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Thursday, 18 December 2014

Activated Microglia and Inflammation in Autism






There have been yet more autism studies recently, highlighting neuroinflammation and the role of cells called microglia.  The result is this rather long post; but there is film to watch, if it gets heavy going.

Glia derives from a Greek word for glue. The original thought was that the glial cells “glued” the neurons together.

It turned out that glial cells do very much more and might be better thought of as “resident immune cells”.  They have other functions including synaptic pruning, which appears to have gone awry in autism.  They also form myelin, and when this goes wrong, big problems follow.

Microglia are inside the blood brain barrier and one of their jobs is to swallow up any foreign bodies that should not be there, before they can do damage.  It appears that this process is mainly modulated via potassium channels.  The majority of research focuses on the calcium-activated K+ channels, particularly KCNN4/KCa2 and 3.1, and ATP-sensitive K+ channels (KATP).  Administration of diazoxide, a classic KATP channel activator, is shown to reduce microglial activation and is neuroprotective in a variety of models involving neuroinflammation. 

However, Kv 1.3 and Kv 1.5 are also involved in activated glia.  We have seen in earlier posts, that blocking Kv 1.3 can be effective in autism (remember those TSO worms).



For the scientists among you:-






Synaptic pruning


A very small Acer Palmatum


Synaptic pruning could itself be the subject of an entire blog.  I will just use the analogy of a different kind of pruning.

With ornamental trees, to obtain the perfect form, pruning is very important.  You have to clear away the dead wood and encourage growth in particular areas to achieve the optimal shape.  You need to know when to cut, where to cut and how much to cut.

The human brain develops with far too many synapses and they too need pruning.  The weak ones need to give way for the strong ones to prosper.  Too many synapses lead to poor brain function.  This process is going on from childhood to early adulthood.  Microglia are heavily involved in this pruning process, as you will see in the video shortly.

We know that synaptic pruning is implicated in autism and very likely in its big brother, schizophrenia.




Activation of Microglia

Microglia can be in either a resting or activated state. In the activated state, for no good reason, they can do damage.  They can also react with mast cells to produce more inflammation.

(here is a link for the mast cell followers of Theoharides; they know who they are)




The subject is very complex.  For those with an hour to spare there is an excellent presentation by Beth Stevens from Harvard.  Click on the link below to go to the SFARI website and the video.











By a bizarre coincidence, there is another B Stevens researching glial cells and autism.  This time it is Bruce Stevens, in Florida.

His paper is interesting because he is using a known anti-oxidant (alpha lipoic acid, ALA) to affect brain glial cells.

One of the odd things is that we know in autism there is both oxidative stress and neuro-inflammation; they are a self-perpetuation combination.  There are numerous effective anti-oxidants; almost too many.  There is, however, a paucity of effective, safe, anti-inflammatory drugs.  In fact the best anti-inflammatory drug is probably an anti-oxidant.  So called Reactive Oxygen Species (ROS) are among the biggest causes of neuroinflammation.  With anti-oxidants you can neutralize the ROS, and thereby you take a big bite out of the neuroinflammation.
  

Abstract
Double-stranded RNAs (dsRNA) serve as viral ligands that trigger innate immunity in astrocytes and microglial, as mediated through Toll-like receptor 3 (TLR3) and dsRNA-dependent protein kinase (PKR). Beneficial transient TLR3 and PKR anti-viral signaling can become deleterious when events devolve into inflammation and cytotoxicity. Viral products in the brain cause glial cell dysfunction, and are a putative etiologic factor in neuropsychiatric disorders, notably schizophrenia, bipolar disorder, Parkinson's, and autism spectrum. Alpha-lipoic acid (LA) has been proposed as a possible therapeutic neuroprotectant. The objective of this study was to test our hypothesis that LA can control untoward antiviral mechanisms associated with neural dysfunction. Utilizing rat brain glial cultures (91% astrocytes:9% microglia) treated with PKR- and TLR3-ligand/viral mimetic dsRNA, polyinosinic-polycytidylic acid (polyI:C), we report in vitro glial antiviral signaling and LA reduction of the effects of this signaling. LA blunted the dsRNA-stimulated expression of IFNα/β-inducible genes Mx1, PKR, and TLR3. And in polyI:C treated cells, LA promoted gene expression of rate-limiting steps that benefit healthy neural redox status in glutamateric systems. To this end, LA decreased dsRNA-induced inflammatory signaling by downregulating IL-1β, IL-6, TNFα, iNOS, and CAT2 transcripts. In the presence of polyI:C, LA prevented cultured glial cytotoxicity which was correlated with increased expression of factors known to cooperatively control glutamate/cysteine/glutathione redox cycling, namely glutamate uptake transporter GLAST/EAAT1, γ-glutamyl cysteine ligase catalytic and regulatory subunits, and IL-10. Glutamate exporting transporter subunits 4F2hc and xCT were downregulated by LA in dsRNA-stimulated glia. l-Glutamate net uptake was inhibited by dsRNA, and this was relieved by LA. Glutathione synthetase mRNA levels were unchanged by dsRNA or LA. This study demonstrates the protective effects of LA in astroglial/microglial cultures, and suggests the potential for LA efficacy in virus-induced CNS pathologies, with the caveat that antiviral benefits are concomitantly blunted. It is concluded that LA averts key aspects of TLR3- and PKR-provoked glial dysfunction, and provides rationale for exploring LA in whole animal and human clinical studies to blunt or avert neuropsychiatric disorders

The obvious question is whether other antioxidants have the same effect.  Most likely nobody knows.  I did ask both B Stevens #1 and B Stevens #2 for their thoughts on this – so far no answer.



Brain inflammation a hallmark of autism, according to large-scale analysis


Finally to the subject of this post, the recent Johns Hopkins study that shows inflammation in the autistic brain.


This is the press release from Johns Hopkins so it is quite readable.

While many different combinations of genetic traits can cause autism, brains affected by autism share a pattern of ramped-up immune responses, an analysis of data from autopsied human brains reveals. The study, a collaborative effort between Johns Hopkins and the University of Alabama at Birmingham, included data from 72 autism and control brains. It was published online today in the journal Nature Communications.

