Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndrome

Today’s post is to refer the scientists among you to a very thorough paper looking at possible drug therapies for two specific variants of autism, Fragile X and Rett Syndrome.

Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes

  

These are single gene autisms and, as such, it is very much easier to study them than classic autism(s) or regressive autism(s).

We have already seen that much can be learnt from Fragile X and Retts.  What helps treat these disorders may give useful pointers to treat other types of autism and some therapies may be directly transferable, in some cases.

Note the use of baclofen, memantine, lovastatin, rapamycin, a PAK inhibitor, two potassium channel drugs, oxytocin, and even lithium.

Ganaxalone is a positive allosteric modulator of the GABA_A receptor, probably affects the neurosteroid site.  It does not have the drawbacks of benzodiazepines.  I wonder whether it exhibits interesting effects at tiny doses? 

Tuning GABAa receptors

Treatment of Autism with low dose Phenytoin

Acamprosate appears to be neuro-protective, but the mechanism of action is unknown and controversial.  It is a drug a drug used for treating alcohol and benzodiazepine dependence.  A surprising number of off-label autism drugs are used for to treat substance abuse.

The paper is well worth a read for those who are heavily into the subject.

Just How Rare are the Known Genetic Causes of Autism?

"Gene" by Courtesy: National Human Genome Research

As we have seen so far in this blog, a great deal is already known about various causes of autism.  It is claimed that only 5-8% of cases are caused by the mutation of a single gene, as in Fragile-X and Retts syndrome.

When I was researching the new drug Arbaclofen, that was being trialed as a therapy for Fragile-X, and autism in general, I was surprised to learn that within Fragile-X there is a wide spectrum.  Some people are very severely affected, both mentally and physically and others are quite mildly affected.

It turns out the same spectrum effect applies to other known genetic causes of autism, including Neurofibromatosis, Tuberous Sclerosis Complex (TSC) and Timothy Syndrome.

We also have the case of Anderson-Tawil syndrome, which was drawn to my attention by a reader of this blog.  This, supposedly extremely rare, syndrome appears to run in families with a high incidence of autism.  Some of the symptoms do overlap with autism.  As with Fragile X, there can be visible physical differences.  The reader informed us that sufferers are often initially misdiagnosed with Fibromyalgia.  This blog did already look at Fibromyalgia, which also seems to run in families where autism is present and particularly affects females.  Doctors tend to diagnose Fibromyalgia when they cannot identify any other cause of the patient’s reported aches and pains, and they want to put an end to the matter.

Further Observations

There is a general perception that people with autism “look different” and I do not mean just act differently, or walk funny.

Indeed, one of the things those rare doctors specialized in autism look for, is a big head (Macrocephaly) as an indicator of possible autism and possible MR.

When Monty, aged 11 with ASD, went to visit the parents of his afternoon assistant, who is a special educator in training, there was an unexpected, but interesting comment:-  “he looks normal”.

I was recently discussing my blog with a relative who works for the UK National Health Service (NHS).  I was asking why children diagnosed with autism were not routinely screened for known genetic causes, like Retts, Fragile-X etc.  I suggested that perhaps if more people were screened, we would find that these “rare” conditions might be more common that we think.

What the Science Tells Us

Since this blog is supposed to be based on science, let’s go see what those clever scientists can tell us.

It pretty much fits in with what I am saying.  They have a new term, “Mendelian diseases” – diseases caused by a single gene.

The Broad Institute (Ivy League types) has found that milder forms of otherwise severe “Mendelian” diseases can be found in autism.  Only a partially-disabling mutation has occurred in those genes.

  

New research investigates inherited causes of autism

One study, led by Mark Daly, a senior associate member of the Broad and co-director of its Medical and Population Genetics program, found that approximately 5% of autism cases could be linked to inherited, recessive mutations that completely disrupt gene function. A second study, led by Broad associate member Christopher A. Walsh, found that autism risk could also be attributed to inherited mutations that resulted in only a partial loss of gene function. Moreover, Walsh’s team found that many of these partially-disabling mutations occurred in genes in which a complete disruption of the gene has been known to cause more severe or even fatal inherited diseases. This suggests that milder forms of some severe, Mendelian diseases – diseases caused by a single gene – may present as autism spectrum disorders.

Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

Tuberous Sclerosis Complex (TSC), as an example

An example of a known genetic mutation leading to autism is Tuberous Sclerosis Complex (TSC).

TSC is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin respectively. These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation.

The graphic below shows the symptoms of TSC and the age at which they tend to present themselves.

  

Source: Wikipedia

The symptom that caught my attention was “Facial angiofibromas”, since these little marks on the face can be easily noticed, if you look at people when you talk to them.

These marks tend to make a butterfly shaped pattern on the face and vary from highly noticeable to nearly invisible,

Here is an example from Wikipedia:-

In the case of Fragile X, prominent characteristics of the syndrome may include an elongated face, large or protruding ears, and low muscle tone.

Why does this matter?

If you are a parent, don’t go worrying about a new syndrome to deal with.

As time goes by, certain types of autism will eventually be matched to effective drug therapies.  So it makes sense to know who is mildly affected by these single-gene disorders, as well as those with the full-blown version, only some of whom have already been diagnosed.

So, if you are mildly TSC, you would follow the TSC research and if you have low muscle tone and a long face, then the forthcoming Fragile X therapies could be relevant.

Since genetic testing is extremely uncommon, the logical way to go is to look at the outward symptoms of these conditions, starting with the very obvious ones.

I do not know many people with autism, but even I can notice some tell-tale physical features, once you know what to look for. As these features are inherited, the physical manifestation may be more visible in siblings, even though the behavioural symptoms are absent.

So those single gene disorders may not be as rare as we thought.

Schizophrenia rather than Fragile-X and Retts Syndrome, as a Reference for ASD

You may, like me, have wondered why so much autism research seems to mention Fragile-X syndrome and Retts syndrome.  

Both Fragile-X and Retts are caused by the mutation of single genes, FMR1 and MECP2 respectively.  Autism can be caused by very many, seemingly unrelated things, both genetic and environmental.

When you look at it objectively, there is a much closer comparison for autism, it is schizophrenia.  

I know from the research I am reading that in fact autism and schizophrenia are intertwined and there is no boundary were one stops and the other starts.  Most likely some of the individual biological dysfunctions in autism are present in a greater/lesser degree in schizophrenia and vice versa.  This will be developed in later posts.

