Thursday, 19 October 2017

Unstable Blood Flow in Autistic Brains?

Today’s post is complicated, but may be of interest to those people interested in Nitric Oxide therapies (Agmatine, Cocoa Flavanols, Beetroot, Taurine, Citrulline etc) and those who think they are treating earlier hypoxia/ischemia.
As usual, I am making simplifications, but the science behind the general ideas already exists. When it comes to the details regarding VEGF and autism, there are big gaps in the science. 
We have already seen that something as simple as improving blood flow appears to be therapeutic in some people with autism. Perhaps there should even be a post called “cold feet and autism”. 
One reader of this blog, Seth, has commented before that he sees autism as essentially vascular in nature.  Today’s research suggests it does indeed include microvascular abnormalities.
Rather than simply reduced blood flow, the problem, in at least some autism, appears to be unstable blood flow, which is much more complex.
I do take a leap in logic to suggest that this is likely linked to the known abnormalities in Vascular Endothelial Growth Factor (VEGF) and in VEGF receptor 1 (VEGFR-1).  It also appears that the VEGF anomalies that lead to angiogenesis may be part of the reason for the increased prevalence of chronic inflammatory diseases including asthma, atopic dermatitis, psoriasis, and rheumatoid arthritis.
Ideally you might want to normalize VEGF, even later in life. The use of anti-angiogenic drugs has been suggested.  Angiogenesis inhibitors were once seen as potential wonder drugs to treat cancer.
It does seem that just simply targeting vascular resistance is helpful for some people with autism.   
VEGF is regulated by many things, some are highly complex and are usually studied with regard to cancer, like Wnt signaling and Ras. Recall that both Wnt and Ras are relevant to autism. One simple thing that influences VEGF is nitric oxide (NO), but it is not a simple relationship. As highlighted by our reader Tyler, intermittent fasting (IF) can also be used to increase VEGF. Research suggests that intermittent fasting (IF) is actually a simple but potent tool to both prevent and treat metabolic disorders, including but not limited to type 2 diabetes.

In the case of autism, where both VEGF and NO are likely to be low, it does seem quite likely that by increasing the production of NO you will increase the expression of VEGF. So the amino acid L-citrulline is likely to increase VEGF.
In the rat study below, L-citrulline increased eNOS and VEGF; we presume NO also increased. 

Blood Flow in Autistic Brains
Now we get to the autism-specific research.

A team of scientists has found evidence that people with autism have unstable vessels in the brain which prevents the proper delivery of blood flow, according to research published in the Journal of Autism and Developmental Disorders
“In a typical brain, blood vessels are stable, thereby ensuring a stable distribution of blood,” said Patricia Whitaker-Azmitia, PhD, professor in the Department of Psychology and director of the Graduate Program in Integrative Neurosciences at Stony Brook University, N.Y.,  in a statement. “Whereas in the autism brain, the cellular structure of blood vessels continually fluctuates, which results in circulation that is fluctuating and, ultimately, neurologically limiting.”

Sustained angiogenesis may contribute to prolonged neuroplasticity in the ASD brain. We propose the sustained splitting angiogenesis is a necessary component to maintain the heightened neuronal activity reported in ASD patients. Many biological and functional indicators are increased in ASD including cerebral metabolic rate, regional synchronous electrical activity sensitivity to sound; cortical activity in deactivation centers at rest, low-level visuospatial processing, visual-tactile interactions; attention to low-level perceptual information and over-connected, redundant cortical networks. It can be suggested that sustained rearrangement of microvasculature permits excessive shorter and local connections to be maintained and prevents the growth of longer and more complex brain connections required for language and social interactions. Use of anti-angiogenic drugs may provide a novel treatment strategy for reducing neuronal activity in ASD patients by inhibiting vascular plasticity.

Brain tissue from children (left) and adults (right) with autism (top) but not controls (bottom) shows dividing cells lining blood vessels.

Angiogenesis and Lymphangiogenesis
It looks like, at least in today’s subgroup of autism, we want less angiogenesis but more lymphangiogenesis.  The ideal way to do this is via VEGF/VEGFRs.
Here it may be helpful to explain the meaning of some new terminology.

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels
Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, it is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer.”
Lymphangiogenesis is the formation of lymphatic vessels from pre-existing lymphatic vessels in a method believed to be similar to angiogenesis (blood vessel development).

Lymphangiogenesis plays an important physiological role in homeostasis, metabolism and immunity. Impaired or excessive lymphatic vessel formation has been implicated in a number of pathological conditions including neoplasm metastasis, oedema, rheumatoid arthritis, psoriasis, lymphangiomatosis and impaired wound healing.”

Lymphatic system and the Brain 
As highlighted recently by our reader Tanya, a pretty basic gap in science’s understanding of how the brain works has just been addressed. It is all about where do the waste products produced in the brain go to.
Scientists have found evidence that the brain is connected to body’s central lymphatic system.
This then begs the question of what happens when this system does not work well. Is this a feature of some neurological disease? If that were the case, it would likely be associated with reduced lymphangiogenesis.

