Disorders leading to Autistic-like Symptoms

When you read the research it eventually becomes clear that "autism" is just a bunch of symptoms, rather than a single disease. So autism, as such, has no cure. A specific cause of autistic symptoms in a particular person, may indeed have a remedy, but most sadly do not.

Many causes of autistic symptoms though will have therapies that can reduce and help manage the symptoms. Combine this with the neuroplasticity of the brain and behavioural therapies and a clear way forward emerges.

You will see below that oxidative damage is the main culprit. In the more rare disorders, a genetic mutation is invariably the cause, but even a mosquito can be guilty.

This blog is focused at finding effective therapies for Classic Autism.  In spite of what could be reasonably expected, this is proving very fruitful and genuinely effective therapies actually do exist.

Notes

Oxidative Brain Injury					Comments
	Classic Autism				In utero malformation of cerebellum following oxidative shock.
					Ongoing neuroinflammation. Mixed outcome.
	Regressive Autism				As for classic autism, but with a shock event that triggers inceased inflammation and prompts regression.  Mixed outcome.
	Asperger's				Mild case of classic autism. Prognosis if usually good.
	ADHD				Mild case of classic autism. Prognosis is good.
Neurological Complication of Parasitic Disease
	Cerebral Malaria				Shock inflammation of the cerebellum causes massive damage.
					Treatable if detected early
Unknown
	Childhood disintegrative disorder				Cause unknown, causes complete loss of all skills
					onset between 2 and 10 years old
Genetic mutations/malfunctions
	tuberous sclerosis complex (TSC)				Multi organ genetic disorder
					Rapamycin is used to shrink the tumors.
	Rett Syndrome				Subjects are mainly girls, male fetuses rarely survive.
					Prognosis is often poor.
	Fragile X				Neurodegeneration increases in middle age.
	Phenylketonuria				Treatable if detected early
	Adenylosuccinate lyase deficiency				Viewed as untreatable
	Guanidinoacetate Methyltransferase Deficiency (GAMT)
					Creatine deficiency syndromes
	Arginine: Glycine Amidinotransferase Deficiency (AGAT)				Treatment of oral creatine supplementation can improve
					symptoms, if initiated early, in GAMT and AGAT patients.
					Treatment for CRTR patients, oral creatine supplementation’s
	Creatine Transporter Deficiency (CRTR)				therapeutic effects are limited.
	Smith–Lemli–Opitz Syndrome				inability to produce or synthesize cholesterol due to
					mutation of the DHCR7 gene. Treatable with cholesterol
	Biotinidase deficiency				treatable with biotin
	Infantile Neuronal Ceroid Lipofuscinoses				very rare and fatal
	Sanfilippo syndrome				possible treatment with flavonoid GENISTEIN
	Histidinemia				Rare generally, except in Japan
	Succinic semialdehyde dehydrogenase deficiency (SSADHD)				Defect in ALDH5A1 gene, causes defect in GABA pathway
	Dihydropyrimidine dehydrogenase deficiency (DPD deficiency)				Genetic mutation of DPYD gene

 

Statins for Neuroprotection in Autism - Part 2

I suggest you start by reading Part 1.  Click here for Part 1



Choice of Statin
 

Some statins are soluble in fats/lipids (lipophilic) and some are more soluble in water.  In order to cross the blood brain barrier (BBB) to reach the cerebellum and the Purkinje Cell Layer (PCL) a lipophilic statin will be required.  There is a choice of three: - atorvastatin, lovastatin, and simvastatin.  These are also among the most commonly prescribed for cholesterol reduction and so are widely available and inexpensive.

I chose atorvastatin.  Some statins are derived from fungi, but atorvastatin is synthetic.  Lovastatin and simvastatin are pro-drugs, whereas atorvastatin is already in an active form straight out of the box. Absorption of atorvastatin decreases when taken with food.  Due to its long half-life, atorvastatin can be administered at any time of day.

Atorvastatin is approved for use in children as young as 10 and in the US is prescribed to children as young as 5.

Atorvastatin, originally made by Pfizer under name Lipitor, is the best-selling drug in the history of the pharmaceutical industry.  It came off patent recently and so the price has collapsed to a very reasonable level.

In some countries the low dose forms are available over the counter, without a prescription.

 

More Related Research

The research effort into degenerative conditions like Alzheimer’s disease (AD) is far more prolific than into autism.  The closest research to my hypothesis that statins will “perk up the Purkinje cells” is this study:-

Atorvastatin and pitavastatin protect cerebellar Purkinje cells in AD model mice and preserve the cytokines MCP-1 and TNF-α.