There are many different ways of getting autism, but we found that they all have the same downstream effect,” says
Dan Arking, Ph.D., an associate professor in the McKusick-Nathans Institute for Genetic Medicine at the Johns Hopkins University School of Medicine. “What we don’t know is whether this immune response is making things better in the short term and worse in the long term.”

The causes of autism, also known as autistic spectrum disorder, remain largely unknown and are a frequent research topic for geneticists and neuroscientists. But Arking had noticed that for autism, studies of whether and how much genes were being used — known as gene expression — had thus far involved too little data to draw many useful conclusions. That’s because unlike a genetic test, which can be done using nearly any cells in the body, gene expression testing has to be performed on the specific tissue of interest — in this case, brains that could only be obtained through autopsies.

To combat this problem, Arking and his colleagues analyzed gene expression in samples from two different tissue banks, comparing gene expression in people with autism to that in controls without the condition. All told, they analyzed data from 104 brain samples from 72 individuals — the largest data set so far for a study of gene expression in autism.

Previous studies had identified autism-associated abnormalities in cells that support neurons in the brain and spinal cord. In this study, Arking says, the research team was able to narrow in on a specific type of support cell known as a microglial cell, which polices the brain for pathogens and other threats. In the autism brains, the microglia appeared to be perpetually activated, with their genes for inflammation responses turned on. “This type of inflammation is not well understood, but it highlights the lack of current understanding about how innate immunity controls neural circuits,” says Andrew West, Ph.D., an associate professor of neurology at the University of Alabama at Birmingham who was involved in the study.

Arking notes that, given the known genetic contributors to autism, inflammation is unlikely to be its root cause. Rather, he says, “This is a downstream consequence of upstream gene mutation.” The next step, he says, would be to find out whether treating the inflammation could ameliorate symptoms of autism.

The full study is here:-




What I liked about the study was the comment made by Arking, a specialist in genetics, that it did not seem to matter what the genetic cause was, all the brain samples exhibited the same inflammation.  So it does not matter which of millions of possible combinations of genetic dysfunction is present, one key physiological result is shared neuroinflammation.

Take home message:  Treat the neuroinflammation in people with Autism.

The question of course is how.

Since it seems easy to treat oxidative stress, a leading cause of neuroinflammation, we should go to extreme lengths to finish that job. 

I started it with NAC and recently added Sulforaphane/broccoli.  I suspect there are more “low hanging fruit” to be gathered here. Perhaps just an additional supplemental (exogenous) antioxidants, or perhaps something clever like increasing the amount DJ-1, which is needed to support Nrf2 which turns on the anti-oxidant genes. Early 2015 will see my oxidative stress therapy optimized.


Treating Neuroinflammation in Autism

There are lots of possible ways to treat neuroinflammation, some of which we have already covered in this blog.  Sometimes it gets called immunomodulatory therapy.

There are some natural options like quercetin and turmeric.  Turmeric is also possibly chemo-protective:-

“Currently there is no research evidence to show that turmeric or curcumin can prevent or treat cancer but early trials have shown some promising results.”

Cancer Research UK


Interestingly, people who eat a lot of curry (Indians) have a very low incidence of cancer.



1.     Steroids, like Prednisone

These are already used, particularly in regressive autism.  They are potent, but have side effects.

2.     Blockers of Potassium channel Kv1.3

This is a clever approach, since it appears that this potassium channel is involved in mediating the inflammatory response. By blocking these channels the response we have seen that the immune response can be moderated and in some people, there autism moderated.

3.     Activators of Potassium channel KATP

We learned earlier in this post about diazoxide

4.     Other Microglial Ion Channels

The various other potassium, calcium and sodium channels need to be considered.

5.     Ibuprofen

This common painkiller reduces inflammation and is used to reduce inflammation associated with autism secondary to mitochondrial disease.

Do not use acetaminophen/paracetamol/Tylenol.  These will increase oxidative stress, since it depletes GSH and also affect mitochondria.


6.     Leukotriene receptor inhibitors (i.e. montelukast, zafirlukast)

These are interesting because they are used to treat asthma and so are very widely used. They are not steroids and so do not have their side effects.  They are proved to have anti-inflammatory effects.

Montelukast/Zafirlukast is used to reduce inflammation associated with autism secondary to mitochondrial disease.


7.     Pregnenolone

I wrote a post a while back on Pregnenolone, which is interesting, since you do not need a prescription.  But does it work?

Well, after I wrote the post below, the results from a clinical trial in adults with autism was finally published.



Abstract
The objective of this study was to assess the tolerability and efficacy of pregnenolone in reducing irritability in adults with autism spectrum disorder (ASD). This was a pilot, open-label, 12-week trial that included twelve subjects with a mean age of 22.5 ± 5.8 years. Two participants dropped out of the study due to reasons unrelated to adverse effects. Pregnenolone yielded a statistically significant improvement in the primary measure, Aberrant Behavior Checklist (ABC)-Irritability [from 17.4 ± 7.4 at baseline to 11.2 ± 7.0 at 12 weeks (p = 0.028)]. Secondary measures were not statistically significant with the exception of ABC-lethargy (p = 0.046) and total Short Sensory Profile score (p = 0.009). No significant vital sign changes occurred during this study. Pregnenolone was not associated with any severe side effects. Single episodes of tiredness, diarrhea and depressive affect that could be related to pregnenolone were reported. Overall, pregnenolone was modestly effective and well-tolerated in individuals with ASD.

Trial doses were:-

Days 1-14: 100 mg
Week 1 and 2: 200 mg
Week 3 and 4: 350 mg
Week 5 and 6: 400 mg
Week 7 -12: 500 mg

So it was modestly effective, but the doses were huge.  It is a hormone and our endocrinologist did not much approve of the idea.

I will give this idea a miss.


8.     Statins

The current treatment for neuroinflammation in my Polypill is Atorvastatin.

I have already written a great deal about why statins may be effective in some people with autism; just make sure you do not have low cholesterol or mitochondrial disease.

Arthritis is another disease mediated by inflammation:-



To me it is no surprise that statins have therapeutic value in rheumatoid arthritis.


9.     NF-κB inhibitors


Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma, atherosclerosis and others.

So perhaps NF-κB is for inflammation ,what Nrf2 is for oxidative stress, a force multiplier?