Running through your body is a network of channels and junctions called the lymphatic system, which siphons off waste and fluids like a biological sewer.
It was long thought the brain was excluded from this web of anatomical plumbing. After being spotted in mice brains two years ago, researchers have now confirmed the presence of lymphatic vessels in human brains, fueling speculation over the kinds of diseases they might be responsible for.

VEGF and VEGF receptors 
There are four types of VEGF and they act through three types of receptors. Confusingly, the receptors have been given multiple names.

In severe autism there is reduced VEGF, but we do not know which type(s) but there is increased expression of the receptor  VEGFR-1 also known as Flt-1. VEGFR-2 expression is normal, this is the best understood receptor.

This receptor VEGFR-1 is activated by VEGF-A and VEGF-B.  


To study vascular endothelial growth factor (VEGF) and its soluble receptors sVEGFR-1 and -2 in autism.

Design and methods:

We measured serum levels of angiogenic molecules in 22 patients with severe autism and 28 controls.


Patients and controls had similar sVEGFR-2 levels, but VEGF levels were lower and sVEGFR-1 higher in patients with autism.


The imbalance between VEGF and its receptor sVEGFR-1 may be involved in the pathophysiology of autism.

Hypoxia related autism 
It is well known that hypoxia-ischemia insults early in life can cause cognitive dysfunction and likely autism.  In the very recent paper below, it is suggested that altered VEGF signaling is the mechanism that causes the damage to the brain. 

Neurovascular dysfunction and the role of vascular endothelial growth factor (VEGF) have been explored in neurodevelopmental disorders including schizophrenia, bipolar disorder, major depressive and mood disorders, and autism. These disorders are correlated with hypoxia-ischemia insults during early life and are strongly associated with cognitive dysfunction. This review focuses on the hypoxia-regulated protein, VEGF, to discuss its crucial roles in brain development and function. These data implicate that alterations to VEGF signaling during early life can impair neural development, underlying the severe cognitive deficits observed in neurodevelopmental disorders.
Recent Findings
VEGF has been linked to neurological processes that influence learning and memory. VEGF is advancing towards being a novel biomarker and possible therapeutic for neurological disorders. Prenatal environmental enrichment positively impacted neurotrophic factors, brain structure, and memory in rodent models.
Understanding the molecular mechanisms of VEGF in neurodevelopment will create intervention strategies for at-risk children born to adverse early-life events. By proactively working with those in a pliable neurodevelopmental state, we hope to ameliorate cognitive deficits to increase their chance to develop into high-functioning adults with disabilities. 

Hypoxia-Induced Angiogenesis - Good and Evil

Hypoxia promotes vessel growth by upregulating multiple pro-angiogenic pathways that mediate key aspects of endothelial, stromal, and vascular support cell biology. Interestingly, recent studies show that hypoxia influences additional aspects of angiogenesis, including vessel patterning, maturation, and function.
VEGF, considered a master regulator of angiogenesis in its own right, causes endothelial cells to detach from the parent vessel and migrate into the neighboring stroma. Hypoxia is the principal regulator of VEGF expression, as it is a direct transcriptional target of both HIF-1α and HIF-2α.

Allergy and inflammation resulting from angiogenesis 
It appears that in some people another consequence of too much angiogenesis is allergy and other inflammatory disease; these are of course often comorbid with autism.  This suggests anti-angiogenic and pro-lymphangiogenic therapies.

Angiogenesis and lymphangiogenesis, the growth of new vessels from preexisting ones, have received increasing interest due to their role in tumor growth and metastatic spread. However, vascular remodeling, associated with vascular hyperpermeability, is also a key feature of many chronic inflammatory diseases including asthma, atopic dermatitis, psoriasis, and rheumatoid arthritis. The major drivers of angiogenesis and lymphangiogenesis are vascular endothelial growth factor- (VEGF-)A and VEGF-C, activating specific VEGF receptors on the lymphatic and blood vascular endothelium. Recent experimental studies found potent anti-inflammatory responses after targeted inhibition of activated blood vessels in models of chronic inflammatory diseases. Importantly, our recent results indicate that specific activation of lymphatic vessels reduces both acute and chronic skin inflammation. Thus, antiangiogenic and prolymphangiogenic therapies might represent a new approach to treat chronic inflammatory disorders, including those due to chronic allergic inflammation.

Figure 1: VEGF-binding properties and distinct VEGF receptor expression on lymphatic and blood vascular endothelium. VEGFs bind to the three VEGF receptor tyrosine kinases, leading to the formation of VEGFR dimers. Blood vascular endothelial cells express VEGFR-1 and VEGFR-2, whereas lymphatic endothelial cells express VEGFR-2 and VEGFR-3. VEGF-A—which binds both VEGFR-1 and VEGFR-2—can directly induce blood and lymphatic vascular remodeling. VEGF-C and -D bind VEGFR-3 and, after proteolytic processing, also VEGFR-2, thus inducing angiogenesis and lymphangiogenesis.

