Autism, a Dynamic Encephalopathy, Indeed

 

With a title like that, not many people will stumble upon this post with Google.

So, for the hard-core of readers, today I am going to develop an idea of Martha Herbert, the pediatric neuroscientist from Harvard, who writes a lot about autism.

Incidentally, most researchers do not like publicity, and particularly those looking at autism.  Martha, herself makes some side remarks as to why this is; as I suggested in earlier posts it dates back 10+ years to a certain Dr Wakefield.

“A further barrier to considering the body’s impact on the brain was the reaction to the work of Wakefield, who argued not only that there was a link  between  autism  and  vaccines  but  also  that  this  link was mediated through the gastrointestinal system. For the better part of a decade any attempt to discuss gastrointestinal or immune issues with autism was construed as a support of Wakefield’s vaccine hypothesis, and it was difficult to discuss, let alone get funding for, clinical or research observations about these problems.  One way around the essentially taboo character of somatic problems in autism was to treat them as coincidental symptoms. For example, one could  talk about gut problems provided one made  it clear that they did not cause the autism in the brain. Improvement after treatment of gut problems, which is often observed, would then be explained as a consequence of reduction of pain and discomfort, but not of any direct impact on core brain mechanisms generating autistic behaviors.”

Another fearless autism researcher, not shy to voice his opinions by blog and tweet, is Paul Whiteley, in Sunderland.   Paul is very much a believer in the role the gut/diet in autism, he and Paul Shattock are the driving force behind the gluten and casein free diet as a therapy for autism.  Given what Martha writes above, and the association between Shattock and Wakefield, is it surprising that the GCF diet remains on the fringes?  I know some parents who wholly endorse it.

Here is a link to one of Martha’s recent works, for Herbert fans:-

From Static Genetic Brain Defect to Dynamic Gene- Environment- Modulated Pathophysiology

Dynamic Encephalopathy

It was Martha who called autism a dynamic Encephalopathy.  Encephalopathy just means a brain disease.

What she means is that over time autism changes, day to day and year to year.  Just as during fever, autism symptoms may wane, other environmental provocations may cause flare ups.  With age come hormonal changes that will inevitably change the central hormonal homeostasis, I hope for the better, as generally is the case.

Other than being a fancy word, Encephalopathy, is probably a much better word than autism.  There are many types of Encephalopathy and there are multiple causes, it refers to a syndrome of global brain dysfunction; this syndrome can have many different organic and inorganic causes.  As with autism the hallmark of encephalopathy is an altered mental state.

 
Forget Autism think Encephalopathy

If you have not already opened up Wikipedia, I suggest you do.

http://en.wikipedia.org/wiki/Encephalopathy

From my desk research and primary research, I know that one factor behind this encephalophy is chronic inflammation, otherwise known as neuroinflammation.

At this point, we should look at what neuroscience can tell us about neuroinflammation

The Dana Foundation is a private philanthropic organization committed to advancing brain research.  Founded in 1950 and with $230+ million in assets I think they should be a good source.  Here  is an excellent paper, that is written for non-scientists. 

 Consequences of the Inflamed Brain

Among the many interesting insights are these:- 

 “Until recently the CNS and peripheral immune sys­tem were thought to operate independently.”

“However, new research has led to important advances in our understanding of how immune-related events in the periphery can influence CNS processes, thereby altering cognition, mood, and behavior, and these advances are suggesting that inflammation may have important long term implica­tions for the brain.”

 “Inflammation in the body can lead to inflammation in the brain”

“The same cytokines that participate in produc­ing the inflammatory response in the body also initiate the communication process to the CNS. They accumu­late in the bloodstream and thereby travel to the brain”

“They cross into the brain in regions where the barrier is weak, and they bind to receptors on the insides of the cerebral vascular blood vessels, thereby inducing the production of soluble mediators within the epithelial cells that can cross into the brain.”

“In addition, there are neural as well as blood-borne communication routes. For example, there are cytokine receptors on nerves, such as the vagus, that innervate peripheral immune organs, and these nerves communicate to the brain and are activated during infection.”

“During a normal infection, neuroinflammation and the resulting adaptive sickness behaviors persist only for several days. However, if these responses become exaggerated or prolonged, the outcomes may well become estab­lished, leading to cognitive impairment instead of brief memory disruption,”

 “… physiology can become pathology when a set of processes designed to be rela­tively brief becomes prolonged.”