There are very many other inflammatory diseases like rheumatoid arthritis and so it is quite a well-trod path looking for inhibitors of NF-κB.

Before we get into that, a quick check on what we already know from research to schizophrenia (adult-onset autism).


Abstract
BACKGROUND:
Many reports suggest that schizophrenia is associated with the inflammatory response mediated by cytokines, and nuclear factor-kappa B (NF-kappaB) regulates the expression of cytokines. However, it remains unclear whether the interaction between NF-kappaB and cytokines is implicated in schizophrenia and whether the effect of neuroleptics treatment for 4 weeks is associated with the alteration of cytokines.
METHODS:
Sixty-five healthy subjects and 83 first-episode schizophrenic patients who met DSM-IV criteria and who were never treated with neuroleptics previously were included. Serum levels of cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were examined by using sandwich enzyme immunoassay (EIA). Peripheral blood mononuclear cell (PBMC) mRNA expressions of cytokines (IL-1beta, TNF-alpha) and NF-kappaB were detected by using semiquantitative reverse transcription polymerase chain reaction (RT-PCR). NF-kappaB activation was examined by using transcription factor assay kits.
RESULTS:
Schizophrenic patients showed significantly higher serum levels and PBMC mRNA expressions of IL-1beta and TNF-alpha compared with healthy subjects. However, treatment with the neuroleptic risperidone for 4 weeks significantly decreased serum levels and PBMC mRNA expressions of IL-1beta in schizophrenic patients. NF-kappaB activation and PBMC mRNA expression in patients were significantly higher than those in healthy subjects. Furthermore, PBMC mRNA expressions of IL-1beta and TNF-alpha were positively correlated to NF-kappaB activation in both schizophrenic patients and healthy control subjects.
CONCLUSIONS:
Schizophrenic patients showed activation of the cytokine system and immune disturbance. NF-kappaB activation may play a pivotal role in schizophrenia through interaction with cytokines.

It seems fair to conclude that NF-κB inhibitors are well worth investigating.

Interestingly, one of my new “pet” compounds, alpha lipoic acid appears to have another role here:-


Evidence that α-lipoic acid inhibitsNF-κB activation independent of its antioxidant function.


Abstract

OBJECTIVE:

α-Lipoic acid (LA) exerts beneficial effects in cardiovascular diseases though its antioxidant and/or anti-inflammatory functions. It is postulated that the anti-inflammatory function of LA results from its antioxidant function. In this study we tested whether inhibition of NF-κB by LA is dependent on its antioxidant function.

METHODS:

Human umbilical vein endothelial cells (HUVECs) were treated with tumor necrosis factor-α (TNFα) in the presence of various antioxidants, including LA, tiron, apocynin, and tempol. The activation of the nuclear factor-κB (NF-κB) signaling pathway was then analyzed.

RESULTS:

LA, but not other tested antioxidants, inhibited TNFα-induced inhibitor-kappaB-α (IκBα) degradation and VCAM-1 and COX2 expression in HUVECs. Although LA activated the phosphatidylinositol-3-kinase (PI3-kinase)/Akt pathway in HUVECs, inhibition of Akt by LY294002 did not affect inhibition of TNFα-induced IκBα degradation by LA. In transient co-transfection assays of a constitutively active mutant of IκB kinase-2 (IKK2), IKK2(EE), and a NF-κB luciferase reporter construct, LA dose-dependently inhibited IKK2(EE)-induced NF-κB activation in addition to inhibiting IKK activity in in vitro assays. Consistent with the effect on luciferase expression, LA inhibited IKK2(EE)-induced cyclo-oxygenase-2 (COX2) expression, suggesting that IKK2 inhibition by LA may be a relevant mechanism that explains its anti-inflammatory effects.

CONCLUSIONS:

LA inhibits NF-κB activation through antioxidant-independent and probably IKK-dependent mechanisms.

 


This really makes ALA look very interesting.  It is cheap, widely available and well tolerated.


10.       Low Dose Naltrextone                       

Your local doctor will probably tell you that Low Dose Naltrexone (LDN) is a load of quack nonsense, partly because it is claimed to help so many unrelated disorders.

I would not have questioned that opinion, before I had started by investigation into the biology of the brain and seen how many apparently unrelated conditions are actually interrelated.  This can be established by science, not quackery.

First to note is that tiny doses of some substances do indeed sometimes have effects quite different to large doses.

We saw earlier how a tiny stimulation of the body’s nicotinic receptors produces a different effect to a large dose.

My own experience showed that a tiny, but specific, dose of Clonazepam has a marked effect, whereas conventional medical wisdom would say such a small dose would do absolutely nothing.  In this case, I was just following the clever idea of Professor Catterall, from the University of Washington.

I also found that tiny doses of a TRH analog had a positive effect and quite different to the “regular” dose.

The advocates of LDN suggest it for conditions including Crohn's disease, fibromyalgia and multiple sclerosis (MS).  As I mentioned earlier in this blog, some Fibromyalgia appears to be a condition that was almost autism; perhaps the final hit, in a multiple-hit process failed to occur.  Crohn’s is an immune disease and is a type of inflammatory bowel disease (IBD).  MS is an inflammatory disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged.

Preliminary research suggests LDN may have an effect on inflammation. Naltrexone has an antagonistic effect on Toll-like receptor 4 (TLR4), which are found on microglia, which can modulate the body's response to inflammation. It has been hypothesized that LDN may have anti-inflammatory effects through this pathway.

  

Conclusion

The immediate conclusion is that there are plenty of ways, already existing, that might very well help reduce neuroinflammation in autism.  They just requires a little further thought and investigation.

The broader conclusion here is about the merit of genetic testing.

Undoubtedly, if you could analyze the entire genome in a person with autism and also measure the expression of those suspect genes in the brain, you would gain a great deal of information.  In a few cases, where there is a single gene causing the “autism”, you might well be able to figure out a therapy.

You cannot take brain biopsies from living people.  We did come across that clever Ricardo Dolmetsch, growing brain samples from skin cells.  He has now moved over to the private sector.


So for the moment genetic testing will just generate a vast amount of data, that in many cases will not be of any immediate clinical relevance.

The good news, as pointed out by Dan Arking, from Johns Hopkins, is that many of these numerous, unrelated, genetic dysfunctions end up with the same biological manifestations.