There is clear evidence that in humans, vascular remodeling occurs in many chronic inflammatory disorders. Even though different anti-inflammatory drugs are on the market, there is no specific therapy that interferes with the pathological vascular changes that occur during inflammation. Angiogenesis and lymphangiogenesis are tightly linked to chronic inflammation, and targeting the blood vessels and lymphatic vessels has been shown to be an effective strategy in different experimental mouse models of chronic inflammation. One has to keep in mind, however, that in most conditions the vascular activation likely represents a downstream event that maintains the inflammatory process, but not the pathogenetic cause of the respective disease, which often has remained unknown. Nonetheless, antiangiogenic and prolymphangiogenic therapies might represent new approaches to treat chronic inflammatory disorders, including those due to chronic allergic inflammation.

I did start this post by saying this subject is complicated.
From the previous post on nitric oxide, it looked like L-citrulline, L-norvaline, Agmatine and other NO increasing substances could be therapeutic. Cold hands and feet seem to be very common in autism.
It seems likely that the NO increasing therapies will likely also increase VEGF, which I think is a good thing.
From today’s post we see that rather than just a single VEGF we have five broad types (A,B,C, D and PIGF), but even just VEGF-A has various different forms. We do not have detailed research on autism and specific subtypes of VEGF. 
We have the four different VEGF receptors and we know VEGFR-1 is over expressed. We do not have a clever way to counter this. More VEGFR-3 expression would be helpful and that is again a case of changing the balance between inflammatory cytokines, which as we know is usually disturbed in autism.
The inflammatory cytokine IL-6 induces VEGF-C production which leads to both angiogenesis and lymphangiogenesis; this is why people with cancer and high IL-6 may have a poor prognosis.
Regarding VEGF and autism we clearly lack 95% of the science. Strange things are afoot and we are just guessing.
For the time being, I see increasing vascular permeability via eNOS as therapeutic, even though today’s post suggests that antiangiogenic therapies could be helpful, which may seem contradictory.
The kind of drugs that would reduce the activity of VEGFR-1/Flt-1 would be very expensive cancer drugs.  Hypoxia also downregulates VEGFR-1/Flt-1.
Inflammatory cytokines regulate VEGFR-3/Flt-4 and hence control of lymphangiogenesis.  Interferon gamma (IFNγ) upregulates VEGFR-3/Flt-4, while Interleukin 1 beta (IL1β) down regulates it. 
So more IFNγ and less IL1β might help.
Although expensive, interferon gamma (IFNγ) has been shown to be effective in treating severe atopic dermatitis. This would make sense since it induces lymphangiogenesis and the research suggests this should improve inflammatory disease.


We conclude that rIFN-gamma appears to be a safe long-term therapy for patients with severe atopic dermatitis.

So perhaps interferon-gamma (IFNγ) for some autism? Quite possibly, just look for the ones with asthma, atopic dermatitis, psoriasis or juvenile arthritis.

Friday, 13 October 2017

Nitric Oxide (NO), Arginase and Endothelial Dysfunction in Autism

Endothelial dysfunction is not something people associate with autism. It is something I have covered previously in this blog and if you search on Google my post is about all you will find.
Endothelial dysfunction is acknowledged to be very important in diabetes, which is characterized by ROS (reactive oxygen species), reduced NO (nitric oxide) , reduced eNOS (endothelial nitric oxide synthase) and too much Arginase. There is also Peroxynitrite (ONOO), an ion we have encountered before.
In autism we do already know from the research that VEGF (Vascular endothelial growth factor) is disturbed and there will be a post on that.
So when you put it all this together, it is odd that nobody has researched endothelial dysfunction and autism.  When I find something like this, my fallback is always schizophrenia. What about Endothelial Dysfunction and Schizophrenia? Sure enough, there is plenty of research on the subject, like this paper.

We tested the hypothesis that subjects with schizophrenia have impaired endothelial function.
Our findings suggest that a diagnosis of schizophrenia is associated with impaired microvascular function as indicated by lower values of VTI, irrespective of many other clinical characteristics. It might be an early indicator of cardiovascular risk in schizophrenia, and might help to identify high-risk individuals.

Endothelial Dysfunction does ultimately cause all kinds of problems in later life.  What is relevant to this blog is the potential neurological benefit of improving endothelial function in younger people, if any.
We need to recall that historically there have been very few older people with more severe autism; they did not live to the age when typical problems caused by endothelial dysfunction become apparent. 

Overlapping causes of Endothelial Dysfunction
The interesting question is just how many of the possible causes of endothelial dysfunction occur in autism. 
So far the following factors seem to apply to autism:-
·        Oxidative stress (ROS)

·        Reduced eNOS and nitic oxide (NO)    

·         VEGF (Vascular endothelial growth factor) is disturbed

·         Even estrogen deficiency can play a role and this is reduced in autism
People with autism who use calcium folinate (Leucoverin) are already quenching  Peroxynitrite (ONOO) another factor in Endothelial Dysfunction.                                                               

Is Arginine/Arginase disturbed in Autism?
One well known anomaly in diabetes is a high level of an enzyme called Arginase, resulting in reduced production of nitric oxide (NO) in endothelial cells.
Here again we have to revert to looking at schizophrenia, as the closest thing to autism. Here there are no surprises. 

