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Tuesday, 28 June 2016

Chemo-Brain and Apparently Cyto-Brain in some Autism and even ADHD




Some readers of this blog have developed quite advanced personalized medication for their child with autism.  As you might expect, given the wide variety of autism sub-types, the medical therapies found to be effective vary widely.  It is interesting that many people see fluctuations in cognitive function and some develop strategies to counter them.

I came across another form of variable cognitive dysfunction, “Chemo-brain”, that occurs in people after cancer treatment.  Chemo brain can also be called chemo fog, chemotherapy-related cognitive impairment or just cognitive dysfunction.

It is interesting for readers of this blog because chemo brain is thought to be caused by changes in inflammatory cytokine expression within the brain, over a few years the symptoms usually fade away.  Some people’s autism just fades away, although tell-tale signs usually remain.

Cytokine expression appears to be both a cause of autism and a consequence of it.  One clever researcher in this field is Paul Ashwood, who recently published another paper, this time regarding their causal effect.


Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation



A confusing term that also appears is dyscognition; this is not a real word, but is either used to describe another condition sometimes called “fibro fog”, or it just means cognitive dysfunction.   Fibro fog is the name given to cognitive dysfunction in fibromyalgia, which occurs alongside fatigue and muscle pain.

Many doctors believe that fibromyalgia is often a made up condition.  I think, in some people, fibromyalgia is one step short, in a multiple hit process, of a progression to autism.  If you look at biological links between neuropathic pain and autism, like purinergic signaling (P2Y2 etc) there are connections between pain and autism.  As we know, people with autism can be both hypo and hyper sensitive to pain.  

This post is really just look to see are there any clever thoughts regarding chemo brain that can be translated to treating cognitive dysfunction in autism, be it the baseline autism or those flare ups.



Further, the cytokine hypothesis suggests a range of potential therapeutic targets. One potential approach would be to prevent the acute change in cytokines related to cancer treatment from occurring. Agents that inhibit cytokine activity, such as monoclonal antibodies and small molecular inhibitors, may confer benefit either alone or as an adjuvant treatment to chemotherapy-induced cognitive decline in cancer patients. TNF-α antagonists (etanercept and infliximab) have been shown to inhibit fatigue and improve depressive symptoms in patients with advanced cancer. P2×7 antagonist that inhibits IL-1b release has been shown to reduce depressive-like profiles and neuropathic pain in animal models. Specific p38 MAPK and NF-κB inhibitors that block inflammatory signaling transduction have generated great interest from their use in the treatment of cytokine-induced depressive behavior and antidepressant-like effects in animal models. Anti-inflammatory cytokines, IL-10, IL-4 and minocycline may also have the potential therapeutic effects on chemotherapy-induced cognitive decline by inhibition of pro-inflammatory cytokine release through modulation of the caspase pathways. Even acupuncture may have therapeutic potential considering its effects on suppressing proinflammatory cytokines, TNF-α, IL-1β, IL-6, and IL-10. Acupuncture has been often used to alleviate the side effects of cancer treatment, including pain, nausea, hot flashes, fatigue, anxiety/mood disorders, and sleep disturbance. A series of interesting studies suggest a therapeutic role in dyscognition, for example, acupuncture improved cognitive function of patients with mild cognitive impairment (MCI) and various dementia, with clinical improvement correlating with alterations in functional connectivity and resting state activity of particular brain regions. Such approaches to the prevention of cancer-therapy dyscognition are reasonable, currently feasible, and scientifically testable.
BDNF and its receptor tropomyosin-related kinase receptor type B (TRKB) play a potential role in the pathogenesis of neurological and neuropsychological disorders . Epigenetic or pharmacological enhancement of BDNF–trkB signaling restores was reported to reverse the aging-related cognitive decline. BDNF polymorphisms are associated with impaired memory and cognition, along with reduced hippocampal activation as measured by fMRI. Age-related BDNF declines have been reported to be associated with declines in hippocampal volume and spatial memory in the elderly. Low BDNF is associated with cognitive impairment in patients with schizophrenia and Alzheimer’s disease. Significantly decreased blood serum BDNF levels have been detected in patients with cognitive impairment due to obstructive sleep apnoea/hypopnoea syndrome. Given its potent effects on neuronal function and survival in various cell systems in the CNS, BDNF has been evaluated in patients with various neurology cal disorders, including amyotrophic lateral sclerosis (ALS), peripheral neuropathy, Parkinson’s disease and Alzheimer’s disease. However, delivery of BDNF remains a substantial challenge for clinical trials because it is a moderately sized and charged protein and only minimal amount of BDNF administrated peripherally crosses the BBB to reach neurons in the brain. Acupuncture has been reported to increase neurotrophic factors  and the levels of nerve growth factors in the brain by altering the permeability of the BBB. In rats, electric acupuncture enhanced motor recovery after cerebral infarction that was associated with increased expression of BDNF in the brain.
With cytokines acting as a trigger to upstream changes, anti-cytokine therapies may have little therapeutic effect once upstream mechanisms responsible for dyscognition have been established, given that the most clinically available anti-cytokine antibodies are not readily to penetrate the blood–brain barrier. Antibody concentrations in the brain are typically about a thousand times lower than in the blood. Therefore, to better prevent development of cognitive dysfunction, anti-cytokine therapies would be best used by blocking cytokine production or inhibiting cytokine release in the peripheral prior to triggering the consequent events in the CNS. However, epigenetic changes are dynamic and the pathological changes caused by epigenetic modifications can be reversed prior to the development of permanent symptoms by targeting enzymes or other factors that control or maintain the epigenetic status. Treatments that seek to reverse casual epigenetic modifications have the potential to be effective. Such treatments are still in their infancy. S-adenosyl methionine (SAM) is an important methyl group donor required for proper DNA methylation and has been used to treat memory and cognitive symptoms in depressed patients. Betaine, another methyl donor, has been shown to improve memory in mice memory impairment induced by lipopolysaccharide. Histone deacetylases (HDACs) inhibitors can also alter epigenetic modifications, which have been studied in memory and cognition . In a mouse model, administration of crebinostat, a HDAC inhibitor, improves memory. Sirtuins, a class III HDAC inhibitors found in red grape skin and wine resveratrol have been found to improve cognitive function in mice and are currently under phase II clinical trial (ADAS-Cog, ClinicalTrials.gov; NCT01504854, 2013).
In summary, cognitive dysfunction remains a common and debilitating effect of cancer treatment, with no effective prevention and treatment, although a variety of pharmacologic and non-pharmacological strategies have been investigated. We present a speculative but testable hypothesis of how cognitive dysfunction may occur following chemotherapy. Unlike other dyscognitive illnesses, it is both scientifically and ethically feasible to study the onset of “chemobrain” by administering a major physiologic stress and observing the biological ramifications. It should be possible to gain a comprehensive understanding of the mechanism underlying cognitive dysfunction in cancer patients. Such knowledge is critical to identifying methods to both prevent and treat cancer-treatment dyscognition and potentially other dyscognitive disorders.