  

Fragile X syndrome

Fragile X syndrome is a genetic syndrome that leads to autistic behaviours.  About 5% of the cases defined as autism are due to this genetic flaw.  It also results in certain physical differences, namely:-

• Large, protruding ears (one or both)
• Long face (vertical maxillary excess)
• High-arched palate (related to the above)
• Hyper extensible finger joints
• Hyper extensible ('Double-jointed') thumbs
• Flat feet
• Soft skin
• Hypotonia (low muscle tone)
• single palm crease (crease goes across entire palm)

 At MIT researchers have found that the statin Lovastatin “can correct Fragile X syndrome”.

 

I presume what is actually happening, is that in Fragile X there is also neuroinflammation and this has been reduced by the statin, rather than correcting the syndrome.

  

Retts Syndrome

Retts syndrome is another genetic disorder that causes regression and autism-like behaviours.  It affects mainly girls, because male fetuses with the disorder rarely survive to term.  The prognosis is not good.

Research is underway with statins and currently shows that statins improve symptoms of Rett syndrome in mice.

 

Statins and depression

A large study of patients with heart disease examined the difference between those on statins and those not.  Very interesting was the finding that those on statins had better mental health (i.e. less depression).

Statins: Mechanisms of neuroprotection

A very thorough presentation of the effect of statins and their possible mechanisms along with a review of their use in Alzheimer’s, Parkinson’s, Multiple Sclerosis and strokes, is in the excellent paper:-  Statins: Mechanisms of neuroprotection

 The anti-oxidant effect of statins

A study called The anti-oxidant effect of statins, looks very interesting, but only the abstract is freely available.  Here is the summary:-  

"A number of recent reports have shown that statins may also have important anti-inflammatory effects, in addition to their effects on plasma lipids. Since inflammation is closely linked to the production of reactive oxygen species (ROS), the molecular basis of the observed anti-inflammatory effects of statins may relate to their ability block the production and/or activity of ROS. In this review, we will discuss both the inhibition of ROS generation by statins, through interference with NAD(P)H oxidase expression and activity, and the actions of statins that serve to blunt the damaging effects of these radicals, including effects on antioxidant enzymes, lipid peroxidation, LDL cholesterol oxidation and nitric oxide synthase. These antioxidant effects of statins likely contribute to their clinical efficacy in treating cardiovascular disease as well as other chronic conditions associated with increased oxidative stress in humans."

 

Conclusion

 
Given the minimal side effects, that was more than enough evidence for me to start some primary research of my own. Step one was to try atorvastatin myself. 

My hypothesis is that atorvastatin will reduce autistic behaviours and that the mechanism is the reduction of neuroinflammation in the cerebellum and particularly in the Purkinje Cell Layer (PCL).  I believe that this will be valid regardless of the type of autism. 

The beneficial secondary effect will be reduction in LDL cholesterol, which is typically elevated in cases of autism.

 

Click here for  -  Statins Part 3



 

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
 

 

Neurogenesis & Neuroplasticity

Today we have two new N- words and we finally get to the bottom of what autism is and what it is not.   There is nothing revolutionary here, it can all be found in the research and indeed most of it can be found in just one book, but then who would read my blog?

We will start with the bad news and finish with the good news.

Neurogenesis

Neurogenesis sounds like a good thing; it is the birth of neurons in the brain.  This is substantially completed in the pre-natal period, but it can continue in certain parts of the brain throughout life.  After a head injury, or trauma, neurogenesis can take place.

In the case of autism the potential benefit exists, but seems likely to be minimal.

Many studies have already established the pattern of deformities in the autistic brain.  One researcher in particular, Eric Courchesne, seems to have chosen to make this his life’s work.  He has carried out repeated studies over many years focused on examination of brain growth, and overgrowth, in autism using post-mortem brains and later MRI (magnetic resonance imaging).
His findings are unequivocal, and in line with those of his peers.  In his autistic subjects, the brain grows much faster in the first couple of years than typical subjects and then the process slows right down and in later life the autistic brain starts to shrink.  His and other studies show that in later life the brain does seem to try to compensate for its defective development; this is seen as ineffective (but how can anyone possibly know?).

He finds a wide pattern of abnormalities, including the expected presence of a reduced number of Purkinje cells.  He goes on to argue that his evidence shows that this damage was done in the pre-natal period, so he will not be popular with the vaccine damage theorists.

“Thus, given the resulting tight bond between the olivary neurons and the Purkinje cells after this time, loss or damage to the cerebellar Purkinje cells results in an obligatory retrograde loss of olivary neurons. Since, in the autistic brain, the number of the olivary neurons is preserved, it is likely that whatever event resulted in the reduction of the Purkinje cells in these cases has to have occurred before this tight bond has been  established, and thus before 28–30 weeks gestation.”