Previous research implicates altered metabolism of l-arginine, a versatile amino acid with a number of bioactive metabolites, in the pathogenesis of schizophrenia. The present study, for we believe the first time, systematically compared the metabolic profile of l-arginine in the frontal cortex (Brodmann's area 8) obtained post-mortem from schizophrenic individuals and age- and gender-matched non-psychiatric controls (n=20 per group). The enzyme assays revealed no change in total nitric oxide synthase (NOS) activity, but significantly increased arginase activity in the schizophrenia group. Western blot showed reduced endothelial NOS protein expression and increased arginase II protein level in the disease group. High-performance liquid chromatography and liquid chromatography/mass spectrometric assays confirmed significantly reduced levels of γ-aminobutyric acid (GABA), but increased agmatine concentration and glutamate/GABA ratio in the schizophrenia cases. Regression analysis indicated positive correlations between arginase activity and the age of disease onset and between l-ornithine level and the duration of illness. Moreover, cluster analyses revealed that l-arginine and its main metabolites l-citrulline, l-ornithine and agmatine formed distinct groups, which were altered in the schizophrenia group. The present study provides further evidence of altered brain arginine metabolism in schizophrenia, which enhances our understanding of the pathogenesis of schizophrenia and may lead to the future development of novel preventions and/or therapeutics for the disease

Arginine metabolic pathways. l-arginine can be metabolized by NOS, arginase and ADC to form a number of bioactive molecules (see the Introduction for detailed description). We found increased levels of arginase activity, arginase II protein expression and agmatine tissue concentration (indicated by the red letters and arrows), and reduced eNOS protein expression and GABA level (indicated by the green letters and arrows) in the schizophrenia cases. ADC, arginine decarboxylase; BA8, Brodmann's area 8; eNOS, endothelial NOS; GABA, γ-aminobutyric acid; iNOS, inducible NOS; NO, nitric oxide; NOS, nitric oxide synthase; nNOS, neuronal NOS.  

It is of interest to note that the plasma agmatine level was increased over threefold in schizophrenic patients relative to healthy controls

The present study, interestingly, found an over 50% increase in arginase activity in BA8 accompanied by a significant upregulation of arginase II in the schizophrenia group. It is currently unclear how arginase changes in blood correlate with those in the brain tissue

Polyamines and agmatine have also been implicated in psychiatric disorders

L-Norvaline for Aspie1983?
One reader has raised issue of whether L-Norvaline would be a good idea.
L-Norvaline is an arginase inhibitor, used by body builders to increase nitric oxide.
L-arginine is used as a substrate by both nitric oxide synthase (NOS) and arginase to produce nitric oxide (NO) and urea, respectively.
If you inhibit arginase you shift the L-arginine over towards nitric oxide production.
People with diabetes and, as we saw above schizophrenia, have elevated levels of arginase. This will cause them to have a reduced level of nitric oxide. Reduced nitric oxide will contribute to Endothelial Dysfunction.
So it looks like L-Norvaline might well be beneficial in diabetes and schizophrenia.
L-Norvaline  might slow the conversion of ammonia to urea, if arginase was low to start with.  If arginase was elevated to start with you might expect no impact on the conversion of ammonia to urea.

Agmatine, Polyamines & L-citrulline 
Agmatine may already be elevated in schizophrenia, but it looks like a little extra can be beneficial in autism.
Polyamines can also be good for you if they increase autophagy. Which specific polyamine you want is an open question.
In the schizophrenia study L-citrulline is reduced. This makes sense because L-arginine has been shifted over towards  urea by elevated arginase. L-citrulline is a byproduct when nitric oxide (NO) is produced.
Perhaps unexpectedly, l-Citrulline is also a potent endogenous precursor of l-arginine. In a recent clinical study, l-citrulline supplementation dose-dependently increases plasma l-arginine levels in healthy human volunteers more effectively than equivalent doses of l-arginine itself.
Aspie1983 might not need to supplement L-citrulline, if he used L-Norvaline .

Altered brain arginine metabolism in autism?
I suspect Aspie1983 is not the only one with an altered brain arginine metabolism.
There appear to be many therapeutic options and they are all body building supplements because they will all increase nitric oxide (NO).
They will all improve Endothelial Dysfunction, which was the original subject of this post.

It certainly seems like Endothelial Dysfunction is present in some autism and that numerous established therapies should help.
We are already targeting oxidative stress with antioxidants and some people use calcium folinate that will target nitrosative stress.
The therapies that increase NO and/or eNOS include:-
·        Agmatine

·        L-arginine

·        L-citrulline

·        L- norvaline

·        Cocoa flavanols

·        Beetroot juice

·        L-taurine does increase eNOS and NO, but it is not clear how

There are products sold to body builders that include several of these and some clever additional ones.

