Tapas Time - Statins Part 4

Today’s post is bite-sized, as opposed to the occasional shock to the digestive system that I serve up.

You may have been wondering how come a few American researchers have managed to keep a lid on the neuroprotective power of statins; or even that Peter and Monty are making it all up.

Well, for a change from the usual Anglo-Saxon research, today I present you a paper from Granada in Spain.

 

Statins as neuroprotectants: acomparative in vitro study of lipophilicity, blood-brain-barrier penetration,lowering of brain cholesterol, and decrease of neuron cell death.

They study which statin should be the most neuroprotective.  Their choice is Simvastatin, which is also known as Zocor.  In the UK, Zocor is now an over the counter (OTC) drug, meaning no prescription required.


The previous posts on Statins are here:-

Statins Part 1
Statins Part 2
Statins Part 3

 


 

Finished switching ears off!

I had another surprise a couple of days ago; I was standing with Monty outside the entrance to a very noisy ice-cream bar.  There were babies crying, a lady begging rather aggressively and an orderly queue to enter the shop.  Finally, the noise abated and I heard Monty say:-

“Finished switching ears off!”

Is there more to this than the emergence of spontaneous and appropriate speech?

Selective Hearing, Elective hearing and (S)elective mutism

I once did a course called Noise Control as part of my Engineering degree.  I recall that at the start of the course, the Professor confessed his desire to be able to turn his hearing on and off; clearly there were some noises he would prefer not to hear.

If you have children you will have discovered “selective hearing”; whenever you want them to come for a meal, they just do not seem to hear you.  If you offer ice cream though, they will hear the first time you call.

There is also the relatively common case of selective mutism, in people with anxiety disorders, they lose the ability to speak in stressful situations.

I think that many non-verbal autistic children probably have elective mutism; they just decide not to speak, or perhaps there is a barrier inside them that they just cannot get over.

Many people with autistic children initially go through a phase of thinking their child is deaf.  I know a child who lost his hearing and then a couple of years later regained it.  I met him just after his hearing was restored and I was convinced he had autism; he had all the characteristics.

Maybe some autistic children have elective deafness and/or elective mutism and perhaps a little pharmacological intervention could actually help them overcome this barrier?

For Monty, thankfully, these problems are in the past.  For him ABA and PECS did the job.

 

 

 

By Jupiter! - Satins Part 3

Makes more sense if you have read:-
Statins Part 1
Statins Part 2

 

For most of you Jupiter is the fifth planet from the Sun, or maybe the largest planet in the Solar System.  To a young boy like Monty, Jupiter is a red fire engine, normally driven by Fireman Sam.

If you are a cardiologist you will have heard of the JUPITER trial. (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial)

It was a huge study looking into the possible benefits of giving statins to older people with low cholesterol.  All the 17,802 subjects had elevated levels of high-sensitivity C-reactive protein (CRP) levels, which is a marker for cardiac (and neuro) inflammation.  Half were given 20mg of a statin and the other half had a placebo.  The study measured their cholesterol, CRP levels and whether they later had a cardiac incident.  The group with the statin lowered their already okay LDL and triglycerides level and also lowered their CRP level by a thumping 37%.

At the time of study termination (median follow up, 1.9 years; maximal follow-up, 5.0 years), 142 first major cardiovascular events had occurred in the statin group, as compared with 251 in the placebo group.

This was interpreted by the authors as evidence that even older people without elevated cholesterol could benefit from statins to reduce their risk of cardiovascular events.

 

 

JUPITER and autism

What JUPITER tells me is that statins were highly effective at reducing inflammation as measured by CRP.

 

Autism and CRP

Now we just need some data on the level of CRP in Autism.  Thanks to those nice people in Iran we have a study called: - The complementary role of high sensitivity C-reactive protein in the diagnosis and severity assessment of autism.

 They concluded:-

► Inflammatory process can play key role in the pathophysiology of autism.
► Higher levels of hs-CRP are detected in autistic children.

► A correlation exists between hs-CRP level and autism severity.

► Hs-CRP can be considered a complementary diagnostic test for autism.
►These findings affirm the role of inflammation in autism.

I guess because Iran is public enemy number two, nobody took much note of this study, except Paul Whiteley of course.

 
 

Autism & Statins

So it looks pretty likely that statins will reduce CRP in autistic subjects and if statins can do this, they will reduce both the neuroinflammation and, by inference, the severity of autistic behaviours.

 

Peter Research

While in the Astra Zeneca-funded JUPITER study there were 17,802 subjects and five years of research; here in the Peter Research Institute we have one subject and one week of research.

As with my Bumetanide research, I am shocked by the almost immediate effect of the drug.  In terms of lowering cholesterol, statins are supposed to take two weeks to reach full effect.  In terms of reducing neuroinflammation the effect appears to be much faster – very encouraging but, to be honest, quite unexpected.  

Back to Cholesterol & Autism

The important thing is that statins appear to reduce autistic behaviours, at least in my subject; it would however also be nice to fully understand why.  The research shows the presence of dyslipidemia (abnormal amounts of lipids) in boys with autism.

 

Alterations in lipid profile of autistic boys: a case control study

The findings were: - LDL normal, HDL low, Triglycerides high, Total cholesterol normal.  The current benchmark used is that Total Cholesterol divided by HDL should be less than 4.5.  With low HDL and high triglycerides, this could put many autistic subjects in the zone of elevated risk.

Also, be aware of the very rare condition called Smith-Lemli-Opitz Syndrome (SLOS), caused by low levels of cholesterol;  it is explained in this open-access paper:-

Abnormalities of Cholesterol Metabolism in Autism Spectrum Disorders

In one of the studies I read that CRP always drops before the fall in cholesterol.  This would imply that in the case of ASD, the cholesterol issue is just a consequence; it is the precursors that actually matter.  At least to me, that makes a lot of sense.



In case you missed the prequels:

Statins Part 1
Statins Part 2


and now there is Part 4  http://epiphanyasd.blogspot.com/2013/05/tapas-time-statins-part-4.html



 

More Music!

I have been helping 12 year old Ted with his algebra, or perhaps, more accurately stated, I have been doing Ted’s homework while he goes “A-ha”.

 
With 9 year Monty, I have been doing algebra of a different kind, this time I get a bit more than an “A-ha” in return.  We have now established the following completely unscientific statement to be true:-

1mg Bumetanide + 3g NAC + 10mg Atorvastatin  =  More Music + More Parties  + More Hugs

Monty has always liked music, but he only wanted to play the piano during a lesson and at first, even during the lessons, he only wanted to escape.  This year he has moved from playing with two fingers to playing with all fingers of both hands. He now plays the piano spontaneously all by himself and the little colour stickers came off the piano keys yesterday, without a comment.

More parties, because if you behave nicely in class, you get invited to parties and even though they are very noisy and full of strangers, you stay calm and under self-control, so nothing can get in the way of having fun and you no longer have to leave early.

More hugs, because now it is easy to express yourself and with tantrums and obsessive behaviour gone, it is possible for spontaneous emotional behaviour to emerge.

 

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