For those interested in learning more about schizophrenia here is a nice PowerPoint presentation.

https://files.itslearning.com/data/1512/469/SCHIZO%20PP.pptx

Here are some excerpts:-

·        A biological disorder of the brain which causes disturbances in thinking, speech, perception of reality, emotion (mood), and behavior.

·        Approximately 1% of the population develops schizophrenia during their lifetime.

·        Although schizophrenia affects men and women with equal frequency, the disorder often appears early in men (usually late teens), than women (generally late twenties/early thirties).

The most ASD-like sub-type is called disorganized schizophrenia; and it principal features are:-

•      Confusion and Incoherence

•      Severe deterioration of adaptive behavior

–     Lack of social skills

–     Poor personal hygiene & self-care

•      Behavior appears silly and/or child-like

•      Highly  inappropriate emotional responses

It is not hard to see the potential overlap between ASD and Disorganized Schizophrenia.

We even have a researcher suggesting a very similar strategy for Schizophrenia, to that I am proposing/developing for autism.

Phenotype of schizophrenia: a review and formulation

The discovery of the pathophysiology(ies) for schizophrenia is necessary to direct rational treatment directions for this brain disorder. Firm knowledge about this illness is limited to areas of phenomenology, clinical electrophysiology, and genetic risk; some aspects of dopamine pharmacology, cognitive symptoms, and risk genes are known. Basic questions remain about diagnostic heterogeneity, tissue neurochemistry, and in vivo brain function. It is an illness ripe for molecular characterization using a rational approach with a confirmatory strategy; drug discovery based on knowledge is the only way to advance fully effective treatments. This paper reviews the status of general knowledge in this area and proposes an approach to discovery, including identifying brain regions of dysfunction and subsequent localized, hypothesis-driven molecular screening.

For psychiatrists, the main difference between autism and schizophrenia seems to be when is the onset of symptoms.  Autism strikes at the age of two or three, whereas schizophrenia occurs much older.  Whether in fact some of the same biological mechanisms might be at work does not seem to be relevant to psychiatrists.  Not surprisingly, they have not made much progress treating either condition.

In the days before the autism was so widely diagnosed, there were many more cases of childhood schizophrenia reported, now it is very rarely diagnosed condition, it became autism.

I did look for some statistics that included autism and schizophrenia, but those clever psychiatrists seem to have separated them, so autism is with developmental disabilities and schizophrenia is not.

But I did find some interesting statistics about developmental disabilities.

When you look at the US statistics (1997 – 2008), based on parent-reported developmental disabilities.

Source:  http://pediatrics.aappublications.org/content/early/2011/05/19/peds.2010-2989.full.pdf+html

You can see that about 15% of kids have some kind of developmental disability.  Cases of autism increase from 0.2% to  0.7% over the ten years, but those with a learning disability is pretty flat at around 7% and mental retardation (MR) / intellectual disability is also pretty flat at 0.7%.

You also see that the incidence of seizures remains flat at about 0.7%.

According to the medical research, about 30% of people with autism will also have seizures; you would expect to see a seizure “epidemic’, if there had been an autism “epidemic”.  Whereas diagnosing autism is highly subjective, recognizing most types of seizure is not.

So clearly the numbers do not add up.  Perhaps now only 10% of people with autism have seizures?  Or perhaps only 30% of people with autism, really have it?   

The same is true with the incidence of mental retardation (intellectual disability) it remains flat at 0.7%.  According to the WHO, 50% of people with autism also have MR.  So, if there had been a big increase in new people with autism, you would expect an increase in MR.  If the level of MR remains flat it would seem that some people with MR have just been given an additional diagnosis of autism.  Either that, or the 50% figure is now much lower in the US, (which is what I expect is the reality).

With even the most basic figures not adding up, is it really surprising how little progress has been made in the hard part – actually finding treatments?

Autism has changed and now means entirely different things, to different people.  In particular, comparisons across countries are completely meaningless.

Schizophrenia

Schizophrenia has also changed and is now considered as a family or spectrum of disorders.

Like autism, nobody really knows what causes schizophrenia and most likely many things do, like autism.  There is no single gene, like with Fragile-X or Retts, and there is no cure.

When researchers compared the mixture of genetic dysfunctions in schizophrenia and autism, they found a clear overlap.  This is interesting and perhaps should not have come as a surprise.

In some ways Fragile-X and Retts are actually the opposite of autism.  For example in the case of Retts, the very important substance, Nerve Growth Factor (NGF), is almost at zero, whereas in autism levels tend to be elevated.

Just as we can learn from the comorbidities of autism, I think we can learn a thing or two from the existing research in Schizophrenia.  Indeed I already have.

MR

If anyone was seriously researching treating Mental Retardation (MR), in physically “normal” people, who have not suffered from a brain infection, toxic exposure, malnutrition or any kind of pre-natal or natal problem, we would have another great resource.  It would probably show that, in some cases, MR is caused by a partially-reversible imbalance in the actions of various neurotransmitters, ion channels, hormones etc.  Some of these imbalances will also exist in numerous cases of autism.

According to the well-known expert, Professor Howlin, only about 20% of people with ASD have an IQ in the normal range (i.e. above 70) and 50% have moderate or greater MR (i.e. IQ less than 50).  It would seem that the missing 30% must have mild MR (i.e. an IQ 50 to 70).

I suspect that the cognitive improvement found by treating some types of autism could be replicated in some cases of MR, without ASD.  If there were any clever therapies for treating MR, I would think they would likely be beneficial in autism.  In most countries, as many children have MR as have ASD, so it is strange nobody is looking how to treat it.  They assume the “defects” are hard-wired into the brain; I looks to me that some are not.

Clinical Trials

Even though ASD is a lifelong condition, nearly all the clinical trials are in children, and most often, in quite young children.  Assessing such people is doubly difficult.  Working with adults should be much easier and provide better quality data.

Other neurological conditions like schizophrenia and bi-polar disorder are regarded as adult conditions, so hopefully the quality of the research data is better.  We will see.

Plenty of adults have ASD and the ones with Asperger’s will have no difficulty articulating the effects of any intervention, so it is a pity they are rarely involved in research. 

   

Conclusion

On a happier note, I believe that if you can tune the autistic brain to its optimal performance, you will see a marked improvement in cognitive ability and, by implication, in measured IQ.  

I have no doubt that a well executed, intensive ABA program, over a few years, could also show a marked improvement in measured IQ, in many cases.  ABA is also a kind of retuning of the brain, but it has to be done right to be effective.

Biological tuning plus ABA should yield the best results.