Like this one, 12 grams made up of:-
1.   L-Citrulline
2.   L-Taurine
3.   Agmatine Sulfate 
4.   Glycerol Monostearate
5.   Dan-Shen, a Chinese cardio-protective herb that increases NO and also behaves like low dose aspirin
6.   Beetroot Powder
7.   L-Norvaline
8.   Hesperidin, a citrus flavonoid that increases NO
9.   Black pepper extract; piperine is known to affect NO release

Dan-Shen :- there are numerous clinical trials on Dan-Shen and its active ingredient. It has even been suggested to treat PANS/PANDAS.

These clinical trials include treating altitude sickness.

Hesperiden is found in oranges and indeed peppermint, but in oranges it is most abundant in the white inner part of the peel. Orange peel is a home remedy to lower cholesterol. Research shows that Hesperiden (and naringin) is a potent cholesterol lowering substance.

You would think that you can have too much of a good thing, that is too much endothelial nitric oxide; ask a body builder.
There is more to this subject, beyond the body builder’s science; the related areas to look at are angiogenesis and lymphangiogenesis. These are very much influenced by VEGF (Vascular Endothelial Growth Factor). In the next post we will see that there is evidence suggesting blood vessel growth can be unchecked in some autism resulting in unstable blood flow, not simply reduced flow.
So while the view from today’s post is that in autism there may be restricted blood flow, rather like in vascular dementia, the real situation is likely more complex.
We also have the issue of how the lymphatic system, that collects waste materials from the body (including the brain), may also be affected. With blood vessels there may be “too much growth” but in the case of lymphatic system there may be too little. This is all governed by VEGF.
We have already seen that autophagy and mitophagy are reduced in some autism and are a defining feature of Huntingdon’s Disease. Accumulation of waste products in the brain has consequences. Improved autophagy, possible via the same polyamines referred to in the earlier graphic, and improved lymphangiogenesis could be therapeutic. It appears that the brain flushes out waste products to the lymphatic system while you sleep; Alzheimer's is most prevalent in people who sleep very little.

Tuesday, 10 October 2017

Back to School (again)

Another September passes and another school year is underway. For Monty, aged 14 with ASD, he moved up to the secondary/high school building with his 12 year old classmates.  He has attended the same small international school for ten years.
The experience autism parents have with schools varies widely, both from country to country and within the same country.
This blog is mainly read by people in North America, where autism is generally much better treated than in the rest of the world.  Publicly funded early intervention in the US is available from birth to three; it actually finishes before most people in the rest of the world even get a diagnosis.
While many people complain about the services they receive, it is ultimately up to the parents to make the best of it, using whatever means they have at their disposal.  The results appear to be extremely varied.
Our method was to go part time to school to the age of twelve, leaving plenty of time to have a home-based learning program.  Up to the age of eight almost all learning actually took place at home; school was more for “socialization”.  Then there was a big behavioral regression for almost a year; school continued but skills were lost. Then I started my Polypill interventions and in that September agreed Monty move back two years at school.
For the last five years Monty has stayed with the same NT peer group who are two years his junior.  Much to everyone’s surprise, he participates in the same assessments as his classmates, something inconceivable up to the age of eight. Moreover he does not get the lowest grades in class, which would have been the case up to the age of 8 had the teacher used the same tests as the rest of the class.
At some point, I assume he will not be able to move forward, but that point has not yet come.  This year we have already had tests in all subjects and the average grade has been “B”, which has surprised everyone. If you treat classic autism you will still have autism, but normal learning becomes possible. 

Progress to date

There is much in previous posts about how people with classic autism start to acquire skills long after their peers, and that even then their rate of acquisition of new skills is much slower. The end result is that the learning gap between people with autism and their NT peers starts out wide and then grows. Many people with classic autism leave high school with a skill level ten years lower.

NT kids start acquiring skills from an earlier age and at a faster rate than those with Classic autism. Adjust for this and “catch up”.