There may be thousands, or even millions of combinations, of genetic dysfunctions that lead to autism with neuro-inflammation.

You can go ahead and treat the neuro-inflammation, without any knowledge of exactly which gene has which SNP (single nucleotide polymorphisms)  or who had what CNV (copy number variant).

For me, the identification of so-called autism genes like PTEN and BCL2 is interesting, as are the single gene causes of autism.  We can then see that a reduced expression of that gene might contribute to autism, caused by multiple gene dysfunction (multiple-hits).  For the great majority of people with ASD, they have had multiple-hits.


I read Ricardo Dolmetsch’s Stanford research into Timothy syndrome, which is caused just by one gene, albeit a very important one.  I considered that perhaps a partial dysfunction might occur, leading to disturbance in the protein expressed by this gene.  I had no idea whether in my son this dysfunction existed, whether it might be caused by a SNP (there are several known ones) or if a dysfunction was caused as a consequence of a metabolic disruption caused by autism, such as oxidative stress or neuroinflammation,  affecting the function of an undamaged gene.

It did not matter; I just carried on and did a little practical test.  This led me to include Verapamil in my Polypill.  No genetic testing was required.

It was suggested to me that genetic testing might help point me in the right direction.  I think it would likely point me in all directions.  We all carry many genetic errors, and most of us thrive regardless, so most genetic errors are irrelevant.

The clever future diagnostic tool is proteomics.

  
Clusters

From now, I will consider autism in terms of a manageable group of clusters.  Once you know, based on symptoms and some measurable biomarkers, which cluster you are in, you would have a good chance of predicting which drugs would be effective.

The underlying genetic causes may, or may not, overlap with other people in that cluster.

Some clusters may overlap. Note the case of siblings with autism, when one is early onset and the other is regressive.  Was the regressive one really symptom free early one? Or, was it just a second hit nudged him “over the edge” and then people noticed?

This would be a practical approach that could be used.  I think when people talk of phenotypes and autisms, they are thinking about very precise biological causes and then it just becomes too complicated to expect your local doctor to ever figure out.

90+% of people quite probably fit into a handful of clusters.  Then you just need a diagnostic flowchart leading to the relevant cluster and then a specific drug toolkit.

My Polypill is the drug toolkit for one cluster; and it is not a rare one.










37 comments:


  1. “…There are currently FDA-approved drugs that reduce M2 activation, such as the dementia drug nicergoline (Sermion, Pfizer Inc), that have been shown to have a neuroprotective effect,…”
    From: http://www.medscape.com/viewarticle/836829?src=wnl_edit_tpal&uac=175219HJ

    Medications for the treatment of peripheral vascular disease (peripheral vasodilators), like Redergin (Dihydroergotoxine) and Trental (Pentoxifylline) have been allrady used for autism.
    Never heard that someone tried Sermion. Maybe it is worth of trying.
    Have you ever tried ALA? I`m considering to try it with my girl (she is ten), but she`s been using already Carnosine and Fluimucil. Would it be too much? Sorry, I`m just thinking loudly…
    What is “too much” when the antioxidants are in question?

    P.S. You were wright: the effect of Fluimucil is bigger when it`s taken per os than via inhalator. Don`t understand why…

    ReplyDelete
    Replies
    1. I am glad the Fluimucil (NAC) helps. I also think that giving ALA is a good idea. I will soon be testing 600mg of ALA.

      ALA (like NAC) does lots of good things like lowering blood sugar/ increasing insulin sensitivity. ALA is probably a good supplement for most adults facing higher cholesterol and higher blood sugar levels.

      Delete
    2. I thought to try ALA with 300mg in the morning, a half our before breakfast. I am a doctor (general practice - with a modest knowledge in neurology ), and I can see the effects of ALA on polyneuropathy in diabetes every day. A friend of mine had ALA infusion in the beginning of the therapy, and he told me that he felt younger,sharper, had a cleaner mind…
      Even I am a doctor, I had no courage to explore things like you, I believed in authority of my teachers – and 10 years have passed. Now I am only regretting that I haven`t fined your blog earlier.
      I have been prescribing Verapamil for so long for different condition, even advised patiens to take it if they have asthma and palpitations. And not for a moment thought that I can use it with my daughter. Now she takes 2 x 10 mg with noticeable effect: rhinosinusitis has alleviated, no more stomach ache, hart rate is not 100/min anymore.
      Carnosine is good antioxidant, my girl become more emotional, more talking, but scripting more. Fluimucil helps a lot with that, even in small dose (2x600mg).
      Pantogam was a good choice (used it for 3 mounths), but effect was too discreet (calming, protecting from overload).
      I am thinking to give a shot with Sermion instead of Pantogam; I shell try to talk with some neurologist.

      Nicergoline (SERMION)

      An ergot derivative that has been used as a cerebral vasodilator and in peripheral vascular disease. It has been suggested to ameliorate cognitive deficits in cerebrovascular disease.
      Further studies indicate that nicergoline can enhance glutamate re-uptake and protect the brain against ischaemia (lack of blood flow).
      Nicergoline has a broad spectrum of action:
      - as an alpha(1)-adrenoceptor antagonist, it induces vasodilation and increases arterial blood flow;
      - it enhances cholinergic and catecholaminergic neurotransmitter function
      - it has neurotrophic and antioxidant properties.

      http://brainenhancingsupplements.com/nicergoline/

      A recent study in Italy showed that nicergoline can also have a neuroprotective effect
      Nicergoline, a drug used for age-dependent cognitive impairment, protects cultured neurons against β-amyloid toxicity
      http://pubget.com/paper/15882840/nicergoline-a-drug-used-for-age-dependent-cognitive-impairment-protects-cultured-neurons-against-amyloid-toxicity
      And, the most importante:
      Protective effects of nicergoline against neuronal cell death induced by activated microglia and astrocytes.
      http://www.ncbi.nlm.nih.gov/pubmed/16325157?dopt=Abstract

      I shell let you know if I try it.
      Thanks a lot and sorry for the long post,
      Maja

      Delete
    3. Try the broccoli sprout powder. Three people tried it from the jar I bought. All three had the same positive result. Other people contacted me from the US, it also worked for them. If your daughter has classic early onset autism, there is a good chance it will work.

