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Showing posts with label TBI. Show all posts
Showing posts with label TBI. Show all posts

Saturday 28 June 2014

Traumatic Brain Injury and Autism, linked again, but not in a good way


It came as no surprise to me that many people involved in high profile mass shootings suffer from mild autism (Asperger’s).  What did surprise me was that so many people with TBI (Traumatic Brain Injury) also commit such crimes.  Indeed in a recent study (see later) of 239 killers, 28% appear to have autism and 21% suffered from TBI.

Indeed the name used by the Austrian, Hans Asperger, in 1943 for his newly identified condition was “Autistic Psychopathy”, it was only many decades later when his work was discovered for the English-speaking world by Lorna Wing in 1981, that the condition became known as Asperger’s.  Wing did not like the term “Autistic Psychopathy” that Asperger had chosen, because she thought it would apply sociopathic (violent) behaviour to the lay public.

Wing recently passed away and the New York Times wrote a nice article about her.



Her paper, that first established Asperger’s syndrome, is here:-



Since this paper was published only in 1981, it is hardly surprising that so few older adults have been diagnosed with Asperger’s.  Indeed it was a full ten years later, in 1991, that an authoritative English translation of Asperger's work was made by Uta Frith; before that Asperger’s Syndrome (AS) remained virtually unknown.

As we have noted before, Psychiatrists and Psychologists like to take their time; no Space Race or Manhattan Project in their little world.  Still, half a century is pretty slow.

People suggesting an autism “epidemic” might take note that only 25 years ago, absolutely nobody bothered to diagnose mild cases of autism, they did not even have a word for it.  Those of you still wondering why your doctor still knows so little about autism, might also take note.

Now I understand why there were no Aspies in my school, when I was a child.  They had not been invented.  I had assumed that Asperger’s syndrome was of the same era as the man himself, but Hans Asperger died in 1980.

I had no idea it took Psychiatrists, Psychologists, and yes, Doctors, half a century to absorb, accept, and begin to act on a new idea;  all because Asperger spoke/wrote in that “extremely rare” German language.  Incidentally, 50 million Americans claim German ancestry, not to mention that the British royal family is actually German; the House of Windsor is really the House of Saxe-Coburg-Gotha, before some image building took place in 1917 during WW1.

So don’t raise your expectations of these people too high, for the next half century.  Hopefully they have figured out Google Translate.

Here is the Pediatrician, Professor Hans Asperger at work in Austria; nice drawing on the black board:-




  





  

Asperger’s (Autistic  Psychopathy) and  TBI among Mass Murderers

In the recent study of 239 mass murderers almost 50% had either ASD or head injury /TBI, the other half suffered from “psychological stresses”.












At least the author has clearly read about Hans Asperger, he suggests a new diagnosis, Criminal Autistic Psychopathy, as a subcategory of Asperger's syndrome.

I will not dwell on the murder angle, other than to say that perhaps if people with Asperger’s were actively included at school, they would ultimately lead happier and more successful lives.  The percentage that currently go on to have very violent thoughts, might not then do so, and the tiny percentage of those might not act on those very thoughts.

I should point out that I do not find it odd at all that the boy with Asperger’s in my elder son’s class keeps telling him “I will kill you and your parents”, to which Ted, now 14,  says “but I won’t let you” and the response is “but I will wait until you are not there”.  I am not seriously worried that he will do this, but if I was his parent, I would be very concerned that he says/thinks such things.

Fortunately there are no serial killers with Classic Autism, so no need to lock up Ted’s brother.


ASD, TBI & PTSD

We have come across TBI several times in this blog, and I note that many people coming to this blog are TBI sufferers.

Both ASD and TBI are associated various degrees of mood disorder.  These feelings are driven by neurological changes that are usually ignored, or treated rather crudely with drugs that rarely seem to work entirely as intended. 

I think the world of autism could learn much from the mood disorders that follow TBI.

Epilepsy occurs very frequently in both ASD and TBI.

The third condition that we might usefully consider is Post Traumatic Stress Disorder (PTSD).  This condition is also associated with severely affected mood.  Army veterans returning from recent conflicts can be greatly affected by PTSD.  We came across the military type of PTSD in the post about the hormone TRH.  One of the many roles of TRH in the body seems to be linked to mood, and very specifically suicide.  The US military is funding development of a TRH nasal spray to reduce the incidence of suicide.  They cannot give antidepressants, like Prozac, because a well-known side effect is suicidal thought.  TRH is included in my autism PolyPill.