The idea of this blog is to use science to close the gap as much as possible, so rather than being left totally behind, aim to leave school with much more than just a very minimal education.
People with Asperger’s clearly do not have these problems and most people diagnosed today with autism have this kind of mild autism.   
One good thing about not being in a selective school is that you have a wide range of intelligence and indeed motivation among the class. If you have a selective school with hard working intelligent kids, you clearly could not include someone with classic autism, but you should be able to have people with Asperger’s.  They were there long before Asperger’s was a diagnosis. 
As I have pointed out in previous back-to-school posts, there may well come a September when moving forward a year may not happen, but for the last five years it has been possible.
The idea of explaining concepts such as elements, compounds, atoms and molecules really would have seemed absurd, just a few years ago. I may even be putting up a poster of the periodic table in Monty’s room.  It is of course just a very basic understanding; so H2O is water where H is hydrogen, O is oxygen.  It was not so long ago that it was proving impossible to teach the concept of bigger and smaller with single digit numbers or the meaning of basic prepositions.
The biggest issue currently involves history, where rather than just learning what happened and when, it is already more about your opinions about why something happened. So the problem is more one of language and I would myself struggle to understand and explain the causes of World War 1 in my second language. People with classic autism really do not have a mother tongue, their first language is silence and so language will remain limited and be matter of fact and literal.
So we will focus on numeracy/math, literacy (English), a second language, science, geography (which is surprisingly teachable) and make something of history. The non-academic subjects, music and physical education/PE work very well and autism is not a limiting factor.  
Because the class is of mixed abilities and perhaps more importantly varying motivations, in spite of his obvious disadvantages, Monty does not come bottom. I think if you come bottom in every subject, then inclusion may not be appropriate.
There is a view that you should give different tasks and simpler assessments to special needs kids included in mainstream classrooms. This is like the old village school where one teacher is teaching different age groups at the same time. This does put a burden on the class teacher and you can see why it does not happen, unless the teacher is very motivated and well supported. I do not see how classes in public schools with 30 kids and two of those have special needs and assistants can function well. The risk is you end up failing the 28 NT kids.
The key to successful inclusion of someone with classic autism seems to be pharmacologically raising their cognitive function (IQ) as much possible, having good one to one classroom assistants and having a smaller class size.
These days most people diagnosed with autism are more likely to have Asperger’s, so they did not have a speech delay and all the biological consequences of that. People with Asperger’s face very different issues at school. In theory these issues are much easier to deal with, but because they appear minor they may get ignored. Issues include sensory gating, sensory overload and bullying; none of which affect my son at school.  Selective schools would seem a good choice for those with Asperger’s, since they will have more in common with at least some of those clever hard working types.  I continue to be surprised that special schools for Asperger’s exist in some countries.  They may be a refuge from bullying, but cannot be a good preparation for future life and employment.
Special schools for more severe autism vary widely.  In some countries there are some very good ones, but this kind of provision is extremely expensive and so is often not available.
I think if you are behaviourally and academically “includable”, mainstreaming is the ideal option. If inclusion is just a class within a class, with the assistant teaching the child in a corner of the mainstream classroom, then it is not going to be a success.  
You have to be behaviourally and academically includable.  If you are just behaviourally includable but understand nothing from the teacher, there is not much point being there.  If you are not behaviourally includable it is not fair on all the NT kids.
In kindergarten and the next couple of years the fact someone has autism does not stand out so much, because many kids behave badly. So you have till the age of 7 to get things in as good a shape as you can.
Treating autism pharmacologically makes learners much more includable and hopefully one day will be available on demand. It can reduce negative behaviors like aggression and anxiety, while raising cognitive functioning.   

The US system is based on the idea of making a huge effort before the age of four in the hope that things will get very much better and fast.  There is indeed evidence that in about 10-15% of people with autism, by the age of five things have pretty much fixed themselves, regardless of intervention.
Few people will be able to keep up the pace of this early intervention for the next ten or more years. It is too expensive and just too labour intensive. In the US there are some publicly funded special schools that do have this level of provision, but not in most countries.
Having been very focused on behavioral intervention until my son was eight, it is clear that the optimal solution is to start pharmacological intervention in parallel, meaning from diagnosis.  Some people in the UK wait for years just for a diagnosis, which is absurd. I think an astute observer can diagnose more severe autism at 18 months of age, with 90% accuracy.  In some countries they wait till five years old before diagnosing autism, preferring to use words like apraxia instead. Outside the US there is no rush to diagnose autism, because there are no services.  If there are no services, nor interventions, there is little point having a diagnosis, it is just a label.
Pharmacological intervention is going to be rather hit and miss, but this is also true in many other medical conditions (dementia, multiple sclerosis, epilepsy, depression …).  For the 85% that are not going to magically recover, pharmacological intervention combined with 1:1 teaching/support is the way to go.  It is the 1:1 part that is expensive, but for many people that is already available in many countries, meaning a teaching assistant in a mainstream classroom.  All the 1:1 therapy is much more effective, when you improve some of biological dysfunctions.
Why more people cannot have a one or two year “catch-up” adjustment in mainstream school is not clear to me. It is a very simple strategy that does not cost anything, since in many countries people with special needs get free education beyond 18 years of age. There is a rigid belief that you must educate a 9 year old with other 9 year olds, rather than matching people by their stage of cognitive development. In my world no NT kid would leave primary/junior school until he had mastered basic numeracy and literacy, which often is not the case, even in developed countries.

Wednesday, 4 October 2017

Sodium Benzoate and GABRA5 - Raising Cognitive Function in Autism

I am still looking for additional cognitive enhancing autism therapies. It seems the best way to find them may actually be to reread my own blog.
A long time ago I suggested that Cinnamon could well be therapeutic in autism, most likely (but not entirely) due to the sodium benzoate (NaB) it produces in your body.

