) is a relentless disease. Over time, patients experience worsening of physical, mental, and mood-related symptoms. There are currently several disease-modifying drugs on the market to help relapsing and remitting MS patients with minor and less severe relapses, but few drugs exist for patients with secondary progressive MS. Yet even as their symptoms progress, the white matter brain lesions found on MRI scans often remain unchanged. However, there is also evidence on the role of inflammation in the gray matter. Suspecting that changes in the brain’s gray matter regions may play a critical role in disease progression, investigators at Brigham and Women’s Hospital conducted an experimental study a few years ago to evaluate differences in microglial cell activity in regions of gray matter of healthy volunteers compared to those with MS. Using a new tracer molecule and PET imaging, the team detected widespread and abnormal activation of microglia in patients with multiple sclerosis and a link to brain atrophy, physical disability and progressive MS.
The study exploited the new radiopharmaceutical [F-18]PBR06, a tracer that targets a specific protein (TSPO) present in activated microglia, the immune cells present in the brain. Many other research projects use carbon C-11, an isotope with a much shorter half-life. However, unlike C-11, the F-18 tracer has a significantly longer half-life and higher clinical potential. For the pilot study, investigators evaluated the results of 12 patients with MS, 7 with relapsing remitting MS and 5 with secondary progressive MS, and compared it to healthy controls using the F-18 tracer. They found more microglial gray matter activation in MS patients than healthy controls, particularly in the hippocampus, parahippocampus, cingulate gyrus and amygdala regions of the brain. These brain regions are known to influence processes such as emotions, memory and cognition, all of which can be affected in MS patients. Structures in the deep gray matter, particularly the thalamus, showed greater activation of microglia in secondary progressive MS, compared to patients with relapsing remitting MS. The thalamus is the station that processes brain functions after processing them.
This correlated significantly with physical disability and brain atrophy. The authors confirmed the result in an additional study in 2019 and another in the early months of this year. If research is to improve knowledge on the diagnostic level, however, we must not think that basic research ceases to understand biological aspects that are still unknown to the disease. There are mechanisms and metabolic / neurochemical aspects still unresolved in this disease, which is well known to be characterized by the attack on the white matter of the brain or myelin. Myelin is composed of 60% dry mass with a high lipid content (70%). The most abundant myelin lipids are galactosyl-ceramides and their sulfated form, sulfatides, which together account for about 27% of the total dry weight of myelin. Decreased sulfatide myelin content in the brain has been implicated as important factors in disrupting myelin stability and function. Interestingly, sulfatide metabolism in the brain has been shown to be regulated by vitamin K. A positive correlation between dietary vitamin K and brain sulfatides has also been shown. However, no studies have investigated whether vitamin K affects sulfatide levels during remyelination.
There is a recent single study performed by a team from the Department of Biological Sciences at Kent State University in Ohio published in 2018. In this research, researchers first induced SM-like brain lesions through the toxin called cuprizone and then treated a portion of the rats with placebo and another with menaquinone-4, a form of vitamin K. Through molecular biology (including lipidomics and mass spectrometry), the researchers found that the concentration of sulfatide increased after 3 weeks of remyelination in brains of mice treated with the vitamin. But not all brain areas were affected by this effect: for example, the corpus callosum did not benefit. In addition, the vitamin K-treated mice varied the myelin composition, shifting the balance more towards sulfatides than glucosyl-ceramides, which served as precursors for the former. Cerebroside sulfotransferase (CEST) is the enzyme responsible for the production of sulfatides in the brain by transferring a sulfate group onto galactosyl-ceramide. The data indicate that vitamin K has an impact on CEST activity during the active recovery process that occurs during the remyelination phase in adult mice. However, it does not affect CEST activity in healthy 14-week-old adult mice in which the myelination process has already been completed.
Finally, as vitamins K and D have been shown to show synergistic effects in some tissues, the team tested whether there are synergistic effects between the effects of vitamins K and D on sulfatide production. The answer is no: the two vitamins administered together did not have an additional (synergistic) effect and vitamin D alone does not appear to have affected the synthesis of sulfatides in the brain. The conclusion of the study is that vitamin K may play a role in promoting the synthesis of certain myelin components. It is interesting to note that historically the first attempt described in the literature to exploit vitamin K dates back to 1968, through an analogue called menadione or vitamin K-3. In 2005, a single study was published that experimentally demonstrated in laboratory animals that the K2 form of the vitamin improved disease symptoms only if given preventively. All animals receiving treatment after inducing disease showed no response to vitamin K2. It is likely that the lack of knowledge on the biology of vitamin K in the brain, and within multiple sclerosis, has led to a lack of interest in further investigation.
In summary, there are no clinical data to support the use of any form of vitamin K in supportive care for MS. This confirms what was said earlier: there are biological and neurochemical aspects of multiple sclerosis that are still unknown, despite the considerable amount of information discovered especially in the last thirty years. But the use of biologically natural agents, and therefore potentially very poor in side effects, represents hope despite everything for those suffering from this disabling disease.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Popescu DC et al. PLoS One 2018 Aug; 13(8):0203057.
Moriya M et al. J Neuroimmunol 2005 Dec; 170(1-2):11-20.
Dott. Gianfrancesco Cormaci
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