 

“In addition, microscopic observations of enlarged cells in some brain regions in autistic children and small pale cells that are reduced in number in these same areas in adults strongly indicate changes with age. Clinically and pathologically, this process does not appear to a degenerative one and may reflect the brain’s attempt to compensate for its atypical circuitry over time.”

“This early cessation of growth results in a 2–4 year old autistic brain size that is not different from a normal adolescent or adult in the majority of cases. Thus, at the age of typical clinical diagnosis of the disorder (i.e. 3–4 years), the period of pathological growth and arrest has likely already passed, leaving clinicians and researchers with an outcome, rather than process, of pathology for study and treatment intervention.”

Here are three of Eric’s studies, which include graphs showing autistic brain development vs. the control group at various ages throughout life.

• When Is the Brain Enlarged in Autism? A Meta-Analysis of All Brain Size Reports

• Unusual brain growth patterns in early life in patients with autistic disorder
• Brain growth across the life span in autism: age-specific changes in anatomical pathology.

Neuroplasticity

If neurogenesis was the bad news then neuroplasticity is certainly the good news. I think that Eric needs to read up on this subject and perk himself up.  It seems even a deformed brain can do some pretty clever stuff.

Neuroplasticity, also known as brain plasticity, refers to changes in neural pathways and synapses which are due to changes in behavior, environment and neural processes, as well as changes resulting from bodily injury.  Neuroplasticity has replaced the formerly-held position that the brain is a physiologically static organ, and explores how - and in which ways - the brain changes throughout life.

In the field of neuroplasticity we have some pioneering work from  Michael Merzenich is a neuroscientist. He has made some of "the most ambitious claims for the field - that brain exercises may be as useful as drugs to treat diseases as severe as schizophrenia - that plasticity exists from cradle to the grave, and that radical improvements in cognitive functioning - how we learn, think, perceive, and remember are possible even in the elderly."  Merzenich’s work was affected by a crucial discovery made by Hubel and Wiesel in their work with kittens. The experiment involved sewing one eye shut and recording the cortical brain maps. Hubel and Wiesel saw that the portion of the kitten’s brain associated with the shut eye was not idle, as expected. Instead, it processed visual information from the open eye. It was"… as though the brain didn’t want to waste any ‘cortical real estate’ and had found a way to rewire itself.

Merzenich created a plasticity-based computer aided learning programme called FastForWord, which  offers seven brain exercises to help with the language and learning deficits of dyslexia.

ABA and neuroplasticity.  Then of course, I started thinking about Monty’s  6 years of ABA and endless hours on his computer based learning programmes.  This of course is the link between neuroscience and ABA - the fuzzy science of neuroplasticity; otherwise known as making the most of what you’ve got. 

 

Conclusion

We have established that autistic behaviours are likely caused by stress and inflammation in the cerebellum, and in particular in the region of the Purkinje Cell Layer (PCL).

We have seen that in classic autism this stress and inflammation is associated with physical brain growth abnormalities that occurred in the pre-natal and early post natal period.  The oxidative stress and inflammation is ongoing throughout adulthood.

We have seen that stress and inflammation in the cerebellum can be caused by entirely different causes, that take effect later in life, such as Tuberous Sclerosis Complex (TSC).  There is another truly horrible one called Childhood Disintegrative Disorder (CDD).

With the availability of noninvasive MRI scans, it would be interesting and highly possible to ascertain the level of brain deformity in milder cases of autism and Asperger’s syndrome. 

Given that by the time autistic behaviors are exhibited, the damage to the brain  has already run its course, our main ally would seem to be neuroplasticity and of course to halt the ongoing oxidative stress and inflammation.

In addition, we need to consider countering the apparent ion-channel disfunction, and maybe give the damaged hippocampus a lesson or two about hormone production.

 

 

 

Pep up those Purkinje cells

In the previous post we established that both oxidative stress and neuroinflammation can be measured.  We learned from the clever people at Johns Hopkins that the site of the greatest inflammation is in the  cerebelleum; as they put it:-

Based on our observations, selective processes of neuronal degeneration and neuroglial activation appear to occur predominantly in the Purkinje cell layer (PCL) and granular cell layer (GCL) areas of the cerebellum in autistic subjects.

Now, you may recall that I recommended an excellent book called "Autism: Oxidative Stress, Inflammation and Immune Abnormalities".  The book is from 2010, and since then the authors have been busy.  In 2012 they published a study called:   Brain Region-Specific Glutathione Redox Imbalance in Autism

This study tells us which parts of the brain are most affected by oxidative stress.  The abnormal level of GSH redox (the marker for oxidative stress) was highest in the cerebellum and in the temporal cortex.