Sodium benzoate (NaB) is both a drug used to reduce ammonia in your blood and a common food additive that acts as a preservative.
NaB has many biological effects.  One effect relates to a protein called DJ-1, which is produced by a Parkinson’s gene (PARK7). I had noticed that when the body tries to turn on its anti-oxidant genes after the switch Nrf2 is activated, the process cannot proceed without enough DJ-1.  This is why Peter Barnes, from my Dean’s list, suggested that patients with COPD might benefit from more DJ-1.  COPD is a kind of severe asthma which occurs with severe oxidative stress, the oxidative stress stops the standard asthma drugs from working, which is why so many people die from COPD. Oxidative stress is a key feature of most autism.
To make more DJ-1 you can use sodium benzoate (NaB) which is produced gradually in the body if you eat cinnamon. So in theory cinnamon is like sustained release NaB, it is also extremely cheap.
Independently of all this NaB has been trialled in schizophrenia and a further larger trial is in progress.  Autism is not schizophrenia, but the hundreds of genes miss-expressed in autism do overlap with the hundreds of genes miss-expressed in schizophrenia, so I call schizophrenia autism’s big brother. 

GABAA α5 subunit
The scientist readers of this blog may recall that there are two sub-units of the GABAA receptor that I am seeking to modify, to improve cognition.  One is the α3 subunit and the other is the α5 subunit. Low dose clonazepam works for α3.
The α5 subunit is the target of a new drug to improve cognition in people with Down Syndrome (DS).
Very recent research links the same sub-unit to autism, so it is not just me looking at this.

Reduced expression of α5GABAA receptors elicits autism-like alterations in EEG patterns and sleep-wake behavior                                                                                                              

As is often the case, it looks like some people might need to “turn up the volume” from α5GABAA receptors and others might need to turn it down.
I had yet to find a practical way to affect α5GABAA. Now I have realized that I have already stumbled upon such a way to do it.
Pahan, a researcher in Chicago, has shown that he can improve cognition in mice using cinnamon. He noted that in poor learners GABRA5 was elevated, but that after one month of cinnamon GABRA5 was normalized. 

Cognitive loss in autism, schizophrenia and Down Syndrome
Most people might associate MR/ID with autism and indeed Down Syndrome; you likely do not really consider people with schizophrenia to have MR/ID. In reality, cognitive loss is a common feature/problem in schizophrenia and indeed bipolar, just not enough to be called MR/ID.
Those researching schizophrenia seem to focus on NMDA receptors, whereas my blog only goes into the great depths of science when it comes to GABAA . To the schizophrenia researchers NaB is interesting because it is a d-amino acid oxidase inhibitor, which means that it will enhance NMDA function.  So if you are one of those people with too little NDMA activity (NMDAR hypofunction) then sodium benzoate should make you feel better.
The schizophrenia researchers think NaB is helpful because of its effect on NMDA, for me it is GABRA5 that is of great interest. The same should be true for parents of kids with Down Syndrome (DS). We have seen that bumetanide should, and indeed does, help DS.  It looks to me that NaB/Cinnamon should further help them and no need to wait for Roche to commercialize their GABRA5 drug. 

NaB and Cinnamon
I am yet to determine how much NaB is produced by say 3g of cinnamon.
The clinical trials of NaB use 1g per day in adults. People using cinnamon, like Dr Pahan, for cognition or just lowing blood pressure and blood sugar use around 3g.
It is quite difficult to give a teaspoonful of cinnamon to a child, whereas NaB dissolves in water and does not taste so bad. 

NaB and Cinnamon Trials
I did trial cinnamon by putting it in in large gelatin capsules and at the time I did think it had an effect, but I doubt I got close to Dr Pahan’s dosage.
A prudent dose of NaB would seem to be 6mg/Kg twice a day. This is similar to what is now being trialed in schizophrenia.
A small number of people do not tolerate NaB and logically also cinnamon.  They are DAAO inhibitors, just like Risperidone. People who are histamine intolerant need to avoid DAAO inhibitors. If you have allergies it does not mean you are histamine intolerant.
I did try NaB on myself and I did not notice any effect.

I had already obtained some NaB to follow up on my earlier trial of cinnamon.  Having read about the effect of NaB on GABRA5 expression, I am even more curious to see if it helps.
Any positive effect might be due to DJ-1 boosting the effect of Nrf-2, it might be boosting NMDA or it might be reducing GABRA5 expression. In some people all three would be useful.

Press release:- 

Pahan a researcher at Rush University and the Jesse Brown VA Medical Center in Chicago, has found that cinnamon turns poor learners into good ones—among mice, that is. He hopes the same will hold true for people.

His group published their latest findings online June 24, 2016, in the Journal of Neuroimmune Pharmacology.

"The increase in learning in poor-learning mice after cinnamon treatment was significant," says Pahan. "For example, poor-learning mice took about 150 seconds to find the right hole in the Barnes maze test. On the other hand, after one month of cinnamon treatment, poor-learning mice were finding the right hole within 60 seconds."