People with Asperger’s do have an elevated risk of suicide, another reason to sniff some TRH, perhaps?


The Link between ASD, TBI and PTSD

The above conditions are very different, but they share some similar symptoms relating to mood disorders.  By understanding the neurological underpinnings of the mood disorder in one condition, we might well learn something useful for the others.

The research into TBI seems to focus on better surviving the first few hours.  We saw in earlier posts that by giving intravenously either statins, or the female hormone progesterone, in the Emergency Room, there was a marked increase in survivability.  Progesterone and statins are both highly neuroprotective.

When Michael Schumacher had his TBI in a recent skiing accident, I was saying to myself “give him progesterone”, I very much doubt the French neurologists did.  They probably do not read American/English research.

In the case of autism, very recent research has shown an excess of male hormones in the amniotic fluid of mothers who give birth to a baby that will later be diagnosed with autism.  We also have seen how some people with mild autism treat themselves with progesterone to feel better.

Many years ago pregnant women were often prescribed progesterone and/or estrogen, now it seems to be limited to some women undergoing infertility treatment.  Perhaps giving progesterone might reduce the incidence of autism?

Statins are a known treatment for cytokine storms and are included in my autism PolyPill.

Once back home, people recovering from TBI and PTSD do seem to face similar treatment to adults with autism; they get ignored.

Due to all the recent conflicts in Iraq and Afghanistan, we do hear quite frequently about the consequences of untreated PTSD.  There are also very many cases of TBI, resulting from motor vehicle accidents (cars, bikes, quad bikes etc), sports accidents (skiing) and shootings (particularly in the US).  It seems that in many cases there can outwardly be a physical recovery, but personality has altered.  As we have seen in this blog, all the various hormones and neurotransmitters are interrelated and so any neurological damage will have multiple knock-on effects.  This will consequently transform, for better or worse, someone’s personality.  I used to know a person once, who was about to marry for the third time.  The second wife had been hit by a bus while crossing the street, and I remember how odd it sounded what he said next, “when she got better, she was a different person and I had to divorce her”.  The change in personality makes perfect sense, we are all the result of the particular homeostasis our brains settled at.  So some people are gregarious, others are loners, and a very small number become psychopaths.

If we more fully understood how the brain works, most types of mood disorder would likely be treatable.  Since people with TBI and mild autism are now easily identifiable, there is yet another reason to accelerate this research.  A frequent justification for the low expenditure on autism research is that “you don’t die from autism”.  Well, the above research shows that plenty of people do die from autism, just not the ones you expected.

Just to give the full picture, sadly people with severer types of autism have substantially elevated risk of mortality in their early years, due to seizures, drowning and other accidents.  There is research showing this, but it also shows up any time you see cause of death on the samples from brain tissue banks, used in autism studies.  This is why it is very important to teach people with severer autism to be confident swimmers, however hard it might seem.






Wednesday 12 March 2014

Single Dose of IL-6 Antibodies or TNF-ᾳ Inhibitor as Potential Disease-Changing Autism Therapies


 
We have noted in earlier posts that autism is a dynamic encephalopathy and this may help explain why a therapy that works in a child aged 10, may be of little help to another child aged 3.  Not only are there many sub-types of autism, but each sub-type is evolving, as the child matures.

None of the autism drug therapies I have implemented have permanent disease changing effects, they all seem to work, but the effect is lost once you stop taking them.  Today’s post is about drugs that you take just once.  For a parent trying to find a drug that works in the sub-type affecting their child, this has a big advantage.  No need to keep trying for months to see if the drug has any effect.
Perhaps the most important time to intervene with drug therapy is as soon as possible after the diagnosis; but with what?
In an earlier post on trying to get a non-verbal child to talk, I suggested the use of corticosteroids to arrest on-going neuroinflammation.  Drugs like prednisone are potent, but they these have nasty side-effects if used long term. In that post, Dr Michael Chez, an eminent neurologist from Sacramento, was upbeat on their potential as immunomodulators.  We will refer back to him in this post as well.
In this post I will give more background about the role of a cytokine called Interleukin 6, or just IL-6, in autism.  You will see how science can both create a mouse with autism using IL-6 and reverse it again using IL-6 antibodies.
We will also look at another cytokine called   TNF-ᾳ and see how a single dose of a TNF-ᾳ inhibitor can improve chronic neurological dysfunction following a stroke, TBI and indeed autism.  It is effective even a decade after the original traumatic event.
Both the IL-6 and TNF-ᾳ drugs are developed for arthritis and these drugs cost tens of thousands of dollars a year, but in the case of neurological conditions they may have a disease-changing effect when used just once. Remarkably, both drugs are already approved for long term use in very young children with Juvenile Idiopathic Arthritis.