      They do ship from Australia to Serbia.

      Delete
    4. Hi Peter, Maja,

      Have you tried the ALA? If so, could you share your experience? What would be a good dose to start?

      Peter, at what point should we be concerned with an excess of antioxidants?

      Delete
    5. RG, I did try ALA instead of NAC. Both are thiol antioxidants, but in theory ALA might have some additional effećts. I did not find any additional effect. You could measure your antioxidant status, my choice is to use observation. With NAC I see a postive effečt with 600mg every 4 hours, if I give a higher dose of NAC in one go, I see the same positive effect, but it lasts longer.
      People should only use antioxidants if there is a clear positive effect, or then have measured their oxidative stress level.

      Delete
  2. Hi Peter,

    You have written up another outstanding blog entry on a very relevant topic.

    With respect to inflammation in autism one low tech approach that I think should be used more frequently is fish oil. Studies indicate results in autism are generally positive if not spectacular: http://www.biologicalpsychiatryjournal.com/article/S0006-3223(06)00591-9/abstract.

    In addition other fatty acids are often low in autism. See: http://www.lipidworld.com/content/10/1/62. So I give my son borage oil and olive oil as well and think they are marginally helpful. Admittedly some say omega 6s upregulate inflammation but I would think if you are deficient in GLA, this could make inflammation more severe.

    If I might toot my own horn a bit, I recently wrote this up and some other ideas as a protocol and put it into an ebook available here: http://www.amazon.com/Autism-Getting-Biomedical-Protocol-Biochemistry-ebook/dp/B00R298YNW. Admittedly the focus is on OTC supplements.

    ReplyDelete
    Replies
    1. Hi Seth

      If you want to write another guest post, about OTC supplements I would be delighted to host it.

      Most people will only be able to access OTC drugs.

      I also think that good oils like olive oil and all the fish oils can only help. This is true for all of us but I think all this dietary advice is most important in mothers before and during pregnancy. This is the most critical period.

      The modern diet is not healthy and adds yet another layer of autism risk. You cannot change your genes, but you can change diet, exposure to pollution, and all forms of oxidative stress (don't work during pregnancy etc).

      Delete
    2. In my case, I had a perfect all organic diet and did not work during my pregnancy, my son was on a very healthy diet since birth, gluten and casein free, all his food and clothes are organic, water is from Norvey in glass bottles, etc. and guess what - my son is more severe than anybody I've met on multiple forums. I've tried every natural remedy out there, started early enough. Nothing works! He is still completely non-verbal at 3.5 years old and I am starting to lose hope :(
      It's just so not fair! My identical twin sister has three boys and none of them even remotely autistic or add. She never bothered about diets and healthy lifestyle. We've been through the same things in life, exposed to the same toxins and heavy metals. I do not understand why this happened to me??? It's not genetic for sure, and apparently lifestyle and diet are not that important. It's just a pure luck, we got punished for no reason at all!

      Delete
  3. Peter,

    First of all, congratulations on this blog. In Australia, after seeing the so-called best in their field neurologists, psychiatrists, peadiatricians etc. have left me finacially less well-off but more importantly no improvement in our 9 year old ASD child. The best they offered was 50mg Zoloft and Risperdal. The Zoloft is useless and the Risperdal is great if you want your child to live in zombie-land. Oh sure, he'll be better behaved but so what if he's unresponsive.

    I note that you comment on your feeling that too few of us act on your postive experiences with certain interventions. This is not our case we believe. Your research on oxidative stress and redox reactions has me reading over and over again to gain greater understanding. I am not intimidated by fancy research and I will take the time to understand fully.

    As a result of your post, we are giving our child 1800mg of PharmaNac. Also, 2.5ml of Brocolli sprout from the source you recommended. We are still giving him the psychiatric drugs also.

    Where we literally bang our heads is with the lack of consistency in his behaviour. He is such a child of extremes. He goes from conversating with us wonderfully as an equal and we become elated as we hardly see the disorder in him. Then he will regress into his shell and delve into his own world and barely acknowledges our prescence to which try as we might, we can't reach him as we did. At this point we feel he is a lost cause.

    He is also a child of extreme fear! A picture of doctor's kids will induce terror in him as will a photo of an exotic looking painting or a photo of an accentuated photo of a woman at the hairdressers. Yet he has no fear of any horror movie and actually seeks them. Naturally we go to all lengths to stop this.

    Can Propranolol help with the fear? He has no GI issues and no known allergies.
    Is there any clinical significance of an MTHFR GENE mutation (677 heterozygous). Fragile X testing yielded in the normal range. Next we plan a CGH microarray genetic test.

    Any thoughts Peter would be appreciated.

    Regards,
    D&G from Colonial Australia

    ReplyDelete
    Replies
    1. Dear D&G

      MTHFR GENE mutation (677 heterozygous) is likely very relevant, there is quite a lot written about it. Since you have what appears to be a kind of intermittent regressive autism, rather than what most other people deal with, it is possible that the solution is less complex. Your child reverts to near NT, in other children it is a case of autism switching to even worse autism.

      If I was you, I would contact the experts in the US, either directly or via your doctor. Some of these people can be extremely helpful, but more so to fellow doctors/academics.

      For example, there is an odd condition called Cerebral folate deficiency (CFD) syndrome. Most people would deny it exists. In the US there is a doctor called Richard Frye at the University of Arkansas. One adult reader of this blog has CFD, and staged a dramatic recovery thanks to Dr Frye. The drug used is leucovorin.

      A more mainstream doctor who knows a very great deal about odd metabolic disorders is Richard Kelley at Johns Hopkins. He could tell you what tests to run when your son is near NT mode and again when he regresses. Then you/he could tell what is going on. Maybe it is an intermittent mitochondrial dsyfunction.

      It might be an allergy you cannot notice, but shows up when you measure the change in histamine/IL6/CRP etc.

      I think your best bet is to contact Dr Kelley. It does not cost you anything and might help a great deal.

      If your child does not have classic autism, then the drugs I suggest in my Polypill are unlikely to work.

      For mitochondrial disease, Kelley has a therapy using OTC drugs that does work.

      If you could figure what causes the switch in your child's behavior then you would know much more.