This is good to hear, since I have assumed that oxidative stress and neuroinflammation are essentially part of the same process and that what halts one, will likely halt the other.
 

Purkinje Cells

Purkinje cells are a class of GABAergic (controlled by the neurotransmitter GABA) located in the cerebellum.

Purkinje cells are some of the largest neurons in the human brain, perhaps this makes them target of stress and inflammation.

Purkinje cells send inhibitory projections to the deep cerebellar nuclei, and constitute the sole output of all motor coordination (and maybe more?) from the cerebellum.

In humans, Purkinje cells are affected in a variety of diseases ranging from toxic exposure (alcohol, lithium), to autoimmune diseases and to genetic mutations (spinocerebellar ataxias, Unverricht-Lundborg disease and autism) and neurodegenerative diseases that are not thought to have a known genetic basis (cerebellar type of multiple system atrophy, sporadic ataxias).

Purkinje Damage in Autism

It has been shown that there is a 35 to 50% reduction in the number of Purkinje cells in the autistic cerebellum when compared with a normal cerebellum.  (this comes from a paper on glutamate neuro-transmitter abnormalities)

Here is an excellent and  very readable study all about Purkinje damage in autism, from 10 years ago:-

 Purkinje cell vulnerability and autism: a possible etiological connection

It is proposed that the cell death in the Purkinje cell layer produces the autistic-like behaviours.

Functions of the and temporal lobe and cerebellum

(where the oxidative stress was measured to be highest)

The temporal lobe seem very much related to the problematic areas of autistim, namely:-

·         Processing sensory input

·         Language comprehension

It also contains the hippocampus.  The hippocampus has made an earlier appearance on this blog since one of its main functions is the realease of hormones including TRH (thyrotropin releasing hormone) CRH (Corticotropin releasing hormone) GHRH (growth hormone releasing hormone).  Disfunction of the hippocampus is known to occur in epilepsy (often comorbid with autism).
If you want to read all about the temporal lobe, try this : Anatomy of the temporal lobe.

The cerebellum is commonly associated with motor control function, but it may have a role in cognitive function, such as language.  Damage to the cerebellum is known to causes disorders in fine movement (sloppy handwriting in autism?)

So it would appear at first glance that inflammation in the temporal lobe and cerebellum could indeed account for many autistic-like behaviors.  

 

Pep up those Purkinje cells  -  Indirect or direct action?

As is often the case, there is the direct approach and the indirect approach.  I usually favour the subtle indirect approach; this would be to work on reducing the oxidation and inflammation. 

There may also a direct approach, using a drug developed as an anti-fungal agent, that turned out to be a potent immunosuppressant.    It prevents activation of T cells and B cells by inhibiting their response to interleukin (IL-2). 

Since nothing in neuroscience is clear cut, there is of course a far more complicated alternative explanation of what is going on.  It could be a genetic disorder that is causing the failure in the Purkinje cells.  Take a look:-

Tuberous sclerosis complex (TSC) is a dominant tumour suppressor disorder caused by mutations in either TSC1 or TSC2. TSC causes substantial neuropathology, often leading to autism spectrum disorders (ASDs) in up to 60% of patients. The anatomic and neurophysiologic links between these two disorders are not well understood…. These studies provide compelling evidence that Purkinje cell loss and/or dysfunction may be an important link between TSC and ASD as well as a general anatomic phenomenon that contributes to the ASD phenotype.

The study is called:  Loss of Tsc2 in Purkinje cells is associated with autistic-like behaviour in a mouse model of tuberous sclerosis complex

The good news is that TSC already has a viable therapy (in mice at least, and in clinical trials), with a drug called rapamycin/sirolimus.  If you look on the web, you will find people experimenting with it.

There have been several studies using mutant mice. 

Autism in mice

In a study of sirolimus as a treatment for TSC, researchers observed a major improvement regarding effects related to autism. The researchers discovered sirolimus regulates one of the same proteins the TSC gene does, but in different parts of the body. They decided to treat mice three to six months old (adulthood in mice lifespans); this increased the autistic mice's intellect to about that of normal mice in as little as three days.

Here are two studies:- 

Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis

Autistic-like behaviour and cerebellar dysfunctionin Purkinje cell Tsc1 mutant mice

Before heading down to the pharmacy to ask about Rapamycin, click on this to see a warning or two.  Also TSC is a genetic condition that usually leads to autism.  This does not mean that if you have autism you also have TSC.  It does mean that better understanding TSC may help to better undertand autism.


It looks like the indirect approach is best again.  Just keep taking the NAC !!