Why am I interested in Cytokine inhibition?
My very first attempt to reduce neuroinflammation in Monty, aged 10 with ASD, was a very surprising, but resounding success.  That followed my research into cytokine storms and statins.  I know it works, because when I stop the statin, the very same behavioural improvement is lost in a day or so.
Are there randomized trials of atorvastatin in autism? Sadly, not; but it is a safe intervention that works in my mouse model.
Are there further potential benefits from such therapy? Quite possibly, but higher doses of statins have side effects.
We saw in recent posts that PEA, quercetin and luteolin also inhibit pro-inflammatory cytokines.  Is there a potential disease-changing therapy?  We will only find one, if we look.


The Cytokine IL-6 and Autism
Thanks to Dr Wei, we have some excellent research linking specifically the cytokine IL-6 to autism.  He suggests that elevated levels of IL-6 may cause much of the damage in autism and he went as far as to prove it in a mouse model.

A single injection of IL-6 into a pregnant mouse, produced a mouse pup with social deficits.  When the mother received a dose of IL-6 antibodies the resulting mouse pup has normal behaviour.  Humans are not mice, but we do already know from Ashwood and others that people with ASD have elevated levels of IL-6 and in particular those people with regressive autism.  
Abstract
Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction, deficits in verbal and non-verbal communication, and repetitive behavior and restricted interests. Emerging evidence suggests that aberrant neuroimmune responses may contribute to phenotypic deficits and could be appropriate targets for pharmacologic intervention. Interleukin (IL)-6, one of the most important neuroimmune factors, has been shown to be involved in physiological brain development and in several neurological disorders. For instance, findings from postmortem and animal studies suggest that brain IL-6 is an important mediator of autism-like behaviors. In this review, a possible pathological mechanism behind autism is proposed, which suggests that IL-6 elevation in the brain, caused by the activated glia and/or maternal immune activation, could be an important inflammatory cytokine response involved in the mediation of autism-like behaviors through impairments of neuroanatomical structures and neuronal plasticity. Further studies to investigate whether IL-6 could be used for therapeutic interventions in autism would be of great significance


Abstract
 
Background: Although the cellular mechanisms responsible for the pathogenesis of autism are not understood, a growing number of studies have suggested that localized inflammation of the central nervous system (CNS) may contribute to the development of autism. Recent evidence shows that IL-6 has a crucial role in the development and plasticity of CNS. 

Methods: Immunohistochemistry studies were employed to detect the IL-6 expression in the cerebellum of study subjects. In vitro adenoviral gene delivery approach was used to over-express IL-6 in cultured cerebellar granule cells. Cell adhesion and migration assays, DiI labeling, TO-PRO-3 staining and immunofluorescence were used to examine cell adhesion and migration, dendritic spine morphology, cell apoptosis and synaptic protein expression respectively.

Results: In this study, we found that IL-6 was significantly increased in the cerebellum of autistic subjects. We investigated how IL-6 affects neural cell development and function by transfecting cultured mouse cerebellar granule cells with an IL-6 viral expression vector. We demonstrated that IL-6 over-expression in granule cells caused impairments in granule cell adhesion and migration but had little effect on the formation of dendritic spines or granule cell apoptosis. However, IL-6 over-expression stimulated the formation of granule cell excitatory synapses, without affecting inhibitory synapses.


Conclusions: Our results provide further evidence that aberrant IL-6 may be associated with autism. In addition, our results suggest that the elevated IL-6 in the autistic brain could alter neural cell adhesion, migration and also cause an imbalance of  excitatory and inhibitory circuits. Thus, increased IL-6 expression may be partially responsible for the pathogenesis of autism.  

Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors.
Abstract
Abnormal immune responses have been reported to be associated with autism. A number of studies showed that cytokines were increased in the blood, brain, and cerebrospinal fluid of autistic subjects. Elevated IL-6 in autistic brain has been a consistent finding. However, the mechanisms by which IL-6 may be involved in the pathogenesis of autism are not well understood. Here we show that mice with elevated IL-6 in the brain display many autistic features, including impaired cognitive abilities, deficits in learning, abnormal anxiety traits and habituations, as well as decreased social interactions. IL-6 elevation caused alterations in excitatory and inhibitory synaptic formations and disrupted the balance of excitatory/inhibitory synaptic transmissions. IL-6 elevation also resulted in an abnormal change in the shape, length and distributing pattern of dendritic spines. These findings suggest that IL-6 elevation in the brain could mediate autistic-like behaviors, possibly through the imbalances of neural circuitry and impairments of synaptic plasticity. 

Abstract


Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism.

Effects of exogenous cytokines

Our pilot studies indicated that maternal administration of IL-6, but not IL-1α, tumor necrosis factor α (TNFα), or IFNγ, causes PPI deficits in the adult offspring. PPI is the inhibition of a startle response when the startling stimulus is immediately preceded by a smaller, nonstartling stimulus of the same modality and is a measure of sensory-motor gating, attention, and distractibility. PPI deficits are observed in several mental disorders, including schizophrenia and autism. Furthermore, PPI deficits in the offspring elicited by maternal influenza infection respond to antipsychotic and psychomimetic drugs, and the PPI deficit resulting from poly(I:C) MIA is present in adult but not juvenile rats, mimicking the adult onset of schizophrenia. The changes seen in this very relevant behavior prompted further study of the effects of maternal IL-6 administration

Thus, a single injection of IL-6 on E12.5 causes deficits in two relevant behaviors (LI and PPI) in the adult offspring.
Abnormal behavior in MIA offspring is prevented by maternal treatment with anti-IL-6 antibody
f, In the social interaction test, control mice show a strong preference for the social chamber [defined as (percentage of time in social chamber) – (percentage of time in opposite chamber)], whereas the offspring of poly(I:C)-treated mice show no such preference. Again, the deficit is corrected by maternal administration of IL-6 antibody

Tocilizumab / Actemra
Wei has made a pretty solid case that IL-6 is implicated in autism and that IL-6 inhibition could be a very interesting therapy.  While we have a range of interventions that can do just that, the ultimate therapy would be IL-6 antibodies.
This therapy does actually exist as a recent option in treating arthritis. Tocilizumab, brand name Actemra, is an immunosuppressive drug made of humanized monoclonal antibodies  against the interleukin-6 receptor (IL-6R)  In 2013 Actemra was approved by the FDA for children as young as 2 years old, as an ongoing treatment for arthritis.

This drug is frighteningly expensive and in arthritis you need to keep taking it regularly.
Now let us look at another related very expensive drug. Etanercept (trade name Enbrel).  Enbrel is another immunosuppressive drug for arthritis , but this time it is not inhibiting IL-6 but rather tumor necrosis factor (TNF).
This drug also treats a condition called psoriasis.  There is a case of a 53 year old Italian lady only partially verbal and by the sound of it, autistic, living with her mother.  She had her psoriasis treated with Enbrel and suddenly she became social and her speech improved.  Now an example of one is definitely interesting, but it does not prove anything.
But, remember Dr Chez from Sacramento?  Tucked away in his excellent paper of immunomodulation in autism.
 

"A single case of repetitive regression, with bouts of inflammatory colitis in an 8-year-old with regressive autism after age 3, has shown elevated serum TN alpha levels and rapid colitis, as well as behavioral and language improvements after injections of etanercept (unpublished data, personal communication Y. Davies and M. Chez 2008)."

At the time, I did not pay much attention since who can afford an ongoing therapy costing tens of thousands of dollars a year?
But, there is more.
In the US, a controversial doctor has been treating various chronic neurological dysfunctions with single dose etanercept.  He was criticized both for his marketing and the lack of published research to back up his claims.  To his credit, he is now publishing his work and has patented his therapy.

Here is a press article.

Here is an abstract of the study:-

Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept.

Abstract

BACKGROUND:


Brain injury from stroke and traumatic brain injury (TBI) may result in a persistent neuroinflammatory response in the injury penumbra. This response may include microglial activation and excess levels of tumour necrosis factor (TNF). Previous experimental data suggest that etanercept, a selective TNF inhibitor, has the ability to ameliorate microglial activation and modulate the adverse synaptic effects of excess TNF. Perispinal administration may enhance etanercept delivery across the blood-CSF barrier.