As for schizophrenia, the biological "overlap" with autism does indeed exist. Two such areas are dysfunctional calcium channels and indeed the glutamate receptor mGluR5.  This will be developed later.

Human Growth Factors, Autism and the Centenarian Nobel Laureate

 

 

 



This post is another one of those long complicated ones, but should be worth reading.

We will look at Human Growth Factors, of which several have been identified by science and quite possibly more remain to be discovered.  Much of the science is well understood and overlaps with areas of interest to autism and another condition called Retts syndrome.

As often seems to be the case, elements of the science has been used by the anti-aging, athletic and body-building fraternities.

A surprise to me is that the science leads back to mast cells and that there some interesting therapeutic avenues already in existence.

We will even involve the seemingly obscure subject of amyloids that I introduced in a recent post.  In that post we discovered that in autism there were strange things going on with Amyloid Precursor Protein (APP).  I will postulate that perhaps amyloid-induced neuroinflammation might be a factor in the neuroinflammation found in autism.  In this post we will learn a potential strategy to control amyloid-induced neuroinflammation, which appears never to have tested in autism.

For a change we have some human interest, in the form of the Centenarian Nobel Laureate from Turin, Nerve Growth Factor and self-treated herself with it for 30 years, until she died aged 103, outliving her twin sister by 13 years.

We will look at:-

·        Human Growth Hormone (GH) and its replacement therapy

·        GABA and Baclofen that stimulate GH

·        Insulin-like Growth Factor 1 (IGF-1) and its replacement therapy

·        Nerve Growth factor (NGF) and its replacement therapy

·        Palmitoylethanolamide (PEA)

·        Brain-Derived Neurotropic Factor  (BDNF)

·        Neurotrophin-3

·        Neurotrophin-4

·        Why Rett Syndrome should not be confused with classic autism

 

That is quite a lot to digest in one post, but it is all interrelated and so should be together.

Basic Biology

As we have already discovered, the version of human biology in the textbooks is often a gross simplification of the reality.  Even in the up to date research papers it is clear that the understanding of human biology is constantly being revised.

For most people Human Growth Hormone, known as GH or HGH is the growth hormone.

Secretion of growth hormone (GH) in the pituitary is regulated by the neurosecretory nuclei of the hypothalamus. These cells release the peptides Growth hormone-releasing hormone (GHRH or somatocrinin) and Growth hormone-inhibiting hormone (GHIH or somatostatin) into the hypophyseal portal venous blood surrounding the pituitary. GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion.

Somatotropic cells in the anterior pituitary gland then synthesize and secrete GH in a pulsatile manner, in response to these stimuli by the hypothalamus.

 

Source: Wikipedia

Main pathways in endocrine regulation of growth.

Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other protein hormones, GH acts by interacting with a specific receptor on the surface of cells.

Increased height during childhood is the most widely known effect of GH. Height appears to be stimulated by at least two mechanisms:

1.     Because polypeptide hormones are not fat-soluble, they cannot penetrate cell membranes. Thus, GH exerts some of its effects by binding to receptors on target cells, where it activates the MAPK/ERK pathway. Through this mechanism GH directly stimulates division and multiplication of chondrocytes of cartilage.

2.     GH also stimulates, through the JAK-STAT signaling pathway, the production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin. The liver is a major target organ of GH for this process and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it what appears to be both an endocrine and an autocrine/paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.

Supplemental GH

Since 1995 Norditropin has been used in children and adults who have a natural deficiency in GH.  Usually it is used to treat a growth failure caused by low or no growth hormone.
 

In the 1990s it was popular in certain circles to use GH to look good and create a leaner body.  Harvard reported estimates that in 2004 20,000 to 30,000 Americans used GH as anti-aging therapy and another that 100,000 people received GH without a valid prescription in 2002.

The problem is that this seems to have been accompanied with side effects, ranging from strange growth effects in various parts of the body, to very early death.   It is much less popular today.

Safer ways to stimulate GH

There are numerous supplements sold that claim to stimulate GH and IGF-1.  These include GABA, Glutamine, Creatine and even Magnesium.

That the neurotransmitter GABA stimulates GH is a scientifically established fact.

Exercise itself stimulates the release of GH.

Some drugs are analogues of GABA, such as Gabapentin and Baclofen.  The GH stimulatory effect of Baclofen in particular has been well studied. 

Growth hormone response tobaclofen: a comparison of 10-mg and 20-mg doses in healthy men.

Here is a recent study still unpublished:-

Effect of Low-Dose Baclofen Administration on the GH-IGF1 Axis Study

For GABA to bind to GABA_B receptors   it is reported to depend on the presence of calcium or magnesium.  Magnesium is known to bind to and active GABA_B receptors  .

This might be another explanation for how magnesium supplements have a profound effect in some people with autism.  They comment on the affect of Mg on sensory overload.  In these people the activation of   GABA_B receptors  would explain this effect.

Quite possibly magnesium might increase/decrease the potency of Baclofen to stimulate GH; this perhaps should be tested.

Too much Baclofen or too much GH?

Baclofen is an analogue of the neurotransmitter GABA.  It is also an agonist for the GABA_B receptors.  As a drug it is primarily used to treat spasticity.

It now gets a little complicated, because within Baclofen are two isomers in equal amounts, R-Baclofen and S-Baclofen.

Isomers have the same chemical formula  C₁₀H₁₂ClNO₂ ^,  but the physical arrangement of the molecule is different and as a result their effect as a drug differs.

It appears that while R-baclofen is potent, the effect of S-Baclofen actually reduces the potency of R-baclofen.

The currently available forms of Baclofen, like Lioresal, from Novartis, is 50% R-Baclofen and 50% S-Baclofen.  So in a 10mg tablet you get 5mg of R-baclofen.  If you had a 5mg tablet of R-baclofen it would be many times more potent  than 10 mg of Lioresal.

This is all interesting, as is the development of Arbaclofen Placarbil, a Novel R-Baclofen prodrug.  This clever drug gets around the short half-life of R-Baclofen.  Drugs like Lioresal have to be taken 2-3 times a day, because the effect wears off fast.  Arbaclofen Placarbil slowly converts into R-Baclofen in the body and allows a much more even dose to be achieved.

Arbaclofen Placarbil, a Novel R-Baclofen Prodrug: Improved Absorption,Distribution, Metabolism, and Elimination Properties Compared with R-Baclofen 

Why so much detail?  Well, there was a very high profile trial in the US of Arbaclofen (R-Baclofen) in autism.  Overall the trial was seen as a failure, by sponsor Roche.  Among the trial group of children, there were some great responders, but there were others whose autism got much worse.

