Who said that the brain doesn’t regenerate? Well, it was the neuroscience Dogma as far back as philosophy. But, not in certain quarters; Santiago Ramon y Cajal (1852-1934), widely believed to be the father of modern neuroscience in his treatise ‘Degeneration and Regeneration of the Nervous System’, alludes to the potential of the brain to regenerate in the ‘general theoretical interpretation of the phenomena of nervous regeneration’.
He noted two important things: 1) Law of continuous growth or the tendency of the axon to grow constantly in a longitudinal direction, and 2) The longitudinal growth of nerve fibres is especially localized in their free ends, where the cone of growth is situated, a constant organ of the axon in embryos as well as in nerves undergoing pathological regeneration. In short, the terminal axon/neuron is differentiated in a special way to facilitate the growth, create exploratory sprouts and orient the axon suitably in space.
What he didn’t know at the time was that situated within and near the growth cone are special proteins that elongate and orient the axon – unimaginatively termed growth cone proteins!
As part of my side job, I’ve been looking at these in MS for the past 10 years and am now writing down here some of my observations.
The protein that drew my interest was NCAM (or neural cell adhesion molecule). It is found mainly in the nervous system, normally in the transmembrane or attached to the surface of the axon. Neuroscientists have been researching NCAM for decades. An MS researcher, Angelo Massaro, felt that NCAM had an important role to play in CNS remyelination. He even found that levels of NCAM were boosted in the CSF of MS patients receiving corticosteroids during a relapse!
Using CSF analysis, I found that NCAM was also less abundant in neurodegenerative conditions, such as Alzheimer’s disease, Parkinson’s disease, motorneurone disease. Levels by comparison were much higher in those without a neurological disorder. This led me to postulate that the soluble version of NCAM found in the CSF must be acting as trophic factor for axons/neurons creating environment favorable for growth/plasticity.
What surprised me was that levels of NCAM in the CSF dropped serially from CIS (first presentation), through RRMS, and into SPMS. Since, I published my observations, others have also found the same though not in all instances (different primary antibodies in their assays)! But, what has been annoying me to date like a festinating thorn in a hard to reach place, was whether you could boost CSF NCAM levels through treatment? Trying to find collaborators from pharma who were willing to test their drugs on this proved impossible. That was not until Prof Jan Lycke’s group from Sweden suggested that they have serial CSF’s before and after natalizumab, fingolimod and mitoxantrone treatments an year apart, and were willing to collaborate.
The samples were analyzed blinded (i.e. not knowing the timing of the samples or their treatments) and you can see the remarkable findings below in the figures.
I will leave you to interpret these findings on your own…
Acta Neurol Scand. 2019 Jan 18. doi: 10.1111/ane.13069. [Epub ahead of print]
Cerebrospinal fluid NCAM levels are modulated by disease modifying therapies.
Axelsson M, Dubuisson N, Novakova-Nyren L, Malmeström C, Giovannoni G, Lycke J, Gnanapavan S
Little is known about what leads to recovery between relapses in multiple sclerosis (MS), particularly following treatment. In the past, it has been demonstrated thatsoluble neural cell adhesion molecule (sNCAM), a putative biomarker of neuroplasticity, increased following steroid treatment in the CSF of MS subjects undergoing acute relapses. Taking this a step further, we have evaluated the effect of disease-modifying treatment (DMTs) on CSF sNCAM levels in various subtypes of MS.
We measured CSF sNCAM levels at baseline and after 12-24 months of DMT in 69 patients, 49 relapsing-remitting MS (RRMS), 20 progressive MS(PMS), and 24 healthy controls (HC) using an in-house ELISA. Of this, 31 patients had received natalizumab, 17 mitoxantrone and 21 fingolimod. Changes in disability were measured using EDSS and disease severity by MSSS. In conjunction, CSF NfL levels were also measured.
At baseline, the mean sNCAM level was 268.7 ng/ml (SD 109 ng/ml) in MS patients compared with 340.6 ng/ml (SD 139 ng/ml) in HC, and PMS had significantly lower sNCAM (239.2 ng/ml, SD 123.0, p=0.019) compared to RRMS (269.4 SD 127.4, p=0.043). After natalizumab and mitoxantrone treatment, we observed an increase of mean sNCAM. However, in the fingolimod treated group, mean sNCAM decreased. There was no correlation was found with EDSS or MSSS, or NfL levels as a whole.
CSF sNCAM were found to be lower in MS than in HC and the lowest sNCAM levels were found in PMS. Following natalizumab and mitoxantrone treatment, we observed an elevation in sNCAM levels, an effect that was not observed following fingolimod treatment. These changes, however, did not appear to correlate with disability in the short-term or NfL levels.