OBJECTIVE:


The objective of this study was to systematically examine the clinical response following perispinal administration of etanercept in a cohort of patients with chronic neurological dysfunction after stroke and TBI.

METHODS:


After approval by an independent external institutional review board (IRB), a chart review of all patients with chronic neurological dysfunction following stroke or TBI who were treated open-label with perispinal etanercept (PSE) from November 1, 2010 to July 14, 2012 at a group medical practice was performed.

RESULTS:


The treated cohort included 629 consecutive patients. Charts of 617 patients following stroke and 12 patients following TBI were reviewed. The mean age of the stroke patients was 65.8 years ± 13.15 (range 13-97). The mean interval between treatment with PSE and stroke was 42.0 ± 57.84 months (range 0.5-419); for TBI the mean interval was 115.2 ± 160.22 months (range 4-537). Statistically significant improvements in motor impairment, spasticity, sensory impairment, cognition, psychological/behavioural function, aphasia and pain were noted in the stroke group, with a wide variety of additional clinical improvements noted in individuals, such as reductions in pseudobulbar affect and urinary incontinence. Improvements in multiple domains were typical. Significant improvement was noted irrespective of the length of time before treatment was initiated; there was evidence of a strong treatment effect even in the subgroup of patients treated more than 10 years after stroke and TBI. In the TBI cohort, motor impairment and spasticity were statistically significantly reduced.

DISCUSSION:


Irrespective of the methodological limitations, the present results provide clinical evidence that stroke and TBI may lead to a persistent and ongoing neuroinflammatory response in the brain that is amenable to therapeutic intervention by selective inhibition of TNF, even years after the acute injury.

CONCLUSION:


Excess TNF contributes to chronic neurological, neuropsychiatric and clinical impairment after stroke and TBI. Perispinal administration of etanercept produces clinical improvement in patients with chronic neurological dysfunction following stroke and TBI. The therapeutic window extends beyond a decade after stroke and TBI. Randomized clinical trials will be necessary to further quantify and characterize the clinical response.

Now I am fully aware that author, Dr Tobinick,  has got into trouble with the Medical Board of California for his marketing approach.  Here is a link for those interested.  This does not mean his off-label use of etanercept is without merit.
Etanercept (trade name Enbrel) is a biopharmaceutical that treats autoimmune diseases by interfering with tumor necrosis factor (TNF; a soluble inflammatory cytokine) by acting as a TNF inhibitor. It has U.S. F.D.A. approval to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. TNF-alpha is the "master regulator" of the inflammatory (immune) response in many organ systems. Autoimmune diseases are caused by an overactive immune response. Etanercept has the potential to treat these diseases by inhibiting TNF-alpha.
 
Other comorbidities

You might view arthritis and psoriasis as as being related rather than being comorbid with autism.  Are there other comorbid conditions where anti-cytokine therapy is used?

One example is Irritable Bowel Disease (IBD), where several anti-TNF-alpha drugs have been shown to be effective and are widely prescribed.  IBD includes ulcerative colitis (UC) and the more severe Crohn’s disease.  UC does appear to be comorbid with autism and indeed UC itself does seem to be associated with mild autistic behaviours.  You will find adults with UC debating whether or not they have Asperger’s.

Here is a short video on anti-TNF therapy in IBD.

 
 
 
  
The complete set of video on IBD can be found here:-

For those scientists among you here is a full paper on this subject:- 
Pro-Inflammatory Cytokines in the Pathogenesis of IBD
 

Conclusion

I am surprised that nobody has sought to do even a very small trial of Etanercept/Enbrel or Tocilizumab/Actemra in autism. These potent immunomodulatory drugs can have side effects with long term use, but the case reports suggest that a single dose can be disease changing in neurological conditions, like autism.
In all likelihood only a single dose would be needed, so you really would not need the usual years of delay to complete a trial.  There is a lot of interest in GH and IGF-1 therapy in autism, which both require ongoing injections. To trial Etanercept and Tocilizumab would be so easy, in comparison.
Because the mechanism of action is fully understood, and IL-6 and TNF-ᾳ are easy to measure, it would later be possible to identify the people most likely to benefit from the cytokine lowering therapy.  Quite possibly it would be people with regressive autism who would benefit most, since they have the highest level of inflammatory markers, as highlighted by Ashwood.
If indeed the therapy worked, it is not going to be cheap; but at least it would be a one-off cost of $1,000 to $2,000, rather than a monthly cost as in severe arthritis.
I think our new friend Dr Wei would favour Tocilizumab/Actemra. If you live in California, Dr Tobinick would be the one to ask about Etanercept/Enbrel, but it won’t be cheap.