I really wonder if they monitored the level of GH in those kids.  Here is some data:- 

They were randomized 1:1 to Arbaclofen or placebo for 12 weeks. Drug doses ranged from 5 to 15 mg two or three times daily, with doses titrated to maximize CGI improvement. Most patients in the 5 to 11 age range ended up at 10 mg three times daily or, in the placebo group, the equivalent number of pills; most older patients received 15 mg three times daily or the placebo equivalent.

 

The older kids had 45mg a day of Arbaclofen.

In the literature the relative potency of R-Baclofen over Baclofen varies, but it is around 5+ times more strong.

This would equate to a dosage of 225mg of baclofen.  This is a HUGE dose.  Assuming it is only the R-Baclofen that stimulates GH, there would have been a massive increase in GH and the IGF-1.

There is something called “too much of a good thing”.  Perhaps the Arbaclofen non-responders were just suffering from a GH overdose.

In Fibromyalgia, the daily dose of Baclofen for adults recommended by Dr Jay Goldstein is 10 mg; so in a child with ASD, who either exhibited signs of Fibromyalgia or indeed spasticity (tense claw fingers or strange gait are quite common features in autism) such a dose would not seem unreasonable.  225g might seem excessive.

IGF-1

IGF-1 is a hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults. A synthetic analog of IGF-1, mecasermin, is used for the treatment of growth failure.

IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a paracrine/autocrine fashion.

Not so simple.

So according to the textbooks IGF-1  is produced in the liver in response to GH.  IGF-1 can freely cross the BBB so therefore IGF-1 levels should be pretty much the same throughout the body and an increase in GH should always produce an increase in IGF-1;  only is does not always.

CIRCULATING INSULIN-LIKE GROWTH FACTOR (IGF)-1 REGULATESHIPPOCAMPAL IGF-1 LEVELS AND BRAIN GENE EXPRESSION DURING ADOLESCENCE

 

"Our results demonstrated that hippocampal IGF-1 protein concentrations during adolescence are highly regulated by circulating IGF-1, which were reduced by GH deficiency and restored by systematic GH replacement

 

Importantly, IGF-1 levels in the cerebral spinal fluid (CSF) were decreased by GH deficiency but not restored by GH replacement. Furthermore, analysis of gene expression using microarrays and RT-PCR indicated that circulating IGF-1 levels did not modify the transcription of IGF-1 or its receptor in the hippocampus but did regulate genes that are involved in microvascular structure and function, brain development, and synaptic plasticity, which potentially support brain structures involved in cognitive function during this important developmental period."

So the role and behavior of IGF-1  is much more complex than the textbook suggests.

How can low levels of IGF-1 in spinal fluid not be restored by GH replacement?

The above study was nothing related to autism, but it shows that the relationship between GH and IGF-1 in the brain, CSF and blood can be different.  Further it means that measuring IGF-1 in the blood does not necessarily indicate the level in the brain or the CSF. 

It appears that IGF-1 is very important to support normal brain function, but just because IGF-1 may be elevated in the blood actually tells you little with certainly about the level in the brain.

 

IGF-1 levels in autism

We already noted in previous post that IGF-1 levels are often elevated in autism.  Does this mean IGF-1 levels are also high in the brain?  It does  not.

Elevated levels of growth-related hormones in autism and autism spectrum disorder

 IGF-1 is already a trial therapy in autism and Retts syndrome; but Retts syndrome is very different to autism.  It is caused by is caused by mutations in the gene MECP2.  It affects almost exclusively girls.  Most important of all is that the growth factor most connected to Retts syndrome is not IGF-1, but its cousin Nerve growth Factor (NGF).

Insulin-like growth factor-1rescues synaptic and motor deficits in a mouse model of autism and developmental delay 

"We observed significant beneficial effects of IGF-1 in a mouse model of ASD and of developmental delay. Studies in mouse and human neuronal models of Rett syndrome also show benefits with IGF-1, raising the possibility that this compound may have benefits broadly in ASD and related conditions, even with differing molecular etiology. Given the extensive safety data for IGF-1 in children with short stature due to primary IGF-1 deficiency, IGF-1 is an attractive candidate for controlled clinical trials in SHANK3-deficiency and in ASD."

 

A Pilot Treatment Study of Insulin-Like Growth Factor-1 (IGF-1) in Autism Spectrum Disorder

"The proposed project will pilot the use of IGF-1 as a novel treatment for core symptoms of autism. We will use a double-blind, placebo-controlled crossover trial design in five children with autism to evaluate the impact of IGF-1 treatment on autism-specific impairments in socialization, language, and repetitive behaviors. We expect to provide evidence for the safety and feasibility of IGF-1 in ameliorating social withdrawal in children with Autistic Disorder. Further, we expect to demonstrate that IGF-1 is associated with improvement on secondary outcomes of social impairment, language delay, and repetitive behavior, as well as on functional outcomes of global severity."

You can supplement your natural IGF-1 with Increlex.  This is an approved therapy for growth delay.

It does appear that IGF-1 therapy looks safer than GH therapy.  There are very many stories of terrible consequences of GH abuse.

 

Nerve growth factor (NGF)

Professor Rita Levi-Montalcini discovered Nerve Growth Factor (NGF) in 1954 and she received the Nobel Prize in Physiology or Medicine in 1986 for the discovery.  She died in 2012 at the age of 103, having had a remarkable life.  She was also a pioneer in the area of mast cells, which it turns out are closely linked to NGF.

She spent much of her very long life researching the brain and concluded that to preserve her own mental capacity in old age she would need a little help. For her final the last 30 years she treated herself with home-made NGF eye drops, which she claimed restored her brain function to that of her youth.  It is notable that she outlived her twin sister by 12 years.  She never retired and in her 90s founded the European Brain Research Institute.

It seems many people have tried to copy her, but NGF is not so easy to obtain.

 

Nerve Growth factor (NGF) is a small secreted protein that is important for the growth, maintenance, and survival of certain target nerve cells. It also functions as a signaling molecule.  Other members of the neurotrophin family that are well recognized include Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin 4/5 (NT-4/5).

NGF is critical for the survival and maintenance of sympathetic and sensory neurons. Without it, these neurons undergo apoptosis.  Nerve growth factor causes axonal growth. Studies have shown that it causes axonal branching and a bit of elongation. NGF binds with at least two classes of receptors: the p75 LNGFR (for "low-affinity nerve growth factor receptor") neurotrophin receptor (p75(NTR)) and TrkA, a transmembrane tyrosine kinase. Both are associated with neurodegenerative disorders.