“However, peripheral inflammation is highly complex and involves many immune cells and their products. Existing anti-inflammatory drugs often target only one of these. For example, non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, inhibit only a hor­mone, prostaglandins, leaving other actors in inflam­mation (cytokines, chemokines, etc.) untouched.”

“A second way that central neuroinflammation could be prolonged is less obvious. The CNS may come to over-respond to the same signal from the peripheral immune system. As noted above, microglia and the cytokines they produce when activated are at the core of the neuroinflammatory response that pro­duces sickness behaviors. If microglia were to become “sensitized,” which means they respond in exagger­ated or prolonged fashion, then sickness behaviors would become intensified and prolonged—pathology instead of physiology.”

“Most encouragingly, studies in numerous animal models show that the development and expression of chronic pain can be blocked with drugs that inhibit either microglial activation within the spinal cord, or the inflammatory cytokines that microglia produce.”

“In addition, microglia also can become sensi­tized without a prolonged peripheral inflammation. For example, aging appears to sensitize microglia so that microglia, particularly in the hippocampus, respond in exaggerated fashion to input. Thus, neuroinflammation produced by surgery, peripheral infection, and the like, is greatly exaggerated in aged subjects. Correspond­ingly, aging also augments the chances of depressive behaviors, cognitive impairments, and pain produced by peripheral inflammatory events. Encouragingly, however, some human studies show that inhibition of microglia and cytokines in the brain blunts such patho­logical outcomes.”

“Blockade of inflammation in the periphery and microglial activation/cytokine action in the CNS, may well become important therapies for a range of disorders not often thought of as mediated by these factors.”

Conclusion

There is nothing new to me in the Dana paper; this in itself is rather a shock.  If you have followed my blog from the start, you should also not be surprised; but I have never seen quite so much scientific good sense written in just four pages.  It tells me a lot and reassures me that I am on the right track with my cytokine blocking therapies, mast cell stabilization and somewhat far fetched, vagus nerve stimmulation ideas.

There are other science-based "inflammation control" therapies and I will be writing about them later.

P.S.  Why no Dean’s List for Martha?

Regular readers of my blog may have noticed that a small number of the several hundred researchers, whose papers are discussed here, are given a pat on the back and moved to the Dean’s List.  Why not Martha?

There is a good reason.  For many years Martha keeps going on about the “Fever Effect” in autism.  This is the strange phenomenon where autistic behaviours abate during fever, i.e. sickness associated with high temperature.  I myself witness this every time Monty, aged 10 with ASD, has a high temperature.  I think that conclusively solving this, might indeed tell us something profound about this wide phenotype of autism.

I think with the resources of Harvard, she should be able to figure this out.  Her TRANSCEND Program gives her a pool of research subjects.

Peter has just one mouse model of autism and, at the age of 10, he is getting a big to be called a mouse.

So Martha, put aside the MRIs and the calcium channelopathies, if you figure it out before me, you get on the Dean’s List.

If I can prove the underlying reason, I will put myself on the Dean’s List.

 

Praise the Lord and pass the Statins - Part 1

If you are not a native English speaker, you may not have heard the praise “praise the Lord and pass the ammunition”.  It originates from a song written after the Japanese attack on Pearl Harbour in 1942.  A warship’s chaplain puts down his bible and mans a gun firing back at the incoming enemy planes saying, "Praise the Lord and pass the ammunition".

According to Wikipedia, the chaplain was Howell Forgy, was aboard the USS New Orleans.

To hear an original recording click here.

In our case the enemy is neuroinflammation, rather than the Japanese.

 

Deborah Fein and Martha Herbert

There are some very good researchers in the field of Autism and these two ladies are on my list of the best.  It looks like this paper was mainly the work of Ms Fein’s colleagues at the University of Connecticut: - Can children with autism recover? If so, How?

The paper is very readable and not science-heavy at all.

One of the explanations put forward for the rare event of recovery, was the possible reduction in neuroinflammation.  This very much fits in with the conclusions so far on my blog;  reduce neuroinflammation and in particular in the cerebellum.

Now we have a brief time-out to introduce you to our new friends, the Statins.