If medicine was a true science, we would have longitudinal autism studies that showed the level of inflammatory cytokines over time.  Then we would be able to say, for example, when regression occurs there is acute neuroinflammation with a spike in IL-6,TNF-ᾳ and other cytokines. 
Perhaps this inflammation does some long term damage that might be halted with immediate immunomodulatory therapy.  If the data did show this, we could look for correlations between later behavioral improvement and falling level in inflammatory cytokines. 
In children with regressive autism and who do not improve much, do the inflammatory cytokines stay at high levels?  Are the behavioral problems caused by the current level of inflammatory cytokines, or is the problem caused by the long term damage the cytokines already caused?  With data, all these questions could be answered.  Without data it is just conjecture.
All you need to do this research are regular blood samples.  The tests themselves are cheap.  Then you could compare cheap immunomodulatory therapy using steroids versus the expensive arthritis injections used one-off.

Monday 20 January 2014

How to avoid Autism (and also treat TBI)



It appears that in classic autism, most of the damage is done before birth, but a gradual second decline does often seem to occur between 24 and 54 months, even in a child who you would not think of as suffering from regressive autism.
When people think back about their child with regressive autism, they often recall examples of odd behaviours occurring long before the big regression occurred.

So my "extrapolation" from this, is that there are actually two waves of neurological damage in these two common types of autism. It is just that in one case there is a tidal wave before birth and a smaller change as a toddler.  In regressive autism, the first wave usually passes unnoticed, and the main, unmistakable damage occurs in the second wave.
Perhaps we can avoid this first wave of damage done before birth, in both classic early onset autism and regressive autism.
In an earlier post, I made my case for why girls do not get mild autism and why mothers, who are alpha-females, are more prone to have kids with ASD.
This was based on reading that the female hormone progesterone is extremely neuro-protective and that oxidative stress, now seen as a cause of autism, has many causes and is extremely damaging to the brain.  A good example of progesterone use, is its experimental use immediately after a traumatic brain injury.  All I did was extend this to autism.  Now it appears I am not the only one.

Here is a paper I spotted in a corner on Paul Whiteley’s ASD blog.

Abstract
Studies show increased autism risk among children born to mothers experiencing obstetrical complications. Although this is usually interpreted as suggesting that the obstetrical complications could be causing autism, it is possible that a single factor could be responsible for both complications and autism. We hypothesized that low levels of the hormone progesterone is responsible since it is supplied to the fetus maternally and does not only support pregnancy but also promotes brain development. Following a review of the literature, we report findings from a survey of mothers of autistic children (n=86) compared to mothers of typically-developing children (n=88) regarding obstetrical histories, including five obstetrical risk factors indicative of low progesterone Using this analysis, the ASD group had significantly more risk factors than controls (1.21 ± 0.09 vs. 0.76 ± 0.08, p< .0001), suggesting low progesterone. Thus, results suggest that low progesterone may be responsible for both obstetrical complications and brain changes associated with autism and that progesterone levels should be routinely monitored in at-risk pregnancies. Our hypothesis also suggests that ensuring adequate levels of progesterone may decrease the likelihood of autism.

The authors’ hypothesis suggests that ensuring adequate levels of progesterone may decrease the likelihood of autism.  Well, I for one, find this interesting.
In another earlier post, I referred to my advice to Ted, the nom de guerre of my very neuro-typical elder son, on how to avoid autism in the next generation.  I think I can now extend that advice further:-

People like Ted, with a close relative with ASD, could do some of the following:-

·        Find a partner who is calm beta-type female

·        Ensure she avoids emotional stress and shocks during pregnancy (particularly early on)

·       Take maternity leave straight after pregnancy is noticed, rather than mainly after birth; or, best of all, have the partner quit work as soon as pregnancy is noted

·        Ensure high levels of neuro-protective agents throughout pregnancy

·        Progesterone



·        Glutathione GSH (i.e. take NAC)

 
You might be expecting me to have statins on my list, since they are also very neuro-protective, but I do not;  even though:-


During pregnancy, statins are detrimental to human placental development.  So although people in high speed skiing accidents, who suffer traumatic brain injuries, would have a clear benefit, for a woman with a 10% chance of having a child with ASD, the risks would outweigh the possible benefit.  Most likely, the primary, cholesterol lowering effect of the statin, is doing the damage, since the baby’s brain does need cholesterol. 