There is evidence that NGF circulates throughout the entire body and is important for maintaining homeostasis.

 

“Normal” in autism but very low in Rett's

When researchers compared the level of NGF in spinal fluid in children with autism and Rett's Syndrome they found normal levels in autism by near negligible values in Rett's Syndrome, they even suggest that NGF be used as a test to discriminate Autism and Retts syndrome.

Levels of cerebrospinal fluidnerve-growth factor differ in infantile autism and Rett syndrome.

Abstract

Autism and Rett syndrome (RS) are both developmental disorders of unknown origin. Autism is a behaviorally defined syndrome. RS, which affects girls only, is characterized by a profound learning disability following early normal development, with a consistent cluster of clinical features. Differentiation of RS from infantile autism in the very early stages of the disorders is not always easy. Both syndromes still lack discriminative laboratory markers for accurate diagnosis and differentiation. We decided to compare the CSF nerve-growth factor (NGF) levels of children with infantile autism and children with RS using enzyme-linked immunosorbent assay (ELISA). Our findings of mainly normal CSF NGF in autism and low to negligible values in RS are in agreement with the different morphological and neurochemical findings (brain growth, affected brain areas, neurotransmitter metabolism) in the two syndromes. CSF NGF could be used as a biochemical marker for differentiation of patients with autism from those with RS.

This finding is confirmed when postmortem brain tissue from Retts was analysed. 

Reduced nerve growth factor in Rett's syndrome postmortem brain tissue.

One therapy currently being trialed in Rett's Syndrome is to give IGF-1 injections; perhaps they should also be trialing NGF injections. 

Normal in autism?  Not so fast

No studies have actually looked at NGF over time in autism and indeed the picture is far from simple. Research in 2013 looked at links between non-verbal communication deficits in people with autism and the gene that controls NGF.  The conclusion of the study was:-

 NGF is a promising risk gene for Non-verbal communication deficits.

Here is the full study:- 

QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders

 

"With regards to previously published genetic evidence supporting a role for NGF in ASD, none of the published GWAS or studies of structural variation have identified clear pathogenic variants in NGF in patients with ASD. However, a hypothesis-driven candidate-gene association study focusing on a variety of neuronal signaling pathways did identify evidence for association in the gene NTRK1, which is the canonical receptor for NGF. Remarkably, NTRK1 was one of only 2 out of approximately 60 genes that survived significance thresholds in the two cohorts investigated in that study. Combined with the current study, these data suggest the involvement of the NGF signaling pathway in ASD pathogenesis."

Also when children with ADHD were examines in research they were found to have elevated levels of NGF.

Serum nerve growth factor (NGF) levels in children with attentiondeficit/hyperactivity disorder (ADHD).

"Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder of childhood. The etiopathogeny of ADHD has not been totally defined. Recent reports have suggested a pathophysiological role of neurotrophins in ADHD. In this study, we evaluated serum levels of nerve growth factor (NGF) in patients with ADHD. The sample population consisted of 44 child or adolescent patients diagnosed with ADHD according to DSM-IV criteria; 36 healthy subjects were included in the study as controls. Venous blood samples were collected, and NGF levels were measured. The mean serum NGF levels of the ADHD patients were significantly higher than those of the controls. Age and gender of the patients were not correlated with serum NGF levels. There were no significant differences in NGF levels among the combined and predominantly inattentive subtypes of ADHD. Our study suggests that there are higher levels of serum NGF in drug naive ADHD patients, and that increased levels of NGF might have an important role in the pathophysiology of ADHD." 

This would imply to me that NGF is indeed very much implicated in autism.  In one piece if research NGF was normal in autism, but the authors of the QTL are suspicious of this.  Since ADHD is so overlapping with autism, the above paper really points to the need to go back and do a more rigorous study on NGF and autism.  For now, I will assume that NGF is indeed elevated in autism at some point. 

Here is rather complex paper that goes into great depth regarding the therapeutic potential of NGF and BDNF:- 

NGF and BDNF: from nerves to adipose tissue, from neurokines to metabokines.

"Thus, it was remarkable to discover that treatment of newborn rats with NGF caused a systemic increase in the number of mast cells Today there is compelling evidence that NGF, in addition to its neurotropic function, enhances survival and activity of a large number of nonneuronal cells, including immune cells, pancreatic beta cells, vascular smooth muscle cells, cardiomyocytes, endothelial cells, epithelia cells, and adipocytes.

The secretory proforms of NGF and BDNF, pro- NGF and pro-BDNF (40), respectively, are cleaved extracellularly through the tissue type plasminogen activator (tPA)-serine protease plasmin pathway; note that today’s widely administrated cholesterol-lowering drugs, collectively named statins, can induce tPA
 

Indeed, NGF and BDNF initially discovered as neural growth factors are also affecting (i) immune cells, (ii) blood vessels/angiogenesis , (iii) synaptic plasticity and consolidation  involved in learning and memory , (iv) wound healing and tissue repair, and (v) glucose, lipid, antioxidant and energy metabolism.

 

Therapy Insight

NGF- and BDNF-based therapeutic pipeline for neuropsychiatric diseases discussed herein (except migraine, cluster headache, and probably epilepsy) may

include (i) applying NGF itself , (ii) targeting the secretory and signaling pathways using existing or novel drugs, (iii) TrkB transactivation , (iv) ampakines, small molecules that stimulate Alpha-amino-3-hydroxy-5-Methyl-4-isoxazole Propionic Acid (AMPA)-type glutamate receptors , (v) selective deacetylase inhibitors, and (vi) “brain food”, that is, neuroprotective nutrients including calorie restriction, also physical activity .Whereas a high-fat diet reduces brain BDNF levels and declines cognitive capacity. Accordingly, the above mentioned classes of drugs, including calorie restriction mimetics – see, for example,O’Brian and Chu and Nikolova  for resveratrol –, require a novel research evaluation as possible pharmaceuticals and nutraceuticals also for cardiometabolic diseases. Meanwhile, NGF and BDNF could be reasonable targets for resveratrol’s therapeutic effects in both neuropsychiatric and cardiometabolic diseases. Further, recent findings have discovered that free fatty acids may influence brain development through binding to G protein- coupled receptor-40 expressed in the hippocampus (151). Interestingly, some widely used drugs for cardiometabolic diseases such as the cholesterol-lowering statins and peroxisome proliferatoractivated receptor gamma agonists as well as two novel common players, acetylcholine and glucagon like peptide-1, have been introduced into diabetes-obesity-dementia link . Another crossroad of nerves and adipose tissue may be adipose-derived mesenchymal stem cells, which can differentiate into neurons in BDNFenriched cultures, and thus representing useful tool to treat neuropsychiatric disorders. Note that pro-NGF can be cleaved proteolytically at dibasic residues and liberates two other peptides beside NGF, LIP1, a 29 amino acid (aa) peptide, and LIP2, a 38 aa peptide; their synthetic forms may be targets for new drugs in NGF-related diseases.

