Trace #4 – Immunity in ALS patients

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Is there anything unusual besides that chronic inflammation what could also support the stealth enemy theory? What scientific observations are known? Let´s take a look.

First of all I would like to emphasize that I don´t try to state (it is too strong word) that the possible stealth or not clearly apparent multi-factor infection is the greatest and dominant problem in ALS. I am more convinced there are many problems where it really is not clear what is the biggest one – I would not be surprised if this dominancy is highly individual among ALS cases (which prevents success of all those simple stats based measurements) but the final sum is the ultimate factor. If there was single dominant problem humans would have probably identifed it already. All findings lead us to theory it is a multi-factor syndrome where many things are wrong within the organism but from some reason science has great troubles with identifying and targeting them. I believe it is a real puzzle with small pieces which all fit together so that such nasty condition is established. This also means the organism as a whole needs to be far from healthy state, far from homeostatic state and we, humans, should be able to see at least some signals which most likely indicate it is not only about some local but extremely complex and hard to decipher problem stemming from mutated/damaged genes in specific cells in brain/spinal cord. Here I tried to focus more specifically on comparing immune systems of healthy people to people with ALS diagnosis. Of course and as usually by searching in available scientific works and articles^​1–6​.

First impression

It is not easy to follow that hardcore scientific jargon and digest something of it but after some time I started to realize couple of things. First is personally appealing for me as these works and related efforts are in my opinion well targeted and there is an apparent desire to understand more what can be wrong in the organism as a whole. It seems that all those genetic studies and efforts are not viewed well by other colleagues/scientists who stand behind these immune system investigations. I noticed this already before in the work of Michal Schwartz^​6​ and here it is apparent as well.

“Many within the field believe that changes in the immune system are a consequence rather than a cause of disease progression,” highlights Feldman. “We hope that our work will convince those working in ALS that the immune system can influence disease progression and can serve as a therapeutic target in the treatment of ALS.”^​4​

People may not recognize any value here but for me this is a great news! This is actually in line with my understanding and experience – there is something wrong in the ill body and we just need to decipher it. It certainly is not about genetic curse.

Generic immunity role

Another positive finding is the following one.

There is no doubt that the immune system kicks into high gear during ALS, but whether the response is helpful or hurtful is unclear. A prevalent hypothesis claims that the immune response protects motor neurons at first, but later exacerbates neurodegeneration (for review, see Hooten et al., 2015, and Murdock et al., 2015). In the spinal cord, agitated microglia and astrocytes inflame the tissue, while immune cells outside of the CNS proliferate as well (Turner et al., 2004; Murdock et al., 2016; May 2017 news). Whether and how those peripheral cells might affect ALS pathology remains unclear, though recent studies indicate that expression of immune genes in peripheral cells comes with faster disease progression (Mar 2017 news). Broad-spectrum immunosuppressive drugs either have been ineffective or worsened disease in ALS patients, indicating that at least part of the immune response helps.^​5​

What this tells us? It is actually in line with my “stealth nanoscopic conflict of huge scale” crazy theory. In other words it all seems the ill organism is fighting hard against SOMETHING. The findings indicate that not only local inflammation in CNS neural tissues is the problem. There is a systemic immune response of the whole organism. Please note those last sentences in the above citation – there were attempts to block the immune response as it was thought it is the source of the damage but it worsened the state so the logical opposite is truth – the immunity is helping, it is fighting on the PATIENT SIDE. What a surprise for all those “body attacks itself” obscurants. In terms of autoimmunity some scientists even consider a positive side of this phenomenon, it is again M. Schwartz who coined term protective autoimmunity as during the research they noticed supporting role of autoreactive cells but there is a fragile border of uknown definition – switch from supporting role to damaging pathogenic role is known. I have not considered these findings in my wild autoimmunity theory but what should be clear is that at some point, when the positive work is finished and these autoreactive cells are not needed any more, they should be removed … and EBV can prevent these graceful removals. Perhaps my thoughts are still not in a big conflict with these progressive theories.