Source: W. Gibson Wood, Ph.D.  Department of Pharmacology, University of Minnesota

Statins

Statins are a class of drug used to lower cholesterol levels by inhibiting an enzyme which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases and statins are therefore used in the prevention of these diseases. Research has found that statins are most effective for treating cardiovascular disease (CVD), with questionable benefit in those without previous CVD, but with elevated cholesterol levels.

Statins act by competitively inhibiting HMG-CoA reductase, the first committed enzyme of the HMG-CoA reductase pathway. Because statins are similar to HMG-CoA on a molecular level, they take the place of HMG-CoA in the enzyme and reduce the rate by which it is able to produce mevalonate, the next molecule in the cascade that eventually produces cholesterol, as well as a number of other compounds. This ultimately reduces cholesterol via several mechanisms.

1.     Inhibiting cholesterol synthesis

By inhibiting HMG-CoA reductase, statins block the pathway for synthesizing cholesterol in the liver. This is significant because most circulating cholesterol comes from internal manufacture rather than the diet. When the liver can no longer produce cholesterol, levels of cholesterol in the blood will fall. Cholesterol synthesis appears to occur mostly at night so statins with short half-lives are usually taken at night to maximize their effect. Studies have shown greater LDL and total cholesterol reductions in the short-acting simvastatin taken at night rather than the morning, but have shown no difference in the long-acting atorvastatin.

2.     Increasing LDL uptake

 

3.    Other effects

Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research)

1. Improve endothelial function
2. Modulate inflammatory responses
3. Maintain plaque stability
4. Prevent thrombus formation

Statins may even benefit those without high cholesterol. In 2008, the JUPITER study showed fewer strokes, heart attacks, and surgeries even for patients who had no history of high cholesterol or heart disease, but only elevated C-reactive protein levels

 

*****************   Now back to today’s post  *******************

 

Neuroinflammation in the Cerebellum

How hard can it be to find a therapy for neuroinflammation in the cerebellum?  Thanks to Google Scholar, the answer is a few clicks away.

First of all we need to find what other diseases affect the cerebellum or cause inflammation there.  I settled on two completely different cases to investigate:-

1.    Cerebral Malaria 

2.    Traumatic Brain Injury (TBI)

 

Cerebral Malaria (CM) 

First let’s look at what happens in cases of cerebral malaria:-

i) Cognitive sequelae
ii) Speech and language impairment
iii) Epilepsy
iv) Behavior and neuro-psychiatric disorders

Now remember we are looking at malaria, not autism; but this list could just a well be a summary of the effects of autism.

An excellent paper on Cerebral Malaria is: - Cerebral Malaria; Mechanisms Of Brain Injury And Strategies For Improved Neuro-Cognitive Outcome

An emerging area of research is the applications of statins to reduce the neuroinflammation caused by this type of malaria.

Here the secondary action of the statin is important; cholesterol reduction is not relevant.  Here are some highlights:-

·         Cognitive impairment in animals rescued from CM by antiplasmodial drug treatment is abrogated by adjuvant lovastatin administration

·         Lovastatin treatment increases functional capillary density and decreases leukocyte-endothelial interactions

·         Lovastatin protects against blood-brain barrier disruption

·         Lovastatin treatment reduces cytokine levels

·         Lovastatin treatment decreases ROS production

 Read the full report:-  Statins Decrease Neuroinflammation and Prevent Cognitive Impairment after Cerebral Malaria

 

Traumatic Brain Injury (TBI)

It is self-evident that a traumatic brain injury, like a car crash, will lead to neuroinflammation.   The search is on here to find optimal ways to treat this inflammation and achieve an optimal outcome.

 

Here is one paper: - Statins in Traumatic Brain Injury

  

"The use of statins remains a novel therapeutic strategy for TBI. There is robust preclinical data demonstrating the efficacy of statins in acute brain injury models that recapitulate the heterogeneous pathology of clinical TBI. Animal studies have defined mechanisms by which statins may improve outcomes after TBI and should guide statin choice and dosing paradigm for clinical translation."

A more general paper is:- Statins and Brain Dysfunction

and for the older readers:-   Statins: The Role in the Treatment and Prevention of Alzheimer's Neurodegeneration

This should be an interesting paper, but only the abstract is free:-  How do statins control neuroinflammation?