The challenge for the future is to understand to what extent the effects of NGF and BDNF are interrelated with regards to their neuro-, synapto-, vasculoand metabotrophic potentials. Further studies should provide answers to the questions of when and how NGF-BDNF/TrkA,B dysfunction appears and leads to both neuropsychiatric and cardiometabolic diseases. It  is hope that by bringing the datasets together in these seemingly diverse disorders we can help develop a conceptual novel basis for future studies in the field.

 

So NGF can be both good and bad.  It looks like statins will stimulate bother NGF and BDNF. Older people and anyone with Retts Syndrome are likely to benefit from more NGF.  In autism it appears possible that there was too much NGF and BDNF at a very early age, with levels then changing.  High levels of NGF and BDNF look a bad idea.  A lot more research is needed to understand what determines  NGF and BDNF levels.  It appears that BDNF may stay high in autism, but NGF levels.
 

NGF therapy

You will naturally be wondering if you can order some NGF with your PayPal account, sadly not.

Rita probably made here NGF eye drops in her kitchen.

An Italian firm called Dompé has recently succeeded in developing a process for the industrial production of recombinant human NGF (rhNGF) at its biotech plant in Italy, and they are in the process of getting NGF eye drops approved as a drug for the treatment of disorders of both the anterior and posterior segments of the eye, including dry eye and glaucoma.

We all know that Rita had entirely different reasons to use her NGF eye drops.

I do like it when scientists/doctors very occasionally doing interesting things like self-experimentation; it shows they have ultimate faith in their own ideas.  I also like it when they use novel methods to deliver the drug into the body.  Eye drops and nasal sprays mean no loss via gut and no issue with passing through into the blood supply and are much more favorable than injections.  It also seems, from both Rita, the Nobel Laureate and Jay Goldstein, the Fibromyalgia doctor, that mixing up your nasal spray or eye drops is simple, effective and cheap.

Back again to Rita - Countering the pro-inflammatory actions of NGF

Mast cells

First Professor Rita Levi-Montalcini discovered that Mast cells synthesize, store, and release nerve growth factor and then her group discovered in 1993 that Palmitoylethanolamide (PEA) acts as a natural modulator of hyperactive mast cells, counteracting the pro-inflammatory actions of NGF.
 

Mast cells synthesize, store,and release nerve growth factor 

Professor Rita Levi-Montalcini on Nerve Growth Factor, Mast Cellsand Palmitoylethanolamide, an Endogenous Anti-Inflammatory and Analgesic Compound

Professor Levi-Montalcini’s focus was on NGF, and already as early as 1977 she pointed out that NGF was an irritative compound inducing mast cell degranulation . The relation between mast cell and NGF, also related to their interactive function in diseases, were topics Rita Levi-Montalcini worked on for many years

“...Unregulated mast-cell activation constitutes a considerable risk to the health of the organism, and it is not unreasonable to expect that nature should have devised a means for the host to defend itself against such damage. It has recently been proposed that saturated N-acyl-ethanolamides like palmitoylethanolamide, which accumulate in tissues following injury and which down modulate mast-cell activation in vitro, exert a local, autacoid, and anti-injury function via mast cells. Palmitoylethanolamide is orally active in reducing tissue inflammation and mast cell degranulation in vivo, in decreasing hyperalgesia that accompanies peripheral nerve compression, and in limiting the neurological deficits of experimental allergic encephalomyelitis. Moreover, palmitoylethanolamide appears to project against excitotoxic neuronal death in vitro and to be produced by cultured CNS neurons upon excitatory amino acid receptor activation. The mechanism of this action of N-acylethanolamides has been termed autacoid local injury antagonism (ALIA).”

 

Based on her work in the 90s PEA is now available as a nutraceutical for indications related to chronic pain and chronic inflammation. PEA has been explored in a variety of indications such as sciatic pain, diabetic pain, neuropathic pain, pain due to arthritis and pain in multiple sclerosis in the period 1992-2010 and around 20 clinical trials have documented its safety and efficacy in these chronic pain states. In the period 1970-1980 its safety and efficacy was already documented in a series of double blind clinical trials in flu and respiratory infections. PEA is therefore most probably the best-documented nutraceutical around, with pharmacological profile described in more than 350 scientific papers 

“...palmitoylethanolamide may behave as local autacoids capable of negatively modulating mast cell activation (ALIA mechanism). In keeping with this hypothesis, palmitoylethanolamide reduces mast cell activation associated with inflammatory processes. With these considerations in mind, the described pharmacological effects of palmitoylethanolamide could be mediated by interactions with CB2 receptors on mast cells.”

 

Professor Levi-Montalcini’s focus was on NGF, and already as early as 1977 she pointed out that NGF was an irritative compound inducing mast cell degranulation. The relation between mast cell and NGF, also related to their interactive function in diseases, were topics Rita Levi-Montalcini worked on for many years

“...Unregulated mast-cell activation constitutes a considerable risk to the health of the organism, and it is not unreasonable to expect that nature should have devised a means for the host to defend itself against such damage. It has recently been proposed that saturated N-acyl-ethanolamides like palmitoylethanolamide, which accumulate in tissues following injury and which down modulate mast-cell activation in vitro, exert a local, autacoid, and anti-injury function via mast cells. Palmitoylethanolamide is orally active in reducing tissue inflammation and mast cell degranulation in vivo, in decreasing hyperalgesia that accompanies peripheral nerve compression, and in limiting the neurological deficits of experimental allergic encephalomyelitis. Moreover, palmitoylethanolamide appears to project against excitotoxic neuronal death in vitro and to be produced by cultured CNS neurons upon excitatory amino acid receptor activation. The mechanism of this action of N-acylethanolamides has been termed autacoid local injury antagonism (ALIA).”