Brain As Immunity NO-GO Zone

As per the sources I went through initially science had also theory that brain should be kept free of regular immune response (immune cells) as these could make harm there (source of inflammation) and should not reach our precious neurons but now this theory is already history. The brain and CNS often requires peripheral immune cells to come and help with fighting pathogens, toxicity or with resolving injuries. This is so logical – why it should be the opposite? It is again this strange thinking of all those scientists who tend to pick the negative reasoning while they know nothing about the observed phenomenon, yet they start making harming statements about it. Good thing is there are opponent voices and efforts – this gives us hope.

When we decided to study the role of immune cells in brain repair and encountered the negative reputation of immune cells in all brain pathologies, we went back to the early definition of inflammation by the Russian biologist Élie Metchnikoff. He referred to physiological inflammation, a process that restores harmony following any threatening condition. When this process is not switched off promptly when the threat is gone, problems arise. Instead of healing, the inflammation response develops into a chronic pathological condition. It is that pathological inflammation that creates a favorable environment in the body for many diseases that plague humanity, including cancer, diabetes, and fatal neurodegenerative diseases, such as Alzheimer’s and ALS.^​6​

Hypoxia

Hypoxia is one observed condition which was detected in ALS patients. It means the organism lacks sufficient amount of oxygene. We should already know that such state provides an excellent environment for many pathogenic processes – pathogens like bacteria in general like such environments and hate oxygene as it helps killing them. I have strange personal experience with this as one thing which I did when I was really bad was deep breathing. I don´t really know why I did it, but I created absolutely trivial exercise for me (100+ deep breaths) and it always helped me. I did that mainly before going to sleep, in order to get more relaxed and fall asleep more easily as there were times I was quite scared (I had real ALS like symtpoms). Breathing is basis of meditation techniques which all is about calming down the mind and body. This is also the reason why I mentioned such a trivial thing in my ALS Survival Guide.

In ALS, there is evidence of hypoxia in neurons, and this is thought to contribute to pathogenesis. This can be seen as increased levels of hypoxia inducible factor−1α (150). There is also thought to be dysregulation of the pathways that protect from hypoxia (151, 152). In the peripheral blood monocytes of ALS patients there is also dysregulation of hypoxia pathways (153). A gene expression study found evidence of hypoxia related genes in peripheral blood of ALS patients (55). In an animal model of ALS, hypoxia aggravates the loss of motor neurons (154). The significance of these findings is presently unclear, but this is further evidence of peripheral immune changes in ALS^​3​.

Later I also found good support in other sources, which perhaps regular science would not consider as purely scientific. I would mention book from Jerry Tennant – doctor who has his own story, non-trivial health issues comprising potential brain infections and various other problems. He also describes the role of oxygene and also explains why anti-oxidants are so important.

One of the things necessary to make cells and keep them working is oxygen. This comes to the cell by way of the hemoglobin in the blood. For the blood to reach the tissue, there must be good circulation. Circulation is accomplished with nitric oxide. Thus have adequate levels of nitric oxide is critical for good health^​7​.

Nitric Oxide (NO) is a gas that serves as a signaling molecule in every cell in the body. It causes arteries and bronchioles to expand. It allows brain cells to communicate with each other. It causes immune cells to kill bacteria and cancer cells.

…

In mammals, NO is an important cellular messenger molecule involved in many physiological and pathological processes. Low levels of NO production are important in protecting an organ such as the liver from ischemic damage. However, sustained levels of increased NO production result in direct tissue damage and contribute to the vascular collapse associated with septic shock, whereas chronic expression of NO is associated with various carcinomas and inflammatory conditions including juvenile diabetes, multiple sclerosis, arthritis and ulcerative colitis.^​7​

As with other “substances” like glutamate it is about the right amount – also homeostatic NO levels are very important. Another reason why I should continue in further exploring of the Hypoxia finding in ALS patients is the possible link with infections – yes that is my starting point, stealth infection, right?