      Delete
    2. Hi Peter,

      Thanks for taking the time to reply.

      Intermittent regressive Autism is probably the most fitting description of our child's disorder/disability I have yet to hear. Thank you. The best our neurologist labelled him as high functioning. I absolutely hate this description. What does it even mean? Just because he answered his battery of questions (while looking at the floor) well so what? He still won't interact with other children. He's petrified of them. A boy offered him some candy while we were looking at Christmas lights and our child became so afraid that he turned 180 deg looked at the floor and let out an almost inaudible 'no thanks'.

      I will look into the suggestions you have made. Is there any biological marker that you know of for fear? Our child is chronically afraid of other people - especially children and also objects that he perceives as threatening such as an accentuated painting of a jelly fish with a large mouth for example. Is there any remedy that can help? As a result of a lack of interaction with others, he is totally socially inept. So what if he can speak, if it's not being put into practice in the social world, how can development occur? I only wish his case was less complex.

      I also note your assertion that Schizophrenia is a kind of adult-onset Autism. Could our child already be manifesting these traits?

      I know some heavy questions Peter. Any thoughts would be appreciated.

      Regards,
      D&G

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    3. Anxiety is very common in people with “high functioning autism”. Fear and anxiety are pretty much overlapping emotions. There is a lot written about anxiety disorders, much of it coming down to using drugs like Prozac.

      There are some excellent behavioral therapists, mainly trained in the US. You do have these down under. We have a great American lady who comes for an extended visit once a year as part of our home-made ABA program. Therapy can be more potent than drugs.

      If you know why your child is afraid of children, in particular, you could work on it. Our son used to hate babies and toddlers, because he hated the sound of crying. He was then trained to cope with the sound and now does not mind it.

      Mood disorders are clearly part of autism and likely a bigger part for those who are fully verbal. In less functioning people, the anxiety becomes aggression and self-injury.

      In classic autism, almost all of the elements of my son’s therapy have improved his mood.

      Things like NAC and the broccoli are very easy to give a quick trial. If they do not help, then oxidative stress is not the problem. I would then suggest a quick trial of the mitochondrial treatments, the most important seems to be carnitine. Mitochondrial disorders can be established by lab tests.

      Since your child has a very unusual intermittent disorder, I would focus on that issue and try and find out if anyone else shares this issue and what they did about it. I believe that Cerebral Folate Deficiency can be associated with strange regressions, but I expect there are many other possible causes.

      Delete
    4. João Santos (Portugal)25 December 2014 at 01:03

      Propranolol is effective on my son for anxiety and fear. He is 4 1/2 and 17 kg. We only give him 10 mg because it is effective at this dose but we could easily go over if necessary (studies on newborns were using higher doses mg/kg of weight). It also calmes him down without making him a zombie).

      Delete
    5. Hi Joao,

      Thank you for replying. We asked our child's psychiatrist for a script of Propranolol based on studies I had read on its effect on fear/anxiety, but he refused and pressed upon us the superiority of Zoloft. I can say Zoloft has been a failure at 25/50/75/100mg dosages. In fact he was the most agitated at the highest dosage.

      Your success with Propranolol has renewed my interest in trialling it. We have changed Doctors so we will press to get it prescribed. His fear/anxiety cripples him. He goes from a verbal and relatively social child at home to being anxious mute and emotionally absent in public.

      Our child just turned 9 and weighs 50kg. What dosage would you suggest? Did you trial any other anxiety treatments prior to Propranolol? The Risperdal is effective but our child is so sensitive to it that at even 0.25ml once a day will render him zombie-like. Weight gain and other side-effects gravely concern us.

      We feel the NAC is working at 1800mg, we just need it to work more. One of the trials I read actually used it in conjunction with Risperdal.

      Regards,
      D&G

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    6. João Santos (Portugal)25 December 2014 at 23:02

      Newborn infants with hemangioma usually receive up to 2 mg ⁄kg ⁄day in divided doses every 12 hours (in your child case it would point to two 50 mg doses a day). Don't do it upfront.

      Studies always suggest starting low and progressively access results. Every child is different.

      You should give him an extra snack in its first days. It will not give him weight but he needs extra sugar in the first week while adapting to its lowering tension effects (very minor effects and temporary in the dose range I give my son but relevant if you give him much more than that).

      I should point out that our boy is on Syntocinon nasal spray (pharmaceutical oxytocin) and it acts on anxiety/fear as well, according to studies.

      Best regards,
      João

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    7. João Santos (Portugal)26 December 2014 at 18:44

      Talking about fear and Oxytocin, I've just found this article:
      http://qz.com/312536/scientists-say-they-have-found-a-cure-for-fear/

      In spite of Oxytocin, I do find value in propranolol and I do see results compared to Oxytocin alone.

      Best regards,
      João

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    8. Hi Joao,

      Thanks for the link to the Oxytocin article. Unfortunately we've already trialled it. A couple of years back our child was involved in a medical trial of Oxytocin nasal spray. It was a blind cross-over trial that lasted several months.

      It was required that we take the nasal spray and administer it at home. At the conclusion of the trial we found the placebo more effective than the Oxytocin. I don't recall the exact dosage but it was low as this was the first occasion they were trialling it on the peadiatric population.

      From some of what I've read on Oxytocin, it's rendered ineffective when raised to room temperature. Although we had ours refrigerated for the length of the trial the trip home from the research centre was lengthy.

      Regards,
      D&G

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    9. João Santos (Portugal)31 December 2014 at 20:02

      I'm sorry Oxytocin didn't work for your child. My 4 1/2 years old has been taking it for 2 years and we saw results a few weeks later and consolidation over time.

      Hope propranolol will help.

      Best regards,
      João

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    10. D&G, MTHFR C677T will be affecting your son's methylation and depending on his other SNPs, the interaction with the other medications. There are a couple of FaceBook groups that have sufferers and practitioners working together. I'm homozygous for MTHFR P39P, which is similar but has a stronger effect. Your son will have difficulties activating synthetic folate, B6 and B12, supplementing the right forms of those for me helped my anxiety levels massively.