 "Prof. Rita Levi-Montalcini is widely known for her work on NGF. Much less is known about two other formidable chapters she added to neurobiology: the central role of the mast cell in much pathology, and the modulating role of the endogenous lipid PEA via the mast cell. Based on her work in the 90s PEA is now available as a nutraceutical for indications related to chronic pain and chronic inflammation. PEA has been explored in a variety of indications such as sciatic pain, diabetic pain, neuropathic pain, pain due to arthritis and pain in multiple sclerosis in the period 1992-2010 and around 20 clinical trials have documented its safety and efficacy in these chronic pain states. In the period 1970-1980 its safety and efficacy was already documented in a series of double blind clinical trials in flu and respiratory infections. PEA is therefore most probably the best-documented nutraceutical around, with pharmacological profile described in more than 350 scientific papers"

 

Reducing Amyloid-Related Brain Damage

In an earlier posts we looked at Amyloids in the brain in autism and Alzheimer’s.  There was a distinct difference in what was going on and definitely worse things were happening in Alzheimer’s, but things were far from normal in autism.

http://epiphanyasd.blogspot.com/2013/12/amyloids-app-adam17-and-autism.html

Several papers have demonstrated that an imbalance of the endocannabinoid system (ECS) and alterations in the levels of PEA occur in acute and chronic inflammation. For instance during β-amyloid-induced neuroinflammation the deregulation of cannabinoid receptors and its endogenous ligands accompanies the development and progression of disease.

Palmitoylethanolamide Protects Against the Amyloid-β25-35-Induced Learning and MemoryImpairment in Mice, an Experimental Model of Alzheimer Disease

The study strongly suggests that people with Alzheimer’s would benefit from the neuroprotective effects.  PEA also reduced Amyloid-Induced Oxidative Stress.
 

PEA as an anti-epileptic

Anticonvulsant activity of N-palmitoylethanolamide, a putative endocannabinoid, in mice

Abstract

PURPOSE:

The purpose of this study was to evaluate in mice the anticonvulsant potential of N-palmitoylethanolamide, a putative endocannabinoid that accumulates in the body during inflammatory processes.

METHODS:

N-palmitoylethanolamide was injected intraperitoneally (i.p.) in mice and evaluated for anticonvulsant activity [in maximal electroshock seizure (MES) and chemical-induced convulsions] and for neurologic impairment (rotorod). It was compared with anandamide and with different palmitic acid analogues as well as with reference anticonvulsants (AEDs) injected under the same conditions.

RESULTS:

The MES test showed, after i.p. administration to mice, that N-palmitoy]ethanolamide had an median effective dose (ED50) value comparable to that of phenytoin (PHT; 8.9 and 9.2 mg/kg, respectively). In the subcutaneous pentylenetetrazol test and in the 3-mercaptropropionic acid test, it was effective only against tonic convulsions. N-palmitoylethanolamide was devoid of neurologic impairment < or = 250 mg/kg, yielding a high protective index.

CONCLUSIONS:

N-palmitoylethanolamide, an endogenous compound with anti-inflammatory and analgesic activities, is a potent AED in mice. Its precise mechanism of action remains to be elucidated.

 
 

Disease-Modifying Agent in Peripheral Neuropathy

We have found before that what is good for treating Peripheral Neuropathy, can also be useful in treating autism.  Anybody remember those posts on antioxidants?  The antioxidants helped reduce diabetic neuropathy and even reduced the amount of insulin people needed, which means something must have happened to improve pancreatic function.  Some people’s autism is apparently linked to pancreatic dysfunction, if you did not know.

Palmitoylethanolamide Is a Disease-Modifying Agent in Peripheral Neuropathy: Pain Relief and Neuroprotection Share a PPAR-Alpha-Mediated Mechanism Researchers discover a way to boost levels of palmitoylethanolamide

 
All in all  PEA has been shown to have anti-inflammatory, anti-nociceptive, neuroprotective, and anticonvulsant properties.  Where can I get some?

 

PEA (palmitoylethanolamide) levels in autism and ADHD

Very helpfully, some researchers in Japan have already done a study to measure the levels of PEA in autism and ADHD.

Decreased beta-phenylethylamine inurine of children with attention deficit hyperactivity disorder and autistic disorder

Beta-phenylethylamine (PEA), a biogenic trace amine, acts as a neuromodulator in the nigrostriatal dopaminergic pathway and stimulates the release of dopamine. To clarify the mechanism of neurochemical metabolism in attention deficit hyperactivity disorder (ADHD), we measured the urine levels of PEA using gas chromatography-chemical ionization-mass spectrometry. The urinary levels of 3-methoxy-4-hydroxyphenyl glycol (MHPG), homovanillic acid (HVA), and 5-hydroxy-indoleacetic acid (5-HIAA) were determined by high performance liquid chromatography. Urine samples were collected in a 24 hour period. Findings were compared with those obtained from controls (N = 15), children with ADHD (N = 15), and children with autistic disorder (AD) (N = 5). The mean urinary levels of MHPG, HVA, and 5-HIAA in the children with ADHD were not significantly different from those of the controls or those with AD, whereas PEA levels were significantly lower in children with ADHD (11.23 +/- 13.40 micrograms/g creatinine) compared with controls (56.01 +/- 52.18 micrograms/g creatinine). PEA and MHPG levels in children with AD (14.75 +/- 14.37 micrograms/g creatine, 1.10 +/- 0.61 micrograms/mg creatine, respectively) were significantly decreased compared to controls (MHPG, 2.2 +/- 0.9 micrograms/mg creatine). The decreased urine PEA in children with ADHD and AD may suggest a common underlying pathophysiology. The decreased urine MHPG in children with AD might indicate the existence of an alteration in central and peripheral noradrenergic function.

This is pretty much as expected and of course does prompt the question of how to raise PEA levels, if PEA is such a handy and helpful molecule.

Boosting the level of PEA

Some of the literature suggests that oral administration of PEA will be rather ineffective, since not much will reach the brain.  On the other hand there are plenty of studies showing PEA is more effective than conventional pain killers, so it must be reaching the brain.

Research indicates that PEA is deactivated by a special protein (N-acylethanolamine-hydrolyzing acid amidase) and it is possible to block the action of this protein and hence raise the level of PEA.addition, they found that PEA - also present in foods like eggs and peanuts - is deactivated by a protein called N-acylethanolamine-hydrolyzing acid amidase, which is an enzyme that breaks down molecules controlling cell inflammation

In addition, they found that PEA - also present in foods like eggs and peanuts - is deactivated by a protein called N-acylethanolamine-hydrolyzing acid amidase, which is an enzyme that breaks down molecules controlling cell inflammation.