Hypoxia, which occurs when cellular oxygen demand exceeds supply, is a common feature during inflammation associated with bacterial infection [1–3]. The reason for the occurrence of hypoxia during infectionassociated inflammation is multifactorial, and involves increased oxygen demand in order to satisfy the requirements of inflamed resident cells, infiltrating inflammatory cells, and, in some cases, multiplying pathogens [3–5]. Furthermore, chronic inflammation associated with long-term infection leads to diminished blood supply to a tissue as a result of the combination of vascular pathology and microthrombosis [4]. The combination of increased oxygen demand and
decreased supply probably contributes to the hypoxia observed during infection.^​8​

Above citation tells us indirectly that hypoxia can be a direct consequence of progressing bacterial infection. I already wrote about the harmful effects of reactive oxygene species (ROS) before – but here again, it is the native immune response weapon against pathogens and therapy based on it is considered to replace ATBs due to growing bacterial resistance to antibiotics^​9​. Perhaps ALS is just about serious disbalance on all possible levels (my speculation) however with multiplicated and unpleasant consequences. Please remember this as there will be other signals of systemic problem in ALS ill people. Perhaps even the lack of energy levels in cells which ALS researchers reported some time ago and again attempted to increase with some latest drug is relevant here. I am adding another articles for reference purpose^{​10–12​}. In the before mentioned book^​7​ the author also writes about oxygene therapy – such a simple thing right? We all remember those oxygene masks in COVID age but it may help with addressing hypoxia.

Antibodies

Monitoring antibodies or so called immunoglobulins in blood is standard diagnostic method. In ALS patients there were two observations made. First there are heightened levels of antibodies to voltage gated calcium channels. Secondly there are heightened levels of IgG antibody class. Those articles do not try to further interpret this but mention that experimental transfers of these IgGs to mice lead to motor neuron degradation and loss of muscle control. This indicates again that immunity aspects play crucial role in this disease but we also know that immunity is further affected and modulated by all the other factors – and we know there is something very wrong in ALS patients on all levels which contributes to problematic immune system behavior.

I cannot just end with such statement so I am more interested in those antibodies to gated calcium channels. Presence of it is a signature finding for disease called Lambert-Eaton syndrome. According to current findings this disease is caused by damage of neuromuscular junctions – places where nerve system connects to muscles. This has serious consequences which will not surprise anyone having basic understanding of ALS – fatigue, muscle weakness, trouble walking, trouble speaking and swallowing. For me it is a reason to think about a link between ALS and LEMS.

Voltage-gated calcium channel

But what are these calcium channels? What are they good for? Let´s consult wikipedia. We can find out these channels are found in major excitable cells like … neuron, muscle, glial. The calcium acts as “chemical input signal” of these cells which results in excitation of the cell. I assume this all enables us to think (neuron fires, transmission of signals through the whole network = thinking) or to move (muscle cells fire or contract and we move etc.). Important sentence which should sound familiar is following.

Excessive activation of VGCCs is a major component of excitotoxicity, as severely elevated levels of intracellular calcium activates enzymes which, at high enough levels, can degrade essential cellular structures.^​13​

Since I am naturaly curious I need to ask why would the organism which I highly appreciate in terms of its architecture create antibodies to those calcium channels? This can be read as an attempt to destroying them, perhaps it is desperate effort to turn off the excessive excitation. Crazy stuff but nobody should question fact that there is an excessive excitation in ALS patients. These are the infamous muscle twitches! I cannot forget the look on my mother arms where muscles were literally dancing, purely involuntary. My intuitive guess here is that the problem is the calcium itself. This also remembers me the crucial importance of calcium to magneisum levels I read about in past. Let´s remember this as it is a real trace for me, while it can be so simple and thus neglected by ALS research who is rather hunting ghosts in DNA as I use to say.