Pahan's research shows that the effect appears to be due mainly to sodium benzoate—a chemical produced as cinnamon is broken down in the body.

In their study, Pahan's group first tested mice in mazes to separate the good and poor learners. Good learners made fewer wrong turns and took less time to find food. 

In analyzing baseline disparities between the good and poor learners, Pahan's team found differences in two brain proteins. The gap was all but erased when cinnamon was given. 

"Little is known about the changes that occur in the brains of poor learners," says Pahan. "We saw increases in GABRA5 and a decrease in CREB in the hippocampus of poor learners. Interestingly, these particular changes were reversed by one month of cinnamon treatment." 

The researchers also examined brain cells taken from the mice. They found that sodium benzoate enhanced the structural integrity of the cells—namely in the dendrites, the tree-like extensions of neurons that enable them to communicate with other brain cells

As for himself, Pahan isn't waiting for clinical trials. He takes about a teaspoonful—about 3.5 grams—of cinnamon powder mixed with honey as a supplement every night.  
Should the research on cinnamon continue to move forward, he envisions a similar remedy being adopted by struggling students worldwide. 

The paper itself:- 

This study underlines the importance of cinnamon, a commonly used natural spice and flavoring material, and its metabolite sodium benzoate (NaB) in converting poor learning mice to good learning ones. NaB, but not sodium formate, was found to upregulate plasticity-related molecules, stimulate NMDA- and AMPA-sensitive calcium influx and increase of spine density in cultured hippocampal neurons. NaB induced the activation of CREB in hippocampal neurons via protein kinase A (PKA), which was responsible for the upregulation of plasticity-related molecules. Finally, spatial memory consolidation-induced activation of CREB and expression of different plasticity-related molecules were less in the hippocampus of poor learning mice as compared to good learning ones. However, oral treatment of cinnamon and NaB increased spatial memory consolidation-induced activation of CREB and expression of plasticity-related molecules in the hippocampus of poor-learning mice and converted poor learners into good learners. These results describe a novel property of cinnamon in switching poor learners to good learners via stimulating hippocampal plasticity. 

We have seen that cinnamon and NaB modify T cells and protect mice from experimental allergic encephalomyelitis, an animal model of multiple sclerosis. Cinnamon and NaB also upregulate neuroprotective molecules (Parkin and DJ-1) and protect dopaminergic neurons in MPTP mouse model of Parkinson’s disease.  Recently, we have seen that cinnamon and NaB attenuate the activation of p21ras, reduce the formation of reactive oxygen species and protect memory and learning in 5XFAD model of AD. Here we delineate that NaB is also capable of improving plasticity in cultured hippocampal neurons. Our conclusion is based on the following: First, NaB upregulated the expression of a number of plasticity-associated molecules (NR2A, GluR1, Arc, and PSD95) in hippocampal neurons. Second, Gabra5 is known to support long-term depression. It is interesting to see that NaB did not stimulate the expression of Gabra5 in hippocampal neurons. Third, NaB increased the number, size and maturation of dendritic spines in cultured hippocampal neurons, suggesting a beneficial role of NaB in regulating the synaptic efficacy of neurons. Fourth, we observed that NaB did not alter the calcium dependent excitability of hippocampal neurons, but rather stimulated inbound calcium currents in these neurons through ionotropic glutamate receptor. Together, these results clearly demonstrate that NaB is capable of increasing neuronal plasticity.

These results suggest that NaB and cinnamon should not cause health problems and that these compounds may have prospects in boosting plasticity in poor learners and in dementia patients. In summary, we have demonstrated that cinnamon metabolite NaB upregulates plasticity-associated molecules and calcium influx in cultured hippocampal neurons via activation of CREB. While spatial memory consolidation-induced activation of CREB and expression of plasticity-related molecules were less in the hippocampus of poor learning mice as compared to good learning ones, oral administration of cinnamon and NaB increased memory consolidation-induced activation of CREB and expression of plasticity-related molecules in vivo in the hippocampus of poor learning mice and improved their memory and learning almost to the level that observed in untreated good learning ones. These results highlight a novel plasticity-boosting property of cinnamon and its metabolite NaB and suggest that this widely-used spice and/or NaB may be explored for stimulating synaptic plasticity and performance in poor learners.

The schizophrenia trials:-

Plenty of people with schizophrenia now self-treat with NaB; just look on google.

There is now is a small trial in autism:-

A Pilot Trial of Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, Added on Augmentative and Alternative Communication Intervention for Non-Communicative Children with Autism Spectrum Disorders

Results: We noted improvement of communication in half of the children on benzoate. An activation effect was reported by caregivers in three of the six children, and was corroborated by clinician’s observation. Conclusion: Though the data are too preliminary to draw any definite conclusions about efficacy, they do suggest this therapy to be safe, and worthy of a double-blind placebo-controlled study with more children participated for clarification of its efficacy.