      Wayne

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  4. João Santos (Portugal)25 December 2014 at 01:13

    My son frequently has different right versus left temporal artery temperatures, with is right measures 0,6 to 0,8 ºC above his left measures. He usually borderlines fever on his right temporal artery (according to a study retrieved from http://cpj.sagepub.com/content/42/5/433.short).
    I'm always unsure what to think of this. Should I consider the "excessive autism neural work theory" or should I consider the "neuroinflamation theory", with the right hemisphere taking the heavier burden (on either theories)?
    Have you ever compared measured and compared temporal arteries temperatures?
    I should point out that I compare with rectal temperature and his temporal measures on both hemispheres are always somewhat superior to what should be expected.

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    1. I have not measured temporal artery temperatures. There must be an explanation for the results you measure, but I have never considered this. Perhaps another reader has some thoughts on this subject.

      Delete
  5. Hi Peter,

    Through investigation into next generation sequencing availability in Australia, I've come across some of the findings of recent research into exome sequencing in the US?

    You may (may not) have come across a very recent ( 2 days ago ) paper titled: "The autism-associated chromatin modifier ​CHD8 regulates other autism risk genes during human neurodevelopment."

    I found it fascinating because it seems intuitive to me that such a heterogenous disorder would involve many risk genes and these genes would be regulated during neurodevelopment. As CHD8 targets ASD risk genes it would stand that a loss or dysregulation of CHD8 would lead to ASD.

    I'm oversimplifying here of course, but the premise appears sound.

    This is the link to the full article:
    www.nature.com/ncomms/2015/150310/ncomms7404/full/ncomms7404.html

    Regards,
    D&G

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    Replies
    1. Thanks for the link. It is very interesting.

      I am looking at epigenetics at the moment and by chance I did see that paper. What struck me was the lead author Noonan has the same unusual surname as the syndrome I was just writing about.

      He is very smart. Here is an interview with him. If only all autism researchers were like him.

      http://sfari.org/news-and-opinion/q-a/2014/questions-for-james-noonan-tracking-a-candidate-genes-rise

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  6. On epigenetics (which is more relevant than genetics) in ASD context, see below recent paper with very good specificity or perhaps sensitivity in the cohort used (75% to 83%). Of course, there are known genetic causes of ASD as well but these are still rare.

    http://www.sciencedaily.com/releases/2015/03/150309134627.htm

    Of note, much like the M2 activation found in post-mortem ASD brain sample, the epigenetic signature changes included epigenetic changes related to inflammation/immunity as well. Don't have access to the full study or the specific epigenetic changes observed here.

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    Replies
    1. Let me know if you read full study or find out what were the "signature" epigenetic changes found. Thx.

      http://www.ncbi.nlm.nih.gov/pubmed/25739104

      K3

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    2. I do not have access to the full study, I expect it will be available later on.

      Delete
  7. Great post!
    Interestingly, I was thinking the same thing just a couple of days ago, that one should build an online questionnaire to be filled out by an autistic parent, where you plug in your symptoms and it gives you the list of drugs to take! LOL
    I am still trying to figure out which "cluster" my son belongs to. So far he seems to be very similar to Monty, except he does not have any SIB and appears to be very happy and mild-tempered.
    I have a question about the dosage of ALA: we are doing the AC chelation protocol. We have already completed 73 rounds and are currently at 12.25 mg of ALA every 3 hours for 3 days. That makes it roughly a 100 mg a day. I wonder if I should increase the dose, in spite of it being the maximum dose for his weight, according to Cutler's rules. After almost 2 years of chelation I no longer believe in this protocol, and only continue it because my son has a very high levels of Hg in his hair (100 percentile according to the latest test). I am not sure if ALA is capable of chelating Mercury. But some kids do improve on this protocol, perhaps because of the antioxidant and other beneficial properties of ALA. I am thinking of modifying the protocol so that I can use other properties of ALA, even if it is not a chelator. I probably do not need to keep a constant low-level of ALA in the blood for 3 days? So far Ive seen zero improvements on this protocol, and neither did from many other biomedical treatments. Now I am ready to move on to the "big guns", meaning pharmaceutical drugs.
    So far I've been hesitant to use drugs, because they have a narrow application area and a wide side effects area. As opposed to the whole plants that have a wide application, as you already noted in your posts, and no side effects.
    But, having not found any natural whole plant based supplements that would help to start my son's speech, I am getting pretty desperate and am willing to try anything at this point.

    Polly

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  8. Until 8 years of age Monty had no SIB. At the age of three he was very happy and easy to look after. Autism can change very much over time and the difference with typical kids grows slowly over time. I think most DAN interventions are a waste of time and money.
    Chelation is a big distraction. People have many odd lab results in autism, very often linked to oxidative stress. If you have low antioxidant levels you are guaranteed to have odd levels of heavy metals.

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  9. At this point, I am mostly concerned about the lack of speech, and I was told that Hg in the front lobe of the brain can prevent a kid from talking, and that chelation would resolve that. People share their stories about non-verbal kids starting to talk once the Mercury was out. They say it might take a lot of rounds, 100-300 total. I do not know at what point I will finally give up, but as long as there is Hg in his tests I will probably continue to detox it, one way or another.

    I am thinking of doing the LDN treatment, since autoimmunity seems to be my son's biggest problem. But we are currently doing PEA and it seems to help with allergies. I was wondering if I could do both PEA and LDN simultaneously? Would it prevent his immune system from the proper response to LDN if he continues with PEA?

    Thanks for sharing your story. I thought that with drugs the symptoms are suppose to get better with age, not worse. So many people report improvements in their kids from various DAN treatments, but I do not see anything in my son. If anything, he is getting worse, not better. I think those kids that improve do not really have autism, but probably a metabolic or some other disorder. The fact that my son does not respond to treatments just shows that he has a classic type of autism. Perhaps some of your PollyPill drugs will help in his case.
    What do you think, can we do PEA and LDN at the same time without them counteracting each other?

    Thanks,

    Polly

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    Replies
    1. Polly, we only started to give drugs at age 9. The drugs have made a big improvement and that would have been possible earlier.

      About 10% of people with "autism" have some transitory disorders that get better all by themselves. This accounts for those recovery stories using anything from bleach to anti-parasite drugs and, who knows, maybe even peanut butter.

      In classic autism kids are usually non verbal at three and a half. If you use PECS, ABA and other therapies speech will very likely follow. Once speech emerges you may give a big sigh of relief, but it is just the beginning.