Magnesium Vs Calcium

Great source of information about magnesium is book^​14​ written by Carolyn Dean with well chosen title The Magnesium Miracle. I personally do not like bombastic names and titles of books, news articles (clickbaits) so this is my default attitude. Of course I make exceptions and I think in this case it is one such exception. I remember those times when I was very bad, sick, had strange issues including muscle twitches. At that time I already had arsenal of knowledge in the form of book library (result of my desperate efforts to help mother). This book was part of the library when I got to problems again and it has proven its value. I am always amazed when I get more information about the importance of such simple building blocks like these core minerals (+ zinc, selenium, copper etc.). Usually just the enumeration of where all given mineral/micronutrient effects is impressive. Those core processes including the critical like immune, digestive, neural are included and the magic is always in the right amounts, so for instance enzymes can do its work optimally etc. During my treatment program I took special care to address potential deficiencies in these minerals and that is why it is inherent part of the guide I wrote for ALS patients (but not just them!) and it is also on the list here, perhaps I should even more emphasize the importance.

In case of magnesium I need to be brief here – I cannot compress the great book contents into few paragraphs. It would really deserve at least dedicated post. Anyway the book at the beginning provides list of 56 health problems which are known to be related with magnesium deficiency. There is no big danger in higher levels (safeguard is diarrhea; grey stole; I never got there despite consumed magnesium in grams per day!). With magnesium problems arise practically always from lack of it but of course nobody should try to overdose. I am listing only few relevant below.

• adrenal fatigue and fatigue in general – chronic stress quickly consumes magnesium amounts available
• detoxification – Mg participates in core detox processes – removing heavy metals, toxic substances like pesticids etc.
• musco-skeletal issues – lack of magnesium and relative abundance of calcium causes permanent muscle contractions
  • HIGH RELEVANCE, result can be all types of problems as known for fibromyalgia, cramps, twitches etc.
• neural problems – again HIGH RELEVANCE, pains and needles & pins feelings – my personal experience!
• hypertension – again disbalance in Mg/Ca contributes to high blood pressure – my personal experience!
• inflammation – Mg/Ca disbalance where Mg is anti-inflammatory while Ca is pro-inflammatory.
  • Isn´t it highly relevant in the context of this article I am writing and where I am investigating observed differences in immunity between ALS and healthy people?
• there is much more …

The author does explain the negative role of excessive calcium and how it can move the body out of homeostatic state. My understanding is if this is not the single problem in the organism one can get to the spiral of very hard to track health issues. Problem is excessive consumption of milk and dairy products (cheese, yoghurts etc.) where Mg to Ca ratio is estimated 1:7. Consuming lot of fibres/proteins (meat) also negatively affects Mg levels. Chronic stress has the same effect. Industrial food including fast food lacks magnesium but often is another source of calcium. Does that sound somewhat familiar to the reader? I hope it does – stress, bad food that is part of our lives and as a result chronic diseases occurence explodes. It also seems it is almost impossible to reach that 1:1 Mg/Ca ratio for a daily consumer of dairy products who may also face stress for long periods.

Another big part of the problem mentioned by the author is the negative role of financial interests. Magnesium is not drug to be monetized well so pharmaceutical industry does not care and milk lobby continues in persuading us their milk products are the best for us despite those better doctors already warn us. I can link everything with my life experience – I see my mother consuming yoghurts, cheese on daily basis – she was a real fan of it. She was a nice person but she also was not really calm person – she overreacted on stress events and unfortunately for her life served her stressful experience and events. I am sure it was small part of the terrible ALS problem in her case. It is interesting for me where I ended with my thoughts based on that finding of voltage-gated calcium channels antibodies in ALS patients. But that is not the end …

Systemic inflammation

Scientific findings indicate there is ongoing systemic inflammation in ALS patient organism. This is another signal of deep and organism wide problem going far beyond what some mutated cells like glial or astrocyte could cause.

