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.
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:-
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.
We have
noted in earlier posts that autism is a dynamic encephalopathyand 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 calledTNF-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.
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.
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 ofexcitatory and inhibitory circuits. Thus, increased IL-6 expression may
be partially responsible for the pathogenesis of autism.
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.
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 antibodiesagainst 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 alphalevels
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.
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:-
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.
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.
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
·GlutathioneGSH(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.
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.
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.
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.
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 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.