      Some people with classic autism never exhibit problematic behaviors, but a large percentage do. A significant number go on to develop epilepsy. I think the risk of this happening can be greatly reduced by treating autism medically, before these problems develop.

      If you are able to start science-based drug therapies at a very early age you will maximize their potential benefit.

      Some people do benefit from LDN, but it seems to be a minority. I have not used it.

      I would start bumetanide straight away. Safe and likely to be effective.

      Delete
  10. Thanks for answering, Peter.
    The problem with Bumetanide, I had to order it from India and it got stuck at the customs somewhere in Europe. I hope it will get here eventually, but I am trying other things while waiting.
    So far, increasing of NAC and giving him PEA seems to have a positive effect. He has not had a single allergy rush since I started PEA. But two days ago I added Periactin and even though it does help as serotonin and histamine antagonist, but, like somebody on this blog has mentioned, in small children histamine a are neuroprotective and reducing the histamine levels might trigger seizures. I am so scared, because his odd electrical activity while sleeping has increased after introducing all the antihistamines, especially last couple of nights, he was constantly jerking and moving in his sleep. I stopped the Periactin and increased PEA, because it is supposed to be neuroprotective. Hopefully it will resolve the problem. I think it's best to start with Bumetadine and then antihistamines.
    Since I do not have Bumetadine, I started Pantogam today. Too early to tell if it helps.
    Have you tried Pantogam on Monty?

    About ABA. We did ABA and many other therapies with my son, starting at the age 2. It was a disaster. Before ABA, he was a curious, happy child, who loved to learn new things and teach himself various things on iPad. He loved puzzles, books, queries about the animals, letter, colors etc. after just one month of ABA he became extremally resistant to trying anything new, his eye contact became forced (because they were forcing him to look against his will), he turned into a psychotic screaming unpleasant to be around kid. They did try to teach him PECS, but it did not work.
    I do not think you can force a chance led to be normal. It's not their choice to act the way the act. ABA does not change a kid biologically, but psychologically it can be devastating and it can do an irreversible damage. Thankfully, we only did it for 5 weeks and after 2-3 months off it he returned back to normal. We also did speech and OT therapies that did nothing good for him. They did not teach him anything in almost a year of therapies. But interestedly, all the improvements came right after we stopped all therapies at the age of 3. Perhaps it happened because we started MB12 shots. He easily learned to do things they were trying to teach him unsuccessfuly for months, he started doing them overnight.
    As for PECS, he just does not want to communicate, it's not like he has no means to do it. He is very resourceful and always finds a way to get his point across if he wants it. He brings me his shoes when he wants to go for a walk, he gives me the control remote to turn on his favorite show, etc. his problem is the lack of interest in socializing, like sharing his feelings, the sharing attention, etc. You can not teach a person that. He starts doing it on his own when he feels better. I just need to find the correct supplement to address his issues.

    Thanks for sharing your experience and research. It helps a lot to read your posts and I am learning a lot of new things here.

    Polly

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    1. Pantogam is a GABAb drug and is similar to Baclofen. I did try Baclofen, but it did not have a big effect. For many people with Asperger's and anxiety, Baclofen seems to help a lot.

      You have started your behavioral therapies so early, this may be why they do not work.

      Your son is communicating. Bringing you his shoes or the remote is communication. You just have to build on that.

      At his very young age, I think the carer has to be the therapist. You cannot expect a two year old with autism to respond well to strangers. We taught Monty PECS, not a therapist. There are training courses for carers.

      If your son likes his iPAD, then use that to teach him. We used touch screen based learning software long before Monty was verbal. He loved it and it made him tune in to the world.

      http://www.laureatelearning.com/

      The initial program we used "First Words" is available for iPAD.

      With software, you get what you pay for. If it is free, it is not same.

      We bought about 20 of these Laureate products and used them over 4 years.

      Also useful is Floortime and the Canadian Hanen Program.

      http://www.hanen.org/Programs/For-Parents/It-Takes-Two-to-Talk.aspx

      You can just buy the Hanen books, they are very easy to follow. Floortime is a whole approach, but similar.

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    2. Thank you for your suggestions, Peter.
      I have downloaded both of the Laurete apps and it seems he likes them. He already knows all of those nouns, but maybe it will teach him to use them in a sentence. I still do not know how to go from him knowing words to speaking. He is also using Autism iHelp apps, they have apps for yes/know questions, emotions, wh questions. Some of the apps are too advanced for him to understand, but he still likes using them. He likes the challenge I guess. I think he already knows some of the written words too. But that does not help with speech.
      Therapies, even at home do not change the kid. He only communicates when he wants something. I feel like he is using me to fulfill his needs. But he has no interest in socializing, in sharing his emotions. And that's not something you can teach a child. I do not see the point of ABA. It does not make a child neurotypical or to have typical behavior and emotions. He needs to be treated medically, not trained. Supplements have done a lot more for him that any therapy. Therapy, in fact, has not done anything for him. The best therapy a parent can provide is for a child to feel secure and accepted. Parent is not a coach, but rather a person to comfort a child. Non-verbal kids like my son do a lot of one-on-one therapy for years and they are still non-verbal as teenagers and as grown-ups. I am sure it's not for the lack of trying on their parents part. It's just that therapy does not help non-verbal kids.
      Using iPad more for teaching him is a good idea. iPad is the best invention for our kids, because they do not learn from other people, but they can learn from iPad. It always surprised me that he can answer iPad questions easily, but when I was trying to ask him the same question, with the same intonation and words, he did not understand. Only certain supplements in the last couple of months have changed that and now he "answers" my question by pointing to the object. He knows a lot of nouns, but not the verbs. I downloaded some verbs apps, but he does not understand them, and it's impossible to explain, since it's not a picture like a noun. The same is with emotions, he does not see them and does not understand it. He always guesses the wrong answer with emotions.
      Hopefully some of the new drugs will help with that.

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  11. Hi Peter, have you done a trial of LDN therapy? Or have you heard from your readers that have? http://jpet.aspetjournals.org/content/293/2/607.long

    thank you

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    1. I have not tried it. It does seem to help people with diseases linked to chronic inflammation like MS. It is entirely plausible that some types of autism will respond to LDN.

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