There is also evidence of increased levels of C reactive protein and erythrocyte sedimentation rate (ESR) in subjects with ALS compared to controls, and evidence that levels correlate with the levels of disability as measured by the ALS functional rating scale (89, 92–94). Levels of lipopolysaccharide are elevated in patients with ALS, (149), as have levels of nitric oxide, suggesting systemic inflammation (78).

Since I have quickly gone through the magnesium book I noticed the mentions of C reactive protein as well which provides us additional trace – everything in the body is connected. Carolyn Dean mentions study which shows therapeutic success of magnesium application in case of heightened C reactive protein levels. She also mentions other interesting properties or even traps in the context of magnesium. These is food which blocks (negatively affects) assimilation of magnesium, there are medicaments and drugs (mainly those fluoride containing) which further negatively affect Mg levels. Another complexity is that when someone runs out of Mg and decides to address it, then he/she should be patient as reaching the optimal levels can take even one year. Last note – simple measurements available are not reliable. In my opinion it is not optimal to rely on tests and instead try to focus on healthy diet addressing many Mg related problems and also supplement this with high quality Mg at least at the first weeks or months (chelated form). I would say that kernel diet which I put together for my personal use is fully compatible with these goals. This is in my opinion the proper science – these disbalances and hidden deficiencies really determine how (un)healthy we are.

Complement protein activation

These complement proteins I suspected before but of course I could not add any great details. I mentioned that in the context of weakened liver as they are mainly produced in liver. This finding kind of negates such hypothesis though. In the same way NK cell levels seem heightened so while immunodeficiency is still considered it may be different type. Another reason why I was speculating on complement proteins is its role in EBV infections (C3d interactions). It is C5 and C3 fragments which were detected to be elevated in ALS patients.

There is clear evidence of activation of innate immune complement system in human subjects with ALS, with raised C5a levels and increased expression of C5a on human leukocytes (74). A two dimensional gel electrophoresis was used to study serum proteins in ALS subjects and found that components of complement C3 were increased compared to controls (75) and another study using nephelometry showed increased levels of complement C3 in the blood of ALS patients (59).^​3​

The C3 is important in bacterial infections and based on Mattman work we know bacterial infection of spirochetal type seems to be a reliable finding in ALS patients CSF. If it is elevated then I would simply speculate the body has another problem and is fighting these bacteria which have stealth capabilities and numerous techniques how to escape the immunity and thus possibly contributing to another long problem of chronic nature.

Metabolism related findings

Findings in this area could be very promising as it is routing the human effort towards the digesting system where obviously the ability to absorb core minerals and nutrients from food plays big role. Also all those microorganisms comprising our microbiom are important. It is the path towards those environmental factors which have been vaguely stated for decades.

There is considerable interaction between the immune system and metabolic pathways, which is a rapidly growing research field being known as “immunometabolism” (167, 168). For survival, metabolism and the immune system need to be linked, because there needs to be a mechanism for balancing the energy needed for basal and defensive processes (169). In ALS, there is evidence of alterations in metabolism (170).^​3​

The gut microbiome is an important source of bioactive metabolites, and its imbalance can contribute to various diseases (Amedei and Boem, 2018; Di Gioia et al., 2020). It represents an important interface between the environment and the immune system, capable of affecting the CNS through microbial toxins or fermentation products, which can in turn trigger protein aggregation, proinflammatory cytokine secretion and microglial activation, among others (Erny et al., 2015). The link between gut microbiome and ALS is nowadays well-established in several animal models.^​2​

These newest theories and findings should also increase people trust in food as a factor because I can very well imagine the reactions of regular people when someone points out food and minerals or core elements in the context of such extremely complex disease with a terrible reputation and also with a reputation that afflicted people had that dark destiny written in genes. I am fighting against such thinking from many logical reasons.