Progesterone would also be a potential therapy for people with ASD.  It might though not be wise for boys around puberty.  There are reports of people with ADHD finding progesterone helpful.
 

Should I happen to have a TBI (traumatic brain injury), please put in my IV drip progesterone, atorvastatin/lovastatin and N-acetylcysteine.


P.S.  During pregnancy, ensuring the mother is not hypothyroid and does take folic acid will also shift the odds away from an outcome with ASD.
 
 


Wednesday 30 October 2013

It’s a Small World – IGF-1 and NNZ-2566 in Autism


You may or may not believe in fate, but some strange things have been happening related to Australia, growth hormones and TBI.

Last week I took Monty, aged 10 with ASD, to have his IGF-1 (insulin-like growth factor) measured.  At the time, this had nothing to do with autism, rather just what the Endocrinologist had requested.  Then I start doing my research on hormones and autism and found, surprisingly, there is an ongoing clinical trial in autism using IGF-1.  Then I start looking again at TBI (Traumatic Brain Injury), which I see as having much in common with ASD.  I looked for similarities in hormone disruptions found in TBI and ASD; I found there are many and they are mainly related to GH (growth hormone) and IGF-1.  The problem with IGF-1 therapy is that it is intravenous; I had told the Endocrinologist that I was not going to measure IGF-1, because I was not very keen on giving Monty intravenous drugs.  In the end, I did the test anyway and I am glad I did.
As I researched TBI, I saw a great deal of interest in using GH as a therapy and the US military is providing a great deal of funding to develop therapies.

Today the postman brings me my first post from Australia in several years.  It contains some children books for Monty (Thank you Lisa).
Now I come across NNZ-2566;  it is a synthetic analogue of a naturally occurring neurotropic peptide derived from IGF-1.   NNZ-2566 is being developed both in intravenous and oral formulations for a range of acute and chronic conditions including TBI, Fragile X and Retts syndrome.  NNZ-2566 exhibits a wide range of important effects including inhibiting neuroinflammation, normalizing the role of microglia and correcting deficits in synaptic function.  NNZ-2566 is being developed guess where? Australia, by Neuren Pharmaceuticals.

Just 10 days ago the company made the following announcement:-
Melbourne, Australia, 18 October 2013: Neuren Pharmaceuticals (ASX: NEU) announced today that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for Neuren’s programme to develop NNZ-2566 for Fragile X Syndrome. Fast Track designation is designed to expedite the development and review of important new medicines that are intended to treat serious diseases and meet unmet medical needs.
A different group of researchers are poised to begin clinical trials of IGF-1 in children with autism early next year. Because IGF-1 is already approved in the United States for use in children with short stature, the U.S. Food and Drug Administration is allowing the researchers to proceed directly to clinical trials for its use as an autism treatment.
What a lot of coincidences.
For those scientists among you, here are more details.

First of all it has been shown that in autism there are elevated levels of growth hormones.  Here is an American study.

 The Australians quote research from Finland that looks to me to contradict the above paper.  One difference is that the US researchers were testing blood and the Finns were testing spinal fluid.  What is clear is that in autism IGF-1 is not normal.