ADHD

Rather by coincidence a very recent study on ADHD was just published and highlighted on the Questioning Answers Blog, it shows something rather similar.  In people with ADHD and allergy, when you treat their allergy with antihistamines and/or steroids their ADHD symptoms improve.  In other words the inflammatory signaling from allergies exacerbates their underlying neurological problems.


Attention-deficit/hyperactivity disorder-related symptoms improved with allergic rhinitis treatment in children.



BACKGROUND:
Increased prevalence of attention-deficit/hyperactivity disorder (ADHD) in children with allergic rhinitis (AR) has been reported. Our previous study showed that children with untreated AR had higher ADHD scores than did the controls.

OBJECTIVE:

This prospective follow-up study aimed to investigate whether elevated ADHD scores in children with AR could be decreased by AR treatment.

METHODS:

Sixty-eight children with AR (age range, 6-14 years) and who were drug naive were enrolled and evaluated by AR symptom score, ADHD symptom scores, and computerized continuous performance test, before and after AR therapy, which included nonpharmacologic intervention, oral antihistamines, and topical steroids. Thirty-one age-matched controls and 13 children with pure ADHD were also enrolled for comparison. The relationship between the AR and ADHD score change was analyzed by a partial correlation test, and univariate and multivariate linear regression models were applied to investigate possible predictors for the improvement of ADHD scores by AR treatment.

RESULTS:

AR symptom scores in children with AR decreased significantly after treatment (p < 0.001), and their ADHD scores also decreased significantly (p < 0.001). An improved AR symptom score was positively correlated with improved detectability (rp = 0.617, p = 0.001) and commission error (rp = 0.511, p = 0.011). Significant predictors for the improvement of ADHD scores included age, AR drugs, AR subtypes, and multiple atopic diseases (ps < 0.05).

CONCLUSION:

Higher ADHD scores in children with AR compared with healthy controls decreased significantly with AR treatment. For children with AR and borderline ADHD symptoms, who do not meet full ADHD diagnostic criteria, we recommend initially treating their AR and monitoring improvement of ADHD symptoms.


I have documented in this blog how allergy can make autism worse and numerous people have left comments that allergic rhinitis treatment in children reduces their autism.