Original cause hesitations

My last comments on those articles will be around the hesitation scientists show regarding the original cause of the inflammation – or even hyperinflammation of chronic nature. Science considers basically two possibilities. First is that the immune response is the original factor which created the problem – this would be more or less in line with classic autoimmunity theory. From some reason immune cells attacked the tissues and entered the deadly loop which humans are unable to break. Second theory says the opposite as it works with version in which there was a typical reason for immune system to get activated and attracted to the site of the problem. Typical reasons are infection, injury, toxicity including cell metabolic waste/debris cleanup. However then the immune response is unable to resolve the issue and during the effort it falls into the deadly loop as well. In other words here the immune response is considered insufficient while in the first theory it is considered to overreact.

It won´t be big surprise which theory I find more promising. It is the second one because there is more logic, mainly if we connect it with other known ALS findings, those risk factors like toxicity, metals, injuries, repeated infections. This all logicaly supports existence of scenario in which immune system is capable to deal with these stimuli for some time but enough is enough, the limits can be fragile and with certain genetical predisposition it can be even more fragile. Here I have no problems with genetics as a contributing factor but it should be obvious that the role is marginal. I explained my view on it here using sun exposure analogy. Some people are just more resistant and their skin is able to withstand longer exposure but at the end it can get burned too. It is just a matter of time. In the same way people may have various level of tolerancy to face those factors which activate immunity. Sooner or later the limits or thresholds are exceeded, repeated exposure to toxicity further strengthen with bad diet, chronic stress or daily strenuous physical activity can result in exhausting all reserves. Similarly as with HIV & AIDS where patient can become easy target of oportunistic infection due to being practically disarmed, with ALS the last drop leading to establishing the deadly loop (or lock, as I wrote in past) can be a very specific problem like infection or injury somewhere in CNS. Since that moment the weak immunity with no reserves is unable to get the dangerous situation under control. Instead it can get spread more. With ALS loss of motor neurons is always stated but less frequently it is stated there are also cases ending with dementia^​15​. Then we also know that Alzheimer disease (or even Parkinson) are somewhat related – with Alzheimer memory and cognitive centers are impacted. As a reader are you realizing how all the diseases with their unique names strangely overlap and get related? This is very natural as the pathogenic state in the organism does not care how it will be labeled by humans – but it has many options (location, direction, intensity) which determine how seriously it will affect the patient. I wrote about this months ago when I was still at the beginning of my research.

This article^​2​ considers risk factors as a secondary hits which may co-create the uncontrolled inflammation phenomenon. The picture below depicts it – I borrowed it as the license permits it.

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I would only add that many ALS stories support such theory as the disease onset is often linked with occurence of some specific secondary hit (injury, infection, stress peak) but sometimes it is just consequence of lengthy issues with no apparent significant recent event or trigger (my mother case). It is in line with the multi-stage theory with triggers as described by pseudoscientist Anthony William. I try to follow science too and there is no big conflict other than various people put more weight on specific factor. The below sentence which one can found here^​6​ is also relevant, I believe.

Because theories for ALS development represent such a wide spectrum of potential causes, scientists are looking for aspects of lifestyle shared among ALS patients that might shed light on the way this illness develops. Excessive exposure to certain metals or chemicals in the workplace, repeated viral infections, smoking, and even strenuous physical activity and military service are all associated with increased risk of ALS.^​6​

…

Here we will show you that neurodegenerative diseases such as Alzheimer’s and ALS share similarities with tumors. Like tumors, they may stay dormant long before their onset due to continuous patrol of the immune system. We are proposing that when such immune patrolling is out of balance, neurodegenerative diseases emerge. By no means am I proposing that the immune system is necessarily the primary cause of such diseases, but rather that the failure of the immune system allows the emergence and fast progression of these diseases.^​6​

…

It now appears that the risk factors for Alzheimer’s disease, ALS, and other chronic neurodegenerative diseases are present for much of our lives, but they are neutralized by a properly functioning immune system. They remain dormant and undetected as long as the immune system can contain them. When the immune system fails, or when immune cells are prevented from finding their way into the brain or spinal cord, these diseases take advantage of our reduced defenses.^​6​

Summary

The goal of this post was to inform about the critical role of immune system in ALS syndrome. All these scientific findings indicate the organism is in deep troubles as a whole despite it may be manifested only with CNS local problem – with serious consequences though.