Conclusion

Statins are among the world’s top selling drugs.  With so many people using them, there are of course reported side effects; but as drugs go, the side effects look pretty minimal.  Those at high risk of heart disease, such as those with Type 1 diabetes, are routinely prescribed statins even from a relatively early age.

It has been claimed that autistic people are already at higher risk of heart disease, due to their low level of good cholesterol (HDL) and sometimes higher level of bad cholesterol (LDL). The research is not 100% consistent; but it is very easy to go and check your child's cholesterol.  Holding him still while they draw the blood is another story ....

So it would appear there is one and maybe two very good reasons for autistic people to take statins.


Click below to see Part 2, to decide which statin to choose (there are many).

Statins for Neuroprotection in Autism - Part 2
 

 

Heretic! Of course the world is flat

I am again recommending to you the excellent collection of scientific research published all in one book called Autism: Oxidative Stress, Inflammation andImmune Abnormalities, edited by Chauhan, Chauhan and Brown.  It is seriously expensive, but if you manage to read it, you will likely know much more than your paediatrician.

Assuming that most of you will not want to buy the book, I will be feeding you edited highlights over the coming weeks.

Today’s insight is about heresy.

Columbus's voyage to the Americas in 1492 and then Magellan’s circumnavigation of the Earth (1519–21) provided the final and indisputable proof that our world is spherical.    At different periods in time before this, the world had been thought of as flat, round, square and possible spherical.

In 748 the then Pope Zachery heard complaints that Vergilius (Virgil) of Salzburg, who happened to be both an Irish churchman and amateur astronomer, was teaching a doctrine about the “rotundity of the earth”.  There still exists the decision of the Pope, written in Latin; translated into English it reads:

"As for the perverse and sinful doctrine which he (Virgil) against God and his own soul has uttered—if it shall be clearly established that he professes belief in another world and other men existing beneath the earth, or in (another) sun and moon there, thou art to hold a council, deprive him of his sacerdotal rank, and expel him from the Church."

In spite of this very close shave, Vergilius survived and later became Bishop of Salzburg and was later canonized by Pope Gregory IX, becoming Saint Vergilius of Salzburg.

The insight is that the only way to prove to everyone beyond doubt that the world is like a giant football, was for someone to sail around it and not disappear off the edge.

Autism:  Die-hards, Heretics and Quacks

As you will have gathered, this blog is anti-quackery; but it is now also anti die-hard.  If English is not your first language, this definition might help:-

Die-hard:

a person who resists change or who holds onto an untenable position or outdated attitude

When I started reading Chauhan’s book, I was very surprised to come across references to a now-discredited English doctor and researcher called Andrew Wakefield.  He is the one blamed for connecting autism with the MMR vaccination.  Some of the other scientists/authors seem to share his concerns that mercury in vaccines was indeed a cause of oxidative stress and that, as such, could reasonably be linked to autism.  That paper went on to mention that mercury has now been replaced by another metal, aluminium, but in much higher concentrations; aluminium is also known to be bad for the brain.  So I had to challenge my preconceptions about Mr Wakefield.

It seems that he raised issues that were already known to other researchers, but he just went a bit further and was more vocal.  He was then totally out of line with the currently accepted views of his profession and probably Big-Pharma as well.  So he lost his job, then the media drove him out of the country and in 2010 he was struck-off as a doctor.  He was branded a heretic. 

Now this brings me to another question, why is it in my trawl through the literature I have seen so few papers with British authors?  Does anyboby want to follow Andrew Wakefield?

Back to Chauhan’s book and the penultimate chapter; it is a paper by Dr Martha Herbert from the Department of Pediatric Neurology, Massachusetts General Hospital, Harvard Medical School.  I was shocked.  If Herbert worked in UK her days in a leading teaching hospital would be numbered.  She would be ridiculed and branded a heretic.

In the US there are plenty of people calling her a quack, but she has managed to keep a good job.  In other literature, she goes even further than in Chauhan’s book. I will summarize the essence of what she believes:-

·         The prevailing view that autism is a static, lifelong, incurable developmental condition is flawed.

·         Perhaps autism is not a unique and distinct syndrome

·         The etiology of autism may not be primarily genetic

·         Autism is a chronic dynamic encephalopathy

·         In other literature she goes all the way and says autism is curable

Martha Herbert has her own website.