This would seem to me to suggest that controlling inflammatory cytokines may ameliorate the issues faced by people with conditions ranging from ADHD and autism to chemotherapy-related cognitive impairment and quite possibly some types of dementia and MCI (mild cognitive impairment) not to mention TBI (traumatic brain injury).

There are numerous possible ways to influence pro and anti-inflammatory cytokines, very likely different people will respond to different therapies.  What helps people with chemobrain may well be worth investigating for people with what I am calling cytobrain.

In the world of autism, as the door appears to be closing on the development of TSO parasites as immuno-modulators another one is opening for probiotic bacteria.  This was discussed in the comments section of the last post.  

Immunomodulatory probiotics for chemobrain perhaps?  Probably worth a try.








17 comments:

  1. A few random comments.

    Many autistic children have parents or siblings who have been diagnosed with fibromyalgia.This is the case in our family.

    Betaine is often used to lower high homocysteine,so common in disorders of folate and B12 metabolism,so frequently seen in autism and schizophrenia.I have been using betaine for this purpose for years.

    As you know,there are an increasing number of subtypes of autism,now linked to what was once thought to be strictly cancer genes.Most have a great deal of immune involvement.I wonder if there is a connection here.

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    1. Roger, what dosage of betaine do you take? Do you notice its effect, so if you did not take it would you feel different?

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    2. I take a high dose,at least 6000 milligrams a day.I ran out a couple of weeks ago.The brand I have been using since 2009 has been discontinued.I am looking for another brand or source.I may have to look into betaine sold to bodybuilders.The betaine both helps fine tune the cognitive improvements from the B12 and leucovorin,and provides considerable improvement as far as mood is concerned.When first tested,my homocysteine was very high,like in the 50s and 60s,so I was a ticking time bomb for all kinds of cardiovascular and cerebrovascular problems.

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    3. I think I am going to go with this.
      http://purebulk.com/trimethylglycine-betaine-anhydrous/

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  2. Well, I have been supplementing B12, Betaine (AKA TMG/Tri-Methyl-Glycine), and Folinic Acid almost from the beginning when I started on this journey and SAMe as well (stopped doing it because it was quite expensive and was too yucky to mask in peanut butter or a drink). I have no idea if it has helped or hurt during all this time, just I know a lot of things can go wrong if those vitamins are depleted and that they easily become depleted in the body and brain under chronic stress (like autism). Also, did Sodium Butyrate (most powerful OTC HDAC inhibitor I am aware of) for a while but stopped because my son got tired of the puke smell and taste of it (again very hard to mask when you kid won't swallow pills). Resveratrol is kinda yucky too but he tolerates it so he has gotten that for quite a while (not for its HDAC inhibition but for other reasons).

    All in all, I think you make a good point about the question of what do you do once excessive cytokine signaling has reared its ugly head, especially with autism where is likely it is one of the prime reasons for developmental dysregulation that occurs long before children are ever diagnosed with autism (and speech therapy and occupational therapy are not exactly going to help with this specific problem even though that is the therapy where parents are directed by their pediatrician).

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  3. Hi Peter, it has been a long time since I wrote here, my son´s autism is a subtype linked to an altered immune system, MTHFR defect, that is clear for me, i have high homocisteyne. 6 months ago, a blood test with elevated eosinophils showed that he had allergy and parasites. I did a very polemic protocol for my son , but for me 3 months were enough, i saw a long parasite with my eyes, now eosinophils are normal, but i wanted to ask you about the connection between parasites and allergy, could still have allergy now that parasites are out? and what medication do you suggest to go on. Valentina

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    1. The parasites could have caused symptoms of allergy, but he may just have allergies unrelated to parasites.

      As you can see above, Roger is taking 6000mg of betaine, better known as TMG/Tri-Methyl-Glycine, to lower homocysteine. So if you know you have high levels then it might be a good idea to follow Roger on this.

      The therapy proposed by Alli using a specific probiotic bacteria to lower the body's immune response may also help. I have been using it for a few days and there is indeed an effect on allergy. You can read Alli's comment which I refer to at the end of the post above these comments.

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    2. I have just ordered betaine from bulk in amazon, do you think that i could use it for my son also? I knew about l.reuteri because a uruguayan cientific of Baylor University, Costa Mattioli, reverted autism syntoms in mice with this probiotic, it seems that it restores oxytocin levels and social behaviours. The aritcle is in Cell magazine, 16 june. The effect on allergy is very interesting, but what about if parasites didnt go completley from the body,? perhaps microscopics could remain, the probiotic could be feeding them? Valentina

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    3. Valentina, there is plenty of food for parasites down there already. That probiotic seems to do several different clever things other than regarding oxytocin. It is very easy to trial it for a few days. In the US many kids are given betaine, I would use it if it had a positive effect, otherwise stop.