There are signs the problems can stem from the most fundamental aspects like optimal homeostatic levels of core minerals, healthy microbiom and avoidance of toxicity and stress of all kinds. No matter how big these problems are it seems the organism of ALS patient does not give up. Instead it is more likely it tries to mobilize all remaining resources available – yet this is insufficient, probably as a result of silently obtained deficiencies in the periods of life prior the disease onset. All findings are compatible with the thesis I shared on this website. I hope it will help people to realize the potential of this information. I can also point to my experience in which I conducted something I would call total mobilization, a soon enough executed extreme reinforcement natural protocol – trully amateur matter but with amazing results for me, a full recovery from strange and dangerous state which I suspect as potential preALS phase. Now excuse me, I am going to get something to drink with magnesium 😊

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References

1. 1.

   A. McCombe P, D. Henderson R. The Role of Immune and Inflammatory Mechanisms in ALS. CMM. Published online April 1, 2011:246-254. doi:10.2174/156652411795243450
2. 2.

   Béland L-C, Markovinovic A, Jakovac H, et al. Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses. Brain Communications. Published online 2020. doi:10.1093/braincomms/fcaa124
3. 3.

   McCombe PA, Lee JD, Woodruff TM, Henderson RD. The Peripheral Immune System and Amyotrophic Lateral Sclerosis. Front Neurol. Published online April 21, 2020. doi:10.3389/fneur.2020.00279
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   Sidaway P. Peripheral immune cell levels correlate with disease progression in ALS. Nat Rev Neurol. Published online October 13, 2017:708-708. doi:10.1038/nrneurol.2017.149
5. 5.

   As ALS Worsens, Immune Cells Multiply in the Blood . AlzForum.org. Published 2017. Accessed July 2021. https://www.alzforum.org/news/research-news/als-worsens-immune-cells-multiply-blood
6. 6.

   Schwartz M, London A. Neuroimmunity: A New Science That Will Revolutionize How We Keep Our Brains Healthy and Young. Yale University Press; 2015.
7. 7.

   Tennant JL. Healing Is Voltage: The Handbook. CreateSpace Independent Publishing Platform; 2010.
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   Schaffer K, Taylor CT. The impact of hypoxia on bacterial infection. FEBS J. Published online April 13, 2015:2260-2266. doi:10.1111/febs.13270
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   Dryden M. Reactive oxygen species: a novel antimicrobial. International Journal of Antimicrobial Agents. Published online March 2018:299-303. doi:10.1016/j.ijantimicag.2017.08.029
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    Vandoorne T, De Bock K, Van Den Bosch L. Energy metabolism in ALS: an underappreciated opportunity? Acta Neuropathol. Published online March 16, 2018:489-509. doi:10.1007/s00401-018-1835-x
11. 11.

    Calió ML, Henriques E, Siena A, Bertoncini CRA, Gil-Mohapel J, Rosenstock TR. Mitochondrial Dysfunction, Neurogenesis, and Epigenetics: Putative Implications for Amyotrophic Lateral Sclerosis Neurodegeneration and Treatment. Front Neurosci. Published online July 15, 2020. doi:10.3389/fnins.2020.00679
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    Mehta AR, Gregory JM, Dando O, et al. Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis. Acta Neuropathol. Published online January 4, 2021:257-279. doi:10.1007/s00401-020-02252-5
13. 13.

    Voltage-gated calcium channel. Wikipedia. Accessed July 2021. https://en.wikipedia.org/wiki/Voltage-gated_calcium_channel
14. 14.

    Dean C. The Magnesium Miracle (Second Edition). 2nd ed. Ballantine Books; 2017.
15. 15.

    Ferrari R, Kapogiannis D, Huey E, Momeni P. FTD and ALS: a tale of two diseases. Curr Alzheimer Res. 2011;8(3):273-294. doi:10.2174/156720511795563700

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