The full paper is here:-

Selective N-acylethanolamine-hydrolyzing acidamidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation

A cynic would point out that since PEA cannot be patented – it is naturally occurring substance – the pharmaceutical industry would prefer to find a patentable substance, to be the adopted therapy, rather than PEA itself.

In the meantime the logical way forward would be just to eat some.  Well, dark chocolate is rich in PEA, but you might have to eat quite a lot of it.  The alternative is a pill.  There is quite a choice:-

http://palmitoylethanolamide4pain.com/about-2/

If you want to buy in bulk you get a discount:-

http://www.rs4supplements.com/en/home

 

Brain-Derived Neurotrophic Factor  (BDNF)

Unusually high levels of the signaling peptide BDNF, or brain-derived neurotropic factor, have been detected in blood samples from children with autism

During brain development, BDNF regulates the birth and differentiation of brain cells, or neurons. Some of BDNF’s target cells, such as cortical interneurons, which transmit information between different layers of the brain cortex, have been implicated in autism. BDNF is also a regulator of brain growth, and children with the disorder tend to have abnormally large brains during early development. What’s more, MeCP2, a gene in which mutations are known to cause the autism-related Rett syndrome, directly regulates the expression of BDNF.

If high BDNF levels do prove to be a cause of the disorder, drugs that block its production or signaling might be an effective treatment for autism.

Misregulation of BDNF in autism spectrum disorders

Is autism caused by early hyperactivity of brain-derived neurotrophic factor?

BDNF is down regulated by stress and up regulated by learning, antidepressants, histone deacetylase inhibitors, physical activity, and dietary calorie restriction

 

Altered Cytokine and BDNF Levelsin Autism Spectrum Disorder

 

Neurotrophin-3

Although the vast majority of neurons in the brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells; a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis.

NT-3 is unique in the number of neurons it can potentially stimulate, given its ability to activate two of the receptor tyrosine kinase neurotrophin receptors (TrkC and TrkB - see below).

 

Increase in cerebellar neurotrophin-3 and oxidative stress markers in autism.

Autism is a neurodevelopmental disorder characterized by social and language deficits, ritualistic-repetitive behaviors and disturbance in motor functions. Data of imaging, head circumference studies, and Purkinje cell analysis suggest impaired brain growth and development. Both genetic predisposition and environmental triggers have been implicated in the etiology of autism, but the underlying cause remains unknown. Recently, we have reported an increase in 3-nitrotyrosine (3-NT), a marker of oxidative stress damage to proteins in autistic cerebella. In the present study, we further explored oxidative damage in the autistic cerebellum by measuring 8-hydroxydeoxyguanosine (8-OH-dG), a marker of DNA modification, in a subset of cases analyzed for 3-NT. We also explored the hypothesis that oxidative damage in autism is associated with altered expression of brain neurotrophins critical for normal brain growth and differentiation. The content of 8-OH-dG in cerebellar DNA isolated by the proteinase K method was measured using an enzyme-linked immunosorbent assay (ELISA); neurotrophin-3 (NT-3) levels in cerebellar homogenates were measured using NT-3 ELISA. Cerebellar 8-OH-dG showed trend towards higher levels with the increase of 63.4% observed in autism. Analysis of cerebellar NT-3 showed a significant (p = 0.034) increase (40.3%) in autism. Furthermore, there was a significant positive correlation between cerebellar NT-3 and 3-NT (r = 0.83; p = 0.0408). These data provide the first quantitative measure of brain NT-3 and show its increase in the autistic brain. Altered levels of brain NT-3 are likely to contribute to autistic pathology not only by affecting brain axonal targeting and synapse formation but also by further exacerbating oxidative stress and possibly contributing to Purkinje cell abnormalities.

 

Neurotrophin-4

Neurotrophin-4 (NT-4), also known as neurotrophin-5 (NT-5), is a protein that in humans is encoded by the NTF4 gene.

It seems that NT-4 levels are elevated in cases of mental retardation and not in cases of autism. 

 Serum neurotrophin concentrations in autism and mental retardation: a pilot study.

Abstract

To evaluate the availability of the serum neurotrophins for the diagnosis of the patients with neurodevelopmental disorder, we measured the serum concentration of brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) in the patients diagnosed with autism (n=18) and mental retardation (n=20), or healthy controls (n=16), using enzyme-linked immunosorbent assay. There tended to be a higher concentration of serum BDNF found in the autistic group (P<0.05 by analysis of variance (ANOVA)) and the mental retardation group (P<0.001 by ANOVA) compared to the control group. Serum NT-4 concentration tended to be increased in the mental retardation group (P<0.05 by ANOVA). We conclude that measuring the serum concentration of two neurotrophins, BDNF and NT-4, might be helpful to diagnose or classify disorders such as autism or mental retardation.

 

 

Conclusion (finally)

After all that information there are some useful conclusions. Slightly raising GH by stimulating the body to produce more, looks much smarter than GH therapy, unless it is absolutely necessary.  The extra GH in most cases should stimulate more IGF-1, but not necessarily where it is needed.  IGF-1 therapy itself looks interesting but currently involves needles.  An oral IGF-1 related analogue has Orphan Drug status in the US and Europe and that may prove very useful, when it becomes available.

If Rett’s Syndrome is the concern, it looks like NGF really is needed ASAP. Rita Levi-Montalcini found a way to treat herself with NGF more than 30 years ago.

As a treatment for cognitive decline, NGF looks very interesting.  I wonder what the effect would be on apparent Mental Retardation, if given young enough.  Perhaps NGF should be measured in cases of suspected MR?

PEA looks very interesting for those who believe Theoharides’ Autism as an Allergy of the Brain hypothesis.  It also looks interesting as a safe pain reducing therapy to test in fibromyalgia and mastocytosis.  PEA also has anti-epileptic properties and in this blog we have seen a great deal can be learnt from thinking about the comorbidities of autism.  PEA might well eventually find a place in my “Autism Toolkit”, if it stabilizes mast cells.  It is quite strange that nobody has investigated the benefit of PEA in a controlled trial on kids with ASD, there are several possible mechanisms whereby it could be helpful.  PEA does not need a doctor’s prescription.

It looks like high NT-3 levels are a result of autism and ongoing oxidative stress in the brain; another reason to treat oxidative stress.

It appears likely that autism is accompanied by an excess of Brain-Derived Neurotropic Factor and if ongoing research proves this, then therapies that block its production or signaling might be an effective treatment for autism.