Abstract
Rett syndrome is characterized by disruption of a period of vigorous brain growth with synapse development. Neurotrophic factors are important regulators of neuronal growth, differentiation, and survival during early brain development. The aims of this study were to study the role of neurotrophic factors in Rett syndrome, specifically whether Rett syndrome has abnormal levels of specific neurotrophic factors in serum and cerebrospinal fluid and whether the changes differ from other neuropediatric patients, for example, those with infantile autism. Four neurotrophic factors were measured: nerve growth factor, brain-derived neurotrophic factor, glial cell line—derived neurotrophic factor, and insulin-like growth factor 1 from the frozen cerebrospinal fluid and from serum (except glial cell line—derived neurotrophic factor) by enzyme-linked immunosorbent assay and cerebrospinal fluid glutamate and aspartate by high-performance liquid chromatography (HPLC) method in patients with Rett syndrome. Insulin-like growth factor 1 was measured from the cerebrospinal fluid of patients with infantile autism. We found low concentrations of cerebrospinal fluid nerve growth factor in patients with Rett syndrome compared with control patients. The serum levels and other cerebrospinal fluid neurotrophic factor levels of the patients did not differ from the controls. Patients with Rett syndrome had high cerebrospinal fluid glutamate levels. Patients with infantile autism had low cerebrospinal fluid insulin-like growth factor 1 levels. Nerve growth factor acts especially on cholinergic neurons of the basal forebrain, whereas insulin-like growth factor 1 acts on cerebellar neurons. In Rett syndrome, the forebrain is more severely affected than the other cortical areas. In autism, many studies show hippocampal or cerebellar pathology. Our findings are in agreement with the different morphologic and neurochemical findings (brain growth, affected brain areas, neurotransmitter metabolism) in the two syndromes. Impairment in dendritic development in Rett syndrome could be the consequence of cholinergic deficiency and of neurotrophic factor/glutamate imbalance. Cholinergic gene expression might be influenced by the Rett syndrome gene directly or via the neurotrophic factor system.
 Then we have research showing GH/IGF-1 has secondary functions beyond those in the text books.  Lots of nice words like neuroprotective, regenerative etc.

Abstract

The growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is not only involved in brain growth, development and myelination, but also in brain plasticity as indexed by neurogenesis. This may have links to various cognitive effects of GH and IGF-1. GH and IGF-1 affect the genesis of neurons, astrocytes, endothelial cells and oligodendrocytes. Specifically, IGF-1 increases progenitor cell proliferation and numbers of new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. In the adult cerebral cortex IGF-1 only affects oligodendrogenesis. Recently, GH therapy has also been shown to induce cell genesis in the adult brain. The profile of effects by GH therapy may be somewhat different than that of IGF-1. In addition, GH secretagogues (GHS) also have neuroprotective and cell regenerative effects per se in the brain. Finally, transgenic disruptions in GH signaling pathways affect neuron and astrocyte cell numbers during development and during adulthood. Altogether, data suggest that both exogenous and endogenous GH and/or IGF-1 may be used as agents to enhance cell genesis and neurogenesis in the adult brain. Theoretically these substances could be used to enhance recovery after brain injuries. However, further experiments with specific animal models for brain injuries are needed before clinical trials can be started. 
For those of you that like mice studies:
Now back down under to let the Aussies make their case:

The Case for IGF-1 and IGF-1 (1-3) Glypromate in Autism
Courtesy of our friends “down under” you can read a presentation explaining the likely merits of both IGF-1 and its “terminal tripeptide” IGF-1 (1-3) as therapeutic agents in autism.  The clever Aussies have gone one better and produced NNZ-2566.  It is an analog of and IGF-1 (1-3).  This means it has that the molecule has been very slightly modified.  In this case this has been done to allow it to be orally available (i.e. not by injection) and to better cross the blood brain barrier (BBB). 

Mount Sinai Hospital Clinical trial of IGF-1
Mount Sinai Hospital is a leading US teaching hospital in New York; they are carrying out a trial of IGF-1 in autism.  They are starting with a sub type with a genetic deficiency called SHANK3, but they will then look at the benefit in other types of ASD. 

"In an important test of one of the first drugs to target core symptoms of autism, researchers at Mount Sinai School of Medicine are undertaking a pilot clinical trial to evaluate insulin-like growth factor (IGF-1) in children who have SHANK3 deficiency (also known as 22q13 Deletion Syndrome or Phelan-McDermid Syndrome), a known cause of autism spectrum disorder (ASD).
The seven-month study, which begins this month, will be conducted under the leadership of the Seaver Autism Center Clinical Director Alex Kolevzon, MD, and will utilize a double-blind, placebo-controlled crossover design in children ages 5 to 17 years old with SHANK3 deletions or mutations. Patients will receive three months of treatment with active medication or placebo, separated by a four-week washout period. Future trials are planned to explore the utility of IGF-1 in ASD without SHANK3 deficiency."

 
Conclusion

For a change, my conclusion is that further study is needed (by me).  Probably all the hormonal disruptions in autism need to be looked at together (serotonin, T3 etc) before any wild conclusions are drawn.