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    4. It´s true, you are right!, unfortunatley, also any thing that is considered to kill them, feed them at last. Personally, i think that candida is worst than parasites. It has to be biogaia gastrus or could be another brand?

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    5. Probiotics all contain their own specific bacteria. When it comes to settling GI problems a wide range of bacteria seem to be effective. When it comes to modulating the immune response it probably makes sense to use the one(s) that have been found to be effective already.

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    6. Anonymous, make sure your order was for Trimethyl Glycine (which is cited as betaine and what is relevant here) and not Betaine HCL which is for helping people with digestion problems by increasing stomach acid production. I made this mistake a long time ago and it took more than 6 months before I realized the error I had made.

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    7. Thankyou Tyler!, my name is Valentina, my order was for TMG, I have the diference clear, Betaine hcl could be useful for my son that had parasites and it would be useful in creating a hostile environment for them. There is a b vitamin, Riboflavin that also lowers high homocisteine, Iam using it until arrives my TMG, have you used it?

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    8. Yes Riboflavin is in his multivitamin. I have never megadosed that particular supplement. B-12 and proper folate metabolism (folinic acid or methylfolate) also is supposed to help in situations where B vitamins can be depleted by chronic stress or poor diet. NAC of course also is supposed to help a lot in this regard.

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  4. Hi! I just stumbled upon this blog, th research and feedback are Ana I got!!
    My son is turn 7 years old, his official diagnosis is "hug functioning ASD. Like all of you parents I spend my time researching/ analyzing every move he makes/ what he eats/etc

    He suffers for horrible environmental allergies, but once we started to get his allergy symptoms under control we noticed his behavior and language skills improved! Even his teachers noticed a "fog" had been lifted. Meds that have helped:
    - neublizer of beudesine (asthma treatment). All Drs that I've seen don't feel this should have any effect on his cognitive functioning, but it does! I wish I could find a neurologist or a dr here in the NY area who researched these effects)

    - patanase- a steroid nasal spray
    - clarinex- we tried ever liquid antihistamines on the market (OTC and RX). This is the only one that did not cause my son to be agitated
    When we increased his dose to 2tsp daily his teachers made the comment of a "fog lifting"

    Part 2: this particular post on "chemo fog/ fibroidmyalgia fog" also hits home. I suffer from chronic EBV (thankfully I do not have the FM pains) but I do suffer from the brain fog when I have a flare up.
    In the past B12 shots 2xweek help. Recently I've need more help..
    My dr has just added the following supplements which seem to be helping.
    ACETYL-L-CARNITINE
    Alpha lipic acid

    Have you ever researched these supplements/ benefits for autism?

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    Replies
    1. Susan, if your son has allergies you might want to consider using a probiotic to dampen his immune system. This may sound odd, but is very simple to do and does work, then you will need less allergy drugs. Read the post on Biogaia.

      http://epiphanyasd.blogspot.com/2016/07/biogaia-trial-for-inflammatory-autism.html

      Allergies make autism worse and so if you treat the allergy you should see many positive behavioral changes. There are many posts in this blog about summertime raging, allergies, antihistamines, mast cell stabilizers etc.

      Verapamil is my silver bullet in the allergy season and does seem to help many other people with allergy+autism.

      Carnitine and alphalipoic acid are widely used in treating regressive autism caused by mitochondrial disease.

      http://epiphanyasd.blogspot.com/p/regressive-autism.html

      They are antioxidants and should help many people. NAC (vet similar to ALA) should also help.

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  5. Peter,
    I want to thank you for enlightening me on NAC. I had heard of it, but never tried it for my 11 year old son. After 10 days on PharmaNAC (3) tablets/day I am quite impressed with how much it has helped his repetitiveness. My son has been repeating his daily schedule over and over in a panicked way for about a year now. It is incredibly difficult as I try so hard to support him emotionally, provide him with a visual, etc... but nothing seemed to help. I had always attributed it to anxiety and unfortunately everything we have tried for anxiety has been a bust. I was starting to feel hopeless. I tried the NAC after reading your blog thinking perhaps this is more of a verbal OCD than just anxiety. It truly works! I really thought it would be another trial of something that worked for a day or two and then stopped. I notice that once it wears off his "schedule talk" comes back, but not nearly as bad as before. Thank you! I feel like every bit of troubling behavior we are able to chip away at, will only help my son and our whole family. Anyone out there with a child who has repetitive behavior should try it. You have nothing to lose and everything to gain. -- Christine

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